In Vitro Cytokine Production by HLA-B8, DR3 Positive Subjects

It is well known that healthy subjects carrying the HLA-B8,DR3 haplotype may show an impairment of immune system, the T cells being the most affected. To gain insight into the mechanism(s) of the impairment displayed by these subjects, efforts have been centered on the study of in vitro cytokine production because of the pivotal role played by these mediators in the activation and control of several immune functions. The available results indicate that the ability to several immune functions. The available results indicate that the ability to produce interleukin-1 (IL-1), IL-2 and the soluble form of its receptor (sIL-2R) is impaired in HLA-B8,DR3 positive healthy subjects. To better charac…

The effect of age on mitogen responsive T cell precursors in human beings is completely restored by interleukin-2.

Abstract It is well known that the function of T lymphocytes is significantly impaired by advancing age. In the present study, attempts have been made to further characterize the T cell impairment of elderly subjects. Thus, we have performed limiting dilution microculture analysis to evaluate the precursor frequency of T lymphocytes responding to a mitogenic stimulus in old and young subjects. Furthermore we have evaluated the activity of recombinant interleukin-2 (rIL-2) on these cells. The results demonstrate that in older subjects the frequency of these precursors is significantly decreased. The in vitro treatment with rIL-2 increased the frequency of mitogen responsive T lymphocyte prec…

A novel B cell population revealed by a CD38/CD24 gating strategy: CD38−CD24− B cells in centenarian offspring and elderly people

The B cell arm of adaptive immunity undergoes significant modifications with age. Elderly people are characterized by impaired B cell responses reflected in a reduced ability to effectively respond against viruses and bacteria. Alterations of immunity with advancing age (immunosenescence) have been widely studied in centenarians who are considered a good example of successful aging. In recent years, attention has shifted to centenarian offspring (CO) as a model of people genetically advantaged for healthy aging and longevity. Here, we describe the preliminary characterization of a proposed new population of memory B cells, defined as CD19(+)CD38(-)CD24(-), which we find at higher frequencie…

Genetic risk profiles for Alzheimer's disease: Integration of APOE genotype and variants that up-regulate inflammation

BACKGROUND: A number of studies associate Alzheimer's disease with APOE polymorphism and alleles which favor the increased expression of immunological mediators such as cytokines or acute phase proteins. We integrated this information to better define risk and determine the relative importance of APOE and immunological mediators. METHODS: We investigated functional gene variants for APOE, IL-10 (3 loci), ACT (2 loci), HMGCR, IL-1alpha, IL-1beta, TNF-alpha, IFN-gamma, and IL-6 found for 260 AD patients and 190 controls enrolled in Northern Italy. A fuzzy latent classification approach, namely grade-of-membership analysis (GoM), was taken to identify extreme pure type risk sets, or profiles. …

Regulatory cytokine gene polymorphisms and risk of colorectal carcinoma.

It is well established that cancer arises in chronically inflamed tissue, and this is particularly notable in the gastrointestinal tract. Classic examples include Helicobacter pylori-associated gastric cancer, hepatocellular carcinoma, and inflammatory bowel disease-associated colorectal cancer. Growing evidence suggests that these associations might be not casual findings. Focusing on individual cytokines has generated evidence that anti-inflammatory cytokine interleukin (IL)-10 and transforming growth factor-beta1 (TGF-beta1) may have a complex role in gastrointestinal carcinogenesis. As an example, IL-10-deficient mice develop severe atrophic gastritis and a chronic enterocolitis, develo…

Glossario

Search for genetic factors associated with susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is a cell-mediated autoimmune disease characterized by type-1 cytokine production. Environmental and individual genetic background might influence this response particularly in cytokine gene polymorphisms. We evaluated whether polymorphisms of interleukin (IL)-10, IL-12, and tumor necrosis factor (TNF)-alpha genes, which might play a role in MS pathogenesis, are associated with MS susceptibility. Genotype frequencies for all the analyzed polymorphisms were not differently distributed between cases and controls. It is reasonable to suppose that the cytokine single-nucleotide polymorphisms (SNPs) studied must be considered against a larger genetic background involving …

HLA, aging, and longevity: a critical reappraisal.

Despite a large number of studies, available data do not allow at present to reach definitive and clear conclusions on role of HLA on longevity, owing to major methodological problems, such as serological and molecular typing of different loci, insufficient sample sizes, different inclusion criteria and age cut-off, inappropriate mixing of data referred to people from 58 to over 100 years of age, inappropriate control matching, and neglected consideration of sex-related effects and the different genetic make-up of studied populations. However, within this confused scenario, some data emerge. First, two studies that do not fit the biases above discussed show that some HLA alleles are associa…

Mediterranean diet and longevity: an example of nutraceuticals?

The Mediterranean diet (Mediet) is an eating pattern characterizing a lifestyle and culture that has been reported to contribute to better health and quality of life. The Mediet reflects food patterns typical of Mediterranean regions, where olive oil plays an essential role in the food pyramid. Olive oil is located in the middle and it is considered the principal source of dietary fat because of its high nutritional quality (particularly extra virgin olive oil). Several studies have shown the effect of the Mediet on healthy status by lowering the rates of coronary heart disease, certain cancers, and some other age-related chronic diseases. Although the scientific literature regarding diet a…

Analysis of HLA-DQA, HLA-DQB frequencies in a group of Sardinian centenarians

Human leukocyte antigen (HLA) alleles, regulating type and intensity of the immune response, might influence life expectancy. In previous case-control studies the authors have demonstrated that both HLA-DR and -DQ alleles are not associated with longevity in the Sardinian population. On the other hand, association studies are subjected (as part of the homogeneity of the population in terms of geographic origin) to a number of possible confounding factors. Therefore, the authors typed the HLA-DQA1 and HLA-DQB1 alleles in 24 sibs (age range 85 to 97) of 17 centenarians by PCR-SSP. Sib pair analysis showed non-significant differences between the observed and expected percentage of DQA* or DQB1…

Association Between Interleukin-10 Polymorphisms and Alzheimer's Disease: A Systematic Review and Meta-Analysis

UNLABELLED It has been hypothesized that polymorphisms of interleukin (IL)-10 genes affect the risk of developing late onset Alzheimer's disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the IL-10 gene with AD risk. Fifteen studies investigating the association between IL-10 polymorphisms (-1082, -819, -592) and AD were found and analyzed. The model-free approach was applied to meta-analyze these case-control genetic association studies. Available data suggested an association between -1082 polymorphism and AD risk with a margi…

Genetic Background of Centenarians May Be Protective Against Cardiovascular Diseases.

Interventions to Slow Aging in Humans: Are We Ready?

The workshop entitled 'Interventions to Slow Aging in Humans: Are We Ready?' was held in Erice, Italy, on October 8-13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consens…

Age and Gender-related Variations of Molecular and Phenotypic Parameters in A Cohort of Sicilian Population: from Young to Centenarians

People are living longer, but lifespan increase does not coincide with a boost in health-span. Thus, improving the quality of life of older people is a priority. Centenarians reach extreme longevity in a relatively good health status, escaping or delaying fatal or strongly invalidating diseases. Therefore, studying processes involved in longevity is important to explain the biological mechanisms of health and well-being, since knowledge born from this approach can provide valuable information on how to slow aging. We performed the present study in a well characterized very homogeneous sample of 173 people from Western Sicily, to update existing literature on some phenotypic aspects of aging…

Association between platelet glycoprotein Ib-alpha and myocardial infarction: results of a pilot study performed in male and female patients from Sicily.

Myocardial infarction (AMI) is a complex multifactorial disorder. Platelet adhesion and thrombosis are pivotal events in the development of atherosclerotic lesions. Occlusive thrombus is almost exclusively initiated by plaque rupture and adhesion of platelets to subendothelial von Willebrand factor (vWf) by its specific platelet receptor, the alpha-chain of glycoprotein (GP) Ib-IX-V complex of the human platelet-specific antigens (HPA). Two polymorphisms have been reported in the sequence of GPIb-alpha. The first, a C/T transition at nucleotide 1018 results in an amino acid dimorphism (Thr/Met) at residue 145 of GPIb-alpha, which is located within the vWF-binding domain of the receptor. The…

Smoking, health and ageing.

Abstract On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related diseases was held in Palermo, Italy. Here, the lecture of V. Nicita-Mauro on Smoking, health and ageing is summarized. Smoking represents an important ageing accelerator, both directly by triggering ana inflammatory responses, and indirectly by favoring the occurrence of several diseases where smoking is a recognized risk factor. Hence, non-smokers can delay the appearance of diseases and of ageing process, so attaining longevity.

IL-10, genetic polymorphism and its relevance to age related diseases.

Pathophysiology of vascular dementia.

The concept of Vascular Dementia (VaD) has been recognized for over a century, but its definition and diagnostic criteria remain unclear.Conventional definitions identify the patients too late, miss subjects with cognitive impairment short of dementia, and emphasize consequences rather than causes, the true bases for treatment and prevention. We should throw out current diagnostic categories and describe cognitive impairment clinically and according to commonly agreed instruments that document the demographic data in a standardized manner and undertake a systematic effort to identify the underlying aetiology in each case.Increased effort should be targeted towards the concept of and criteri…

Centenarian offspring: A model for understanding longevity

Abstract: A main objective of current medical research is to improve the life quality of elderly people as priority of the continuous increase of ageing population. This phenomenon implies several medical, economic and social problems because of dramatic increase in number of non autonomous individuals affected by various pathologies. Accordingly, the research interest is focused on understanding the biological mechanisms involved in determining the positive ageing phenotype, i.e. the centenarian phenotype. In achieving this goal the choice of an appropriate study models is fundamental. Centenarians have been used as an optimal model for successful ageing. However, this model shows several …

IL-10 and TNF-α polymorphisms in a sample of sicilian patients affected by tuberculosis: implication for ageing and life span expectancy

Abstract Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses, in particular cytokine gene polymorphisms. In fact, modification of cytokine network is a constant report in studies on age related modification of immune response. Moreover cytokine polymorphisms studies are indicating their involvement in the reshaping of cytokines network as an integral part of the scenario related to a successful ageing. A particular role might be attributed to the influence of cytokine polymorphisms on the efficiency o…

Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population

Abstract A proinflammatory genotype seems to contribute significantly to the risk of developing coronary heart disease (CHD). Conversely, the susceptibility alleles to inflammatory disease should be infrequent in the genetic background favoring longevity. In fact, in a modern environment, attainment of longevity is facilitated by an anti-inflammatory status. To evaluate whether inflammatory alleles of pyrin, the gene responsible for familial Mediterranean fever (FMF) may play an opposite role in CHD and in longevity, we examined three FMF-associated mutations, M694V (A2080G), M694I (G2082A), and V726A (T2177C), encoded by the FMF gene (MEFV) in 121 patients affected by acute myocardial infa…

Double Negative (IgG+IgD-CD27-) B Cells are Increased in a Cohort of Moderate-Severe Alzheimer’s Disease Patients and Show a Pro-Inflammatory Trafficking Receptor Phenotype

Alzheimer's disease (AD) is a progressive, irreversible, and debilitating disease for which no effective preventive or disease modifying therapies or treatments have so far been detected. The crucial step in AD pathogenesis is the production of amyloid-42 peptide, which causes chronic inflammation. Activated cells in the central nervous system (CNS) produce pro- inflammatory mediators that lead to the recruitment of myeloid or lymphocytic cells. As a consequence, the communication between the CNS and peripheral blood of AD subjects could influence the lymphocyte distribution and/or the expression of phenotypic markers. In the present paper, we show a significant decrease in total CD19 + B l…

Inflammation and Life-Span

In their Review “Inflammatory exposure and historical changes in human life-spans” (17 Sept., p. [1736][1]), C. E. Finch and E. M. Crimmins reinforce earlier suggestions that many diseases and disabilities of older age have their roots in previous exposures to infectious agents and other sources

Blood group does not appear to affect longevity a pilot study in centenarians from Western Sicily.

Centenarians are the best example of extreme human longevity, and they represent a selected population in which the appearance of major age-related diseases, such as cancer, and cardiovascular diseases among others, has been consistently delayed or escaped. The study of the long-lived individual genetic profile has the purpose to possibly identify the genes and the allelic variations influencing extended life expectancy, hence considering them as biomarkers of age-related diseases onset and development. The present study shows no significant differences between allelic variations of ABO blood groups among a group of centenarians from Western Sicily.

Age-related changes in the expression of CD95 (APO1/FAS) on blood lymphocytes☆

Abstract Aging is associated with alterations of the immune system, thought to be related to an increased susceptibility to infectious diseases, and possibly to cancer and autoimmunity in the elderly. In the present paper we report data obtained on freshly collected blood from 148 healthy subjects of different ages (from cord blood to 102 years old). The subjects were divided into seven age classes (cord blood, 3–11 years, 15–39 years, 41–60 years, 61–74 years, 75–84 years, 85–102 years) and their lymphocyte subsets and the expression of the apoptosis-related molecule CD95 were evaluated. In respect of lymphocyte subsets, the major differences were found in the cord-blood samples compared w…

'Immunogenetics of Aging': report on the activities of the 15th International HLA and Immunogenetics Working Group and 15th International HLA and Immunogenetics Workshop.

'Immunogenetics of Aging' is a component that was first included in the 14th International HLA and Immunogenetics Workshop (IHIWS) and developed further within the 15th Workshop. The aim of this component was to assess the impact of human leukocyte antigen (HLA) genes, cytokine genes, and some innate immunity genes such as killer-cell immunoglobulin-like receptors (KIRs) and mannose-binding lectin 2 (MBL2) in successful aging and their contribution to the better understanding of immune dysfunction in old age. Within the 15th IHIWS new populations were included in the analysis. Additional cytokine gene polymorphisms were assessed and innate immunity genes were analyzed for possible relevance…

La diagnosi di Laboratorio della malattia di Alzheimer: ruolo dei markers infiammatori.

The Genetics of Innate Immunity and Inflammation in Ageing, Age-Related Diseases and Longevity

Inflammation is a key component of age-related diseases such as atherosclerosis and Alzheimer’s disease (AD) and genes coding for inflammatory or anti-inflammatory molecules are, therefore, good candidates for influencing the risk of developing these pathologies. Findings discussed in this chapter suggest that different alleles of genes coding for pro-or anti-inflammatory genes may affect individual life-span expectancy by influencing the type and intensity of immune-inflammatory responses against environmental stressors involved in the development of age-related disease. Our immune system has evolved to control pathogens and so pro-inflammatory responses are likely to be evolutionarily pro…

Acute Myocardial Infarction and Proinflammatory Gene Variants

We identified four genetic risk sets for acute myocardial infarction (AMI) from information on functional gene variants that favor inflammation or modulate cholesterol metabolism: IL6 -174 G/C, TNF -308 G/A, IL10 -1082 G/A, SERPINA3 -51 G/T, IFNG +874 T/A, HMGCR -911 C/A, and APOE ε2/3/4; 316 patients and 461 healthy subjects, all Italian. Putative risk alleles are shown underlined. The sets were identified using grade-of-membership analysis. Membership scores in the sets are automatically generated for individuals. The ''low intrinsic risk'' set had alleles that downregulate inflammation and cholesterol synthesis (IL6, TNF, ILl0, HMGCR). ''AMI across a broad age range'' carried multiple pr…

Lessons from Sicilian centenarians for anti-ageing medicine. The Oxi-inflammatory status

Population ageing is a great achievement of humanity, but it also represents a challenge that the Western world is currently facing, as ageing is associated with increased susceptibility to age-related inflammatory diseases. Therefore, it is necessary to fully understand the mechanisms of healthy ageing to prevent the harmful aspects of ageing. The study of long living individuals (LLIs) is a great model for trying to achieve this goal. Accordingly, the oxy-inflammatory status of Sicilian LLIs was reviewed in the present paper. Based on the reported data, anti-inflammatory and anti-oxidative stress strategies have been discussed, useful for delaying or avoiding the onset of age-related dise…

Mutations in the HFE gene and cardiovascular disease risk: an individual patient data meta-analysis of 53 880 subjects.

Background— Whether mutations in the hemochromatosis (HFE) gene increase cardiovascular disease risk is still undetermined. The main reason is the low frequency of the mutations, in particular of the compound C282Y/H63D genotype. We combined the data of 11 observational studies for an individual patient data meta-analysis. Methods and Results— Individual patient data were obtained from published as well as unpublished studies that had information available on the C282Y mutation as well as the H63D mutation in relation to coronary heart disease risk. Individual records were provided on each of the 53 880 participants in 11 studies. In total, 10 541 patients with coronary events were documen…

Role of TLR Polymorphisms in Aging and Age-Related Diseases

Innate immunity provides the first line of host defense against infection by recognizing and killing microbes, and simultaneously activating an instructive immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition, and they mainly function by detecting exogenous pathogen-associated molecular patterns. Recognition of their ligands actives signaling ways, which culminate in evocating acute host responses, involved in killing pathogens. Here, we describe the involvement of TLR4 polymorphisms in aging, and particularly in immunosenescence and age-related diseases, suggesting the crucial role of molecules of innate immunity in the pathophysiology of these…

Autoimmune diseases and 8.1 ancestral haplotype: an update

The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid haplotype carried by most people who type for HLA-B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome-wide-association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within …

Fisiopatologia dell'apparato endocrino

Apoptosis and ageing.

Stimulation of T cells from aged individuals leads to different kinds and/or size of responses if compared with the responses of T cells obtained from young individuals. In fact elderly is associated with a progressive decline of immune response besides an increasing incidence of autoimmune phenomena. These differences might be the result of modified cellular mechanisms controlling the immune system in the course of ageing. The apoptotic deletion of activated T cells has been proposed as the key mechanism to maintain T cell homeostasis, and in this respect CD95 (Fas antigen) seems to play a major role in this course of events. In this study we show that just collected lymphocytes from old s…

Association between the interleukin-1beta polymorphisms and Alzheimer's disease: a systematic review and meta-analysis.

Abstract The pro-inflammatory cytokine interleukin(IL)-1β is a main component in inflammatory pathways and is overexpressed in the brain of Alzheimer's disease (AD) patients. Several studies report associations between IL-1β polymorphisms and AD, but findings from different studies are controversial. Our aim was to verify the correlation between the single nucleotide polymorphisms (SNPs) of the IL-1β, at sites − 511 and + 3953, and AD by meta-analysis. Computerized bibliographic searches of PUBMED and AlzGene database ( http://www.alzgene.org ) were supplemented with manual searches of reference lists. There is evidence for association between IL-1β + 3953 SNP and AD, with an OR = 1.60 (95%…

Changes of inflammatory mediators in obese patients after laparoscopic cholecystectomy.

Background Obesity is associated with the impairment of immunological functions. The aim of this study was to analyze some inflammatory mediators in obese subjects who underwent laparoscopic cholecystectomy. Methods Seventeen consecutive female patients with a BMI ranging from 35 to 45 kg/m2 (obese) and 17 consecutive female patients with BMI ranging from 20 to 25 kg/m2 (nonobese) were included in the study. All patients were affected by symptomatic gallbladder stone disease and underwent laparoscopic cholecystectomy. Changes in levels of leukocytes, neutrophils, IL-6, IL-10, leptin, and adiponectin were evaluated. Results We observed a significant increase in leukocyte and neutrophil level…

Allele frequencies of +874T→A single nucleotide polymorphism at the first intron of interferon-γ gene in a group of Italian centenarians

Ageing is characterized by a pro-inflammatory status which could contribute to the onset of major age-related diseases such as cardiovascular diseases, neurodegeneration, osteoarthritis and osteoporosis, and diabetes. Thus, it can be hypothesized that genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. We have studied the distribution of +874T--A interferon-gamma (IFN-gamma) polymorphisms in a large number of Italian centenarians to evaluate if the two alleles might be differently represented in people selected for longevity. DNA samples were obtained from 174 Italian centenarians (99 years old, 142 women and 32 men) and from 24860-year…

Genetic Determined Downregulation of Both Type 1 and Type 2 Cytokine Pathways Might Be Protective against Pancreatic Cancer

Many cytokine polymorphisms have been studied for associations with susceptibility to breast, gastric, liver, lung, prostate, and ovarian cancer without conclusive results. The cytokine network, indeed, is characterized by complex interactions, and the final biological effect of a single genetic variation depends on the balance among different molecular signals. As is well known, Th1/Th2 cytokine unbalanced production might predispose to different pathologies, cancer included. In general, a prolonged type 1 inflammatory response might allow that cells accumulating enough "genetic hits" are promoted to neoplastic transformation. On the other hand, IL-13-producing cells through the IL-13/IL-4…

Gender-specific association between -1082 IL-10 promoter polymorphism and longevity.

Ageing is characterized by a pro-inflammatory status, which could contribute to the onset of major age-related diseases. Thus, genetic variations in pro- or anti-inflammatory cytokines might influence successful ageing and longevity. IL-10 is an appropriate candidate because it exerts powerful inhibitory effects on pro-inflammatory function. IL-10 production is controlled by several polymorphic elements in the 5' flanking region of IL-10 gene on 1q32 locus, involving alleles at two microsatellite regions and several polymorphisms in promoter region. We analysed in 190 Italian centenarians (99 years old, 159 women and 31 men) and in 26060 years old control subjects (99 women and 161 men), ma…

Systemic Immune Responses in Alzheimer's Disease: In Vitro Mononuclear Cell Activation and Cytokine Production

To investigate the systemic signs of immune-inflammatory responses in Alzheimer's disease (AD), in the present study we have analyzed blood lymphocyte subsets and the expression of activation markers on peripheral blood mononuclear cells (PBMCs) from AD patients and age-matched healthy controls (HC) activated in vitro by recombinant amyloid-beta peptide (rAbeta42). Our study of AD lymphocyte subpopulations confirms the already described decrease of the absolute number and percentage of B cells when compared to HC lymphocytes, whereas the other subsets are not significantly different in patients and controls. We report the increased expression of the activation marker CD69 and of the chemoki…

Pro-inflammatory gene variants in myocardial infarction and longevity: implications for pharmacogenomics.

Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). However, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. Cyclo-oxygenases (COXs) and 5-lipoxygenase (5-LO) are the key enzymes in the conversion of arachidonic acid to prostaglandins (PG) and leukotrienes (LT) and are implicated in a wide variety of inflammatory disorders, including atherosclerosis. In fact, PGE2 activates Matrix Metallo-proteinases whereas LTB4 is a chemoactractant for monocytes and activates gene expression in inflammatory c…

Inflammation, genes and zinc in Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and metal biological pathway. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Amyloid deposition, due to the accumulation of Abeta peptide, is the main pathogenetic mechanism. Inflammation clearly occurs in pathologically vulnerable regions of AD and several i…

Interleukin-10 promoter polymorphism in sporadic Alzheimer's disease.

Proinflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their high production have been shown to be associated with AD. Thus, AD patients display a proinflammatory genotype and the control of inflammation might play a protective role in AD development. By sequence-specific probes, we have evaluated the role of anti-inflammatory cytokine interleukin(IL)-10 in AD, by analysing in 132 AD patients and 213 healthy controls the prevalence of three different haplotypes, involving three single-nucleotide polymorphisms (SNPs) at -1082 (G--A), -819 (C--T) and -592 (C--A) nucleotides of IL-10…

Ambiente, invecchiamento e longevità

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B8, DR3 antigens and production of human leucocyte migration inhibitory factor (LIF) by mononuclear cells stimulated with concanavalin A (Con A)

LIF release by Con A stimulated mononuclear cells was evaluated in 67 randomly selected healthy Sicilians typed for HLA antigens. The results show that B8 and/or DR3 positive subjects release less LIF than negative ones, suggesting that this immunological response might be controlled by HLA-linked immune response (Ir) gene(s).

Cytokine serum profile in a group of Sicilian Nonagenarians

The aim of our study was to evaluate the possibility of using multiplex analysis of the cytokine profile as a marker for successful aging by comparing cytokine plasmatic levels of a group of Sicilian nonagenarians with those of young controls. We analyzed a panel of 17 cytokines, comprehensive of haematopoietic factors T helper 1 (Th1), Th2, inflammation regulatory cytokines, and chemokines. The assay was carried out using the Luminex system. Interleukin (IL)-6 levels (p = 0.01) were increased in nonagenarians, whereas no modifications of other proinflammatory cytokines and chemokines were observed. Interferon-gamma (IFN-gamma) and IL-2 levels are unmodified, suggesting a substantial mainte…

Inflamm-aging ed immunosenescenza

Nell’anziano sono descritte alterazioni dell’immunità naturale ed acquisita generalmente percepite come una condizione di deterioramento del sistema immune. A questa condizione si affianca anche uno stato infiammatorio cronico, configurando la cosiddetta immunosenescenza, che diventa il principale responsabile dell’insorgenza di patologie a carattere infettivo ed infiammatorio età correlate. Certamente una migliore conoscenza dell’immunosenescenza e lo sviluppo di adeguate strategie per contrastarla sono essenziali per migliorare la qualità della vita degli anziani e per permettere la formulazione di strategie anti-invecchiamento finalizzate non tanto a «ringiovanire» l’individuo, ma a rita…

Albumin versus solvent/detergent-treated pooled plasma as replacement fluid for long-term plasma exchange therapy in a patient with primary hypertriglyceridemia and recurrent hyperlipidemic pancreatitis

BACKGROUND Chylomicronemia syndrome is a metabolic condition characterized by severe fasting hypertrigliceridemia (≥1000 mg/dL) and other clinical features including chronic abdominal pain and recurrent acute pancreatitis. In patients with acute or recurrent pancreatitis, plasma exchange (PEx) is indicated for the treatment of acute disease and prevention of recurrence. The use of plasma instead of albumin as replacement fluid has been suggested for its putative ability to replace the deficient enzyme possibly leading to better clinical improvement. CASE REPORT A 40-year-old man with chylomicronemia syndrome due to a newly identified loss-of-function mutation in the lipoprotein lipase (LPL)…

Alzheimer’s disease and infections, where we stand and where we go

Editorial Alzheimer’s disease (AD) is a progressive neurological disorder, which represents the most common form of dementia, one of the major causes of disability in later life. Age is the greatest risk factor for AD, which typically affects people aged 65 years and over, with an age-standardised prevalence of 4.4 [1]. However, AD is not a normal part of ageing and advanced age alone does not justify the disease. Several pathways have been implicated in AD pathophysiology, the most described is the neurodegenerative one, which lead to the brain accumulation of beta-amyloid and neurofibrillary tangles, aggregations of hyperphosphorylated tau protein, macroscopically resulting in brain atrop…

HLA-DR phenotypes and blood levels of T cell subsets

Blood mononuclear cell and T cell subsets values were analyzed in 53 Sicilian individuals according to HLA-DR phenotypes. The results demonstrate that DR1-positive subjects show a significant increase of blood T cell subsets whereas DR3-positive subjects show a non-significant decrease of these values. These results suggest that gene(s) associated with HLA-DR could be one of the factors which affect blood levels of T cell subsets.

Sex, gender and immunosenescence: a key to understand the different lifespan between men and women?

Gender and sex are known to be associated with longevity. While males are usually stronger, females live longer. In the Western world, the life expectancy of individual born between 2005 and 2010 is 80.4 for women and 73.4 for men [1]. Potential factors have been examined to explain this disagreement. It is possible distinguish advantage in longevity related to biological traits and factors related to socio-cultural characteristics of the population. Males and females have different behavioral tendencies, social responsibilities and expectation. So, differences in mortality between men and women can be not only a matter of sex that refers to biological differences, but also a matter of “soc…

Morphea after silicone gel breast implantation for cosmetic reasons in an HLA-B8,DR3-positive woman

We describe an HLA-B8, DR3-positive patient with localized morphea after silicone gel breast implantation for cosmetic reasons. We believe that this case suggests that a genetic background, i.e. HLA-B8, DR3 haplotype, is involved in the autoimmune response to silicone.

Genetics of exceptional longevity: possible role of GM allotypes

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1267 HSP70-2 polymorphism as a risk factor for carotid plaque rupture and cerebral ischaemia in old type 2 diabetes-atherosclerotic patients.

Patients with type 2 diabetes mellitus (NIDDM) are at risk for macrovascular disease complications, such as myocardial infarction (MI) or stroke from plaque rupture. Cytokines play a key role in plaque vulnerability. IFN-gamma inhibits collagen synthesis thereby affecting plaque stability. High IL-6, TNF-alpha, and dyslipidemia are risk factors for thrombosis. Abnormal increments of HSP70 in atherosclerotic plaques might lead to plaque instability and rupture caused by chronic inflammation, which up-regulates the expression of pro-inflammatory cytokines (IL-6 and TNF-alpha) in human monocytes. Studies of a polymorphic PstI site lying in the coding region at position 1267 of the HSP70-2 gene…

Genetic variation in human leukocyte antigen and susceptibility to acute myeloid leukemia.

In this issue of Acta Haematologica, Authors report the association between the Human Major Histocompatibility complex (MHC) HLA-C3 and Acute Myeloid Leukemia (AML) in Korean population, confirming previous studies on association between HLA-C and AML.

Targeting aging with functional food: Pasta with opuntia single-arm pilot study

Interventions to extend life span represent the new perspective in aging investigation. Healthy dietary habits are important modifiable factors that can favor a healthy aging phenotype. Many studies have demonstrated benefits for metabolic syndrome and type 2 diabetes mellitus resulting from the traditional Mediterranean foods. Opuntia Ficus Indica (OFI), widespread in the Mediterranean basin, belongs to the Cactaceae family. It is known for its antioxidant and anti-inflammatory properties. Moreover, products containing extracts from OFI fruits or cladodes have been used to control obesity and other metabolic parameters, such as glycemia and lipid profile. The aim of this study was to analy…

Administration of a Synbiotic to Free-Living Elderly and Evaluation of Serum Cytokines. A Pilot Study

Ten free-living elderly were administered with a synbiotic [fermented milk containing Lactobacillus rhamnosus Gorbach and Goldin (LGG)] and oligofructose as a prebiotic for one month. Serum cytokines were evaluated before (T(0)) and after (T(1)) synbiotic administration. At T(0), values of Interleukin (IL)-12, IL-6, IL-10, IL-1beta and Tumor Necrosis Factor (TNF)-alpha were lower than normal controls, with the exception of IL-8, thus confirming previous results on the impairment of both innate and adaptive responses in elderly. At T(1), the synbiotic was able to significantly increase, depressed values of IL-1, IL-6 and IL-8 with a trend to a modest increase for the restant cytokines. In co…

B cell alloantigens in Sicilian patients with Crohn's disease.

Clinical importance of eosinophil count in nasal fluid in patients with allergic and non-allergic rhinitis

Eosinophil count in nasal fluid (ECNF) was used to differentiate nasal pathologies. Receiver Operating Characteristic (ROC) curve analysis and the area under the curve (AUC) were performed to evaluate the ECNF's accuracy in distinguishing allergic rhinitis (AR) from non-allergic rhinitis (NAR). We also evaluated the accuracy of ECNF in recognizing patients with mild and severe symptoms of rhinitis and patients with ineffective and effective clinical responses to antihistamines. 1,170 consecutive adult patients with a clinical history of rhinitis were studied. ECNF's median in AR was 6.0 and 2.0 in NAR and the best cut-off value was > 3.0, AUC = 0.75. ECNF's median in AR with mild nasal …

Inflammation, genetics, and longevity: further studies on the protective effects in men of IL-10 -1082 promoter SNP and its interaction with TNF-alpha -308 promoter SNP.

Ageing is associated with chronic, low grade inflammatory activity leading to long term tissue damage, and systemic chronic inflammation has been found to be related to mortality risk from all causes in older persons.1 Also, the genetic constitution of the organism interacting with systemic inflammation may cause defined organ specific illnesses. Thus, age related diseases such as Alzheimer’s disease (AD), Parkinson’s disease, atherosclerosis, type 2 diabetes, sarcopenia, and osteoporosis, are initiated or worsened by systemic inflammation, suggesting the critical importance of unregulated systemic inflammation in the shortening of survival in humans.1–3 Accordingly, proinflammatory cytokin…

Invecchiamento e Sistema Immunitario

Defective expression of CD95 (FAS/APO-1) molecule suggests apoptosis impairment of T and B cells in HLA-B8, DR3-positive individuals.

Activation-induced apoptosis is one of the primary control mechanisms for the negative selection of an immune response, leading to maintenance of immune homeostasis and selective T cell deletion. The interaction between the surface molecule Fas and its ligand (FasL) has been proposed as a primary mechanism initiating T cell apoptosis. The T cell receptor modulates the expression and function of these molecules. Defects in the Fas/FasL apoptosis pathway have been shown to result in autoimmune disease in humans and in murine models. Because subjects carrying the HLA-B8, DR3 haplotype show a number of immune dysfunctions, including membrano-proliferative glomerulonephritis, systemic lupus eryt…

Soluble Interleukin-2 Receptor Secretion Defectin Vitroin HLA-B8, DR3 Positive Subjects

Several studies have shown that HLA-B8,DR3 positive subjects may display T cell dysfunctions. Recently, a soluble form of the receptor for IL-2 (sIL-2R) has been demonstrated in human sera and in vitro-stimulated culture supernatant from human T lymphocytes. In the present paper we report sIL-2R serum levels and sIL-2R production from peripheral blood mononuclear cells in HLA-B8,DR3 positive subjects. We found that HLA-B8,DR3 positive subjects have the highest values of serum sIL-2R, but comparing the values of these subjects with those of negative ones no significant difference was observed. As regards the in vitro production of sIL-2R, no difference exists for unstimulated cultures, where…

Le metastasi

Dietary inflammatory index and cancer risk in the elderly: A pooled-analysis of Italian case-control studies

Abstract Objectives The aim of this study was to evaluate whether the association between the inflammatory potential of one's diet and cancer risk varies across age groups in a population characterized by widespread use of the Mediterranean diet. Methods We analyzed data from a network of case-control studies conducted in Italy between 1991 and 2014. The studies included cancers of the oral cavity (n = 509), pharynx (n = 436), nasopharynx (n = 198), larynx (n = 459), esophagus (n = 304), stomach (n = 230), colon (n = 1225), rectum (n = 728), liver (n = 184), pancreas (n = 326), breast (n = 2569), endometrium (n = 454), ovary (n = 1031), prostate (n = 1294), kidney (n = 767), and bladder (n …

HLA-B8,DR3 phenotype and lymphocyte responses to phytohaemagglutinin.

Several reports have shown that HLA-B8,DR3 positive subjects may display some changes in immune parameters when compared with HLA-B8,DR3 negative ones and are prone to develop several immunological diseases. In the present study we have analysed the proliferative response to phytohaemagglutin (PHA) in HLA-typed healthy subjects. A twin method was also employed to assess the role of genetic and environmental factors in the regulation of the response to the mitogen. It was not possible to demonstrate any difference in proliferative response to optimal doses of PHA between groups of subjects carrying or not carrying the HLA-B8,DR3 phenotype. When suboptimal responses were studied, however, the…

Vascular Aging effect on Medial aorta degeneration: focus on blood keukocyte telomere lenght in Hypertensive and old patients with sporadic thoracic aortic aneurysm

Report from the second cytomegalovirus and immunosenescence workshop

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.; International audience; The Second International Workshop on CMV & Immunosenescence was held in Cambridge, UK, 2-4th December, 2010. The presentations covered four separate sessions: cytomegalovirus and T cell phenotypes; T cell memory frequency, inflation and immunosenescence; cytomegalovirus in aging, mortality and disease states; and the immunobiology of cytomegalovirus-specific T cells and effects of the virus on vacc…

Il Core Curriculum degli studi di Medicina. Stato dell'arte e prospettive

Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia

A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs …

The Phenotypic Characterization of the Cammalleri Sisters, an Example of Exceptional Longevity

This article shows demographic, clinical, anamnestic, cognitive, and functional data as well as biochemical, genetic, and epigenetic parameters of two exceptional siblings: Diega (supercentenarian) and Filippa (semisupercentenarian) Cammalleri. The purpose of this study is to provide new insights into the extreme phenotypes represented by semisupercentenarians and supercentenarians. Different studies have been published on supercentenarians, but to the best of our knowledge, this is the only concerning two sisters and the most detailed from a phenotypic point of view. Our findings agree with the suggestion that supercentenarians have an increasing relative resistance to age-related diseases…

Analysis of HLA-DRB1,DQA1,DQB1 haplotypes in Sardinian centenarians

Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1 *15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a ro…

La malattia

Zinc and inflammatory/immune response in aging

Life-long antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and proinflammatory cytokine production. A large number of studies have documented changes in zinc metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory conditions. In particular, modification of zinc plasma concentration, as well as intracellular disturbance of antioxidant intracellular pathways, has been found in aging and in some age-related diseases. Zinc deficiency is diffused in aged individuals in order to avoid meat and other high zinc content foods due to fear of cholesterol. Rather, they increase the consumption of r…

A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence.

The literature on immunosenescence has focused mainly on T cell impairment. With the aim of gaining insight into B cell immunosenescence, we investigated the serum immunoglobulin levels in a cohort of 166 subjects (20-106 years). Serum IgG (and IgG subclasses) were quantified by the nephelometric technique, IgE by CAP system fluorescence enzyme immunoassay, and IgD by radial immunodiffusion (RID). There was an age-related increase of IgG and IgA; the IgG age-related increase was significant only in men, but IgG1 levels showed an age-related increase both in men and women, whereas IgG3 showed an age-related increase only in men. IgE levels remain unchanged, whereas IgD and IgM serum levels d…

Tumor necrosis-factor-alpha -308 A/G polymorphism is associated with age at onset of Alzheimer's disease.

Abstract Pro-inflammatory cytokines and acute-phase proteins play an important role in Alzheimer's disease (AD) neurodegeneration, and common polymorphisms of genes controlling their production have been shown to be associated with AD. Tumor necrosis factor (TNF)-α is an inflammatory cytokine involved in the local immune response occurring in the central nervous system of AD patients. Genetic variation could contribute to the risk of developing AD or influence the age at the onset of the disease. We genotyped 222 patients (152 women, 70 men; age range 60–87) and 240 non-demented age-matched healthy controls for TNF-α −308 G/A single nucleotide polymorphism (SNP). No significant differences …

Frequency of the HFE Gene Mutations in Five Italian Populations

Abstract ABSTRACT Genetic hemochromatosis is an autosomal recessive disorder characterized by iron overload and a variety of clinical manifestations such as liver cirrhosis and arthropathy. It is the most common genetic disease of northern European populations. The principal gene responsible for hereditary hemochromatosis, designated HFE, is located on chromosome 6 in the HLA region. The single point mutation 845A, changing cysteine at position 282 to tyrosine (C282Y), in this gene has been identified as the main genetic basis of hereditary hemochromatosis. Two other mutations, 187G, a histidine to aspartate at amino acid 63 (H63D), and 193T, a serine to cysteine at amino acid 65 (S65C), ap…

Genotypic and phenotypic aspects of longevity: results from a Sicilian survey and implication for the prevention and the treatment of age-related diseases

Background:It is well known that long living individuals are a model of successful ageing and that the identification of both genetic variants and environmental factors that predispose to a long and healthy life is of tremendous interest for translational medicine.Methods:We present the preliminary findings obtained from an ongoing study on longevity conducted on a sample of Sicilian long-lived individuals.Results:We review the characteristics of longevity in Sicily, taking into account lifestyle, environment, genetics, hematochemical values, body composition and immunophenotype. In addition, we discuss the possible implications of our data for the prevention and/or treatment of age-related…

Association between genetic variations in the insulin/insulin-like growth factor (Igf-1) signaling pathway and longevity: a systematic review and meta-analysis.

Some studies have shown that polymorphisms in the insulin growth factor-1 (IGF-1) signaling pathway genes could influence human longevity. However, the results of different studies are often inconsistent. Our aim was to investigate by systematic review and meta-analysis the association of the common polymorphisms defining the genetic variability of the IGF-1 signaling pathway associated with human longevity. Eleven studies investigating the association between the polymorphisms in the IGF-1 signaling pathway genes (IGF-1, IGF-1 receptor (IGF-1R), Forkhead box O3A (FOXO3A) and Silent mating type Information Regulation 1 (SIRT1) and longevity were found and analyzed. The modelfree approach wa…

Genotyping of sex hormone-related pathways in benign and malignant human prostate tissues: data of a preliminary study.

Prostate cancer (PCa) is a major health issue in Westernized countries, representing a common cause of morbidity and mortality in the elderly male population. Endogenous sex steroids, along with environmental factors (notably diet) and host immune and inflammatory responses, are likely to cooperate in the pathogenesis of the disease. Based on the assumption that a complex endocrine–inflammatory-immune interaction is primarily implicated in human PCa, we have investigated the interplay between sex steroids and inflammation in development and growth of human PCa. To this end, we have assessed nine functional single nucleotide polymorphisms (SNP)s of five genes involved in sex hormone-related …

Thrombotic thrombocytopenic purpura: a review of the literature in the light of our experience with plasma exchange

Immunotherapy in patients with Alzheimer's disease (AD) is rapidly becoming a hot topic of modern geriatric and clinical gerontology. Current views see immunization with Aβ peptide, the amyloidogenic protein found in senile plaque of AD patient's brains, or the infusion of preformed antibody specific for human Aβ, as possible therapeutic approaches to improve the cognitive status in the disease. Animal models of the disease have provided positive results from both approaches. Thus, an initial clinical trial using immunization with human Aβ in AD patients was started, but then shortly halted because of an unusually high incidence (6%) of meningoencephalitis. A long and currently ongoing deba…

Immune-Inflammatory Responses and Oxidative Stress in Alzheimers Disease: Therapeutic Implications

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. AD has been linked to inflammation and oxidative stress. Neuro-pathological hallmarks are senile plaques, resulting from the accumulation of several proteins and an inflammatory reaction around deposits of amyloid, a fibrillar protein, Abeta, product of cleavage of a much larger protein, the beta-amyloid precursor protein (APP) and neurofibrillary tangles. Inflammation clearly occurs in pathologically vulnerable regions of AD and several inflammatory factors influencing AD development, i.e. environmental factors (pro-inflammatory phenotype) an…

Effects of Oleuropein and Hydroxytyrosol on Inflammatory Mediators: Consequences on Inflammaging

Aging is associated with a low-grade, systemic inflammatory state defined as “inflammaging”, ruled by the loss of proper regulation of the immune system leading to the accumulation of pro-inflammatory mediators. Such a condition is closely connected to an increased risk of developing chronic diseases. A number of studies demonstrate that olive oil phenolic compound oleuropein and its derivative hydroxytyrosol contribute to modulating tissue inflammation and oxidative stress, thus becoming attractive potential candidates to be used in the context of nutraceutical interventions, in order to ameliorate systemic inflammation in aging subjects. In this review, we aim to summarize the available d…

Genetic control of immune response in carriers of the 8.1 ancestral haplotype: correlation with levels of IgG subclasses: its relevance in the pathogenesis of autoimmune diseases.

Ancestral haplotype (AH) 8.1(HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201) seems to be associated with susceptibility to autoimmune diseases. Different mechanisms are probably involved in increasing autoimmunity, such as unbalanced cytokine production and the lack of C4A protein. So AH 8.1 modifies immune response in many ways. In this study we demonstrate that IgG2 serum levels were significantly lower in 8.1 AH carriers than in 8.1 AH non-carriers. On the contrary, as regards IgG1, IgG3, IgG4 serum levels, no significant differences were observed between the two groups. In AH 8.1 carriers low IgG2 levels might take to slower cl…

Interleukin-10 and interleukin-18 promoter polymorphisms in an Italian cohort of patients with undifferentiated carcinoma of nasopharyngeal type.

Purpose: Cytokines such as IL-10 and IL-18 seem to be involved in the inflammatory response of undifferentiated carcinoma of nasopharyngeal type (UCNT). The aim of this study was to evaluate the correlation between functional single nucleotide polymorphisms (SNPs) in the promoter region of IL-10 and IL-18 genes and the virological and clinical characteristics in a large case series of Caucasian patients suffering from UCNT, a tumor regularly associated with the Epstein Barr Virus (EBV). Methods: Eighty-nine patients with histologically confirmed UCNT and 130 healthy donors were included in our study. DNA was examined for the polymorphisms of IL-10 gene at positions –1082, −819, −592 by dire…

CCR5 Proinflammatory Allele in Prostate Cancer Risk

Prostate cancer (PCa) is the most common malignant neoplasm in older men in Western countries. The number of affected older men is increasing. Therefore, strategies for prevention of prostate cancer are crucial. To this purpose it is essential to know the mechanisms involved in development and progression of this malignancy. Recently, an increasing body of genetic and epidemiological studies proposed new hypotheses for prostate carcinogenesis. It has been suggested that genetic factors as well as exposure to environmental factors such as infectious agents, dietary carcinogens, and hormonal imbalances participate in PCa development. Besides, chronic inflammation plays a key role in PCa. Taki…

B cell immunosenescence in the elderly and in centenarians.

The elderly suffer from an increased susceptibility to infectious disease and cancer. Aging of the immune system contributes to this state of affairs due to immunosenescence. Because repeated intermittent or chronic antigen exposure may lead to lymphocyte clonal exhaustion, chronic antigenic stress plays a part in the compromised immunity of the elderly, who have accumulated a lifetime's exposure to infectious agents, autoantigens, and cancer antigens. Literature on immunosenescence has focused mainly on T cell impairment, but B cell compartment is also affected. The age-dependent B cell changes documented by the present review indicate that advanced age per se is a condition characterized …

Polymorphisms of genes of TGF-beta pathway and susceptibility to colorectal cancer

Background: Genetic background implicated in cytokine network may have a key role in the susceptibility to colorectal cancer (CRC). The TGF-β pathway is involved in several biological processes, including cell proliferation, differentiation, migration and apoptosis. Methods: rs1800471 SNP polymorphism of TGF-ß1 rs334348 and rs334349 of TGF-βR1, rs900 of TGF-β2 and rs4522809 of TGF-β2R2 were typed in a group of 82 patients affected by sporadic CRC and in 237 age- and sex-matched healthy controls, using a competitive allele specific PCR assays (KASPar), developed by KBioscience (England). Results: No significant genetic contribution has been observed for 3 of the 5 SNPs tested. Indeed, a sign…

Biomarkers and Inflammatory Network in Aging

Abstract Humans are characterized by a large heterogeneity in lifespans. The aging rate, measured as a decline of functional capacity and stress resistance, is different in every individual. Several attempts have been made to define the so-called biological age, but without achieving real success. Biomarkers of aging, which are represented by biological indicators selected using appropriate criteria, should help to characterize the biological age. Since age is a major risk factor in many degenerative diseases, such biomarkers could subsequently be used to identify individuals at a high risk of developing age-associated diseases or disabilities. In this chapter, some inflammatory biomarkers …

Randomized placebo-controlled trial comparing fluticasone aqueous nasal spray in mono-therapy, fluticasone plus cetirizine, fluticasone plus montelukast and cetirizine plus montelukast for seasonal allergic rhinitis.

BACKGROUND: Corticosteroids are considered to be particularly effective in reducing nasal congestion and are therefore recommended as first-line treatment in allergic rhinitis patients with moderate to severe and/or persistent symptoms. OBJECTIVE: We compared the clinical efficacy of fluticasone propionate aqueous nasal spray (FPANS) 200 microg given once daily, administered in mono-therapy or combined therapy with a H1 receptor antagonist (cetirizine, CTZ) or with a leukotriene antagonist (montelukast, MSK), and the combined therapy of CTZ plus MSK in the treatment of patients affected by allergic rhinitis to Parietaria during natural pollen exposure. In addition, we examined the effect of…

The Role of Adipose Tissue and Adipokines in Obesity-Related Inflammatory Diseases

Obesity is an energy-rich condition associated with overnutrition, which impairs systemic metabolic homeostasis and elicits stress. It also activates an inflammatory process in metabolically active sites, such as white adipose tissue, liver, and immune cells. As consequence, increased circulating levels of proinflammatory cytokines, hormone-like molecules, and other inflammatory markers are induced. This determines a chronic active inflammatory condition, associated with the development of the obesity-related inflammatory diseases. This paper describes the role of adipose tissue and the biological effects of many adipokines in these diseases.

Cytokine production pathway in the elderly.

It is well known that aging is associated with various alterations in lymphoid cell functions, particularly with a progressive decline in immune responsiveness to exogenous antigens and increasing incidence of autoimmune phenomena. Many studies have been focused on the mechanisms of the immunologic features of aging. this review describes our results of studies performed to determine the influence of age on the capacity to produce interleukin-2 (IL-2), interferon-gamma (IFN-gamma), interleukin-4 (IL-4), interleukin-t (IL-5), interleukin-6 (IL-6) and tumor necrosis factor (TNF). Mitogen-stimulated cultures of mononuclear cells (MNC) from human beings were assessed for cytokine-producing capa…

Age-Related Inflammation: the Contribution of Different Organs, Tissues and Systems. How to Face it for Therapeutic Approaches

A typical feature of ageing is a chronic, low-grade inflammation characterized by a general increase in the production of pro-inflammatory cytokines and inflammatory markers ("inflamm-ageing"). This status may slowly damage one or several organs, especially when unfavorable genetic polymorphisms and epigenetic alterations are concomitant, leading to an increased risk of frailty together with the onset of age-related chronic diseases. The contribution of different tissues (adipose tissue, muscle), organs (brain, liver), immune system and ecosystems (gut microbiota) to age-related inflammation ("inflamm-ageing") will be discussed in this review in the context of its onset/progression leading …

Bone marrow B lymphocytes in multiple myeloma and MGUS: Focus on distribution of naïve cells and memory subsets.

Multiple myeloma (MM) is caused by proliferation of clonal plasma cells (cPCs) in bone marrow (BM), associated with numerical and functional defects in immune subsets. An impairment of B cell compartment is involved in onset/progression of the disease.By flow cytometry, we studied distribution of naïve/transitional (IgD(+)CD27(-)), memory unswitched (IgD(+)CD27(+)), memory switched (IgD(-)CD27(+)) and double negative (DN) (IgD(-)CD27(-)) B lymphocytes in BM of control subjects, and responding and relapsing patients.We observed an increased percentage of IgD(+)CD27(+) B cells in healthy controls vs responding patients (p0.05). Treated non complete responders exhibited an expanded DN compartm…

Prevalence of organ-specific and non organ-specific autoantibodies in healthy centenarians.

In the present study we have investigated the prevalence of organ-specific and non organ-specific autoantibodies in 26 healthy centenarians (6 men, 20 women; age range 101-106 years), using as controls 54 healthy old (33 men and 21 women, age range 71-93) and 56 young subjects (29 men and 27 women, age range 26-60). We assayed sera of each group for the following organ-specific autoantibodies, anti-gastric mucosa (anti-PCA), anti-thyroglobulin (anti-Tg) and non organ-specific autoantibodies, anti-cardiolipin (anti-APA IgG and IgM), anti-nuclear antigens (anti-ANA), anti-double strand DNA (anti-ds-DNA), anti-extractable nuclear antigens (anti-ENA). Finally, natural anti-alpha-galactosyl (ant…

HLA and KIR Interaction in Patients with Ischemic Stroke

Background: T-cells expressing the KIR2DS2 activating receptor were found to be prevalent in the coronary culprit atherosclerotic plaque in patients with acute coronary syndromes (ACS), suggesting a possible cytolytic activity against the endothelium of the plaque, leading to plaque rupture and in turn to superimposed thrombosis and sudden occlusion of the artery. To explore if a similar pathogenetic mechanism occurs in acute ischemic stroke, we analyzed the possible association between the genetic KIR and HLA repertoire and the susceptibility to ischemic stroke. Methods: Fourteen patients with ischemic stroke and ten controls with atherosclerotic disease without ischemic stroke matched for…

B cells and immunosenescence: a focus on IgG+IgD-CD27- (DN) B cells in aged humans.

Immunosenescence contributes to the decreased ability of the elderly to control infectious diseases, which is also reflected in their generally poor response to new antigens and vaccination. It is known that the T cell branch of the immune system is impaired in the elderly mainly due to expansion of memory/effector cells that renders the immune system less able to respond to new antigens. B lymphocytes are also impaired in the elderly in terms of their response to new antigens. In this paper we review recent work on B cell immunosenescence focusing our attention on memory B cells and a subset of memory B cells (namely IgG(+)IgD(-)CD27(-)) that we have demonstrated is increased in healthy el…

Therapeutic potential of dietary polyphenols against brain ageing and neurodegenerative disorders

In recent years there has been a growing interest, supported by a large number of experimental and epidemiological studies, in the beneficial effects of some commonly used food-derived products in preventing various age-related pathologic conditions, ranging from cancer to neurodegenerative diseases. Spices and herbs often contain active phenolic substances endowed with potent antioxidative and chemopreventive properties. Curcumin is a phytochemical compound extracted from the rhizome of Curcuma Longa. It is the pigment responsible for the characteristic yellow color of Indian curry. Data from our and other laboratories demonstrated that curcumin, as well as some other polyphenols, strongly…

Immunity and Aging

In the elderly, many alterations of innate and acquired immunity have been described and viewed as deleterious, hence the term immunosenescence. Immunosenescence is a complex process involving multiple reorganizational and developmentally regulated changes, rather than simple unidirectional decline of complete immune function. On the other hand, some immunological parameters are commonly notably reduced in the elderly, and reciprocally good function is tightly correlated to health status. Whereas innate immunity is relatively well preserved in elderly, acquired immunity is more susceptible due to both the functional decline associated with the passage of time, and to antigen burden to which…

Immunosenescenza e Inflammaging

With the descriptive term "immunosenescence" we classically define all those modifications, related to age, which cause reduced efficiency of immune responses with an increased risk of infectious diseases, which in the old age become the first cause of death, of autoimmune phenomena and, presumably, of tumors; all accompanied by a characteristic pro-inflammatory state.

Association between the Polymorphism of CCR5 and Alzheimer's Disease: results of a study performed on male and female patients from Northern Italy

In vitro treatment with interleukin-2 normalizes type-1 cytokine production by lymphocytes from elderly

The term immunosenescence is taken to mean the deterioration of immune function seen in elderly, which is manifested in increased susceptibility to infectious diseases, neoplasias, and autoimmune diseases. It is only recently that we have begun to understand the cellular and molecular changes involved. Of special interest in this regard are observations of a decline in synthesis of Type-1 cytokines which predisposes to diminished cell mediated immunity. We have evaluated the production of type 1 cytokines in old and young donors either in presence or in absence of recombinant interleukin-2 (rIL-2). Lymphocytes were stimulated with plastic bound anti-CD3 and after 48 h the supernatants were …

Genes involved in immune response/inflammation, IGF1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians

In this paper, we review data of recent literature on the distribution in centenarians of candidate germ-line polymorphisms that likely affect the individual chance to reach the extreme limit of human life. On the basis of previous observations on the immunology, endocrinology and cellular biology of centenarians we focused on genes that regulate immune responses and inflammation (IL-6, IL-1 cluster, IL-10), genes involved in the insulin/IGF-I signalling pathway and genes that counteract oxidative stress (PON1). On the whole, data indicate that polymorphisms of these genes likely contribute to human longevity, in accord with observations emerging from a variety of animal models, and suggest…

How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells

Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on t…

Markers of T Lymphocyte Activation in HLA-B8, DR3 Positive Individuals

Many autoimmune diseases are associated in Caucasians with HLA-B8 and/or HLA-DR3 antigens. There is evidence that bearers of these antigens may display significant changes in immune parameters when compared to individuals not having these antigens. Recently, increased numbers of blood activated T lymphocytes have been reported in the majority of these diseases. The increase in activated blood T lymphocytes is paradoxically characterized by an in vitro impairment of T cell activation. Particularly, an inadequate production of interleukins has been observed. We have studied blood levels of activated T cells in HLA-typed, healthy subjects. The results show that the percentage of activated T ce…

Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians

Background and aims: Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity reside in those polymorphisms for the immune system genes which regulate immuneinflammatory responses, in particular cytokine gene polymorphisms. The frequency of − 174C single nucleotide polymorphism (SNP) in the promoter region of the interleukin(IL)-6 gene is increased in Italian male centenarians. Moreover, the frequency of − 1082G SNP at the 5′ flanking region of the IL-10 gene coding sequence is increased among male centenarians, and that of +874A SNP at the interferon (IFN)- γ gene was found more frequently in femal…

T-cell activation in HLA-B8,DR3-positive individuals early antigen expression defect in vitro

The HLA-B8, DR3 haplotype is overrepresented in several autoimmune diseases, implying that genes predisposing to these disorders are linked to this haplotype. In the patients affected by these diseases, as well as in healthy HLA-B8, DR3 individuals, various dysfunctions reflecting an impairment of T-cell activation have been found. To better characterize T-cell impairment of HLA-B8, DR3-positive healthy individuals, we analyzed the surface expression of early (CD69) and late (CD71) activation phenotypes. MNC cultures were stimulated with PHA and used for T-cell phenotyping by flow cytometry analysis. The results showed that the percentage of CD69+ T cells was significantly decreased in MNC …

Looking for immunological risk genotypes

Role of persistent CMV infection in configuring T cell immunity in the elderly

Abstract Ageing is associated with declines in many physiological parameters, including multiple immune system functions. The rate of acceleration of the frequency of death due to cardiovascular disease or cancer seems to increase with age from middle age up to around 80 years, plateauing thereafter. Mortality due to infectious disease, however, does not plateau, but continues to accelerate indefinitely. The elderly commonly possess oligoclonal expansions of T cells, especially of CD8 cells, which, surprisingly, are often associated with cytomegalovirus (CMV) seropositivity. This in turn is associated with many of the same phenotypic and functional alterations to T cell immunity that have b…

Pro-inflammatory genetic background and zinc status in old atherosclerotic subjects.

Inflammation and genetics are prominent mechanisms in the pathogenesis of atherosclerosis (AT) and its complications. In this review we discuss the possible impact on AT development of several genetic determinants involved in inflammation, oxidative stress and cytoprotection (IL-6, TNF-alpha, IL-10, CD14, TLR4, MT, HSP70). Genetic polymorphisms of these genes may affect a differential inflammatory response predisposing to AT. However, allelic polymorphisms of genes which increase the risk of AT frequently occur in the general population but, only adequate gene-environment-polymorphism interactions promote the onset of the disease. Zinc deficiency has been suggested as an environmental risk …

Involvement of -308 TNF-alpha and 1267 Hsp70-2 polymorphisms and zinc status in the susceptibility of coronary artery disease (CAD) in old patients.

Coronary artery disease (CAD) is characterized by an inflammatory status and it represents the major cause of death in elderly. Zinc deficiency and inflammatory genes within major histocompatibility complex (MHC) region are implicated in ischaemic heart diseases. TNF-alpha is present in coronary artery plaques and may provoke plaque instability. Hsp70 plays instead a pro-atherogenic role, via proinflammatory cytokine production, in atherosclerotic lesions contributing to plaque rupture. Contradictory data report the association between -308 TNF-alpha polymorphism and CAD, while no investigations exist on Hsp70-2 gene in CAD. In the current study, we analysed -308 TNF-alpha and 1267 Hsp70-2 …

Alpha1-antitrypsin heterozygosity plays a positive role in attainment of longevity.

Genes involved in cardiovascular diseases (CVD) play an opposite role in human longevity. The alpha1-antitrypsin (AAT) is a serine-protease inhibitor required for the prevention of proteolytic tissue damage, by neutrophil elastase. The role of AAT in CVD has not been definitively assessed and its effect on longevity has not yet fully been studied. To clarify these points, we have studied the distribution of AAT allele variants in 3 cohorts: 127 young patients affected by acute myocardial infarction (AMI), 255 young controls and 143 centenarians from Sicily. The Z allele frequency was most frequent in centenarians (13.3%), intermediate in healthy young controls (3.1%) and less frequent in AM…

Healthy ageing and Mediterranean diet: A focus on hormetic phytochemicals

Abstract Mediterranean diet (MedDiet) is rich in fruits and vegetables associated with longevity and a reduced risk of several age-related diseases. It is demonstrated that phytochemicals in these plant products enhance the positive effects of MedDiet by acting on the inflammatory state and reducing oxidative stress. Evidence support that these natural compounds act as hormetins, triggering one or more adaptive stress-response pathways at low doses. Activated stress-response pathways increase the expression of cytoprotective proteins and multiple genes that act as lifespan regulators, essential for the ageing process. In these ways, the hormetic response by phytochemicals such as resveratro…

TRafficking profile in naive and memory B cells in young and old subjects

Opposite role of CCR5 polymorphisms in cardiovascular diseases and longevity.

Plasma proteome profiling of healthy individuals across the life span in a Sicilian cohort with long‐lived individuals

The study of healthy human aging is important for shedding light on the molecular mechanisms behind aging to promote well-being and to possibly predict and/or avoid the development of age-related disorders such as atherosclerosis and diabetes. Herein, we have employed an untargeted mass spectrometry-based approach to study age-related protein changes in a healthy Sicilian plasma cohort including long-lived individuals. This approach confirmed some of the previously known proteins correlated with age including fibulin-1, dystroglycan, and gamma-glutamyl hydrolase. Furthermore, our findings include novel proteins that correlate with age and/or with location and uric acid, which could represen…

Alzheimer’s disease and genetics of inflammation: a pharmacogenomic vision

Inflammation plays a key role in Alzheimer disease, and dissecting the genetics of inflammation may provide an answer to the possible treatment. The next-generation therapy is based on a pharmacogenomics that will reconure new approaches to a drug used on definite people with specific dosage. The translation of pharmacogenomics into clinical practice will allow bold steps to be taken toward personalized medicine. In response to tissue injury elicited by trauma or infection, the inflammatory response sets in as a complex network of molecular and cellular interactions, directed to facilitate a return to physiological homeostasis and tissue repair. The role of an individual’s genetic backgroun…

Can Be miR-126-3p a Biomarker of Premature Aging? An Ex Vivo and In Vitro Study in Fabry Disease

Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by lysosomal accumulation of glycosphingolipids in a wide variety of cytotypes, including endothelial cells (ECs). FD patients experience a significantly reduced life expectancy compared to the general population

Is immunotherapy an effective treatment for Alzheimer's disease?

Abstract Immunotherapy in patients with Alzheimer's disease (AD) is rapidly becoming a hot topic of modern geriatric and clinical gerontology. Current views see immunization with Aβ peptide, the amyloidogenic protein found in senile plaque of AD patient's brains, or the infusion of preformed antibody specific for human Aβ, as possible therapeutic approaches to improve the cognitive status in the disease. Animal models of the disease have provided positive results from both approaches. Thus, an initial clinical trial using immunization with human Aβ in AD patients was started, but then shortly halted because of an unusually high incidence (6%) of meningoencephalitis. A long and currently ong…

The emerging role of Notch pathway in ageing: Focus on the related mechanisms in age-related diseases

Notch signaling is an evolutionarily conserved pathway, which is fundamental for the development of all tissues, organs and systems of human body. Recently, a considerable and still growing number of studies have highlighted the contribution of Notch signaling in various pathological processes of the adult life, such as age-related diseases. In particular, the Notch pathway has emerged as major player in the maintenance of tissue specific homeostasis, through the control of proliferation, migration, phenotypes and functions of tissue cells, as well as in the cross-talk between inflammatory cells and the innate immune system, and in onset of inflammatory age-related diseases. However, until …

Mechanisms of immunosenescence

Abstract On April 7,8, 2009 a Symposium entitled "Pathophysiology of Successful and Unsuccessful Ageing" took place in Palermo, Italy. Here, the lectures of G. Pawelec, D. Dunn-Walters and. G. Colonna-Romano on T and B immunosenescence are summarized. In the elderly, many alterations of both innate and acquired immunity have been described. Alterations to the immune system in the older person are generally viewed as a deterioration of immunity, leading to the use of the catch-all term immunosenescence. Indeed, many immunological parameters are often markedly different in elderly compared to young people, and some, mostly circumstantial, evidence suggests that retained function of both innat…

A Pilot Study on Prostate Cancer Risk and Pro-Inflammatory Genotypes: Pathophysiology and Therapeutic Implications

Host genetic factors are crucial risk determinants for many human cancers. In this framework, an interesting model is represented by prostate cancer (PC), which is featured by a complex pathophysiology with a strong genetic component. Multiple genes seem to influence PC risk and several single nucleotide polymorphisms (SNPs) of candidate genes modifying PC susceptibility have been identified. It is noteworthy the potential association of common SNPs in pro-inflammatory genes with PC risk, since chronic inflammation is assumed to play a key role in prostate carcinogenesis. With the aim to identify candidate genes as an experimental basis to develop new strategies for both prevention and trea…

How Important Are Genes to Achieve Longevity?

Several studies on the genetics of longevity have been reviewed in this paper. The results show that, despite efforts and new technologies, only two genes, APOE and FOXO3A, involved in the protection of cardiovascular diseases, have been shown to be associated with longevity in nearly all studies. This happens because the genetic determinants of longevity are dynamic and depend on the environmental history of a given population. In fact, population-specific genes are thought to play a greater role in the attainment of longevity than those shared between different populations. Hence, it is not surprising that GWAS replicated associations of common variants with longevity have been few, if an…

B cell immunosenescence: different features of naive and memory B cells in elderly.

Elderly people show a reduced protection against new infections and a decreased response to vaccines as a consequence of impairment of both cellular and humoral immunity. In this paper we have studied memory/naive B cells in the elderly, evaluating surface immunoglobulin expression, production of the pro- and anti-inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-10, and presence of somatic hypermutation, focusing on the IgG(+)IgD(-)CD27(-) double negative (DN) B cells that are expanded in the elderly. Our results show that naive B cells from young donors need a sufficiently strong stimulus to be activated "in vitro", while naive B cells from old subjects are able t…

Role of prothrombotic polymorphisms in successful or unsuccessful aging.

The study of the genetic profile of centenarians aims to identify the genes and allelic variants which may influence a greater life expectancy and that can be considered as predisposing factors associated to the aging diseases, such as Alzheimer. Centenarians, that represent a cohort of selected survivors, show an hypercoagulability state characterised by striking signs of high coagulation enzyme activity, as directly assessed by the tested higher plasma level of some important factors involved in the haemostasis balance. Anyway, these individuals seem to have a reduced susceptibility to dementia, as well as to cardiovascular events. In this study we analyze the frequencies of Leiden Factor…

Looking for Immunological Risk Genotypes

Several functional markers of the immune system may be used either as markers of successful aging or conversely as markers of unsuccessful aging. Particularly, a combination of high CD8 and low CD4 and poor T cell proliferation has been associated with a higher two-year mortality in very old subjects. Therefore, genetic determinants of longevity should reside in those polymorphisms for the immune system genes that regulate immune responses. Concerning these changes in T cell subpopulations, how much they depend on the immunogenetic background and how much they depend on individual antigenic load, such as chronic infections, should be assessed. As previously demonstrated in our population, t…

Conclusions. Slowing aging and fighting age-related diseases, from bench to bedside?

Abstract The multiple wide-ranging and diverse aspects of aging discussed in this volume are overviewed and integrated in order to move toward a better understanding of how to achieve successful aging. To this end, potential strategies capable of slowing aging and preventing age-related diseases are considered and actions proposed.

Gamma/delta T lymphocytes are affected in the elderly

gammadelta T lymphocytes are considered to represent a link between the inflammatory response and adaptive immunity. In the present paper we investigated whether these cells play any role in the remodeling of the immune system described in the elderly. We show that the absolute number of gammadelta T cells in peripheral blood of old and very old subjects is reduced. Moreover, gammadelta T cells from old people and centenarians show enhanced levels of the early activation marker CD69 both after culture in medium alone and in LPS-stimulated cells. Furthermore, they show a basal increased production of tumor necrosis factor (TNF)-alpha as evaluated at the single cell level. Additionally, the r…

Immunological and immunogenetic markers in sporadic Alzheimer’s disease

Background: Common polymorphisms of genes controlling inflammation-modulating cytokines and acute-phase proteins which play important roles in the pathogenesis of Alzheimer''s disease (AD) have been shown to be associated with AD. Aims: The immunological and immunogenetic markers potentially useful for the AD risk evaluation and diagnosis are briefly reviewed. Conclusion: The state-of-the-art of immunological and immunogenetic markers of AD indicates that new tools and strategies are necessary to identify gene products useful as diagnostic tools.

Effects of in vitro treatment with fluticasone propionate on natural killer and lymphokine-induced killer activity in asthmatic and healthy individuals.

Background: Topical corticosteroids are beneficial in the treatment of allergic respiratory disorders; they exert effects on a number of cells involved in allergic inflammatory reactions. On the other hand, major histocompatibility complex (MHC)-unrestricted cytotoxicity (i.e., natural killer [NK] cell activity) may play a role in the inflammatory allergic reaction. The objective was to gain insight into the mechanisms of the therapeutic effects of fluticasone propionate (FP), an inhaled corticosteroid used in asthma and rhinitis therapy. Therefore, we evaluated the NK and lymphokine-activated killer (LAK) activity of effector cells in vitro treated or not with FP. Methods: Evaluations were…

Mediterranean nutraceutical foods: Strategy to improve vascular ageing.

Ageing is characterized by a decline in all systemic functions. A greater susceptibility to apoptosis and senescence may contribute to proliferative and functional impairment of endothelial progenitor cells. They play an important role in neo-angiogenesis and endothelial repair. Vascular ageing is associated with changes in the structure and functions of vessels' wall. There are many possible causes of this damage. For sure, inflammation and oxidative stress play a fundamental role in the pathogenesis of endothelial dysfunction, commonly attributed to a reduced availability of nitric oxide. Inflammageing, the chronic low-grade inflammation that characterizes elderly people, aggravates vascu…

Delayed-type skin reactions in bursectomized or thymectomized chickens.

Chickens can easily be induced to develop delayed-type skin reactions to oxazolone when animals are sensitized 7 days before the challenge. The reaction is quantitated by assessing the increase in wattle thickness: maximum reactions occur 24 h after challenge. The reaction is inhibited by neonatal thymectomy or bursectomy; these findings therefore suggest also an important B-derived component in delayed hypersensitivity to oxazolone.

Genetic Pattern and Haemorheological Determinants in Type 1 Diabetics

Apolipoprotein E Genotypic Frequencies Among Down Syndrome Patients Imply Early Unsuccessful Aging for ApoE4 Carriers

Down syndrome (DS) might be considered a model for unsuccessful and early aging, possibly accelerated for those who carry the APOE4 allele associated with common age-related diseases, e.g., Alzheimer's disease and a poor prognosis after acute myocardial infarction, causing lower ApoE4 frequencies among the very old in general populations. We compared ApoE genotypic frequencies found for healthy adults (n = 211, age 90) to those found for DS patients (n = 106, mean age 9 years), all living in western Sicily. We found that the frequency of the ApoE23 genotype increased with age among the healthy adults (8.5%, 6.4%, 19.7%; p = 0.024) while ApoE34 frequency decreased (16.1%, 12.6%, 4.1%; p = 0.…

Innate and Adaptive Immunity in Aging and Longevity: The Foundation of Resilience

The interrelation of the processes of immunity and senescence now receives an unprecedented emphasis during the COVID-19 pandemic, which brings to the fore the critical need to combat immunosenescence and improve the immune function and resilience of older persons. Here we review the historical origins and the current state of the science of innate and adaptive immunity in aging and longevity. From the modern point of view, innate and adaptive immunity are not only affected by aging but also are important parts of its underlying mechanisms. Excessive levels or activity of antimicrobial peptides, C-reactive protein, complement system, TLR/NF-κB, cGAS/STING/IFN 1,3 and AGEs/RAGE pathways, mye…

CD14 C (-260)T polymorphism, atherosclerosis, elderly: Role of cytokines and metallothioneins.

Abstract Background CD14 receptor is a mediator of the inflammatory response to bacterial products. A functional polymorphism in the promoter of the CD14 gene (CD14 C-260T) was associated with coronary heart disease and atherosclerosis albeit with conflicting data. Methods To better clarify the role of CD14 in atherosclerosis, we typed CD14 C-260T polymorphism in old Italian (Central of Italy) atherosclerotic patients with carotid stenosis related to lipid assessment, inflammation (soluble CD14, IL-6 serum levels) and IL-6, TNF-α, IL-10, Metallothioneins (MT) gene expressions in carotid plaques. Results There was an increased frequency of TT homozygotes in patients when compared to controls…

Memory B Cell Subpopulations in the Aged

The literature on immunosenescence has focused mainly on T cell impairment. With the aim of gaining insight into B cell immunosenescence, the authors investigated the serum IgD levels in 24 young and 21 old people and analyzed their relationship with the number of CD19 CD27 memory cells. Serum IgD were quantified by the use of radial immunodiffusion and the lymphocyte population CD19 CD27 was identified by a FACScan flow cytometer. Serum IgD levels were significantly lower (p 0.0001) in old subjects, and the percentage of CD19 CD27 lymphocytes were significantly increased (p 0.01) in old subjects. Finally, a significant negative correlation was found (p 0.01) between serum concentrations of…

Study of the Association with -330T/G IL-2 in a Population of Centenarians from Centre and South Italy.

Immune response in elderly is characterised by a progressive loss of the ability to cope environmental stressors with a characteristic remodelling of cytokine network. One of the data constantly reported in literature is the decrease of IL-2 production. An IL-2 central role in the reconstitution of T cell function in vitro is largely documented. Studies on a T → G polymorphism at - 330 nt of IL-2 gene promoter region have demonstrated that T lymphocytes from 330GG homozygous subjects are able to produce in vitro higher amount of IL-2, than -330TG heterozygous or -330TT homozygous subjects. As a genetic background conditioning the maintaining of an efficient immune response would exert posit…

Mediterranean Diet and Longevity in Sicily: Survey in a Sicani Mountains Population

Over the past several years, increasing evidence suggests that the Mediterranean diet has a beneficial influence on several age-related diseases, showing protective effect on health and longevity. Mediterranean diet refers to dietary patterns found in olive-growing regions of the Mediterranean countries. Previous data reported that in Sicily, Italy, the largest Mediterranean island, there are some mountainous regions where there is a high frequency of male centenarians with respect to the Italian average. The aim of the present study was to characterize centenarians living in one of this region, the Sicani Mountains, located in western Sicily. Present data shows that in this zone there are …

Association between the HLA-DR alleles and longevity: a study in Sardinian population

Human longevity may be correlated with optimal functioning of the immune system, suggesting that genetic determinants of longevity also resides in those polymorphisms for the immune system genes that regulate immune responses as histocompatibility (HLA) antigens. However, conflicting results have been obtained. Some well planned and designed association studies performed in Caucasians suggest that longevity is associated with positive selection of alleles (i.e. HLA-DR11) or haplotypes (i.e. HLA-B8,DR3) that confer resistance to infectious diseases, respectively, via peptide presentation or via antigen non-specific control of immune response. Association studies are subjected to a number of …

Biomarkers and Inflammatory Network in Aging: Targets for Therapies in Inflammation, advancing age and nutrition

Association between +1059G/C CRP polymorphism and acute myocardial infarction in a cohort of patients from Sicily: a pilot study.

Inflammation plays a role in all the phases of atherosclerosis, and increased production of the acute-phase reactant, C-reactive protein (CRP), predicts future cardiovascular events. Furthermore, CRP has been claimed to play a role in the pathogenesis of atherosclerosis; therefore, CRP polymorphisms might be associated with acute myocardial infarction (AMI). We have analyzed male patients affected by AMI and healthy age-related male controls from Sicily for +1059G/C CRP single-nucleotide polymorphism (SNP). There was a significantly higher frequency of +1059C SNP (P = 0.0008; OR 3.86) in patients compared to controls. CRP serum levels were significantly higher in C+ healthy subjects rather …

Major histocompatibility complex regulation of cytokine production.

This review describes the phenomenon of the major histocompatibility complex (MHC) control of cytokine production both in experimental animals and in humans. H-2 (mouse MHC) regulates which type of cytokine is selectively produced in response to the hapten trinitrophenyl (TNP). T cells from TNP-immune H-2k mice produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-3, IL-5, tumor necrosis factor-alpha (TNF-alpha), IL-10, and very low levels of IL-4 on reexposure to the specific antigen in vitro. By contrast, T cells from H-2d mice produce IL-3, TNF-alpha, IL-10, and IL-4 but very low levels of IL-2, IL-5 and IFN-gamma. As MHC-congenic matched strains (BALB/k and BALB/c) are used, th…

Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population

BackgroundAlbeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis.Methodology/principal findingsImmunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendroc…

La nuova medicina orientata alla longevità e alla salute

Myocardial infarction marker levels are influenced by prothrombin and tumor necrosis factor-α gene polymorphisms in young patients.

Polymorphisms of genes encoding key factors for the control and activation of inflammatory response and coagulation cascade regulation may play a role in genetic susceptibility to acute myocardial infarction (AMI). This study sought to analyze the effect of TNF - 308G/A and pro-thrombin (FII) 20210G/A polymorphisms on the laboratory parameters of young patients affected by AMI. Results indicated that TNF - 308A positive genotype frequencies were increased in these patients and that a genetically determined higher production of TNF-alpha is associated in young subjects to a more severe cardiac damage as depicted by higher levels of troponin, Creatine kinase-MB Isoenzyme (mCK-MB) and a signif…

Remodelling of biological parameters during human ageing: evidence for complex regulation in longevity and in type 2 diabetes.

Factor structure analyses have revealed the presence of specific biological system markers in healthy humans and diseases. However, this type of approach in very old persons and in type 2 diabetes (T2DM) is lacking. A total sample of 2,137 Italians consisted of two groups: 1,604 healthy and 533 with T2DM. Age (years) was categorized as adults (≤65), old (66-85), oldest old (>85-98) and centenarians (≥99). Specific biomarkers of routine haematological and biochemical testing were tested across each age group. Exploratory factorial analysis (EFA) by principal component method with Varimax rotation was used to identify factors including related variables. Structural equation modelling (SEM) wa…

Production of Anti-Endomysial Antibodies in Cultured Duodenal Mucosa: Usefulness in Coeliac Disease Diagnosis

Although anti-endomysial antibodies (EmA) have been found in the supernatants of cultured intestinal mucosa from patients with coeliac disease (CD), in no study has the clinical reliability of this new diagnostic tool been investigated. Our aims were to evaluate the clinical usefulness of the in vitro production of EmA in CD diagnosis in consecutive patients with suspected CD, and to evaluate the reliability of the in vitro challenge in CD patients on a gluten-free diet (GFD).For the former aim, consecutive patients who were due to undergo intestinal biopsy for suspected diagnosis of CD were enrolled: according to the final diagnosis, these patients were divided into two groups: Group 1 com…

Frequency of polymorphisms of signal peptide of TGF-beta1 and -1082G/A SNP at the promoter region of Il-10 gene in patients with carotid stenosis

The role of inflammation in atherosclerosis is well recognized. We have evaluated the allele frequencies of the +869T/C and +915G/C polymorphisms (SNPs) at the TGF-beta1 gene and -1082G/A SNP at IL-10 promoter sequence, two well-known immunosuppressive and anti-inflammatory cytokines, in patients with carotid stenosis. Our data suggest a lack of association between these SNPs and the susceptibility to atherosclerosis although other reports have demonstrated this association. These results may be due to the pleiotropic effects of the cytokines and/or differences in haplotype combination that should be investigated to elucidate the role of TGF-beta1 and IL-10 polymorphisms in atherosclerosis.

Pharmacogenomics: a tool to prevent and cure coronary heart disease.

Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). This is supported by epidemiological studies which have thoroughly investigated the association between CHD and gene polymorphisms of the inflammatory molecules. Moreover, efforts to find elective therapy have not been rewarding and, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. A critical search of published literature has suggested few inflammatory genes directly involved in the risk to develop CHD and MI. The selected genes are, the pro- …

Insulin/IGF-1 Signaling: More than a Metabolic Pathway

Background: Dietary intervention and genetic alterations in gene encoding proteins involved in nutrient-sensing pathways can modulate lifespan, influencing longevity. It depends on under/over-expression of regulatory molecules that lead to different expression of homeostatic genes. Insulin/IGF-1 pathway was associated with longevity and lifespan modulation in model organisms. In humans, a key molecule in this pathway is FOXO3A that acts as a TF on homeostatic genes in response to decreased signaling increasing life span. Interestingly, other genes that increase lifespan interact with FOXO3A such as SIRT1, which modulates the oxidative stress response. Methods: We used meta-analytical and ca…

Opposite role of pyrin M694V allele in acute myocardial infarction and longevity: results of a pilot study performed in Sicily.

Longevity hotspot in Sicily. The exploration of a new possible blu zone

We are conducting a survey in some mountainous Sicilian populations, particularly in villages sited in the Palermo province, part of the Madonie Park. To ascertain the true longevity rate, we checked the born and death registers, analyzing about 37,000 newborns between 1881 and 1917 in a sample of five small municipalities located in Madonie. About 1,700 individuals died at the age of 90 years and over, and about one hundred were centenarians. Therefore, the probability to reach 90 and 100 years old was of 4.6% and 0.22% respectively. Accordingly, we observed significant lower mortality rates for all causes of death when compared to those measured in Palermo town. Therefore, the population …

Impact of different texture of polypropylene mesh on the inflammatory response.

Obesità, Microbiota e Aging

Evidence for Less Marked Potential Signs of T-Cell Immunosenescence in Centenarian Offspring Than in the General Age-Matched Population

People may reach the upper limits of the human life span at least partly because they have maintained more appropriate immune function, avoiding changes to immunity termed "immunosenescence." Exceptionally long-lived people may be enriched for genes that contribute to their longevity, some of which may bear on immune function. Centenarian offspring would be expected to inherit some of these, which might be reflected in their resistance to immunosenescence, and contribute to their potential longevity. We have tested this hypothesis by comparing centenarian offspring with age-matched controls. We report differences in the numbers and proportions of both CD4(+) and CD8(+) early- and late-diffe…

Nutrigerontology: A key for achieving successful ageing and longevity

During the last two centuries the average lifespan has increased at a rate of approximately 3 months/year in both sexes, hence oldest old people are becoming the population with the fastest growth in Western World. Although the average life expectancy is increasing dramatically, the healthy lifespan is not going at the same pace. This underscores the importance of studies on the prevention of age-related diseases, in order to satisfactorily decrease the medical, economic and social problems associated to advancing age, related to an increased number of individuals not autonomous and affected by invalidating pathologies. In particular, data from experimental studies in model organisms have c…

The immunoglobulin γ marker 17 allotype and KIR/HLA genes prevent the development of chronic hepatitis B in humans

Hepatitis B virus (HBV) infection causes a self-limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin-like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA-A-Bw4 and HLA-C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the …

Nutraceutical properties of extra-virgin olive oil: a natural remedy for age-related disease?

The health benefits of the Mediterranean diet can be largely ascribed to the nutraceutical properties of extra-virgin olive oil (EVOO). Mono-unsaturated fatty acids and various phenolic compounds, such as oleocanthal, oleuropein, hydroxytyrosol, and tyrosol, are the main nutraceutical substances of EVOO. These substances have been suggested to have the ability to modulate aging-associated processes. In experimental models, it has been shown that EVOO with high concentrations of polyphenols has anti-inflammatory and anti-oxidant properties. Indeed, it was observed that hydroxytyrosol and oleocanthal inhibit the cyclooxygenases (COX-1 and -2) responsible for prostaglandin production; oleurope…

Immune profiling of Alzheimer patients

Abstract Alzheimer's disease (AD) is characterized by extracellular senile plaques in the brain, containing amyloid-β peptide (Aβ). We identify immunological differences between AD patients and age-matched controls greater than those related to age itself. The biggest differences were in the CD4 + rather than the CD8 + T cell compartment resulting in lower proportions of naive cells, more late-differentiated cells and higher percentages of activated CD4 + CD25 + T cells without a Treg phenotype in AD patients. Changes to CD4 + cells might be the result of chronic stimulation by Aβ present in the blood. These findings have implications for diagnosis and understanding the aetiology of the dis…

Immune parameters identify Italian centenarians with a longer five-year survival independent of their health and functional status

Centenarians are rare and exceptional individuals characterized by a peculiar phenotype. They are the best example of healthy aging in humans as most of them have escaped or substantially delayed the onset of major age-related diseases. Within this scenario, the purpose of the present work was to understand if immune status is associated with survival and health status in centenarians. To this aim, 116 centenarians were concomitantly characterized for their immunological, health and functional status, and followed-up for five-year survival. On the basis of previous knowledge we focused on a core of fundamental and basic immune parameters (number of leukocytes, monocytes, total lymphocytes, …

“Positive biology”: the centenarian lesson

Abstract The extraordinary increase of the elderly in developed countries underscore the importance of studies on ageing and longevity and the need for the prompt spread of knowledge about ageing in order to satisfactorily decrease the medical, economic and social problems associated to advancing years, because of the increased number of individuals not autonomous and affected by invalidating pathologies. Centenarians are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases. Thus, they are the best example of extreme longevity, representing select…

Taste receptors, innate immunity and longevity: the case of TAS2R16 gene

Abstract Background Innate immunity utilizes components of sensory signal transduction such as bitter and sweet taste receptors. In fact, empirical evidence has shown bitter and sweet taste receptors to be an integral component of antimicrobial immune response in upper respiratory tract infections. Since an efficient immune response plays a key role in the attainment of longevity, it is not surprising that the rs978739 polymorphism of the bitter taste receptor TAS2R16 gene has been shown to be associated with longevity in a population of 941 individuals ranging in age from 20 to 106 years from Calabria (Italy). There are many possible candidate genes for human longevity, however of the many…

KIR2DL3 and the KIR ligand groups HLA-A-Bw4 and HLA-C2 predict the outcome of hepatitis B virus infection.

Killer immunoglobulin-like receptors (KIRs) regulate the activation of Natural Killer cells through their interaction with human leukocyte antigens (HLA). KIR and HLA loci are highly polymorphic and certain HLA-KIR combinations have been found to protect against viral infections. In this study we analyzed whether the KIR/HLA repertoire may influence the course of hepatitis B virus (HBV) infection. Fifty-seven subjects with chronic hepatitis B (CHB), 44 subjects with resolved HBV infection, and 60 healthy uninfected controls (HC) were genotyped for KIR and their HLA ligands. The frequency of the HLA-A-Bw4 ligand group was higher in CHB (58%) than subjects with resolved infection (23%) (crude…

Inflammation, longevity and cardiovascular diseases: role of polymorphisms of TLR4

Gender-Related Immune-Inflammatory Factors, Age-Related Diseases, and Longevity

This review discusses the role of estrogens as pro- or antiinflammatory players in immune-inflammatory responses. In particular, their role in Alzheimer’s disease (AD), an example of immune-inflammatory disease, is discussed briefly. AD is a progressive neurodegenerative disease, which in Western societies accounts for the majority of cases of clinical senile dementia. However, sexual dimorphism of diseases may also depend on factors independent of sex hormones (i.e., a gender effect), as demonstrated by our data on differential longevity in females and males. In fact, differences in mortality between men and women are not only a question of sex that refers to biological differences, but ra…

Effects of nutraceuticals of Mediterranean diet on aging and longevity

Abstract Among the many existing dietary interventions, Mediterranean diet has received much attention because of its beneficial influence on healthy aging and longevity. Mediterranean dietary pattern, characterized by low glycemic index and low-animal protein intake, is rich in nutraceuticals and functional foods, and bioactive compounds able to reduce the signaling of molecular pathways, such as nutrient-sensing ones, affecting aging process. Therefore a close adherence to a Mediterranean-style diet allows avoiding cardiovascular disorders and other age-related diseases, and it is responsible for the high rate of long-living individuals scattered throughout the Mediterranean basin. For th…

Role of Toll-like receptor 4 in acute myocardial infarction and longevity.

Biomarkers of aging

Aging is a complex process that negatively impacts the development of the different systems and its ability to function. Moreover, the Aging rate in humans is not the same, principally due to genetic heterogeneity and environmental factors. The aging rate is measured as the decline of functional capacity and stress resistance. Therefore, several attempts have been made to analyse the individual age, ( so-called biological age) compared to chronological age. The biomarkers of aging are age-related body function or composition, these markers aim to assess the biological age and predict the onset of age-related diseases and/or residual lifetime. Such biomarkers should help in one hand to chara…

TLR4 polymorphisms and ageing: implications for the pathophysiology of age-related diseases.

Innate immunity provides a first line of host defense against infection by recognizing and killing microbes while simultaneously activating an instructive immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition and function mainly by detection of pathogen-associated molecular patterns that do not exist in the host. Recognition of their ligands leads to a series of signaling events resulting in acute host responses, involved in killing pathogens. Discussion We describe the involvement of TLR4 polymorphisms in ageing, and in particular in age-related diseases, suggesting the crucial role of molecules of innate immunity in pathophysiology of these dis…

Role of cyclooxygenae-2 and 5-lypoxygenase polymorphisms in Alzheimer's disease in a population from northern Italy:implications for pharmacogenomics

Alzheimer's disease (AD) is a neurodegenerative disorder clinically characterized by cognitive deficit with progressive worsening of memory. Recent data indicate that neurons, as well as other brain cells, can express enzymes such as cyclooxygenases (COXs) and 5-lipoxygenase (5-LO) which are considered important in inflammatory cells. Moreover, it has been demonstrated that COX-2 and 5-LO enzymes play a considerable role in the pathophysiology of AD. In order to assess the possible role of COX-2 and 5-LO single nucleotide polymorphisms (SNPs) in AD, we examined their distribution in 341 AD patients and 190 controls from Northern Italy. A significant difference was observed in the distributi…

Genes, Ageing and Longevity in Humans: Problems, Advantages and Perspectives.

Many epidemiological data indicate the presence of a strong familial component of longevity that is largely determined by genetics, and a number of possible associations between longevity and allelic variants of genes have been described. A breakthrough strategy to get insight into the genetics of longevity is the study of centenarians, the best example of successful ageing. We review the main results regarding nuclear genes as well as the mitochondrial genome, focusing on the investigations performed on Italian centenarians, compared to those from other countries. These studies produced interesting results on many putative "longevity genes". Nevertheless, many discrepancies are reported, l…

Immunosenescence and anti-immunosenescence therapies: the case of probiotics.

ABSTRACT Aging is a complex process that negatively impacts the development of the immune system and its ability to function. Progressive changes in the T and B cell systems over the life span have a major impact on the capacity to respond to immune challenge. These cumulative age-associated changes in immune competence are termed immunosenescence. This process is mostly characterized by: (1) shrinkage of the T cell repertoire and accumulation of oligoclonal expansions of memory/effector cells directed toward ubiquitary infectious agents; (2) involution of the thymus and the exhaustion of naive T cells; and (3) chronic inflammatory status. Here we discuss possible strategies to counteract t…

Immunogenetics of longevity. Is major histocompatibility complex polymorphism relevant to the control of human longevity? A review of literature data.

Literature data suggest that human longevity may be directly correlated with optimal functioning of the immune system. Therefore, it is likely that one of the genetic determinants of longevity resides in those polymorphisms for the immune system genes that regulate immune responses. Accordingly, studies performed on mice have suggested that the Major Histocompatibility Complex (MHC), known to control a variety of immune functions, is associated with the life span of the strains. In the last 25 years, a fair number of cross-sectional studies that searched for the role of HLA (the human MHC) genes on human longevity by comparing HLA antigen frequencies between groups of young and elderly pers…

Fisiopatologia del Sistema Cardiovascolare e del Sangue

Autoantibody production in aging: effect of cytokine gene polymorphisms in Sicilian ultra-nonagenarians

Hla-Bb, Dr3 T Cell Impairhent is Completely Restored by in Vitho Treatment with Interleukin-2

AbstractThe activity of recombinant interleukin-2 (rIL-2) on the in vitro lymphocyte proliferative response to phytohemagglutinin mitogen was investigated in healthy HLA-BB, DR3 positive and negative subjects. the response to mitogen, significantly decreased in HLA-BB, DR3 positive subjects, was completely restored by adding rIL-2. Moreover, in HLA-BB, DR3 positive subjects the in vitro treatment with rIL-2 significantly increased the reduced frequency of mitogen responsive T lymphocyte precursors, as assessed by limiting dilution analysis. These data suggest that a decrease in the size of the pool of T cell precursors able to produce IL-2 is responsible for the impairment of T cell functio…

Pro-inflammatory status is not a limit for longevity: case report of a Sicilian centenarian

Most studies on centenarians represent them as the best model of ageing. They are defined “delayers”, if they exhibit age-related diseases between 80 and 99 years, “survivors” if they show clinically demonstrable diseases before the age of 80 years, and “escapers” when they attain their 100th year of life without any common age-associated pathologies.

Associazione dei polimorfismi dei geni INF-γ ed IL-10 con la suscettibilità alla Febbre bottonosa.

Senescenza ed allergia respiratoria.

The Role of Matrix Metalloproteinases (MMP-2 and MMP-9) in Ageing and Longevity: Focus on Sicilian Long-Living Individuals (LLIs)

Extracellular matrix metalloproteinases (MMPs) are a group of proteins that activate substrates by enzymatic cleavage and, on the basis of their activities, have been demonstrated to play a role in ageing. Thus, in order to gain insight into the pathophysiology of ageing and to identify new markers of longevity, we analysed the activity levels of MMP-2 and MMP-9 in association with some relevant haematochemical parameters in a Sicilian population, including long-living individuals (LLIs, ≥95 years old). A cohort of 154 healthy subjects (72 men and 82 women) of different ages (age range 20-112) was recruited. The cohort was divided into five subgroups: the first group with subjects less than…

Polymorphisms of cyclo-oxygenases and 5-lipo-oxygenase-activating protein are associated with chronic spontaneous urticaria and urinary leukotriene E4

The mechanisms of chronic spontaneous urticaria (CSU) continue to be unknown. Our working hypothesis is that polymorphisms of cyclo-oxygenases and 5-lipo-oxygenase-activating protein may be involved in the pathways leading to CSU. We examined five candidate polymorphisms of cyclo-oxygenases 1 and 2 and of 5-lipo-oxygenase-activating protein in 109 controls and in 94 CSU patients from Northern Italy. We also examined the levels of urinary leukotriene E4 (LTE4) before and after challenge with ASA. A multiple regression model was found to show that COX-2 5'UTR T/G, COX-2 Exon 10 T/C, and FLAP -336 G/A polymorphisms were significantly associated with CSU, with the minor allele more represented …

The Nutraceutical Properties of Rhus coriaria Linn: Potential Application on Human Health and Aging Biomedicine

Rhus coriaria Linn is a little plant growing in the Mediterranean basin, including Sicily, where it is known as Sicilian Sumac. Since antiquity, it has been used as a medicinal herb, considering its pharmacological properties and its recognized anti-inflammatory, antioxidant, and antimicrobial effects. Multiple studies have highlighted that the beneficial properties of Sumac extracts depend on the abundance of phytochemicals such as polyphenols, fatty acids, minerals, and fibers. Despite its wide use as a spice, the literature on Sumac effects on humans’ health and aging is still scarce. Considering its great nutraceutical potential, Sumac could be used to treat age-related diseases such as…

The role of immunogenetics in covid‐19

Coronavirus disease 2019 (COVID-19) is induced by SARS-CoV-2 and may arise as a variety of clinical manifestations, ranging from an asymptomatic condition to a life-threatening disease associated with cytokine storm, multiorgan and respiratory failure. The molecular mechanism behind such variability is still under investigation. Several pieces of experimental evidence suggest that genetic variants influencing the onset, maintenance and resolution of the immune response may be fundamental in predicting the evolution of the disease. The identification of genetic variants behind immune system reactivity and function in COVID-19 may help in the elaboration of personalized therapeutic strategies…

HLA and killer cell immunoglobulin-like receptors influence the natural course of CMV infection.

Background. Natural killer (NK) cells provide a major defense against cytomegalovirus (CMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulinlike receptors (KIRs), and human leukocyte antigens (HLA) class I molecules. This study assessed whether the KIR and HLA repertoire may influence the risk of developing symptomatic or asymptomatic disease after primary CMV infection in the immunocompetent host. Methods. Sixty immunocompetent patients with primary symptomatic CMV infection were genotyped for KIR and their HLA ligands, along with 60 subjects with a previous asymptomatic infection as controls. Results. The frequency…

TGF-B pathway polymorphisms as markers for gender differential susceptibility to sporadic thoracic aortic aneurysm

LA MALATTIA in: Compendio di Patologia generale (Caruso C. e Licastro F. eds.)

Relevance of gamma interferon, tumor necrosis factor alpha, and interleukin-10 gene polymorphisms to susceptibility to Mediterranean spotted fever.

Several studies have demonstrated that cellular immunity plays a critical role in the protective immune response against Rickettsia conorii. Immune CD4+ and CD8+ T cells are both involved in the control of rickettsial infection (38). Perivascular infiltrated CD4+ and CD8+ T lymphocytes, macrophages, and natural killer cells produce chemokines and cytokines that activate endothelial rickettsicidal activities. Infected human cells, including endothelial cells, hepatocytes, and macrophages, activated by gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β), kill intracellular rickettsiae by one or a combination of three mechanisms, involving nitric oxide syn…

Role of TLR Polymorphisms in Immunosenescence

Innate immunity provides a first line of host defense against infection through microbial recognition and killing while simultaneously activating a clonotypic immune response. Toll-like receptors (TLRs) are principal mediators of rapid microbial recognition and function mainly by detection of pathogen-associated molecular patterns (PAMPs) that do not exist in the host. The different members of TLRs recognize several PAMPs, such as peptidoglycan for TLR2, lipopolysaccharide (LPS) for TLR4, flagellin for TLR5, and CpGDNA-repeats for TLR9. Several endogenous ligands of various TLRs have been also identified in the host. In this chapter, we describe the involvement of TLR-4 polymorphisms in imm…

Role of TLR4 Receptor Polymorphisms in Boutonneuse Fever

The genetics of the interaction between host and microbes plays an essential role in the survival of the individual and attainment of longevity. The activation of toll-like receptor (TLR)4 plays a key role in natural and clonotypic immune responses. We evaluated whether TLR4 genotype is a component of genetic background protective versus rickettsiosis and whether this background influences longevity. We genotyped for +896A/G TLR4 polymorphism 78 patients affected by Boutonneuse fever, 78 age-matched controls and 78 advanced age individuals from Sicily. The +869G allele, that attenuates receptor signalling, was significantly overrepresented in patients in comparison with age-matched control…

Human immunosenescence: is it infectious?

Morbidity and mortality due to infectious disease is greater in the elderly than in the young, at least partly because of age-associated decreased immune competence, which renders individuals more susceptible to pathogens. This susceptibility is particularly evident for novel infectious agents such as in severe acute respiratory syndrome but is also all too apparent for common pathogens such as influenza. Many years ago, it was noted that the elderly possessed oligoclonal expansions of T cells, especially of CD8(+) cells. At the same time, it was established that cytomegalovirus (CMV) seropositivity was associated with many of the same phenotypic and functional alterations to T-cell immunit…

miR-126-3p and miR-21-5p as Hallmarks of Bio-Positive Ageing; Correlation Analysis and Machine Learning Prediction in Young to Ultra-Centenarian Sicilian Population

Human ageing can be characterized by a profile of circulating microRNAs (miRNAs), which are potentially predictors of biological age. They can be used as a biomarker of risk for age-related inflammatory outcomes, and senescent endothelial cells (ECs) have emerged as a possible source of circulating miRNAs. In this paper, a panel of four circulating miRNAs including miR-146a-5p, miR-126-3p, miR-21-5p, and miR-181a-5p, involved in several pathways related to inflammation, and ECs senescence that seem to be characteristic of the healthy ageing phenotype. The circulating levels of these miRNAs were determined in 78 healthy subjects aged between 22 to 111 years. Contextually, extracellular miR-1…

B Cells in Centenarians and Their Offspring

IL-10 and TNF-α polymorphisms and the recovery from HCV infection

Hepatitis C virus (HCV) infection becomes chronic in about 85% of infected individuals, whereas only 15% of infected people clear spontaneously the virus. It is conceivable that the host immunogenetic background influences the course of infection in term of recovery. Thus, in this study we have evaluated the effect of functionally relevant polymorphisms at tumor necrosis factor-alpha (TNF-alpha, i.e., 2 biallelic polymorphisms at nt -863 and nt-308 of the promoter) and interleukin-10 (IL-10) loci (i.e., 1 biallelic polymorphism at nt -1082 of the promoter), on the clearance of HCV infection. To this purpose, we compared 18 Sicilian patients who had spontaneously recovered from previous HCV …

Association between γ marker, human leucocyte antigens and killer immunoglobulin‐like receptors and the natural course of human cytomegalovirus infection: a pilot study performed in a Sicilian population

Natural killer (NK) cells provide a major defence against cytomegalovirus (HCMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leukocyte antigens (HLA) class I molecules. Also GM allotypes, able to influence the NK antibody-dependent cell-mediated cytotoxicity (ADCC), appear to be involved in the immunological control of virus infections, including HCMV. In some cases, their contribution requires epistatic interaction with other genes of the immune system, such as HLA. In the present report, with the aim to gain insight into the immune mechanisms controlling HCMV, we have studied t…

Possible role of ABO system in age-related diseases and longevity: a narrative review

ABO blood group antigens are expressed either on the surface of red blood cells either on a variety of other cells. Based on the available knowledge of the genes involved in their biosynthesis and their tissue distribution, their polymorphism has been suggested to provide intraspecies diversity allowing to cope with diverse and rapidly evolving pathogens. Accordingly, the different prevalence of ABO group genotypes among the populations has been demonstrated to be driven by malaria selection. In the similar manner, a particular ABO blood group may contribute to favour life-extension via biological mechanisms important for surviving or eluding serious disease. In this review, we will suggest…

Association Between the HLA-A2 Allele and Alzheimer Disease

In the elderly, the most common cause of dementia is Alzheimer disease (AD), which is responsible for the age-related progressive neurodegenerative inflammatory condition mediated by the disease. It has been seen that several genetic and environmental factors are involved in AD onset. Epidemiologic data suggest that some genetic determinants of AD might reside in those polymorphisms that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, several MHC polymorphisms have been in the spotlight of a large number of AD association studies. A possible association of HLA-A2 allele with increased susceptibility to AD has been the subject of debate …

Major histocompatibility complex and sporadic Alzheimer's disease: a critical reappraisal

Epidemiological data suggest that some genetic determinants of Alzheimer's disease (AD) might reside in those polymorphisms for the immune system genes that regulate immune inflammatory responses, such as the major histocompatibility complex (MHC). Therefore, MHC polymorphisms have been the focus of a large number of AD association studies. Class Ia, Ib (hemochromatosis gene (HFE)), class II and class III (complement, tumour necrosis factor and heat shock proteins) alleles have been studied. Nearly every positive result has been followed by several studies that have failed to replicate it or that have contradicted it. Several factors, including methodological biases, might explain these dis…

Immunoinflammatory activation during the acute phase of lacunar and non-lacunar ischemic stroke: Association with time of onset and diabetic state

Several studies have stressed the involvement of inflammation in the pathophysiology of acute brain ischemia, but the role of immunoinflammatory activation in diabetic stroke patients has not yet been fully evaluated. The aim of our study was to evaluate immunoinflammatory activation of acute phase of stroke in relation to time of symptoms onset, diabetic state and diagnostic subtype. We enrolled 60 patients (32 diabetics; 28 non- diabetics) with acute ischemic stroke and 123 subjects without acute ischemic stroke, and measured levels of IL-1β, TNF-α, IL-6, IL-10, E-selectin, P-selectin, sICAM-1, sVCAM-1, VWF, 24–72 h and 7–10 days after stroke onset; TPA, PAI-1 plasma levels at 24–72h. Ou…

Immunosenescence, inflammation and Alzheimer’s disease

Abstract Ageing impacts negatively on the development of the immune system and its ability to fight pathogens. Progressive changes in the T-cell and B-cell systems over the lifespan of individuals have a major impact on the capacity to respond to immune challenges. The cumulative age-associated changes in immune competence are termed immunosenescence that is characterized by changes where adaptive immunity deteriorates, while innate immunity is largely conserved or even upregulated with age. On the other hand, ageing is also characterized by “inflamm-ageing”, a term coined to explain the inflammation commonly present in many age-associated diseases. It is believed that immune inflammatory p…

Immunosenescence and Cytomegalovirus

Since Looney at al. published their seminal paper a decade ago [1] it has become clear that many of the differences in T cell immunological parameters observed between young and old people are related to the age-associated increasing prevalence of infection with the persistent β-herpesvirus HHV-5 (Cytomegalovirus). Ten years later, studies suggest that hallmark age-associated changes in peripheral blood T cell subset distribution may not occur at all in people who are not infected with this virus [[2]; Derhovanessian et al., in press]. Whether the observed changes are actually caused by CMV is an open question, but very similar, rapid changes observed in uninfected patients receiving CMV-in…

Inflammation, ageing and cancer

Cancer is generally recognized as an age-related disease. In fact, incidence and mortality rates of most human cancers increase consistently with age up to 90 years, but they plateau and decline thereafter. A low-grade systemic inflammation characterizes ageing and this pro-inflammatory status underlies biological mechanisms responsible for age-related inflammatory diseases. On the other hand, clinical and epidemiological studies show a strong association between chronic infection, inflammation and cancer and indicate that even in tumours not directly linked to pathogens, the microenvironment is characterized by the presence of a smouldering inflammation, fuelled primarily by stromal leukoc…

ACUTE PHASE RESPONSE IN OLDEST-OLD INDIVIDUALS AFTER SURGICAL STRESS

Does the longevity of one or both parents influence the health status of their offspring?

According to the findings of some recent studies, the centenarians' offspring appear to represent a promising model for research on longevity and healthy aging. This study compares the health status and the functional status of three groups of subjects: 1. individuals with two long-lived parents (one of whom centenarian), 2. individuals with only one long-lived (centenarian) parent, and 3. individuals with no long-lived parents. The goal is to verify whether the centenarians' offspring display any advantage over the offspring of both non-long-lived parents and to evaluate whether the longevity of the non centenarian parent provides a further advantage. A total of 374 subjects (mean age appr…

HLA and KIR Frequencies in Sicilian Centenarians

Several studies suggest that human longevity appears to be linked inextricably with optimal functioning of the immune system, suggesting that specific genetic determinants may reside in loci that regulate the immune response, as human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genes. It has been suggested that longevity is associated with positive selection of alleles (i.e., HLA-DR11) or haplotypes (i.e., HLA-B8,DR3) that confer resistance to infectious disease(s). On the other hand, the cytolytic activity of natural killer (NK) cells is controlled by activating and inhibitory cell-surface receptors, including KIR. The genetic diversity of the KIR loci with r…

Genetic control of immune response in carriers of ancestral haplotype 8.1: the study of chemotaxis.

In all caucasian populations the association of an impressive number of autoimmune diseases with genes from the HLA-B8, DR3 hap- lotype that is part of the ancestral haplotype (AH) 8.1 HLA-A1, Cw7, B8, TNFAB∗a2b3, TNFN∗S, C2∗C, Bf∗s, C4A∗Q0, C4B∗1, DRB1∗0301, DRB3∗0101, DQA1∗0501, DQB1∗0201 has been reported by different research groups. This haplotype, which is more common in northern Europe, is also associated with a number of immune system dysfunctions in healthy subjects. Analyzing the data according to gender, some dysfunc- tions are observed in women but not in men, in agreement with the role of X-linked genes and/or estrogens in the development and progression of autoimmune diseases.…

CCR5 Receptor: Biologic and Genetic Implications in Age-Related Diseases

The CC chemokine receptor 5 (CCR5) is a member of CC-chemokine receptor family. CCR5 has the characteristic structure of a seven transmembrane G protein-coupled receptor (GPCR), which regulates trafficking and effector functions of memory/effector Th1 cells, macrophages, NK cells, and immature dendritic cells. CCR5 and its ligands are important molecules in viral pathogenesis. CCR5 represents the co-receptor for macrophage (M) and dual (T cell and M)-tropic immunodeficiency viruses. Recent evidence has also demonstrated the role of CCR5 in a variety of human diseases, ranging from infectious and inflammatory diseases to cancer. In this article, we describe the involvement of CCR5 in two age…

1267 HSP70-2 POLYMORPHISM AS A RISK FACTOR FOR CAROTID PLAQUE RUPTURE AND CELEBRAL ISCHAEMIA IN OLD TIPE 2 DIABETES-ATHEROSCLEROTIC PATIENTS

ATHEROSCLEROSIS in: Cytokine gene polymorphisms in multifactorial conditions (K. Vandenbroeck ed.)

Role of proinflammatory alleles in longevity and atherosclerosis: results of studies performed on -1562C/T MMP-9 in centenarians and myocardial infarction patients from Sicily.

Centenarians are characterized by marked delay or escape from age-associated diseases that cause mortality at earlier ages. Jointly, atherosclerosis and its complications, such as myocardial infarction (AMI), significantly contribute to mortality in the elderly. Inflammation is a key component of atherosclerosis and inflammatory genes are good candidates for the risk of the development of atherosclerosis. Genetic traits contribute to the risk of AMI and allelic variations in inflammatory genes should boost the risk of disease. If proinflammatory genotypes significantly contribute to the risk of AMI, alleles associated with disease susceptibility should not be included in the genetic backgro…

Centenarians born before 1919 are resistant to COVID-19.

Although mortality from COVID-19 progressively increases with age, there are controversial data in the literature on the probability of centenarians dying from COVID-19. Moreover, it has been claimed that men in their 90s and 100s are more resilient than women. To gain insight into this matter, we analysed, according to gender, mortality data during the first year of pandemic of Sicilian nonagenarians and centenarians. We used mortality data from the 2019 as a control. The crude excess mortality between the two years was calculated. Data on deaths of Sicilian 90 + years show that, in line with what is known about the different response to infections between the two genders, oldest females a…

Association between the HFE mutations and longevity: a study in Sardinian population

Hereditary hemochromatosis is an HLA-linked inherited disease characterised by inappropriately high absorption of iron by the gastrointestinal mucosa. The cysteine-to-tyrosine substitution at codon 282 of the HFE encoding gene sequence is responsible for the disease, although other variants, as H63D and S65C, may modify the affinity of the protein for transferrin receptors. We have recently reported that C282Y mutation is significantly increased in very old (>90 years) Sicilian women, suggesting a role in attainment of longevity. In addition, an increase of H63D polymorphism was also observed in these women but the difference was not significant. To validate and extend these results we inve…

Human longevity within an evolutionary perspective: The peculiar paradigm of a postreproductive genetics

The data we collected on the genetics of human longevity, mostly resulting from studies on centenarians, indicate that: (1) centenarians and long-living sib-pairs are a good choice for the study of human longevity, because they represent an extreme phenotype, i.e., the survival tail of the population who escaped neonatal mortality, pre-antibiotic era illnesses, and fatal outcomes of age-related complex diseases. (2) The model of centenarians is not simply an additional model with respect to well-studied organisms, and the study of humans has revealed characteristics of ageing and longevity (geographical and sex differences, role of antigenic load and inflammation, role of mtDNA variants) wh…

Is immunosenescence infectious?

Abstract Herpes viruses are endemic. Once established, the virus is never eliminated but persists throughout life. The fraction of infected individuals gradually increases with age, such that the majority of elderly people are cytomegalovirus (CMV) + , Epstein–Barr virus (EBV) + and Varicella + . Clinically relevant reactivation of Varicella causes painful shingles; CMV reactivation can cause fatal pneumonia. Overt reactivation, even in the very elderly, occurs only in immunocompromised individuals; however, the necessity for maintaining immunity to these viruses is costly. We argue that this cost is not only reflected in the requirement for continuous immunosurveillance against these virus…

Agenti cancerogeni e cancerogenesi

Ageing, longevity, exceptional longevity and related genetic and non genetics markers: panel statement

In May 2012, a group of scientists and clinicians met in Athens (Greece) to consider the relevance of ageing, longevity, exceptional longevity and related genetic and non genetic markers. During this meeting, we firstly reviewed recent epidemiological and clinical studies on ageing, longevity and exceptional longevity, briefly analysed the ageing theories and discussed successful and unsuccessful ageing also taking into account the evolutionary perspective. Secondly, we considered the three phenotypes based on the definition of ageing, longevity and exceptional longevity and the associated biomarkers. Third, we discussed proposed treatments suitable to counteract or slow down ageing. Finall…

Reviewer acknowledgment

Contributing reviewers Immunity & Ageing would like to thank the following for their assistance with peer review of manuscripts for the journal in 2012.

Evidences of +896 A/G TLR4 Polymorphism as an Indicative of Prevalence of Complications in T2DM Patients

T2DM is today considered as world-wide health problem, with complications responsible of an enhanced mortality and morbidity. Thus, new strategies for its prevention and therapy are necessary. For this reason, the research interest has focused its attention on TLR4 and its polymorphisms, particularly the rs4986790. However, no conclusive findings have been reported until now about the role of this polymorphism in development of T2DM and its complications, even if a recent meta-analysis showed its T2DM association in Caucasians. In this study, we sought to evaluate the weight of rs4986790 polymorphism in the risk of the major T2DM complications, including 367 T2DM patients complicated for th…

Palermo-2010 conference on biogerontology

We, as the guest editors, are pleased to introduce this special issue of Biogerontology, which is the outcome from the 7th European Congress of Biogerontology, held from 14th to 17th October, 2010 in Palermo, Italy. The thematic aim of the Palermo-conference was to get an overview of the present state of research in the development of effective therapies to postpone or treat human ageing, focusing on predictive medicine and prevention of age-related diseases, immunosenescence, longevity, model systems, ageing and wellness, and vaccination in the elderly. Understanding the determinants of ageing in humans in relation to the living environment and the individual life history was the additiona…

HLA-C1 ligands are associated with increased susceptibility to systemic lupus erythematosus.

Recently, the role of killer cell immunoglobulin-like receptor (KIR) in autoimmune diseases has received increasing attention. The present study was undertaken to determine the association of KIR genes and the human leukocytes antigen (HLA) ligands with Systemic Lupus Erythematosus (SLE) and accompanying oxidative stress. Presence or absence of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method by case-control study. A total of 45 SLE patients, and 60 healthy controls, all of Sicilian descent, were enrolled. Plasma values of the anti-oxidant molecule Taurine were determined in all subjects by capillary electrophoresis UV detecti…

Uncoupling Protein 2 as genetic risk factor for systemic lupus erythematosus: association with malondialdehyde levels and intima media thickness

BACKGROUND Increased oxidative stress potentially leads to accelerated atherosclerosis and, consequently, cardiovascular diseases, the main cause of death in systemic lupus erythematous (SLE). To gain insight into these mechanisms, we studied the association of uncoupling protein (UCP) 2 genetic variants, gene involved in the mitochondrial production of reactive oxygen species, and oxidative stress with SLE and the presence of atherosclerosis. METHODS Genetic analysis of the UCP2 -866G/A and UCP2 Ins/Del polymorphisms was performed in 45 SLE patients and 36 healthy controls by RFLP-PCR. Oxidation status was determined by measuring malondialdehyde (MDA) levels. Presence of subclinical athero…

Longevity in: Cytokine Gene Polymorphisms in multifactorial conditions. (K. Vandenbroeck ed.)

Cancro e Invecchiamento

Gli studi epidemiologici hanno dimostrato che la mortalità per cancro aumenta con l’età fino al novantesimo anno, in cui raggiunge il plateau e quindi declina (Fig. 61.1). La mortalità per cancro è di circa il 40% dai 50 ai 70 anni e inferiore al 4% nei centenari. Questo non è strano perché è noto che i longevi ritardano o evitano quasi tutte le malattie infiammatorie legate all’età e il can-cro è una malattia in cui la componente infiammatoria gioca un ruolo rilevante........................................

POLYPHENOLS FROM RED WINE MODULATE IMMUNE RESPONSIVENESS: BIOLOGICAL AND CLINICAL SIGNIFICANCE.

Many studies have been conducted on the effects of red wine polyphenols on certain diseases, primarily, coronary heart disease (CHD) and, in this respect, evidence has been demonstrated that intake of red wine is associated with a reduction of CHD symptomatology. In this framework, the purpose of this review is to illustrate the effects of polyphenols on immune cells from human healthy peripheral blood. Data will show that polyphenols are able to stimulate both innate and adaptive immune responses. In particular, the release of cytokines such as interleukin (IL)-12, interferon (IFN)-gamma, and IL-10 as well as immunoglobulins may be important for host protection in different immune related …

Immunosenescence and its hallmarks: How to oppose aging strategically? A review of potential options for therapeutic intervention

Aging is accompanied by remodeling of the immune system. With time, this leads to a decline in immune efficacy, resulting in increased vulnerability to infectious diseases, diminished responses to vaccination, and a susceptibility to age-related inflammatory diseases. An age-associated immune alteration, extensively reported in previous studies, is the reduction in the number of peripheral blood naive cells, with a relative increase in the frequency of memory cells. These two alterations, together with inflamm-aging, are considered the hallmarks of immunosenescence. Because aging is a plastic process, it is influenced by both nutritional and pharmacological interventions. Therefore, the rol…

Association between the HFE mutations and unsuccessful ageing: a study in Alzheimer's disease patients from Northern Italy

Mutations in the class I-like Major Histocompatibility Complex gene HFE are associated with hereditary hemochromatosis (HH), a disorder caused by excessive iron uptake. Three common mutations have been found: C282Y, H63D, and S65C. Moreover, several studies have suggested that HFE mutations may be involved in several age-related chronic diseases such as Alzheimer's disease (AD) and coronary heart disease, but apparently paradoxically also with longevity. In particular, in AD, patients carrying the H63D allele have been suggested to have a mean age at onset of 72 vs. 77 years for those who were homozygous for the wild-type allele. Thus, it seems that H63D mutations may anticipate sporadic AD…

Polymorphisms of pro-inflammatory genes and Alzheimer's disease risk: A pharmacogenomic approach.

Clinically and pathologically Alzheimer's disease (AD) represents a sequential progressive neurodegenerative disorder. AD is etiologically heterogeneous and accounts for a majority of dementia in western societies. Inflammation clearly occurs in pathologically vulnerable regions of the AD brain and the search for genetic factors influencing the pathogenesis of AD has lead to the identification of numerous gene polymorphisms that might act as susceptibility modifiers. Accordingly, several reports have indicated that the risk of AD is substantially influenced by several genetic polymorphisms in the promoter region, or other untranslated regions, of genes encoding inflammatory mediators, altho…

Association between the polymorphism of CCR5 and Alzheimer's disease: results of a study performed on male and female patients from Northern Italy.

Alzheimer's disease (AD) is the most common cause of dementia in Western society. The prevalence of AD is greater in women than in men, largely due to longevity and survival differences favoring women. However, some studies suggest that incidence rates may really be increased in women. One possible factor influencing AD incidence in women is the loss of ovarian estrogens production after menopause, which might be involved in AD pathogenesis. Estrogens seem to influence some neuronal functions. Many of these actions appear beneficial (i.e., neuroprotective action against a variety of insults, as oxidative stress, and reduction of beta-amyloid plaques formation). Furthermore, several studies …

Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis.

Udgivelsesdato: 2009-Jan Several studies have assessed changes in frequency of -174 interleukin (IL)-6 single nucleotide polymorphism (SNP) with age. If IL-6 tracks with disability and age-related diseases, then there should be reduction, in the oldest old, of the frequency of homozygous GG subjects, who produce higher IL-6 levels. However, discordant results have been obtained. To explore the relationship between this polymorphism and longevity, we analyzed individual data on long-living subjects and controls from eight case-control studies conducted in Europeans, using meta-analysis. There was no significant difference in the IL-6 genotype between the oldest old and controls (Odds Ratio […

Role of environmental and genetic factor interaction in age-related disease development: the gastric cancer paradigm.

The association of Helicobacter pylori (Hp) infection with gastric cancer is well known and might be considered a paradigmatic example of the role that interaction among environmental factors and individual background might play in inducing age-associated disease. To evaluate the role of interaction of Hp infection with genetic background, gastric cancer and chronic gastritis patients as well as random selected controls were typed for five inflammation-related polymorphisms of IL-1 and IL-10 cytokine genes. No association among IL-10 or IL-1 variants with an increased risk of gastric cancer was found, whereas an Hp-independent association of IL-1beta -511T positive genotypes to an increased…

Laboratory parameters in centenarians of Italian ancestry

Studies aimed at collecting reference parameters for haematochemical analysis in the elderly are scarce and for the oldest old subjects even more rare. In order to establish the reference values for the most common laboratory text in long living individuals, we measured haematochemical parameters in >100 years old subjects and in aged subjects as control. Six hundred and two centenarians accepted to be enrolled in the study. A case history containing the complete anamnesis, clinical examinations, evaluation of the clinical cognitive and functional tests, was prepared for each centenarian. Blood samples from 120 > 100 years old subjects free of chronic or acute Illness (i.e. Alzheimer’s dise…

Inflammation, Cytokines, Immune Response, Apolipoprotein E, Cholesterol, and Oxidative Stress in Alzheimer Disease: Therapeutic Implications

Alzheimer disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for senile dementia. Today many countries have rising aging populations and are facing an increased prevalence of age-related diseases, such as AD, with increasing health-care costs. Understanding the pathophysiology process of AD plays a prominent role in new strategies for extending the health of the elderly population. Considering the future epidemic of AD, prevention and treatment are important goals of ongoing research. However, a better understanding of AD pathophysiology must be accomplished to make this objective feasible. In this paper, we review some hot to…

Polymorphisms of pro-inflammatory genes and prostate cancer risk: a pharmacogenomic approach.

In this paper, we consider the role of the genetics of inflammation in the pathophysiology of prostate cancer (PCa). This paper is not an extensive review of the literature, rather it is an expert opinion based on data from authors' laboratories on age-related diseases and inflammation. The aim is the detection of a risk profile that potentially allows both the early identification of individuals at risk for disease and the possible discovery of potential targets for medication. In fact, a major goal of clinical research is to improve early detection of age-related diseases, cancer included, by developing tools to move diagnosis backward in disease temporal course, i.e., before the clinical…

Cellular immune activation in Sardinian middle-aged, older adults and centenarians

In addition to viral infections, malignant disorders, autoimmune diseases, and allograft rejection episodes, neopterin increases in older people where it is found to be predictive of overall mortality. Thus, the serum concentrations of this biomarker of systemic immune and inflammation activation, were measured in a small cohort of Sardinian middle-aged, older adults and centenarians. There was a significant positive correlation between neopterin concentrations and age with the subjects in the 95-year-old group with the highest values. Notably, the group of centenarians had neopterin values comparable to those of 80- and 90-year-old groups, and significantly lower than that of 95-year-old g…

Age-Related Inflammatory Diseases: Role of Genetics and Gender in the Pathophysiology of Alzheimer's Disease

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western societies mainly accounts for clinical dementia. A high proportion of women are affected by this disease, especially at a very advanced age, which might to a large extent be associated with the fact that women live longer. However, some studies suggest that incidence rates may be really increased in women. For this reason the influence of estrogens on the brain and the decrease of it during menopause are of special interest. After menopause, circulating levels of estrogens markedly decline, influencing several brain processes predicted to influence AD risk. The control of estrogens on oxid…

Immunopathology and Immunosenescence, the Immunological Key Words of Severe COVID-19. Is There a Role for Stem Cell Transplantation?

The outcomes of Coronavirus disease-2019 (COVID-19) vary depending on the age, health status and sex of an individual, ranging from asymptomatic to lethal. From an immunologic viewpoint, the final severe lung damage observed in COVID-19 should be caused by cytokine storm, driven mainly by interleukin-6 and other pro-inflammatory cytokines. However, which immunopathogenic status precedes this “cytokine storm” and why the male older population is more severely affected, are currently unanswered questions. The aging of the immune system, i.e., immunosenescence, closely associated with a low-grade inflammatory status called “inflammageing,” should play a key role. The remodeling of both innate …

Alzheimer's disease: new diagnostic and therapeutic tools.

Abstract On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related diseases was held in Palermo, Italy. Here, the lectures of M. Racchi on History and future perspectives of Alzheimer Biomarkers and of G. Scapagnini on Cellular Stress Response and Brain Ageing are summarized. Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease, which in Western society mainly accounts for clinica dementia. AD prevention is an important goal of ongoing research. Two objectives must be accomplished to make prevention feasible: i) individuals at high risk of AD need to be identified before the earliest symptoms become evident, by which time extensive neurodege…

Biologia e Genetica dell'Invecchiamento: ruolo dei geni della risposta immune. in: Le basi biologiche e genetiche dell'invecchiamento

Ruolo dell'interazione NK/KIR nella storia naturale delle infezioni virali

Immunological mechanisms involved in the genesis of the immune response against viral infections take into account the activation of both innate adaptative response. Innate immune defenses trigger a rapid local response, which is often sufficient to control viral infection, and promotes the subsequent activation of specific immune defenses. Natural killer (NK) cells that constitute a subpopulation of lymphocyte-related cells are a key factor of innate immune response and play a role in defense against viral infections by killing infected cells or by producing cytokines and interacting with adaptative immune system's cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation …

Inflammatory mediators as biomarkers in brain disorders.

Neurodegenerative diseases such as Alzheimer, Parkinson, amyotrophic lateral sclerosis, and Huntington are incurable and debilitating conditions that result in progressive death of the neurons. The definite diagnosis of a neurodegenerative disorder is disadvantaged by the difficulty in obtaining biopsies and thereby to validate the clinical diagnosis with pathological results. Biomarkers are valuable indicators for detecting different phases of a disease such as prevention, early onset, treatment, progression, and monitoring the effect of pharmacological responses to a therapeutic intervention. Inflammation occurs in neurodegenerative diseases, and identification and validation of molecules…

Centenarians and diet: what they eat in the Western part of Sicily.

Abstract This paper pays attention to the modifiable lifestyle factors such as diet and nutrition that might influence life extension and successful ageing. Previous data reported that in Sicily, the biggest Mediterranean island, there are some places where there is a high frequency of male centenarians with respect to the Italian average. The present data show that in Sicani Mountain zone there are more centenarians with respect to the Italian average. In fact, in five villages of Sicani Mountains, there were 19 people with an age range of 100–107 years old from a total population of 18,328 inhabitants. So, the centenarian number was 4.32-fold higher than the national average (10.37 vs. 2.…

In the elderly, many alterations of both innate and clonotypic immunity have been described. Alterations to the immune system in the elderly are generally viewed as a deterioration of immunity, leading to the use of the term immunosenescence. However, although many immunological parameters are often notably reduced in the elderly, retained function of both innate and clonotypic immunity in the elderly is tightly correlated to health status. Recognising the important role of the immune system in ageing, over the last few years, journals oriented towards gerontology and geriatric sciences have increasingly published articles dealing with the immunology of ageing, but a specialised journal in …

Similarity and differences in elderly patients with fixed airflow obstruction by asthma and by chronic obstructive pulmonary disease

SummaryBackgroundEpidemiologic studies have demonstrated that elderly patients with fixed airflow obstruction can be affected by asthma or chronic obstructive pulmonary disease (COPD).MethodsWe studied 49 consecutive elderly outpatients, presenting fixed airflow obstruction, by clinical history (smoking), pulmonary function tests, blood gas analysis, and induced sputum.ResultsThe age was not different in patients with COPD (n=28) and asthma (n=21) (70.2±3.9 years vs. 69.6±3.7 years), also the degree of fixed airflow obstruction was similar (FEV1: 58.3±1.5% vs. 59.0±1.4% of predicted). Patients with asthma had significantly more eosinophils in peripheral blood (0.43±0.05×10−3μL vs. 0.27±0.1×…

Pro-Inflammatory Genetic Markers of Atherosclerosis

Atherosclerosis (AS) is a chronic, progressive, multifactorial disease mostly affecting large and medium-sized elastic and muscular arteries. It has formerly been considered a bland lipid storage disease. Currently, multiple independent pathways of evidence suggest this pathological condition is a peculiar form of inflammation, triggered by cholesterol-rich lipoproteins and influenced both by environmental and genetic factors. The Human Genome Project opened up the opportunity to dissect complex human traits and to understand basic pathways of multifactorial diseases such as AS. Population-based association studies have emerged as powerful tools for examining genes with a role in common mul…

Corrigendum to “Immune parameters identify Italian centenarians with a longer five-year survival independent of their health and functional status” [Exp. Gerontol. 54C (2014) 14–20]

8 a Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy 9 b CIG—Interdepartmental Centre L. Galvani, University of Bologna, Bologna, Italy 10 c Physics and Astronomy Department, University of Bologna, Bologna, Italy 11 d Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy 12 e Immunosenescence Unit, Department of Pathobiology and Biomedical Methodologies, University of Palermo, Palermo, Italy 13 f Geriatric Unit IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, University of Milan, Italy 14 g Department of Clinical Sciences and Community Health, University of Milan, Italy 15 h Experimental Laboratory o…

LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: Biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects

Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer's disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-α, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimul…

Role of environmental and genetic factor interaction in the aging related disease development: The gastric cancer paradigm.

Inflammation, genes and zinc in ageing and age-related diseases.

Lifelong antigenic burden determines a condition of chronic inflammation, with increased lymphocyte activation and pro-inflammatory cytokine production. A large number of studies have documented changes in Zn metabolism in experimental animal models of acute and chronic inflammation and in human chronic inflammatory diseases. In particular, modification of zinc plasma concentration as well as intracellular disturbance of antioxidant intracellular pathways have been found associated to age-related inflammatory diseases, like atherosclerosis. Zinc deficiency is extremely diffused in aged people that are educated to avoid meat and other high Zn-content foods due to fear of cholesterol. Rather,…

β-glucans: Ex vivo inflammatory and oxidative stress results after pasta intake

Background: It is well known that Mediterranean Diet can positively influence the health of each individual, in particular it is know that fibers have an important role. However, in Mediterranean cities most people do not have a close adherence to Mediterranean diet. Thus, in our study, we considered fibers like β-glucans that have been added to pasta with a percentage of 6 %. Our study aimed to evaluate the capacity of β-glucans intake on oxidative stress and inflammation in a cohort of middle aged slightly overweight subjects. Methods: We used a longitudinal study design. The study lasted 30 days during which time, each participant acted with no food restriction. Participants underwent mo…

Granulocyte and natural killer activity in the elderly

The deterioration of the immune system in ageing, 'immunosenescence', is thought to contribute to increased morbidity and mortality from infections and possibly autoimmune diseases and cancer. The most profound changes involve effector and immunoregulatory T-cell functions. Immunosenescence appears also to be related to changes in non specific immunity as well. In the present study we have assessed superoxide production, chemotaxis and the expression of the apoptosis-related molecule APO1/Fas (CD95) on neutrophils (PMN) from young and old subjects. Furthermore, we have measured the basal natural killer (NK) activity of young and elderly subjects and we have compared the number of CD16+ cell…

How Can We Improve the Vaccination Response in Older People? Part II: Targeting Immunosenescence of Adaptive Immunity Cells.

The number of people that are 65 years old or older has been increasing due to the improvement in medicine and public health. However, this trend is not accompanied by an increase in quality of life, and this population is vulnerable to most illnesses, especially to infectious diseases. Vaccination is the best strategy to prevent this fact, but older people present a less efficient response, as their immune system is weaker due mainly to a phenomenon known as immunosenescence. The adaptive immune system is constituted by two types of lymphocytes, T and B cells, and the function and fitness of these cell populations are affected during ageing. Here, we review the impact of ageing on T and B …

Drug targets in ageing and age-associated diseases.

Utilità della citologia nasale.

Familial mediterranean fever, longevity and cardiovascular diseases: a pilot study in the Sicilian population

Genotype frequencies of the +874T→A single nucleotide polymorphism in the first intron of the interferon-γ gene in a sample of Sicilian patients affected by tuberculosis

In the light of the key role played by interferon (IFN)-gamma in the control of tuberculosis, in the present paper we have evaluated the distribution of the functional +874T --> A IFN-gamma single nucleotide polymorphism (SNP) in Sicilian patients affected by tuberculosis. Our aim was to determine whether there is an association between the TT genotype, which has been suggested to be linked to an increased production of IFN-gamma, and resistance to chronic tuberculosis. DNA samples were obtained from 45 patients and 97 healthy controls. Polymorphism at +874 was identified using amplification refractory mutational system methodology. The +874T SNP was less frequent in patients than in contro…

Slow-Ageing Diets

Ageing is a complex, unavoidable phenomenon than cannot be exhaustively defined. However, it has been described as a process leading to death, characterized by a gradual decrease of the ability to adapt to stress, causing a decline in functional capacity. This event, marked by a progressive loss of physiological integrity of many interrelated systems, determines an increased risk of morbidity and mortality (Avery et al. 2014). With increase of the proportion of older adults worldwide (United Nations 2017), it is necessary to carry out prevention policy for a healthy ageing (HA). Good nutrition plays a significant role in determining the well-being of older people, and in delaying and reduci…

Association between platelet endothelial cellular adhesion molecule 1 (PECAM-1/CD31) polymorphisms and acute myocardial infarction: a study in patients from Sicily

Summary Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulating leucocytes, mediate cell recruitment and their transendothelial migration. Platelet endothelial cellular adhesion molecule 1 (PECAM-1/CD31), involved in this migration, has been associated with the developmental course of atherosclerosis. A few studies have investigated an association between coronary heart disease and single nucleotide polymorphisms (SNPs) located in functionally important domains of the PECAM-1/CD31 gene. In particular, Ser563Asn and Gly670Arg SNPs have been described as s…

Measurement of inflammatory mediators of eosinophils and lymphocytes in blood in acute asthma: serum levels of ECP influence the bronchodilator response.

The aim of this study was to assess the relevance of immunoinflammatory markers on the response to short acting β<sub>2</sub>-agonist in acute asthma exacerbation. Thus, we measured serum eosinophil cationic protein (ECP) levels and sIL-2R at acute exacerbation in 52 adult patients with atopic asthma, and assessed forced expiratory volume in 1 s (FEV<sub>1</sub>) before and after the administration of aerosolized salbutamol. After a cumulative dose of salbutamol causing a 10% improvement in FEV<sub>1</sub> from baseline [CD10, i.e. cumulative doses of salbutamol (800 µg) causing an improvement in FEV<sub>1</sub> from baseline to 10%] the patie…

Major Histocompatibility Complex Polymorphisms and Ageing.

ASTRACT Longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Accordingly, mouse lifespan is influenced by MHC (major histocompatibility complex) genotype. The HLA (the human MHC) region encompasses over 4 Mb of DNA on the chromosome band 6p21.3 and its extensive characterisation has recently culminated in the determination of the nucleotide sequence of the entire region, confirming the presence of ~ 220 genes. The MHC is traditionally divided into the class I, class II and class III regions. Most HLA genes …

An immunologist's guide to immunosenescence and its treatment

Abstract Introduction: Aging causes several changes in the immune system, although immune aging is strongly influenced by individual immunological history, as well as genetic and environmental factors leading to inter-individual variability. Areas covered: We focused on the biological and clinical meaning of immunosenescence. SARS-CoV-2 and Yellow Fever vaccine have demonstrated the clinical relevance of immunosenescence, while inconsistent results, obtained from longitudinal studies aimed at looking for immune risk phenotypes, have revealed that immunosenescence is highly context-dependent. Large projects allowed the delineation of the drivers of immune system variance, including genetic a…

Immunological and immunogenetic markers of successful and unsuccessful ageing

Febbre ed apatia aiutano a guarire

Immunogenetics, Gender, and Longevity

In this article we discuss relevant data on aging, longevity, and gender with particular focus on inflammation gene polymorphisms which could affect an individual's chance to reach the extreme limit of human life. The present review is not an extensive revision of the literature, but rather an expert opinion based on selected data from the authors' laboratories. In 2000-2005 in the more developed regions, the life expectancy at birth is 71.9 years for men (78.3 in Japan) and 79.3 years for women (86.3 in Japan). Indeed, gender accounts for important differences in the prevalence of a variety of age-related diseases. Considering people of far-advanced age, demographic data document a clear-c…

Biomarkes of aging

Ageing is a complex process that negatively impacts the development of the different systems and its ability to function. On the other hand, the rate of ageing in humans is not uniform, due to genetic heterogeneity and the influence of environmental factors. Thus, the ageing rate, measured as the decline of functional capacity and stress resistance, seems to be different in every individual. Therefore, attempts have been made to analyse this individual age, the so-called biological age, in comparison to chronological age. Age-related changes in body function or composition that could serve as a measure of biological age and predict the onset of age-related diseases and/or residual lifetime …

Effect of Extra Virgin Olive Oil and Table Olives on the ImmuneInflammatory Responses: Potential Clinical Applications

Background and Objective: Extra virgin olive oil (EVOO) is the common element among the Mediterranean countries. It can be considered a nutraceutical and functional food, thanks to its bioactive compounds. It can act and modulate different processes linked to ageing and age-related diseases related to a common chronic low grade inflammation. Depending on the cultivar, the growth conditions, the period of harvesting, the productive process and time of product storage, EVOO could contain different amount of vegetal components. Of course, the same is for table olives. Methods: The aim of our review is to summarize the effects of EVOO and table olives on the immunemediated inflammatory respons…

CALPAIN ACTIVITY MAINTAINS GOOD HEALTH OF CENTENARIAN T CELLS; SUMMARY OF THE CALPACENT PROJECT

Causes of aging-associated deterioration of human immunity, and the reasons why the immune system of the oldest old individuals (centenarians) is relatively robust, remain moot. Intracellular proteolysis system of two proteases – µ- and m-calpain – and their inhibitor – calpastatin (the calpain-calpastatin system (CCS)) - is active in resting human peripheral blood T cells, participating in maintenance of their readiness to proliferate and secrete cytokines in response to stimulation. The amounts of the CCS proteins decrease in resting T lymphocytes of healthy elderly, only to return in the centenarians to those levels seen in the young individuals. We compared the calpain activities and th…

Is human immunosenescence clinically relevant? Looking for ‘immunological risk phenotypes’

Abstract The 3rd ImAginE Conference on ‘Basic Biology and Clinical Impact of Immunosenescence' was held at Palermo University, Italy from 10–13 April 2002.

Association Between Platelet Endothelial Cellular Adhesion Molecule-1 Polymorphisms and Atherosclerosis: Results of a Study on Patients from Northern Italy

Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulating leukocytes, mediate cell recruitment and their transendothelial migration. Platelet endothelial cellular adhesion molecule-1 (PECAM-1), involved in this migration, has been associated with the development of atherosclerosis. Studies have investigated an association between coronary artery disease (CAD) and single-nucleotide polymorphisms (SNPs) located in functionally important domains of the PECAM-1 gene with inconsistent results. Thus, we have analyzed the distribution of V125L, N563S, and G670R S…

Inflammation and prostate cancer

Prostate cancer remains a major health concern for the male population throughout the Western world. It is today widely accepted that inflammation has a role in many human cancers. In fact, inflammation is thought to incite carcinogenesis by causing cell and genome damage, promoting cellular turnover and creating a tissue microenvironment that can enhance cell replication, angiogenesis and tissue repair. Accordingly, there is a body of literature suggesting a link between chronic inflammation and prostate cancer, in which prostate inflammation may contribute to the promotion of prostate cancer development. On the other hand, high levels of endogenous gonadal steroids are considered as risk…

Chronic kidney disease and inflammation: Role of +896A/G pro-inflammatory polymorphism of TLR4 gene and Δ32 deletion of CCR5 gene

bstract Chronic inflammation seems implicated in the pathophysiology of chronic kidney diseases (CKD) and the development of its complications, such as cardiovascular diseases (CVD). Genes encoding inflammatory molecules are, hence, good candidates for CVD risk in haemodialysis patients (HD). We therefore evaluated whether +896A/G TLR4 polymorphism and CCR5A32 deletion are risk factors for CKD and CVD. We examined the two gene variants in 72 HD patients and in 125 controls from Sicily. No significant differences in the genotype distribution and allele frequencies of the two gene variants were observed between patients and controls. The same results were obtained by analysing the combined ef…

Double Negative (CD19+IgG+IgD-CD27-) B Lymphocytes: A New Insight from Telomerase in Healthy Elderly, in Centenarian Offspring, and in Alzheimer’s Disease Patients

Background: We have previously reported the increase of IgD-CD27- (Double Negative, DN) B cell population in the aged. These memory B cells have short telomeres and poor abilities to proliferate in vitro. Here, we investigated whether the low ability of DN B cells to proliferate depends on the expression levels of the CD307d and CD22 inhibitory receptors or whether DN B cells can proliferate and reactivate telomerase by the engagement of both innate and adaptive immune receptors. Methods: Phenotypic analyses were made by using flow cytometry. Quantitative analysis of telomerase activity was made by using a TRAP and a photometric enzyme immunoassay in young, healthy elderly, centenarian offs…

The role of macrophage colony-stimulating factor in patients with acute myocardial infarction: a pilot study.

We assessed whether macrophage colony-stimulating factor (M-CSF) levels are associated with left ventricular systolic dysfunction (LVSD) in patients with acute myocardial infarction (AMI). We studied 56 patients with AMI (mean age: 67 ± 12 years) and identified those with clinical (Killip class >II) or echocardiographic signs (ejection fraction ≤45%) of LVSD. We evaluated the established cardiovascular risk factors and measured several cardiovascular biomarkers, including M-CSF. Serum M-CSF concentrations (pg/mL) were significantly increased in patients with both clinical and echocardiographic signs of LVSD (460 ± 265 vs 290 ± 210, P = .0103 and 493 ± 299 vs 287 ± 174, P = .0028, respec…

Genetics of Neurodegenerative Disorders

Predictive diagnostics and personalized medicine for the prevention of chronic degenerative diseases

Abstract Progressive increase of mean age and life expectancy in both industrialized and emerging societies parallels an increment of chronic degenerative diseases (CDD) such as cancer, cardiovascular, autoimmune or neurodegenerative diseases among the elderly. CDD are of complex diagnosis, difficult to treat and absorbing an increasing proportion in the health care budgets worldwide. However, recent development in modern medicine especially in genetics, proteomics, and informatics is leading to the discovery of biomarkers associated with different CDD that can be used as indicator of disease’s risk in healthy subjects. Therefore, predictive medicine is merging and medical doctors may for t…

Immune-inflammatory responses in the elderly: An update

EDITORIAL NO ABSTRACT

Pathophysiology of ageing, longevity and age related diseases

Abstract On April 18, 2007 an international meeting on Pathophysiology of Ageing, Longevity and Age-Related Diseases was held in Palermo, Italy. Several interesting topics on Cancer, Immunosenescence, Age-related inflammatory diseases and longevity were discussed. In this report we summarize the most important issues. However, ageing must be considered an unavoidable end point of the life history of each individual, nevertheless the increasing knowledge on ageing mechanisms, allows envisaging many different strategies to cope with, and delay it. So, a better understanding of pathophysiology of ageing and age-related disease is essential for giving everybody a reasonable chance for living a …

Immunity & Ageing: a new journal looking at ageing from an immunological point of view. Immunity & Ageing

Special Issue "Centenarians-A Model to Study the Molecular Basis of Lifespan and Healthspan".

People are living longer, not, as was previously the case, due to reduced child mortality, but because we are postponing the ill-health of old age [...]

Inflammation, Longevity, and Cardiovascular Diseases: Role of Polymorphisms of TLR4

The total burden of infection at various sites may affect the progression of atherosclerosis, the risk being modulated by host genotype. The role of lipopolysaccaride receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria; and TLR4 polymorphisms, as ASP299GLY, suggested to attenuate receptor signaling, have been described. We demonstrated that TLR4 ASP299GLY polymorphism shows a significantly lower frequency in patients affected by myocardial infarction compared to controls, whereas centenarians show a higher frequency. Thus, people genetically predisposed to developing weak inflammatory activity, seem to have fewer chances of developing cardio…

Altered cytokine production in leukocyte obtained from Alzheimer’s disease patients.

A study of age-related IgE pathophysiological changes.

Abstract The literature on immunosenescence has focused mainly on T cell impairment. However, it is well known that B function is also profoundly affected. In particular, several studies have shown age-related changes in immunoglobulin serum levels. Concerning allergic diseases, the incidence of onset of allergic symptoms, as well as their severity, seems to decrease with age. So, the decline of onset of allergic symptoms observed in ageing might result from a decrease of serum total IgE due to an unbalance of cytokines and soluble factors involved in its production. To gain insight into the mechanisms of age related incidence of onset of allergic symptoms, as well as their severity, in thi…

HLA antigens in Sicilian patients affected by chronic myelogenous leukaemia.

SUMMARY HLA antigens were investigated in Sicilian patients with chronic myelogenous leukaemia (CML) and in Sicilian healthy controls. The frequency of the HLA-DRw6 antigen was significantly decreased in the group of patients. These results suggest that DRw6 may be a marker for decreased susceptibility to the etiological or pathogenic mechanism(s) which produce CMLs.

SARS CoV2 infection _The longevity study perspectives

Graphical abstract

Measurement of inflammatory mediators of mast cells and eosinophils in native nasal lavage fluid in nasal polyposis.

<i>Background:</i> Nasal polyposis (NP) often coexists with asthma, rhinitis and sinusitis. Polyp histology typically shows chronic, eosinophilic inflammation. The inflammatory cell infiltrate generally includes eosinophils, lymphocytes, plasma cells and mast cells. <i>Objective:</i> To gain insight into the natural history of NP, we analysed mediator levels and leukocyte values in nasal fluids and eosinophil cationic protein (ECP), total IgE levels and eosinophils in the blood in several groups of both allergic and non-allergic patients with nasal polyps and in patients with allergic rhinitis (AR). <i>Methods:</i> Thirty-two patients with nasal polyps en…

Analysis of polymorphisms Leiden Factor V G1691A and prothrombin G20210A as risk factors for acute myocardial infarction.

Thrombotic risk increases in elderly, therefore, the understanding of the genetic predisposition of hypercoagulability could make the difference in the prevention of venous and/or arterial thrombotic events. Laboratory evaluation of hyperfibrinogenemia, increased Factor VII levels, antiphospholipid antibodies presence and hyperhomocysteinemia are considered to have a consistent high predictivity for arterial thrombophilic diseases. Anyway, a large debate exists on the validity of testing Leiden Factor V (FV) G1691A and/or prothrombin (FII) G20210A polymorphisms in patients affected by arterial thrombotic diseases, despite of the several observations described. Here we report data strongly s…

Aging and Anti-Aging Strategies second edition

Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promotes wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, we summarize, in this chapter, related mechanisms involved, discuss on potentential treatment until now disposable, and suggest preventive measures.

Aging and chronic inflammation: highlights from a multidisciplinary workshop

Abstract: Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed “inflammaging”. After decades of accumulating evide…

HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute ischemic stroke

Abstract Introduction In humans, a major component of natural killer (NK) and T cell target recognition depends on the surveillance of human leukocyte antigen (HLA) class I molecules by killer immunoglobulin-like receptors (KIRs). Aims To implement the knowledge about the immunological genetic background of acute ischemic stroke susceptibility in relation to the frequency of the KIR genes and HLA alleles. Methods Subjects with acute ischemic stroke and subjects without stroke were genotyped for the presence of KIR genes and of the three major KIR ligand groups, HLA-C1, HLA-C2, and HLA-Bw4, both HLA-B and HLA-A loci. Results Between November 2013 and February 2016, consecutive patients with …

Cytokine Gene Polymorphisms and Breast Cancer Susceptibility

Human breast cancer (BC) is characterized by a considerable clinical heterogeneity. Steroid hormone receptor expression and growth factor receptor expression have been considered suitable diagnostic and prognostic markers, whereas mutations of oncosuppressor and gatekeeper genes have been found associated with an increased risk for this malignancy. To evaluate the role that polymorphisms of genes involved in the regulation of inflammatory response might play in BC susceptibility, we investigated associations between cytokine functionally relevant polymorphisms in 84 BC patients compared to 110 age- and sex-matched controls. TNF-alpha (-308G/A), TGF-beta1 (+869C/T), IL-10 (-1117G/A; -854C/T;…

Anti-Inflammatory Effects of Nutritionally Relevant Concentrations of Oleuropein and Hydroxytyrosol on Peripheral Blood Mononuclear Cells: An Age-Related Analysis

: Immunosenescence and inflammaging facilitate the insurgence of chronic diseases. The Mediterranean diet is a non-invasive intervention to improve the chronic low-grade inflammatory status associated with aging. Olive oil oleuropein (OLE) and hydroxytyrosol (HT) demonstrated a controversial modulatory action on inflammation in vitro when tested at concentrations exceeding those detectable in human plasma. We studied the potential anti-inflammatory effects of OLE and HT at nutritionally relevant concentrations on peripheral blood mononuclear cells (PBMCs) as regards cell viability, frequency of leukocyte subsets, and cytokine release, performing an age-focused analysis on two groups of subj…

Age-related inflammatory disease: role of genetics and gender in the pathophisiology of Alzheimer’s disease

Taste receptor polymorphisms and longevity: a systematic review and meta-analysis

AbstractBitter taste receptors (TAS2R) are involved in a variety of non-tasting physiological processes, including immune-inflammatory ones. Therefore, their genetic variations might influence various traits. In particular, in different populations of South Italy (Calabria, Cilento, and Sardinia), polymorphisms of TAS2R16 and TAS238 have been analysed in association with longevity with inconsistent results. A meta-analytic approach to quantitatively synthesize the possible effect of the previous variants and, possibly, to reconcile the inconsistencies has been used in the present paper. TAS2R38 variants in the Cilento population were also analysed for their possible association with longevi…

Expression of calpain-calpastatin system (CCS) member proteins in human lymphocytes of young and elderly individuals; pilot baseline data for the CALPACENT project

Abstract Background Ubiquitous system of regulatory, calcium-dependent, cytoplasmic proteases – calpains – and their endogenous inhibitor – calpastatin – is implicated in the proteolytic regulation of activation, proliferation, and apoptosis of many cell types. However, it has not been thoroughly studied in resting and activated human lymphocytes yet, especially in relation to the subjects’ ageing process. The CALPACENT project is an international (Polish-Italian) project aiming at verifying the hypothesis of the role of calpains in the function of peripheral blood immune cells of Polish (Pomeranian) and Italian (Sicilian) centenarians, apparently relatively preserved in comparison to the g…

I processi patologici dell'invecchiamento.

Role of sex and age in fatal outcomes of COVID-19: women and older centenarians are more resilient.

In the present paper, we have analysed the role of age and sex in the fatal outcome of COVID-19, as there are conflicting results in the literature. As such, we have answered three controversial questions regarding this aspect of the COVID-19 pandemic: (1) Have women been more resilient than men? (2) Did centenarians die less than the remaining older people? (3) Were older centenarians more resistant to SARS-CoV-2 than younger centenarians? The literature review demonstrated that: (1) it is women who are more resilient, in agreement with data showing that women live longer than men even during severe famines and epidemics; however, there are conflicting data regarding centenarian men; (2) c…

Clinical Course and Genetic Susceptibility of Primary Biliary Cirrhosis: Analysis of a Prospective Cohort

Background: Natural history of primary biliary cirrhosis (PBC) is partially characterized in patients from the Mediterranean area whose genetic background differs from that of Northern Europeans. Objectives: We aimed to describe genetic susceptibility and clinical course of PBC in patients from Southern Italy. Methods: Socio-demographic, clinical, biochemical and histological data at diagnosis as well as disease progression of 81 PBC consecutive patients were collected. All subjects were treated with Ursodeoxycholic acid at a dose of 15 mg/kg. HLA class II DRB1 alleles were compared with those of 237 healthy control subjects. IL28B genotyping for IL28B rs12979860 C/T and rs80899917 G/T was …

Association between HFE mutations and acute myocardial infarction: a study in patients from Northern and Southern Italy.

There is interest in the role of iron in age-related diseases such as atherosclerosis. Tissue iron deposition could be harmful, because Fe(2+) can react with H(2)O(2) to form OH(-) radicals and Fe(2+) can react with O(2) to form reactive oxygen species. Free radicals react with cell membranes and cell organelles and could lead to the development of atherosclerosis by initiating lipid peroxidation. Hereditary hemochromatosis provides an opportunity for studying the effects of iron on cardiovascular disease. Some studies have shown that individuals who carried HFE mutations may be at greater risk of developing coronary heart disease than those without the mutations. In contrast, a large numbe…

Misdiagnosis of familial Mediterranean fever in patients with Anderson-Fabry disease

Fabry disease (FD) is an underdiagnosed pathology due to its symptomatology that overlaps with various systemic and rheumatic disorders, including familial Mediterranean fever (FMF). We examined the Mediterranean fever (MEFV) and α-galactosidase A (GLA) genes, whose mutations are responsible for FMF and FD, respectively, in 42 unrelated patients diagnosed with FMF, which revealed significant ambiguity regarding some of the symptoms which are also present in FD. The objective of this study was to determine the spectrum of mutations present in these genes, in order to identify cases of mistaken diagnosis of FMF and/or missed diagnosis of FD. Ten out of 42 patients had one mutation in homozygo…

Analysis of T and NK cell subsets in Sicilian population from young to supercentenarian: the role of age and gender

Summary Ageing dramatically affects number and function of both innate and adaptive arms of immune system, particularly T cell subsets, contributing to reduced vaccination efficacy, decreased resistance to infections and increased prevalence of cancer in older people. In the present paper, we analysed the age‐related changes in the absolute number of lymphocytes in 214 Sicilian subjects, and in the percentages of T and natural killer (NK) cells in a subcohort of donors. We compared these results with the immunophenotype of the oldest living Italian supercentenarian (aged 111 years). The results were also sorted by gender. The correlation between number/percentage of cells and age in all ind…

Taking Advantage of Viral Immune Evasion: Virus-Derived Proteins Represent Novel Biopharmaceuticals

In healthy individuals, natural and adaptive immune responses are able to control virus entry into the host. In particular, CD8(+)-mediated cytotoxicity, sustained by the intervention of CD4+ cells, represents the major key event leading to virus eradication. On the other hand, viruses are able to evade from host immune response via several mechanisms, and special emphasis will be placed on hepatitis C virus and chronic Epstein-Barr infections also in view of personal data. Virokines, viroreceptors, and serpins greatly contribute to viral immune escape, and, among virokines, interleukin (IL)-10 has been object of intensive studies. Finally, all these products have been used as biopharmaceut…

B cells in the aged: CD27, CD5, and CD40 expression.

Ageing is characterized by numerous changes in lymphocyte subpopulations. In the present paper we have focused on B cells carrying the surface markers CD27, CD5 and CD40. CD27 is considered a marker of primed (memory) cells and its engagement promotes the differentiation of memory B cells into plasma cells. CD5 is expressed on B1 cells, which are considered to be responsible for T cell-independent antibody production other than autoantibodies. The CD40 molecule binds CD40L (CD154) and is necessary for T-dependent antibody responses. Here we show that the absolute number of CD5+ and CD40+ B cells is decreased in the elderly, while CD27+ B lymphocytes only marginally decrease in centenarians.…

Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer's disease.

Alzheimer's disease (AD) is a heterogeneous and progressive neurodegenerative disease which in Western society mainly accounts for clinical dementia. Inflammation plays a key role in AD and dissecting the genetics of inflammation may provide an answer to the possible treatment. Hence, the better understanding of different molecular and cellular inflammatory mechanisms is crucial for complete knowledge of AD pathophysiology, and for its prevention and drug therapy. Accordingly, in the present study we evaluated whether the pro-inflammatory polymorphisms of lipopolysaccaride-receptors, +896A/G Toll-Like Receptor (TLR4) and -260C/T CD14, are risk factors for AD. The study included both 626 AD …

Ageing, longevity, inflammation and cancer

A close connection: Alzheimer’s disease and type 2 diabetes

In the recent years a growing body of evidence links insulin resistance and insulin action to neurodegenerative diseases, especially Alzheimer’s disease (AD). The importance of insulin in ageing as well as its role in cognition and other aspects of normal brain functions are well established. The hippocampus and cerebral cortex-distributed insulin and insulin receptor (IR) have been shown to be involved in brain cognitive functions. Conversely, deterioration of IR signaling is involved in agingrelated brain degeneration such as in AD and cognitive impairment in type 2 diabetes patients. Insulin administration, while maintaining euglycemia, improves memory in both healthy adults and Alzheime…

Urinary metabolites of histamine and leukotrienes before and after placebo-controlled challenge with ASA and food additives in chronic urticaria patients

Background: The recovery of mediator metabolites from urine has the potential to provide a rapid, safe, and easily available index of release of mediators. We aimed to determine urinary metabolites of both histamine and leukotrienes (LTs) in patients affected by chronic urticaria (CU). Methods: Twenty patients with CU were studied. They were selected on the basis of double-blind placebo-controlled challenge (DBPC) with acetyl salicylic acid (ASA) and food additives. Ten patients (group B) were negative to both challenges. Ten patients (group C) presented urticaria and/or the appearance of angioedema during or 24 h after challenge, with reactions to ASA (five patients) or food additives (fiv…

Interleukin 2 and soluble interleukin 2-receptor secretion defect in vitro in newly diagnosed type I diabetic patients

In this study, we investigated whether an interleukin 2 (IL-2) secretion defect by peripheral blood mononuclear cells (PBMCs) after in vitro stimulation with phytohemagglutinin (PHA-M) occurs in either newly diagnosed or long-standing type I (insulin-dependent) diabetic patients and whether it is accompanied by a dysregulation of soluble IL-2— receptor (IL-2RS) production. PBMC cultures (2.5 × 106 cells), unstimulated or stimulated with PHA-M (25 μg/ml), from 20 type I diabetic patients (10 with time since onset <3 mo and 10 with long-term diabetes of <3 yr) and 10 control subjects were studied for the production of IL-2 and IL-2RS in their respective supernatants. No differen…

HLA-B8,DR3 haplotype affects lymphocyte blood levels

The number of lymphocytes in the blood is constant, pointing to an effective control of circulating lymphocyte values. The mechanisms of this regulation are uncertain, although it is likely that the number of blood lymphocytes is conditioned by hormones, homing factors and cytokines whose production is at least partly restrained by genetic factors. Particularly genetic factors linked to major histocompatibility complex (MHC) appear to be involved. In human beings a decreased number of blood lymphocytes has been described in healthy subjects carrying the Human Leucocyte Antigens (HLA) haplotype HLA-B8,DR3. In the present study, to inquire into the mechanisms of this lymphocyte decreased numb…

From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing”

Ageing is a complex process characterized by a general decline in physiological functions with increasing morbidity and mortality. The most important aspect of ageing is the chronic inflammatory status, named “inflamm-ageing”, strictly associated with the deterioration of the immune function, termed “immunosenescence”. Both are causes of increased susceptibility of elderly to infectious diseases, cancer, dementia, cardiovascular diseases and autoimmunity, and of a decreased response to vaccination. It has been widely demonstrated that ageing has a strong impact on the remodelling of the B cell branch of immune system. The first evident effect is the significant decrease in circulati…

Fisiopatologia del rene e dei polmoni

Centenarians' offspring as a model of healthy aging: a reappraisal of the data on Italian subjects and a comprehensive overview.

Within the scenario of an increasing life expectancy worldwide it is mandatory to identify determinants of healthy aging. Centenarian offspring (CO) is one of the most informative model to identify trajectories of healthy aging and their determinants (genetic and environmental), being representative of elderly in their 70th whose lifestyle can be still modified to attain a better health. This study is the first comprehensive investigation of the health status of 267 CO (mean age: 70.2 years) and adopts the innovative approach of comparing CO with 107 age‐matched offspring of non‐long‐lived parents (hereafter indicated as NCO controls), recruited according to strict inclusion demographic cri…

Biology of Longevity: Role of the Innate Immune System

Genetic factors play a relevant role in the attainment of longevity because they are involved in cell maintenance systems, including the immune system. In fact, longevity may be correlated with optimal functioning of clonotypic and natural immunity. The aging of the immune system, known as immunosenescence, is the consequence of the continuous attrition caused by chronic antigenic overload. The antigenic load results in the progressive generation of inflammatory responses involved in age-related diseases. Most of the parameters influencing immunosenescence appear to be under genetic control, and immunosenescence fits with the basic assumptions of evolutionary theories of aging, such as anta…

β-Glucans and Post Prandial Satiety: The Role of Intestinal Hormones in Healthy Volunteers

Recent interest in intestinal hormones has risen with the idea that they modulate glucose tolerance and food intake through a variety of mechanisms, and such hormones like peptide YY (PYY), ghrelin, glucagon-like peptide (GLP)-1 and 2, and cholecystokinin (CKK) are therefore excellent therapeutic candidates for the treatment of diabetes and obesity. Furthermore, in the recent years, multiple studies suggest that the microbiota is critically important for normal host functions, while impaired host microbiota interactions contribute to the pathogenesis of numerous common metabolic disorders. In this study, we considered the nutraceutical effects of β-glucans added to pasta at the con…

Possible Association of Telomere Length with Sleep Duration. A Preliminary Pilot study in a Sicilian Cohort with Centenarians

Telomere length (TL) is considered a biomarker of ageing although this topic is still debated. Also, sleep pattern changes are physiological part of the normal ageing process. In fact, it is widely recognized that sleep duration declines with age, leading to dysregulation of circadian rhythms. The aim of our study was to analyse the possible association of sleep duration with TL in a sample of 135 subjects with ages ranging from 20 to 111 years, recruited from Palermo and neighbouring municipalities in Sicily (Italy). Preliminary data suggest that relative TL (RTL) decreases with age in both men and women. However, at older ages, the difference between men and women tends to narrow. Nonagen…

Association between +1059G/C CRP polymorphism and acute myocardial infarction in a cohort of patients from Sicily: a pilot study.

Changes in natriuretic peptide and cytokine plasma levels in patients with heart failure, after treatment with high dose of furosemide plus hypertonic saline solution (HSS) and after a saline loading

BACKGROUND AND AIMS: Neurohormonal activation and inflammation characterizes heart failure, relates to outcome, and is a therapeutic target. The aim of this study was to evaluate the effects of high-dose furosemide plus small-volume hypertonic saline solutions (HSS) on natriuretic peptides and immuno-inflammatory marker levels and to analyze, after treatment, the response to acute saline loading. METHODS AND RESULTS: 120 patients with heart failure treated with high-dose furosemide+HSS (Furosemide/HSS group) were matched with: 30 subjects with heart failure treated with high-dose furosemide (furosemide group), 30 controls with asymptomatic left-ventricular dysfunction (ALVD) (asymptomatic g…

Impact of Different Texture of Polypropylene Mesh on the Inflammatory Response

Over the past decade, hernia surgery has undergone a considerable transformation with the use of prosthetic materials. The most used polypropylene meshes induce a rapid acute inflammatory response followed by chronic foreign body reaction. Many factors influence this response such as density, size, physical characteristics, different texture and porosity of each biomaterial. The aim of this study is to assess whether the implant of monofilament or multifilament meshes, in the inguinal hernioplasty, determine a different inflammatory response. Thirty-two male patients were included in the study and were randomly divided into two groups. In the first group (MO) inguinal hernioplasty was perf…

Association of immunoglobulin GM allotypes with longevity in long-living individuals from Southern Italy

Abstract Background The aim of this study was to analyse the role of GM allotypes, i.e. the hereditary antigenic determinants expressed on immunoglobulin polypeptide chains, in the attainment of longevity. The role played by immunoglobulin allotypes in the control of immune responses is well known as well as the role of an efficient immune response in longevity achievement. So, it is conceivable that particular GM allotypes may contribute to the generation of an efficient immune response that supports successful ageing, hence longevity. Methods In order to show if GM allotypes play a role in the achievement of longevity, we typed the DNA of 95 Long-living individuals (LLIs) and 96 young con…

The -308G/A polymorphism of TNF-alpha influences immunological parameters in old subjects affected by infectious diseases.

Abnormal increments of pro-inflammatory cytokines (IL-6 and TNF-alpha) characterize the outbreak of infectious diseases, which are the major cause of death in the elderly. A counterbalance to the inflammation is exerted by IL-10 with an inhibitory role on TNF-alpha production. As is well known, some cytokine gene polymorphisms influence the cytokine production, playing a role as susceptibility or resistance factors against immune-mediated and infectious disease. Genetic variations in the -308A/G locus for TNF-alpha seems to affect the clinical outcome of some infectious diseases. In fact, the -308A allele is associated with severe septic shock and death. On this basis, we have screened heal…

INNATE IMMUNITY AND INFLAMMATION IN AGEING: A KEY FOR UNDERSTANDING AGE-RELATED DISEASES.

Abstract The process of maintaining life for the individual is a constant struggle to preserve his/her integrity. This can come at a price when immunity is involved, namely systemic inflammation. Inflammation is not per se a negative phenomenon: it is the response of the immune system to the invasion of viruses or bacteria and other pathogens. During evolution the human organism was set to live 40 or 50 years; today, however, the immune system must remain active for much a longer time. This very long activity leads to a chronic inflammation that slowly but inexorably damages one or several organs: this is a typical phenomenon linked to ageing and it is considered the major risk factor for a…

Role of TLR4 polymorphisms in inflammatory responses: implications for unsuccessful aging.

The total burden of infection at various sites may affect the progression of atherosclerosis and Alzheimer's disease (AD), the risk being modulated by host genotype. The role of lipopolysaccharide (LPS) receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria, and TLR4 single nucleotide polymorphisms (SNPs), such as +896A/G, known to attenuate receptor signaling, have been described. This SNP shows a significantly lower frequency in patients affected by myocardial infarction or AD. Thus, people genetically predisposed to developing lower inflammatory activity seem to have less chance of developing cardiovascular disease (CVD) or AD. In the presen…

Immune-inflammatory responses in successful and unsuccessful ageing

A dramatic increase in mean life span and life expectancy, coupled with a significant reduction in early mortality, has lead to a large increase in number of elderly people in modern societies. This demographic phenomenon has been paralleled by an epidemic of chronic diseases associated with advancing age. Both innate and instructive immunity are implicated in almost all age-related diseases. The modifications of the immune system in the elderly are evaluated as a deterioration of the immune system, the so-called immunosenescence, which is thought to be mostly the result of the declining effectiveness of T cells and it is responsible for the increased susceptibility of elderly to infectious…

Aging and anti-aging strategies

Prevalence of residual B-cell function related to age at onset and genetic profile in newly diagnosed type I diabetics.

Patients with type I (insulin-dependent) diabetes mellitus maintain B-cell function for a varying period of time after onset. This is commonly held to account for post-initial remission. To estimate residual B-cell function we measured plasma and 24-h urinary C-peptide in 68 type I diabetic patients (age range 4-35 years, within 10-180 days of the onset of symptoms, typed for HLA-A, -B, -C and DR loci. A positive correlation (r = 0.26; p less than 0.05) was found between urinary C-peptide levels and the age of the patient. The analysis of variance of urinary C-peptide values on the basis of the presence or absence of DR3 and DR4 antigens revealed that the DR3-positive patients had reduced e…

The KIR-ligand HLA-A Bw4 predicts the outcome of hepatitis B infection.

Killer Immunoglobulin like Receptors (KIR) are membrane proteins expressed on Natural Killer (NK) cells and on a small subset of CD8 lymphocytes. They influence the activation or inhibition of both cell types through interaction with their ligands, represented by Human Leukocyte Antigen (HLA) class I molecules. Several studies have shown that KIR/HLA interactions are involved in the pathogenesis and progression of different diseases as viral infections, autoimmune-disorders, or cancer, conditioning susceptibly to or protection against the outcome of the disease. HBV infection represents a major health problem with 2 billion people infected and 3 hundred and fifty million people with chronic…

Impairment of gamma/delta T lymphocytes in elderly: implications for immunosenescence

Gamma/delta T lymphocytes cells recognize the antigen in a non-classical way and are considered the third branch of the immune system devoted to defend the integrity of the body. Ageing is characterized by an impairment of the main way of protection (the adaptive branch) but, successfully aged people show compensatory mechanisms of defense such as proneness to inflammation. Moreover, very old subjects show an increased number of NK cells. We have previously demonstrated that gamma delta T lymphocytes are reduced in elderly. In the present paper we have studied some characteristics of these cells to evaluate the possibility that these cells might balance the decreased action of the adaptive …

A genetically determined high setting of TNF-alpha influences immunologic parameters of HLA-B8,DR3 positive subjects: implications for autoimmunity.

The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It seems unique in its association with a wide range of immunopathologic diseases. Healthy subjects bearing this haplotype demonstrate several alterations of immune response. This article will focus on the identification of the mechanism(s) of disease susceptibility of 8.1 AH. In 13 carriers of 8.1 AH, and 43 negative patients, enzyme immune assays serum levels of tumor necrosis factor (TNF)-alpha, soluble endothelial leukocyte adhesion molecule-1 (sELAM-1), cortisol, and interleukin(IL)-10 were determined. In addition, quantification of cytokine produced in vitro after mitogen s…

La risposta immune naturale e specifica: cellule e tessuti del sistema immune

Hla-Bb,Dr3 Phenotype and the Antibody Response Against Epstein-Barr Virus

Antibodies against the viral capsid antigen (VCA) and nuclear antigens (EBNAs) of the Epstein-Barr virus (EBV) were determined in a sample of Sicilian population. A significant correlation was observed between HLA-BB,DR3 phenotype and reduced titres of antibodies to EBNAs, whereas HLA-BB,DR3 positive individuals displayed levels of antibodies to VCA comparable to those of HLA-BB,DR3 negative ones. These results further strenghten the suggestion that HLA-BB,DR3 positive subjects are low responders and that the depth of immune response depends on on the fashion of antigenic challenge.

The role of IL-1 gene cluster in longevity: a study in Italian population.

In this study, we analysed the polymorphic variants of IL-1alpha (C-T transition at position -889), IL-1beta (C-T transition at position -511) and IL-1 receptor antagonist (Ra) (86-bp repeated sequence in intron 2) in 1131 subjects (453 females and 678 males) from Northern and Central Italy, including 134 centenarians, to evaluate whether IL-1 cluster alleles might be differently represented in people selected for longevity. In addition, IL-1Ra and IL-1beta plasma levels were quantified by ELISA in 130 randomly selected subjects. No significant differences in the genotype and allele frequency distributions were observed between young, elderly and centenarian subjects. IL-1Ra plasma levels s…

Frequency of polymorphisms of signal peptide of TGF-β1 and –1082G/A SNP at the promoter region of IL-10 gene in a group of patients with carotid stenosis.

Age at onset of Alzheimer disease and Tumor Necrosis Factor-Alpha -308A/G Polymorphism. Alzheimer’s and Parkinson diseases:

A scientific approach to anti-ageing therapies: state of the art.

A lasting dream of human beings is to reverse or at least postpone ageing. During the last years, an increasing number of scientific meetings, articles, and books have been devoted to anti-ageing therapies. This subject, full of misleading, simplistic, or wrong ideas, is very popular among the general public, whose imagery has been fascinated by all possible tools to delay ageing, getting immortality. Here, we discuss anti-ageing strategies aimed not to rejuvenate but to slow ageing and delay the onset of age-related diseases. These approaches should be able to substantially slow down the ageing process, extending our productive, youthful lives.

Insegnare nelle Università la Fitoterapia e l’Agopuntura?

According to National Center for Complementary and Alternative Medicine (CAM) of NIH, the CAM terms are used to mean the array of health care approaches with a history of use or origins outside of mainstream medicine. Numerous surveys document high level of interest in use of CAM among the Western public, hence raising the matter of their study in the medical education. Several scientists have subjected CAM interventions to the same methodological scrutiny responsible for the progress of Western clinical medicine (that is evidence based), i.e. with the standard of randomized controlled trials. So, the purpose of this paper was to review the scientific evidences of two particular CAM, Phytot…

HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute viral encephalitis

// Antonino Tuttolomondo 1 , Claudia Colomba 2 , Danilo Di Bona 6 , Alessandra Casuccio 4 , Domenico Di Raimondo 1 , Giuseppe Clemente 1 , Valentina Arnao 5 , Rosaria Pecoraro 1 , Paolo Ragonese 5 , Anna Aiello 3 , Giulia Accardi 3 , Rosario Maugeri 5 , Carlo Maida 1 , Irene Simonetta 1 , Vittoriano Della Corte 1 , Domenico Gerardo Iacopino 5 , Calogero Caruso 3 , Antonio Cascio 2 and Antonio Pinto 1 on behalf of KIRIIND (KIR Infectious and Inflammatory Diseases) Collaborative Group 1 U.O.C di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Universita degli Studi di Palermo, Palermo, Italy 2 U.O.C di Malattie Infettive, Dipartiment…

Association between C1019T polymorphism of connexin37 and acute myocardial infarction: a study in patients from Sicily

Abstract During atherogenesis, a critical role is played by intercellular communication via gap junctions, cell membrane channels linking the cytoplasmic compartments of adjacent cells. The component protein subunits of these channels, called connexin (Cx), belong to a multigene family. Cx37 is involved in growth, regeneration after injury and ageing of the endothelial cells, suggesting its role in atherosclerosis. The C1019 single nucleotide polymorphism (SNP) of Cx37 gene was associated with thickening of the carotid intima in Swedish men and was also associated with coronary artery disease in a Taiwanese population. On the other hand, in two more recent studies performed in male Japanese…

Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: effect of multiple gene interactions.

Genetic studies have shown that individuals with certain HLA alleles have a higher risk of specific autoimmune disease than those without these alleles. Particularly, the association in all Caucasian populations of an impressive number of autoimmune diseases with genes from the HLA-B8,DR3 haplotype that is part of the ancestral haplotype (AH) 8.1 HLA-A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201 has been reported by different research groups. This haplotype, the more common one in northern Europe, is also associated in healthy subjects with a number of immune system dysfunctions. It has been proposed that a small number of genes withi…

Clinical features and outcomes of patients with drug-induced autoimmune hepatitis: a retrospective cohort study.

Abstract Background Drugs and herbal products can induce autoimmune hepatitis. We assessed frequency and clinical outcomes of patients suffering from drug-induced autoimmune hepatitis. Methods All patients with drug-induced liver injury admitted between 2000 and 2011 were retrospectively studied. Diagnoses of drug-induced autoimmune hepatitis and idiopathic autoimmune hepatitis were made according to simplified criteria. After discharge, all patients had regular follow-up and were contacted to update outcomes. Results Among 10,270 in-hospital patients, 136 (1.3%) were diagnosed with drug-induced liver injury. Among them, 12 (8.8%) were diagnosed as drug-induced autoimmune hepatitis (41.7% m…

Opposite Role of Pro-Inflammatory Alleles in Acute Myocardial Infarction and Longevity: Results of Studies Performed in a Sicilian Population

The major trait characterizing offspring in centenarians is a reduction in the prevalence of cardiovascular disease. Because a pro-inflammatory genotype seems to contribute significantly to the risk of coronary heart disease, alleles associated with disease susceptibility would not be included in the genetic background favoring longevity, as suggested by our previous studies on inflammatory cytokines. To confirm whether genotypes of inflammatory molecules play an opposite role in atherosclerosis and longevity, we are studying the role of other proinflammatory alleles, such as pyrin and CCR5, in acute myocardial infarction and longevity. The results support the hypothesis that the genetic ba…

Connexin37 1019 gene polymorphism in myocardial infarction patients and centenarians

Metabolic syndrome in the offspring of centenarians: focus on prevalence, components, and adipokines

With aging, an increased prevalence of a clustering of metabolic abnormalities has been observed. These abnormalities include obesity, dyslipidemia, hypertension, and insulin resistance and are collectively known as metabolic syndrome (MetS), a low-grade, systemic, inflammatory condition associated with an increased risk of cardiovascular disease, diabetes, and other adverse health outcomes. A number of studies have demonstrated that centenarians’ offspring have a significant survival advantage and a lower risk of developing the most important age-related diseases. They therefore represent one of the best models with which to study the familiar component of human longevity. The aim of this …

Impact of CMV and EBV seropositivity on CD8 T lymphocytes in an old population from West-Sicily.

Abstract Herpes viruses (particularly CMV and to some extent EBV) might play a role in accelerating the deterioration of immune functions with age. Indeed, it has been demonstrated that chronic infection with CMV causes an expansion of specific CD8 T lymphocytes and that this is related to a shrinkage of the T cell repertoire in very elderly people, predicting mortality. We have analysed CD8 T cells in young and old healthy Sicilians who were both CMV- and EBV-seropositive. Our data confirm expansions of T cells specific for the HLA-A2-restricted pp65 (495–503) CMV epitope up to nearly 14% of total peripheral CD8 cells in certain elderly individuals (range 0–14%). However, the mean percenta…

Aging, longevity, inflammation, and cancer.

Cancer rates increase sharply with age in both sexes, and the majority of cases of cancer occur in patients over the age of 65 years. However, the incidence and mortality for cancer level off around 85-90 years of age, followed by a plateau, or even a decline in the last decades of life. Therefore, it seems reasonable to conclude that centenarians are endowed with a peculiar resistance to cancer. Tumor progression is a complex process that depends on interactions between tumor and host cells. One aspect of the host response, the inflammatory response, is of particular interest because it includes the release of proinflammatory cytokines, some of which may promote tumor growth and hence infl…

Diet and Immunosenescence

Ageing is a systemic condition leading to a gradual loss of molecular and cellular fidelity. A feature of ageing is immunosenescence, consisting in several modifications that increase morbidity and mortality in elderly. Environment, genetic background, immune system, and intestinal microbiota play a fundamental role in immunosenescence. The development of a chronic, low-grade, inflammatory status, known as “inflamm-ageing,” is a typical aspect of immunosenescence mostly due to the pro-inflammatory cytokine production linked to the chronic antigenic load. Nutrition can act on ageing, immunity, and health in general. Unbalanced diet with an insufficient intake of micro- and macronutrient and …

Serum Levels of Soluble CD23 in Patients with Asthma or Rhinitis Monosensitive to Parietaria. Its Relation to Total Serum IgE levels and Eosinophil Cationic Protein during and out of the Pollen Season

The diagnostic value for allergies of the low affinity IgE receptor and its soluble circulating fragment (sCD23) remains unclear. In particular, little is know about seasonal influences on serum sCD23 levels in subjects with pollen allergy. In the present study, to gain insight into pathophysiological role of sCD23, we have analyzed, in blood from patients allergic to Parietaria sCD23, IgE, and eosinophil cationic protein (ECP) serum levels. IgE were assessed as atopy markers and ECP as an inflammation marker. Patients were studied during and out of pollen season, and results were compared to those obtained in nonallergic subjects. The study population included 42 nonsmoking outpatients, li…

Interleukin-5 production by mononuclear cells from aged individuals: implication for autoimmunity.

It is well known that in the elderly a deterioration of immune functions may occur. Particularly, stimulation of T cells from aged individuals leads to different kind and/or size of responses if compared with the responses obtained from T cells from young individuals. At the same time, an increase in prevalence of autoantibodies occurs in elderly. The altered production of certain cytokines might explain this paradox of decreased responsiveness to foreign antigens in the face of an increased response to self-antigens. We and others have suggested that this kind of immune response might depend on an age-associated impairment of Th-1 type function that selectively affects production of cytoki…

Caratteristiche generali delle cellule neoplastiche. Classificazione dei tumori

Nutraceutical effects of table green olives: a pilot study with Nocellara del Belice olives

Background: The aim of this study was to analyse the nutraceutical properties of table green olives Nocellara del Belice, a traditional Mediterranean food. The Mediterranean Diet has as key elements olives and extra virgin olive oil, common to all Mediterranean countries. Olive oil is the main source of fat and can modulate oxidative stress and inflammation, whereas little is known about the role of olives. Moreover, emerging evidences underline the association between gut microbiota and food as the basis of many phenomena that affect health and delay or avoid the onset of some age-related chronic diseases. Methods: In order to show if table green olives have nutraceutical properties and/or…

Natural killer and lymphokine-activated killer activity in HLA-B8,DR3-positive subjects.

Abstract The haplotype HLA-B8,DR3 is over-represented in several autoimmune diseases, implying that genes predisposing people to these disorders are linked to this haplotype. In these diseases, various dysfunctions reflecting an impairment of the immune system have been found. Several reports indicate also that in HLA-B8,DR3-positive healthy subjects similar disorders may be demonstrated. In the present work, we have evaluated NK and LAK activity in these subjects. The study has been performed on monocyte-depleted peripheral blood MNCs by using the K-562 cell line as a target for NK activity and the HL-60 cell line for as a target LAK activity. LAK cells were obtained by incubating MNCs for…

Xenobiotici e Cancerogenesi

Il termine esposoma è stato coniato dall’epidemiologo Christopher Wild nel 2005 per indica-re “la totalità delle esposizioni ambientali cui è sottoposto l’uomo dal concepimento in poi”1. É importante tener presente che anche il genoma è sottoposto a tale esposizione, a partire dal pe-riodo prenatale. Nel 2012 Wild definisce tre sottoinsiemi, talvolta intersecati, all’interno del con-cetto di esposoma e che devono essere presi in considerazione per misurarlo nella sua totalità: ......................

The role of platelet gel in osteoarticular injuries of young and old patients

Background: The use of autologous platelet gel in orthopedics is effective in accelerating the healing process of osteochondral, muscle, tendon and ligament lesions. The aim of our study was to verify whether the variability in response to infiltration with platelet gel was dependent on the underlying disease treated, sex and age of the patients. During four years, 140 patients have been treated for musculoskeletal injuries by infiltration of gel platelet and lysate platelet obtained from autologous thrombin, with echo-ultrasound guided. The response to treatment was assessed at different time points T0, T1, T2 with respect to pain estimation (VAS), joint mobility (ROM scale) and echo-ultra…

Genetic signatures of centenarians: Implications for achieving successful aging

The extraordinary rise in the old population in the Western world underscores the importance of studies on aging and longevity to decrease the medical, economic and social problems associated with the increased number of non-autonomous individuals affected by invalidating pathologies. Centenarians have reached the extreme limits of the human life span. They are the best example of extreme longevity, representing selected individuals in which the appearance of major age-related diseases has been consistently delayed or avoided. There is growing evidence that the genetic component of longevity becomes higher with survival at the age of over 90 years. For centenaries, it reaches up to 33% for…

What olive oil for healthy ageing

The olive tree originated in Asia Minor around 6000 years ago and then spread to all the Mediterranean basin. Olive oil is extracted from the pulp of its fruits [1–3]. Many studies show that the nutritional pattern of the so-called Mediterranean Diet is associated with a lower incidence of age-related diseases related to inflammation and oxidative stress, such as cardiovascular disease, Parkinson's disease, Alzheimer's disease and cancer [4–7]. It is now clear that olive oil, as a main source of fat, must play a key role in explaining the health benefits of the Mediterranean Diet.

Age-related Diseases: Key Role of Insulin Resistance for the Association Between Type II Diabetes and Alzheimer’s Disease

Background: Alzheimer’s disease (AD) and Type 2 diabetes mellitus (T2DM) present many relationships. Insulin resistance (IR) plays a key role in neuronal degeneration and death. Reduced energy makes neurons more sensible to oxidation causing mitochondrial damages. Moreover AD brain has lower insulin utilization, reduced expression of its receptors and of IGF 1 and 2, all necessary for neuronal survival and learning and memory processes. Hyperinsulinemia is correlated with increase of hyerphosphorilated tau-protein. SHIP2, a phosphatase, is an antagonist of PI3K. Since the PI3K plays a key role in the biological effects of insulin, its attenuation could be associated with IR in T2DM. Methods…

TLR2 and age-related diseases: potential effects of Arg753Gln and Arg677Trp polymorphisms in acute myocardial infarction.

ABSTRACT Inflammation is a key component of immune system. It is involved in both defense and pathophysiological events maintaining the dynamic homeostasis of host organism. Its function is controlled by innate immunity genes. Both their polymorphisms and environmental conditions give rise to different phenotypes in human population. Proinflammatory genotype may be beneficial in early life but not in old people. With advancing age, indeed, it increases the vulnerability and the intensity to inflammatory reactions responsible for the chronic inflammatory diseases, such as atherosclerosis and myocardial infarction (MI). Several studies have looked for detecting a genetic risk profile that mig…

HLA-Cw4 Association with Acute Lymphoblastic Leukaemia in Sicilian Patients

The HLA frequencies of 50 Sicilian patients affected with acute lymphoblastic leukaemia (ALL) were examined. The frequency of Cw4 antigen was significantly increased in patients. Thus results obtained in our homogeneous population confirm in part previous reports suggesting that Cw4-related genetic factors might be involved in the susceptibility to aetiological or pathogenetic mechanisms which play a role in some haematological malignancies.

The nACHR4 594C/T polymorphism in Alzheimer disease

Alzheimer disease (AD) is the most common form of dementia with complex etiology and multifactorial origin. Although several neurochemical deficits have been described in AD patients, explanation of the nature of the cognitive disturbance is focused on the "cholinergic hypothesis." The neuronal nicotinic acetylcholine receptor (neuronal nAChR) belongs to the superfamily of ionic channel activated by ligand. This paper presents a population-based population association study, testing the hypothesis that variants of the nAChR gene confer genetic susceptibility to AD. The authors analyzed two cohorts constituted by 60 controls and 80 AD patients in which significant increase of 594T polymorphi…

Low Grade Inflammation as a Common Pathogenetic Denominator in Age-Related Diseases: Novel Drug Targets for Anti-Ageing Strategies and Successful Ageing Achievement

Nowadays, people are living much longer than they used to do, however they are not free from ageing. Ageing, an inexorable intrinsic process that affects all cells, tissues, organs and individuals, is a post-maturational process that, due to a diminished homeostasis and increased organism frailty, causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. However, the high incidence of death due to infectious, cardiovascular and cancer diseases underlies a common feature in these pathologies that is represented by dysregulation of both instructive and innate immunity. Several studies show that a low-grade s…

Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype.

Abstract Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8,DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers…

Linkage of HFE with HLA antigens: a study in Sicilian population.

Aging and longevity: An evolutionary approach

Abstract In the chapter, first of all, the definition of aging, longevity, and the various types of aging are discussed. Then, analyzing various theories of aging, it is recalled how evolution teaches us that there should be no genes selected to promote aging. Aging is not planned but derives from the accumulation of physical damage, due to limited investments in maintenance and repair as well as from the epigenetic changes. After sufficient time has passed, the increasing levels of these defects interfere with the performance of tissues and organs, resulting in a breakdown of self-organizing system and a reduced ability to adapt to the environment.

PECAM-1/CD31 in infarction and longevity.

: Inflammation has recently proven to be associated with the pathogenesis of atherosclerosis and inflammatory genes are good candidates for the risk of developing atherosclerosis. The early phase of atherosclerosis involves the recruitment of inflammatory cells from the circulation and their transendothelial migration. This process is mainly mediated by cellular adhesion molecules, which are expressed by the vascular endothelium and by circulating leukocytes in response to several inflammatory stimuli. Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulat…

Analysis of interleukin 10 (IL-10) -1082G/A single nucleotide polymorphism (SNP) genotypes in breast cancer (BC) patients (pts) and in >95 years old cancer free women

9656 Background:the anti-inflammatory IL-10 -1082 (G/A) SNP might be associated with different risk for breast tumor development. The -1082GG homozygous genotype is associated with an higher IL-10 ...

Characterization of two alternative Interleukin(IL)-10 5′UTR mRNA sequences, induced by lipopolysaccharide (LPS) stimulation of peripheral blood mononuclear cells

Abstract IL-10 production shows a broad-spectrum of individual response, suggesting a genetic component of approximately 75%. Different polymorphisms located close to, or within the IL-10 gene has been demonstrated to influence its transcription rate whereas the post-transcriptional regulation of IL-10 production has not well elucidated. The main responsible elements at this control level are both the 5′- and 3′-untranslated regions (UTR's) of mRNAs, and as the 3′-UTR regions are mainly involved in the stability and decay rate of mRNAs, the 5′-UTR regions mediate the binding rate of the molecule with ribosomal 40S subunit as a cis-acting element. Herein are report data on the identification…

Correlation between CD117+ myeloma plasma cells and hematopoietic progenitor cells in different categories of patients

Background Multiple myeloma (MM) is a neoplastic disorder of plasma cells interesting mainly the elderly. MM remains an incurable disease, mostly because of the strong interplay between clonal plasma cells (cPCs) and bone marrow (BM) microenvironment. Multiparameter flow cytometry (MFC) allows the simultaneous study of the cPC immunophenotype and alterations involving other cells in BM, but rarely these data are interpreted as connected. One exception to this habit are previous studies about relationship between CD117 cPC positivity and hematopoietic progenitor cell (HPC) distribution in newly diagnosed patients. Thus we were interested in verifying the distribution of BM CD34+ HPCs in heal…

A double-negative (IgD−CD27−) B cell population is increased in the peripheral blood of elderly people

The T cell branch of the immune system has been extensively studied in the elderly and it is known that the elderly have impaired immune function, mainly due to the chronic antigenic load that ultimately causes shrinkage of the T cell repertoire and filling of the immunologic space with memory T cells. In the present paper, we describe the IgD(-)CD27(-) double-negative B cell population which (as we have recently described) is higher in the elderly. Most of these cells were IgG(+). Evaluation of the telomere length and expression of the ABCB1 transporter and anti-apoptotic molecule, Bcl2, shows that they have the markers of memory B cells. We also show that these cells do not act as antigen…

Risk profiles in type 2 diabetes (metabolic syndrome): integration of IL-10 polymorphisms and laboratory parameters to identify vascular damages related complications

Recently it has been reported that low serum IL-10 levels are associated with an increased susceptibility for metabolic syndrome and type 2 diabetes mellitus (T2DM). We investigated whether the -1087G/A (rs1800896), -824C/T (rs1800871), -597C/A (rs1800872) IL-10 polymorphisms were associated with type 2 diabetes in a study on a cohort of Italian Caucasians comprising 490 type 2 diabetic and 349 control subjects. Stratifying the data according to IL-10 genotypes, trends for the progressive increase of glucose and neutrophil levels were observed in -1087GG vs. -1087GA vs. -1087AA positive diabetic patients (-1087GG < -1087GA < -1087AA). In addition, evaluating the laboratory parameters accord…

Inflammation, genetic background and longevity

Ageing is an inexorable intrinsic process that affects all cells, tissues, organs and individuals. Due to a diminished homeostasis and increased organism frailty, ageing causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. Actually, it is characterized by a state of reduced ability to maintain health and general homeodynamics of the organism. A large part of the ageing phenotype is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status of ageing, "inflamm-ageing". It is strictly linked to immunosenescence, and on th…

Age-associated changes in circulatory fatty acids: new insights on adults and long-lived individuals

Long-lived individuals (LLIs) are considered an ideal model to study healthy human aging. Blood fatty acid (FA) profile of a cohort of LLIs (90–111 years old, n = 49) from Sicily was compared to adults (18–64 years old, n = 69) and older adults (65–89 years old, n = 54) from the same area. Genetic variants in key enzymes related to FA biosynthesis and metabolism were also genotyped to investigate a potential genetic predisposition in determining the FA profile. Gas chromatography was employed to determine the FA profile, and genotyping was performed using high-resolution melt (HRM) analysis. Blood levels of total polyunsaturated FA (PUFA) and total trans-FA decreased with age, while the lev…

Mediterranean diet and healthy ageing: a Sicilian perspective.

Traditional Mediterranean diet (MedDiet) is a common dietary pattern characterizing a lifestyle and culture proven to contribute to better health and quality of life in Mediterranean countries. By analyzing the diet of centenarians from the Sicani Mountains and eating habits of inhabitants of Palermo, it is reported that a close adherence to MedDiet is observed in the countryside, whereas in big towns this adherence is not so close. This has an effect on the rates of mortality at old age (and reciprocally longevity) that are lower in the countryside than in big towns. Concerning the health effects of the diet, the low content of animal protein and the low glycaemic index of the Sicilian Med…

Sicilian centenarian offspring are more resistant to immune ageing

Background: Immunosenescence constitutes a major indirect cause of morbidity and mortality in the elderly. Previous analysis of immune signatures in a cohort of centenarian offspring showed an intermediate immunophenotype between age-matched and younger controls. Aims: To confirm and extend the previous studies performing further phenotypical analysis in centenarian offspring and controls. Methods: Analysis of Treg cells, γδ T cells, mucosal-associated invariant T cells, and senescent immune T cells was performed in centenarian offspring and controls. Results: We report significant differences between elderly and centenarian offspring in most of the studied subsets, showing that centenarian…

Opposite effects of interleukin 10 common gene polymorphisms in cardiovascular diseases and in successful ageing: genetic background of male centenarians is protective against coronary heart disease

Many aspects of ageing involve inflammatory processes. We evaluated the association with longevity of alleles of IL10 and TNFa, known to have opposite functions in inflammatory reactions, IL-10 acting predominantly as an anti-inflammatory and TNF-a as a proinflammatory factor. The number of male centenarians homozygous for the –1082G genotype, suggested to be associated with high IL-10 production, was significantly increased in comparison with younger control subjects. No significant differences were observed between women and controls. The genotypic frequencies of the TNFa promoter SNPs 308G and 308A, suggested to be associated with low and high TNF-a production respectively, were not sign…

B Cells Compartment in Centenarian Offspring and Old People

Immunosenescence is considered a major contributory factor to the increased frequency of morbidity and mortality among elderly. On the other hand centenarians are considered the best example of successful ageing. To gain insight into mechanisms of immunosenescence and its clinical relevance, a possible model is represented by centenarians and/or their offspring. Nowadays centenarians are not more a curiosity, but in Europe are 1/8000 inhabitants and it has been demonstrated that the centenarian offspring, who are typically in their 70s and 80s, have a survival advantage when compared with age-matched controls whose parents died at an average life expectancy. Then again, studies on immunosen…

Vaccination in old age: Challenges and promises

Abstract Vaccination is one of the most effective medical interventions ever introduced, preventing millions of cases of infections worldwide every year. However, vaccines are commonly believed to be less effective in providing protection in older adults, due to the perceived decline seen in immunity in this population (“immunosenescence”). Accordingly, this chapter considers how to identify hallmarks of immunosenescence and approach their resolution strategically. It was reviewed potential options for therapeutic intervention to restore appropriate responses to vaccines in older adults.

Biological Basis of the HLA-B8,DR3-Associated Progression of Acquired Immune Deficiency Syndrome

The factors influencing the evolution of human immunodeficiency virus (HIV) infection are not fully known, but the host genotype undoubtedly plays a role in determining the outcome of the disease by affecting the immune response to HIV. The role of the host human leukocyte antigen (HLA) genotype in the regulation of susceptibility to HIV infection and expression has been studied extensively in different major risk groups. Certain HLA alleles and haplotypes, being associated with aberrant immune responses independently from HIV infection, have been reported to facilitate the rapid progression of disorders related to HIV infection. Particularly, the association of rapid acquired immunodeficie…

Dietary Supplements as Surrogate of Mediterranean Diet in Healthy Smoking Subjects

The interventions to slow aging, favoring active life expectancy, represent the new perspectives in ageing investigation. Some mechanisms that delay or prevent the onset of aging pathologies have been identified. Between them, a healthy lifestyle seems to reduce many risk factors. In particular, eating habits represent the most concrete, low-cost way to act on aging process. Mediterranean diet has received much attention since its antioxidant and anti-inflammatory effects have been consistently demonstrated. Unfortunately, many people follow a Western diet, poor in phytochemicals that represent the main source of beneficial effects of this dietary pattern. So, supplements administration sho…

Genetics of Inflammation in Age-Related Atherosclerosis: Its Relevance to Pharmacogenomics

In response to tissue injury elicited by trauma or infection, the inflammatory response, as a complex network of molecular and cellular interactions, sets an answer directed to facilitate a return to physiological homeostasis and tissue repair. The role of the genetic background and the subsequent predisposition toward the extent of the inflammatory response is determined by gene variability encoding endogenous mediators involved in the inflammatory pathway. Due to its clinical relevance, the genetics of inflammation in aging will be studied using an inflammatory disease like atherosclerosis as an example. Several studies have reported a significant difference in distribution, between patie…

Association between Platelet Glycoprotein Ib-α and Myocardial Infarction: results of a pilot study performed in male and female patients from Sicily

Chance and Causality in Ageing and Longevity

Longevity is not a matter of genes. This is the message that appeared last year in all the newspapers of the world, according to a study due to a joint venture between the statisticians of Ancestry and Calico Life Sciences that has dissected the genealogical trees of 400 million individuals, tracing back generations, and including dates of birth, death, places, and family ties. The genes would have little to do with longevity: in a percentage perhaps even less than 10% [1]. However, this extensive study has analysed the influence of genetics in terms of lifespan, but not in terms of longevity. Longevity may be defined in relative and absolute terms [2]. Longevity, indeed, may be considered …

The Challenges in Moving from Ageing to Successful Longevity

During the last decades survival has significantly improved and centenarians are becoming a fast-growing group of the population. Human life span is mainly dependent on environmental and genetic factors. Favourable modifications of lifestyle factors (e.g. physical activity, diet and not smoking) and healthcare (e.g. effective vascular disease prevention) have also increased human life span. Genetic factors contribute to the variation of human life span by around 25%, which is believed to be more profound after 85 years of age. It is likely that multiple factors influence life span and we need answers to questions such as: 1) What does it take to reach 100?, 2) Do centenarians have better he…

Analysis of Candidate Genes in Celiac Disease: A Tool to Identify Life-Threatening Associated Genes?

The authors have recently reported that celiac patients show a proinflammatory cytokine genetic profile characterized by the contemporaneous presence of both the tumour necrosis factor-alpha-308A and the interferon-gamma +874T allele-positive genotypes. The same alleles are considered risk factors for aging associated disease, whereas an anti-inflammatory cytokine genotype profile might be associated with an extended life expectancy. This paper reports data on the 1249-1250InsACAA/Non-Ins transforming growth factor (TGF)-beta2, a multifunctional anti-inflammatory cytokine, polymorphism distribution in 88 celiac disease (CD) patients, 99 age- and sex-matched controls, and 2895-year-old healt…

gamma-Interferon, interleukin-4 and interleukin-6 in vitro production in old subjects.

It is well known that ageing is associated with various alterations of the lymphoid cell functions. Although both B and T cell are affected, the last appear to be more sensitive to ageing process. During the past years, to gain insight into thé mechanism(s) of this impairment, effort has been centered on the helper T cells specifically engaged in the production of interleukin-2 (IL-2) because of the pivotal role played by this cytokine in the activation of several immune functions. The results have demonstrated that the ability to produce IL-2 declines with age. In this paper we report the results of a study performed to determine the influence of age on the capacity to produce gamma-interf…

Sharing pathogenetic mechanisms between acute myocardial infarction and Alzheimer's disease as shown by partially overlapping of gene variant profiles.

Abstract Gene variants that promote inflammation and cholesterol metabolism have been associated with acute myocardial infarction (AMI) and Alzheimer's disease (AD). We investigated a panel of relevant polymorphisms to distinguish genetic backgrounds for AMI and AD: IL10 -1082G/A, IL6 -174G/C, TNF -308G/A, IFNG +874T/A, SERPINA3 -51G/T, HMGCR -911C/A, APOE e2/3/4 (280 AMI cases, 257 AD cases, and 1307 population controls, all Italian (presumed risk alleles are shown in bold). Six genetic risk sets I to VI were identified by fuzzy latent classification: I had low risk; II and III had low risk before age 65 (II, III); low risk sets lacked pro-inflammatory alleles for HMGCR-TNF-APOE. Pro-infla…

HLA antigens in ulcerative colitis: a study in the Sicilian population

HLA antigens were investigated in 41 Sicilian patients with ulcerative colitis and in 151 healthy controls. Frequencies of HLA-B5 and DR2 were increased in the group of patients with ulcerative colitis whereas the DR3 antigen frequency was decreased. However the corrected p values were not significant. Thus, present results indicate that in ulcerative colitis HLA linked genetic factors play a marginal role, if any.

Fibres as functional foods and the effects on gut hormones: The example of β-glucans in a single arm pilot study

Abstract Nutritional styles as Mediterranean and DASH diets are associated with lower incidences of certain chronic diseases and long life expectancy. The reason lays on their different contribution in fibers, polyphenols (from vegetables and fruit) and proteins. Barley is high fiber cereal that contains high amount of β-glucans and insoluble fibers that it was recognized having healthy benefits. The aim of the study was to evaluate the effects of β-glucans intake on glycaemic response, cholesterol and intestinal hormones levels. A single arm pilot study was performed with ten healthy individual which, consumed pasta enriched with 6% β-glucans for 30 days. Blood was collected at fasting and…

Pathobiology of aging: An introduction to age-related diseases

Abstract The aging process is considered a universal and inevitable process of physiological decline associated with a greater vulnerability to disease and death. Efforts to understand aging have suggested the need to distinguish aging from age-related diseases. However, in our opinion, we do not need to distinguish between aging and age-related diseases because, in protected environment, humans and animals die from age-related diseases, which are manifestations of aging. A series of critical questions have arisen in the field of aging regarding the physiological sources of aging-causing damage, the compensatory responses that try to re-establish homeostasis, the interconnection between the…

Association between the MHC class I gene HFE polymorphisms and longevity: a study in Sicilian population.

Classes I and II human leukocyte antigens (HLA) genes encode highly polymorphic heterodimeric glycoproteins involved in the control of immune responses. The HLA class I gene HFE seemingly no longer participates in immunity because it has lost its ability to bind peptides and it has acquired the ability to form complex with the receptor for iron-binding transferrin by regulating iron uptake by intestinal cells. Thus, it indirectly regulates immune responses too, because iron availability plays a role in specific and non-specific immune responses. The distribution of HFE polymorphisms in Sicilian centenarians and nonagenarians was studied to evaluate if HFE alleles might be represented differ…

Acute phase response in oldest-old individuals after surgical stress.

Old and new immunophenotypic markers in multiple myeloma for discrimination of responding and relapsing patients: The importance of “normal” residual plasma cell analysis

Background Multiple myeloma is an incurable disease characterized by proliferation of clonal malignant plasma cells (CPCs), which can be immunophenotypically distinguished from polyclonal plasma cells (PPCs) by multiparameter flow cytometry (MFC). The utility of PPCs analysis in detecting prognostic and predictive information is still a matter of debate. Methods: we tested the ability of 11 MFC markers in detecting differences in the immunophenotype of CPCs and PPCs among patients in various disease stages; we verified if these markers could be associated with disease stage/response to therapy despite the role of clinical parameters. Results: significant changes in the expression of markers…

Genetic risk factors and candidate biomarkers for Alzheimer s disease

Alzheimer's disease is a multifactorial and progressive neurodegenerative disease, extremely diffused and with an increasing prevalence worldwide. There is an urgent need for biomarkers to diagnose AD early in its course. Furthermore, accurate biomarkers would be able to determine the clinical efficacy of novel neuroprotective strategies. Although the heritability of late-onset AD is high, our knowledge of the underlying putative susceptibility genes remains incomplete and the only unequivocally established late-onset AD gene is APOE. Nevertheless a number of susceptibility loci seems to influence the pathogenesis of AD, and variations in numerous genes have been considered to be important …

Can Alzheimer disease be a form of type 3 diabetes?

Alzheimer disease (AD) and metabolic syndrome are two highly prevalent pathological conditions of Western society due to incorrect diet, lifestyle, and vascular risk factors. Recent data have suggested metabolic syndrome as an independent risk factor for AD and pre-AD syndrome. Furthermore, biological plausibility for this relationship has been framed within the “metabolic cognitive syndrome” concept. Due to the increasing aging of populations, prevalence of AD in Western industrialized countries will rise in the near future. Thus, new knowledge in the area of molecular biology and epigenetics will probably help to make an early molecular diagnosis of dementia. An association between metabo…

Sicilian semi- and supercentenarians: identification of age-related T cell immunophenotype to define longevity trait

: The immunophenotype of oldest centenarians, i.e., semi- and supercentenarians, could provide important information about their ability to adapt to factors associated with immune changes, including ageing per se and chronic Cytomegalovirus infection. We investigated, by flow cytometry, variations in percentages and absolute numbers of immune cell subsets, focusing on T cells, and pro-inflammatory parameters in a cohort of 28 women and 26 men (age range 19-110 years). We observed variability in hallmarks of immunosenescence related to age and Cytomegalovirus serological status. The eight oldest centenarians showed the lowest percentages of naïve T cells, due to their age, and the highest pe…

Systematic review by meta-analyses on the possible role of TNF-alpha polymorphisms in association with Alzheimer's disease.

It has been hypothesized that polymorphisms of Tumor Necrosis Factor (TNF)-alpha gene affect the risk of developing Alzheimer's disease (AD). However, results of different studies are often inconsistent. Our aim was to investigate by meta-analysis the association of the common polymorphisms comprehensively defining the genetic variability of the TNF-alpha gene with AD risk. Hence, the results being stated are of a meta-analysis across studies, and that this meta-analysis does not invalidate the results of the individual studies previously performed. Seventeen studies that investigated the association between 5 TNF-alpha polymorphisms (-850, -308, -863, -238, and -1031) and AD were retrieved…

Trafficking phenotype and production of granzyme B by double negative B cells (IgG(+)IgD(-)CD27(-)) in the elderly.

The impairment of humoral immune response in elderly humans has been extensively demonstrated. We have reported the increase of memory B cells (IgG(+)IgD(-)CD27(-), double negative, DN) population in the elderly, in which there is also a typical inflammatory micro-environment. In order to evaluate whether this pro-inflammatory status could influence the trafficking phenotype of naïve/memory B cells, we have assessed the expression of CCR7, CCR6, CXCR3, CXCR4, CXCR5 and CD62L on naïve/memory B cell subpopulations in young and elderly subjects. Moreover, the combination of pro-inflammatory interleukin-21 (IL-21) and B cell receptor (BCR) stimulation enables B cells to produce and secrete gran…

Molecular Biomarkers of Aging

Sergio Davinelli1, Sonya Vasto2, Calogero Caruso2, Davide Zella3 and Giovanni Scapagnini1 1Department of Health Sciences, University of Molise, Campobasso, 2Department of Pathobiology and Biomedical Methodologies, Immunosenescence Unit, University of Palermo, Palermo, 3Department of Biochemistry and Molecular Biology, Institute of Human Virology-School of Medicine, University of Maryland, Baltimore, MD, 1,2Italy 3USA

Role of polymorphisms of CC-chemokine receptor-5 gene in acute myocardial infarction and biological implications for longevity

A key component of atherosclerosis is inflammation. So, genes encoding inflammatory or antiinflammatory molecules are good candidates for the risk of cardiovascular diseases (CVD), as acute myocardial infarction (AMI). In this study we demonstrated that genetic variations in CCR5 gene affect atherosclerosis and risk of AMI, hence consenting the attainment of longevity.

Interleukin-12 release by mitogen-stimulated mononuclear cells in the elderly.

Abstract Defects involving cellular expression of activation molecules, cell mediated immune response and natural killer (NK) activity are commonly observed in the elderly. Herein, data are reported on the evaluation of IL-12 production by old subjects. IL-12 is, actually, considered the key molecule for the induction of a T helper 1 (Th1) -type and NK response. IL-12 production from old subjects peripheral blood mononuclear cells (PBMNC) was evaluated using T-independent (bacterial lipopolysaccharide, LPS) or -dependent (phytoemagglutinin, PHA; immobilized anti-CD3 monoclonal antibodies, anti-CD3) mitogens. The IL-12 production after LPS stimulation was not reduced in cultures from old sub…

Translation of Basic Research into Clinics: Killer Immunoglobulin-like Receptors Genes in Autoimmune and Infectious Diseases

Killer immunoglobulin-like receptors (KIRs) regulate the activation of natural killer cells through their interaction with human leucocyte antigens (HLA). KIRs and HLA loci are highly polymorphic, and some of their combinations have been found to protect against viral infections or to predispose to autoimmune disorders. In particular, some activating KIRs profiles may be detrimental in autoimmune pathogenesis, and specific KIRs may be particularly aggressive in the clearance of different microorganisms, protecting individuals in the control of a given pathogen. So, considering that in the pathogenesis of many autoimmune disorders and infections innate immunity plays a key role, the recent …

Centenarians as a model to discover genetic and epigenetic signatures of healthy ageing.

Abstract Centenarians are a model of successful ageing. The data favours the theory that, in order to live to 100, it is mandatory to inherit the right genetic variants from parents or acquire epigenetic variants through the environment. Therefore, the study of epigenetic signatures of healthy ageing is becoming an important aspect to identify the role of chromatin modification in ageing and understand how manage this fine-tuning system. So, according to the concept of developmental plasticity, establishment of a longevity phenotype requires a combination of stochastic and non-stochastic events that modulate the genetic substrate and leads to a different outcome. It can be concluded that ce…

Inflammatory networks in ageing, age-related diseases and longevity

Inflammation is considered a response set by the tissues in response to injury elicited by trauma or infection. It is a complex network of molecular and cellular interactions that facilitates a return to physiological homeostasis and tissue repair. The individual response against infection and trauma is also determined by gene variability. Ageing is accompanied by chronic low-grade inflammation state clearly showed by 2-4-fold increase in serum levels of inflammatory mediators. A wide range of factors has been claimed to contribute to this state; however, the most important role seems to be played by the chronic antigenic stress, which affects immune system thorough out life with a progress…

Modulation of Nrf2/ARE pathway by food polyphenols: a nutritional neuroprotective strategy for cognitive and neurodegenerative disorders

In recent years, there has been a growing interest, supported by a large number of experimental and epidemi-ological studies, for the beneficial effects of some phenolic substances, contained in commonly used spices and herbs, in preventing various age-related pathologic conditions, ranging from cancer to neurodegenerative diseases. Although the exact mechanisms by which polyphenols promote these effects remain to be elucidated, several reports have shown their ability to stimulate a general xenobiotic response in the target cells, activating multiple defense genes. Data from our and other laboratories have previously demonstrated that curcumin, the yellow pigment of curry, strongly induces…

Interleukin-6 gene polymorphism is an age-dependent risk factor for myocardial infarction in men.

Summary Several studies show that inflammatory components may contribute to atherosclerosis and increase the risk for myocardial infarction (MI). Interleukin-6 (IL-6) is a key pro-inflammatory and immune-modulatory cytokine of relevance for cardiovascular diseases. In this case-control study, 200 patients with MI and 257 healthy controls were genotyped for the polymorphism present in −174 promoter region of the IL-6 gene. Plasma concentrations of IL-6 and C-reactive protein (CRP) in a group of patients and controls were measured. The −174 C allele was associated with an increased risk of developing MI (OR = 2.886, c.i. = 1.801–4.624, P = 0.0001) in older patients, while no association was f…

Preventive Medicine and Healthy Longevity: Basis for Sustainable Anti-Aging Strategies

In the last century, both human life expectancy and maximum life span potential increased [1]. The analysis of North European mortality curves suggests that a relevant role for this phenomenon was played by the reduction of lifetime pathogen burden [2]. Whatever was the real cause, at the end of 1900, the improved hygienic conditions, the proper diet, the better health condition, and the decreased infant mortality elevated life expectation up to 80 years, with a consequent raise in elderly population of industrialized countries. In the society, the public perception of advanced aging involves the inability to survive alone due to chronic diseases and the combined loss of mobility, sensory f…

Pathophysiological implications of inflammation and genetic inflammatory factors in hypertensive and old patients affected by sporadic thoracic aortic aneurysm

Nutrient sensing pathways as therapeutic targets for healthy ageing

Introduction: In the present paper, the authors have discussed anti-aging strategies which aim to slow the aging process and to delay the onset of age-related diseases, focusing on nutrient sensing pathways (NSPs) as therapeutic targets. Indeed, several studies have already demonstrated that both in animal models and humans, dietary interventions might have a positive impact on the aging process through the modulation of these pathways. Areas covered: Achieving healthy aging is the main challenge of the twenty-first century because lifespan is increasing, but not in tandem with good health. The authors have illustrated different approaches that can act on NSPs, modulating the rate of the ag…

Role of Immunogenetics in the Outcome of HCMV Infection: Implications for Ageing

The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an important pathogen from a clinical point of view, as it causes significant morbidity and mortality in immunosuppressed or immunosenescent individuals, such as the transplanted patients and the elderly, respectively. It is, therefore, important to understand the mechanisms of virus infection control. In this review, we discuss recent advances in the immunobiology of HCMV-host interactions, with partic…

Distribution of KIR Genes and Their HLA Ligands in Different Viral Infectious Diseases: Frequency Study in Sicilian Population

Natural killer (NK) cells play a role in defence against viral infections by killing infected cells or by producing cytokines and interacting with adaptive immune cells. Killer immunoglobulin-like receptors (KIRs) regulate the activation of NK cells through their interaction with human leucocyte antigens (HLA). Ninety-six Sicilian patients positive to Human Immunodeficiency Virus-1 (HIV) and ninety-two Sicilian patients positive to SARS-CoV-2 were genotyped for KIRs and their HLA ligands. We also included fifty-six Sicilian patients with chronic hepatitis B (CHB) already recruited in our previous study. The aim of this study was to compare the distribution of KIR–HLA genes/groups of these t…

Early activation of γδ T lymphocytes in the elderly

T cell function is altered in vivo and in vitro in elderly compared with young subjects, and this alteration is believed to contribute to morbidity and mortality in man due to the greater incidence of infection, as well as autoimmunity and cancer in elderly. The majority of T cells express TCRalphabeta whereas TCRgammadelta is expressed on a minority of T cells. Moreover, it is known that gammadelta T lymphocytes display major histocompatibility complex (MHC)- unrestricted cytotoxicity that is reminiscent of natural killer (NK) activity. In view of earlier findings on both T cells and NK cells in the elderly, we hypothesised a different behaviour of gammadelta T lymphocytes from old subject…

Bronchial reactivity and intracellular magnesium: a possible mechanism for the bronchodilating effects of magnesium in asthma

1.Increased bronchial smooth muscle contractility with consequent bronchial hyperreactivity are characteristic physiopathological events of asthma. Since magnesium intervenes in calcium transport mechanisms and intracellular phosphorylation reactions, it constitutes an important determinant of the contraction/relaxation state of bronchial smooth muscle. In the present study we investigated the relationship between bronchial reactivity, assessed by methacholine-provocation test, and magnesium concentrations both at extracellular and intracellular levels measured by spectrophotometry. Twenty-two patients with mild-to-moderate asthma and 38 non-asthmatic subjects with allergic rhinitis (24 all…

FREQUENZA DEI POLIMORFISMI DEL PEPTIDE SEGNALE DEL TGF-β1 IN UN GRUPPO DI PAZIENTI AFFETTI DA STENOSI CAROTIDEA

PROTECTIVE DETERMINANTS AGAINST CARDIOVASCULAR DISEASES ARE PRESENT IN GENETIC BACKGROUND OF CENTENARIANS

IL-2 HIGH PRODUCER GENETIC BACKGROUND IS NEGATIVELY ASSOCIATED TO LONGEVITY

OPPOSITE ROLE OF TRL4 RECEPTOR IN ACUTE MYOCARDIAL INFARCTION AND LONGEVITY

Inflammatory network in age-related diseases

ANALYSIS OF HLA-DQA, HLA-DQB FREQUENCIES IN A GROUP OF SARDINIAN CENTENARIANS

GENETIC BACKGROUND OF CENTENARIANS MAY BE PROTECTIVE AGAINST CARDIOVASCULAR DISEASES

LONGEVITY AND MYOCARDIAL INFARCTION: ROLE OF ALPHA1-ANTITRYPSIN DEFICENCY

SEARCHING FOR PRO-INFLAMMATORY GENOTYPE IN ACUTE MYOCARDIAL INFARCTION: A STUDY IN THE SICILIAN POPULATION