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…

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…

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 …

Ambiente, invecchiamento e longevità

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Marine inspired antiplasmodial thiazinoquinones: synthesis, computational studies and electrochemical assays

In the search for new antimalarials, we used the quinone scaffold of marine secondary metabolites as a chemical starting point to synthesize new thiazinoquinone compounds. Most of synthetic derivatives have shown a significant pharmacological activity and some structural requirements, critical for both the antiplasmodial effect and cytotoxicity, have been evidenced. The redox properties of the prepared compounds have been investigated by computational studies and electrochemical assays, which indicated that a higher antiplasmodial activity of some thiazinoquinones is related to their greater ability to form the semiquinone species and strongly interact with free Fe(III)-protoporphyrin IX.

Novel bioactive bromopyrrole alkaloids from the Mediterranean sponge Axinella verrucosa

The Mediterranean sponge Axinella verrucosa has been investigated for its alkaloid composition and has been found to produce a complex mixture of bromopyrrole alkaloids. Along with the previously isolated compounds 5-18, four novel alkaloids of this class, compounds 1-4, have been isolated, and their structures established through spectroscopic methods. Compounds 1-4 were found to display neuroprotective activity against the agonists serotonin and glutamate in vitro.

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…

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…

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…

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…

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…

Aging Successfully: The Role of Genetics and Environment in the Era of the Aging-Boom. Potential Therapeutic Implications

Aging is one of the main health-related challenges in the world. The average life expectancy of the global population at birth is increasing up to 72 years, in 2016 and it increases about two years every decade. The healthcare costs in many countries are very high because of the increased number of unhealthy populations, and the consequent increase of severe age-related disabilities [1]. Therefore, the goal of the future should be the achievement of the so-called “health-span” (healthy-life-span), more than the treatment of age-related disease to prevent the collapse of the health system. In order to achieve this objective, it is necessary to identify new targets and biomarkers and to addre…

Mumijo traditional medicine: fossil deposits from Antarctica (chemical composition and beneficial bioactivity)

Mumijo is a widely used traditional medicine, especially in Russia, Altai Mountains, Mongolia, Iran Kasachstan and in Kirgistan. Mumijo preparations have been successfully used for the prevention and treatment of infectious diseases; they display immune-stimulating and antiallergic activity as well. In the present study, we investigate the chemical composition and the biomedical potential of a Mumijo(-related) product collected from the Antarctica. The yellow material originates from the snow petrels,Pagodroma nivea. Extensive purification and chemical analysis revealed that the fossil samples are a mixture of glycerol derivatives.In vitroexperiments showed that the Mumijo extract caused in…

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…

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…

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…

Molecular/chemical ecology in sponges. Evidence for an adaptive antibacterial response in Suberites domuncola

Sponges (Porifera) represent the evolutionary oldest metazoan phylum still extant today. They have developed a complex Bauplan, based on the existence of structural and regulatory molecules; many of these have been cloned and analyzed in the past years. The demosponge Suberites domuncula has been used as a suitable model to demonstrate that these animals not only possess an adaptive immune response on the level of cytokines, but also, as pointed out here, on the level of synthesis of bioactive alkyl-lipid derivatives. From specimens of S. domuncula the two lyso-PAF (platelet-activating factor) compounds, 1-O-hexadecyl-sn-glycero-3-phosphocholine and 1-O-octadecyl-sn-glycero-3-phosphocholine…

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

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…

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…

Ways to become old: Role of lifestyle in modulation of the hallmarks of aging

Abstract Lifestyle represents one of the most relevant aspects in aging research since it is an important modifiable factor that affects aging process. A healthy lifestyle can limit the damage caused by environmental influences that face us each day. As gerontology says, there are two ways to become old, without success (unsuccessful aging), manifested by people that develop one or more age-related diseases, and with success (successful aging), defined as the process of developing and maintaining the functional ability, which enables well-being in older age. Among the lifestyle factors that may influence successful aging and longevity, physical activity and healthy dietary habits have a gre…

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…

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 …

Obesità, Microbiota e Aging

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 …

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…

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…

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.

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…

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…

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…

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…

Insight into the Mechanism of Action of Marine Cytotoxic Thiazinoquinones

The electrochemical response of four natural cytotoxic thiazinoquinones isolated from the Aplidium species was studied using conventional solution-phase and solid-state techniques, based on the voltammetry of immobilized particles methodology. The interaction with O-2 and electrochemically generated reactive oxygen species (ROS) was electrochemically monitored. At the same time, a molecular modeling study including density functional theory (DFT) calculations was performed in order to analyze the conformational and electronic properties of the natural thiazinoquinones, as well as those of their reduced intermediates. The obtained electrochemical and computational results were analyzed and c…

Sustainable production of bioactive compounds from sponges: primmorphs as bioreactors

Sponges [phylum Porifera] are a rich source for the isolation of biologically active and pharmacologically valuable compounds with a high potential to become effective drugs for therapeutic use. However, until now, only one compound has been introduced into clinics because of the limited amounts of starting material available for extraction. To overcome this serious problem in line with the rules for a sustainable use of marine resources, the following routes can be pursued; first, chemical synthesis, second, cultivation of sponges in the sea (mariculture), third, growth of sponge specimens in a bioreactor, and fourth, cultivation of sponge cells in vitro in a bioreactor.

Centenarian Offspring as a Model of Successful Ageing

The rapid increase in global average life expectancy, observed during the last years, due to improvements in sanitation and medical care, pushes the scientific community to understand the basis of the ageing process. In particular, in order to improve the life quality of elderly people, current ageing research is focused on the identification of biological mechanisms involved in successful ageing, a complex process influenced by several factors, including genetic, environment, and lifestyle. Centenarians, i.e., subjects who have reached ten or more decades of life, escaping the common age-related diseases, are the leading exponent of successful ageing. However, the rarity of such exponents,…

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…

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…

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........................................

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…

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 …

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 …

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…

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…

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…

AGE6. Skin Ageing: Focus on the Role of Inflammatory Genetic Factors in Cutaneous Neoplasia

AGE6. Skin Ageing: Focus on the Role of Inflammatory Genetic Factors in Cutaneous Neoplasia C. M. Gambino1, F. Crapanzano1, G. Accardi1, A. Aiello1, C. Virruso1, G. Pistone1, M. R. Bongiorno1, D. Lio1, C. R. Balistreri1, G. Candore1 1University of Palermo, Palermo, Italy Background: Skin aging is a complex process that involves intrinsic and exogenous causes. Photo-oxidative damage caused by UV is the leading cause of extrinsic aging of the skin, known as photo-ageing. UV damages can be linked mostly to overproduction of ROS that induces a complex molecular cascade able to accelerate physiological aging, determining a typical dermal/epidermal inflammation with an increased risk of getting s…

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 …

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…

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…

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…

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…

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 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 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…

Damipipecolin and damituricin, novel bioactive bromopyrrole alkaloids from the Mediterranean sponge Axinella damicornis

Two new bromopyrrole alkaloids, damipipecolin (1) and damituricin (2), have been isolated from the Mediterranean sponge Axinella damicornis, and their structures established through spectroscopic methods. Compounds 1 and 2 extend the structural variety of the so far known pyrrole alkaloids; in these compounds, the 4-bromopyrrole 2-carboxylic acid is directly condensed with a non-protein cyclic alpha-amino acid, the (2R, 4R)-trans-4-hydroxypipecolic acid and (2R, 4R)-cis-N,N'-dimethyl-4-hydroxyproline (D-turicine) in 1 and 2, respectively. Compounds 1 and 2 were found to display a modulating effect of the serotonin receptor activity in vitro.

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…

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…

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-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…

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…

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.

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…

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 …

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…

TGF-β/VEGF-A Genetic Variants Interplay in Genetic Susceptibility to Non-Melanocytic Skin Cancer

Differential genetically determined expression of transforming growth factor-β (TGF-β pathway and of vascular endothelial growth factor-A (VEGF-A) might modulate the molecular “milieu” involved in the etio-pathogenesis of non-melanoma skin cancer (NMSC). We have evaluated the frequency of some functionally relevant SNPs of TGF-β and VEGF-A genes in 70 NMSC patients and 161 healthy controls, typed for TGF-β1 rs1800471, TGF-β2 rs900, TGF-βR1 rs334348 and rs334349, TGF-βR2 rs4522809 and VEGF-A rs3025039 SNPs. TGF-βR2 rs1800629G allele and related genotypes were found to be associated with a possible protective role against NMSC, whereas VEGF-…

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…

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 …

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…