Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-223 expressions : a study on postmenopausal monozygotic twin pairs

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the act…

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…

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…

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…

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…

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…

Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging

Human aging is a lifelong process characterized by a continuous trade-off between pro-and anti-inflammatory responses, where the best-adapted and/or remodeled genetic/epigenetic profile may develop a longevity phenotype. Centenarians and their offspring represent such a phenotype and their comparison to patients with age-related diseases (ARDs) is expected to maximize the chance to unravel the genetic makeup that better associates with healthy aging trajectories. Seemingly, such comparison is expected to allow the discovery of new biomarkers of longevity together with risk factor for the most common ARDs. MicroRNAs (miRNAs) and their shuttles (extracellular vesicles in particular) are curre…

Endothelial progenitor cells in ageing

“The senescence status of somatic stem/progenitor cells contributes to ageing process”, and “an individual is as old as old are its stem cells”. These quotes represent the concepts, which are actually object of investigations of researchers involved in ageing studies.

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…

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…

Circulating miR-21, miR-146a and Fas ligand respond to postmenopausal estrogen-based hormone replacement therapy--a study with monozygotic twin pairs.

Biological aging is associated with physiological deteriorations and its’ remodeling, which are partly due to changes in the hormonal profile. MicroRNAs are known to post-transcriptionally regulate various cellular processes associated with cell senescence; differentiation, replication and apoptosis. Measured from the serum, microRNAs have the potential to serve as noninvasive markers for diagnostics/prognostics and therapeutic targets. We analysed the association of estrogen-based hormone replacement therapy (HRT) with selected microRNAs and inflammation markers from the serum, leukocytes and muscle tissue biopsy samples obtained from 54-62 year-old postmenopausal monozygotic twins (n=11 p…

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…

Cellular Senescence and Inflammaging in Age-Related Diseases

An APOE haplotype associated with decreased ε4 expression increases the risk of late onset Alzheimer's disease.

This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the e4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (-491 rs449647, -427 rs769446, -219 rs405509, and e rs429358-rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants -219T and e4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in phase); 2) the correlation between the haplotype (-219T/e4) and AD risk p…

Hormone replacement therapy enhances IGF-1 signaling in skeletal muscle by diminishing miR-182 and miR-233 expressions: A study on postmenopausal monozygotic twin pairs

MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case–control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54–62- years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen’s causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the ac…