Search

Long-lived subjects have been shown to have peculiar anthropometric features (i.e. lower body mass index (BMI)) and metabolic parameters (i.e. improved insulin sensitivity). Life style and a genetic background potentially protective against the age-related metabolic derangement might contribute to such a particular phenotype. Peroxisome proliferator-activated receptor (PPAR)gamma-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response. Thus, the potential role of genetic variability at Pro/Ala loci of PPARG gene on longevity was studied in 222 long-lived subjects and 250 aged subjects. We found a different Pro/Ala genotype frequency distribution between long-lived and aged men subjects, long-lived men having an increased frequency of Pro/Ala genotype (20 vs 8.5%); no differences was found when allele and genotype distribution of Pro/Ala gene polymorphism were analyzed in the two age group of women. Interestingly, subjects with Pro/Ala polymorphism had significantly lower BMI than Ala/Ala and Pro/Pro polymorphism. In conclusion, our study demonstrated that paraoxonase Pro/Ala gene polyporphism is associated with human longevity. Such an effect is probably due to the effect of Pro/Ala polymorphism on body composition and appears to be gender specific.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that some key features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men. At least four well-recognized aging-related characteristics that are strongly expressed in older men go some way towards explaining why these patients account for the vast majority of fatalities: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of ACE2 (SARS-CoV-2 receptor), which triggers inflammation, particularly in patients with age-related comorbid diseases such as type II diabetes; and iv. accelerated biological aging, as measured by epigenetic and senescence markers (e.g. telomere shortening) associated to the chronic inflammatory state. Though typical of the aged, especially of elderly men, it is conceivable that these features are also shared by some subsets of the younger population. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.

The stratification of mortality risk in COVID-19 patients remains extremely challenging for physicians, especially in older patients. Innovative minimally invasive molecular biomarkers are needed to improve the prediction of mortality risk and better customize patient management. In this study, aimed at identifying circulating miRNAs associated with the risk of COVID-19 in-hospital mortality, we analyzed serum samples of 12 COVID-19 patients by small RNA-seq and validated the findings in an independent cohort of 116 COVID-19 patients by qRT-PCR. Thirty-four significantly deregulated miRNAs, 25 downregulated and 9 upregulated in deceased COVID-19 patients compared to survivors, were identified in the discovery cohort. Based on the highest fold-changes and on the highest expression levels, 5 of these 34 miRNAs were selected for the analysis in the validation cohort. MiR-320b and miR-483-5p were confirmed to be significantly hyper-expressed in deceased patients compared to survived ones. Kaplan-Meier and Cox regression models, adjusted for relevant confounders, confirmed that patients with the 20% highest miR-320b and miR-483-5p serum levels had three-fold increased risk to die during in-hospital stay for COVID-19. In conclusion, high levels of circulating miR-320b and miR-483-5p can be useful as minimally invasive biomarkers to stratify older COVID-19 patients with an increased risk of in-hospital mortality.

Current literature agrees on the notion that efficient DNA repair favors longevity across evolution. The DNA damage response machinery activates inflammation and type I interferon signaling. Both pathways play an acknowledged role in the pathogenesis of a variety of age-related diseases and are expected to be detrimental for human longevity. Here, we report on the anti-inflammatory molecular make-up of centenarian’s fibroblasts (low levels of IL-6, type 1 interferon beta, and pro-inflammatory microRNAs), which is coupled with low level of DNA damage (measured by comet assay and histone-2AX activation) and preserved telomere length. In the same cells, high levels of the RNAseH2C enzyme subunit and low amounts of RNAseH2 substrates, i.e. cytoplasmic RNA:DNA hybrids are present. Moreover, RNAseH2C locus is hypo-methylated and RNAseH2C knock-down up-regulates IL-6 and type 1 interferon beta in centenarian’s fibroblasts. Interestingly, RNAseH2C locus is hyper-methylated in vitro senescent cells and in tissues from atherosclerotic plaques and breast tumors. Finally, extracellular vesicles from centenarian’s cells up-regulate RNAseH2C expression and dampen the pro-inflammatory phenotype of fibroblasts, myeloid, and cancer cells. These data suggest that centenarians are endowed with restrained DNA damage-induced inflammatory response, that may facilitate their escape from the deleterious effects of age-related chronic inflammation.

Epidemiological data convey severe prognosis and high mortality rate for COVID-19 in elderly men affected by age-related diseases. These subjects develop local and systemic hyper-inflammation, which are associated with thrombotic complications and multi-organ failure. Therefore, understanding SARS-CoV-2 induced hyper-inflammation in elderly men is a pressing need. Here we focus on the role of extracellular DNA, mainly mitochondrial DNA (mtDNA) and telomeric DNA (telDNA) in the modulation of systemic inflammation in these subjects. In particular, extracellular mtDNA is regarded as a powerful trigger of the inflammatory response. On the contrary, extracellular telDNA pool is estimated to be capable of inhibiting a variety of inflammatory pathways. In turn, we underpin that telDNA reservoir is progressively depleted during aging, and that it is scarcer in men than in women. We propose that an increase in extracellular mtDNA, concomitant with the reduction of the anti-inflammatory telDNA reservoir may explain hyper-inflammation in elderly male affected by COVID-19. This scenario is reminiscent of inflamm-aging, the portmanteau word that depicts how aging and aging related diseases are intimately linked to inflammation.

The possibility that a receptor for androgen is expressed in Breast Cancer (BC) is fascinating given that the tumor is predominantly estrogen-dependent. The androgen receptor (AR) is emerging as a new marker and a potential new therapeutic target in the treatment of BC patients. The recent availability of selective AR inhibitors (e.g. bicalutamide, enzalutamide, apalutamide) approved for the treatment of prostate cancer has opened up the possibility to use them in BC patients whose tumors express AR. However, AR appears to have various functions according to the BC subtype, e.g. ER-positive or triple negative BC and the patient prognosis is different on the basis of the presence or absence of estrogen and progesterone receptors. Moreover, a different AR expression was seen according to the various ethnicities. Of note, in population at low economical income, the availability of anti-AR compounds at low cost could open the possibility to treat AR-positive triple negative BC that are highly present in these populations. Up to now, AR detection is not routinely performed in BC. The standardization of AR detection methods could render AR an easily detectable marker in primary BC and metastatic samples. Nevertheless, the overall concordance of 60% of AR expression in primary tumor and metastasis implies that a clinician who need the AR value to give anti-AR therapy should have the data on both the tumor materials. Following the comprehensive studies on prostate cancer the possibility to test AR on liquid biopsies suggest the use of this biomarker for a real-time disease monitoring. Finally, considering the possibility to treat patients with immune checkpoint inhibitors there is the need to know the relation between microenvironment and AR in BC.

Recent studies in mice have challenged the ability of bone marrow cells (BMCs) to differentiate into myocytes and coronary vessels. The claim has also been made that BMCs acquire a cell phenotype different from the blood lineages only by fusing with resident cells. Technical problems exist in the induction of myocardial infarction and the successful injection of BMCs in the mouse heart. Similarly, the accurate analysis of the cell populations implicated in the regeneration of the dead tissue is complex and these factors together may account for the negative findings. In this study, we have implemented a simple protocol that can easily be reproduced and have reevaluated whether injection of BMCs restores the infarcted myocardium in mice and whether cell fusion is involved in tissue reconstitution. For this purpose, c-kit–positive BMCs were obtained from male transgenic mice expressing enhanced green fluorescence protein (EGFP). EGFP and the Y-chromosome were used as markers of the progeny of the transplanted cells in the recipient heart. By this approach, we have demonstrated that BMCs, when properly administrated in the infarcted heart, efficiently differentiate into myocytes and coronary vessels with no detectable differentiation into hemopoietic lineages. However, BMCs have no apparent paracrine effect on the growth behavior of the surviving myocardium. Within the infarct, in 10 days, nearly 4.5 million biochemically and morphologically differentiated myocytes together with coronary arterioles and capillary structures were generated independently of cell fusion. In conclusion, BMCs adopt the cardiac cell lineages and have an important therapeutic impact on ischemic heart failure.

Background. PON1, an arylesterase, associated with high density lipoprotein (HDL), protects low density lipoprotein (LDL) against oxidative modification. Common polymorphisms PON1 55 (L/M) and 192 (Q/R) in the PON1 gene associate with atherosclerosis and heart disease. Because long-lived people seem protected from premature vascular death, we conducted a pooled statistical analysis to assess any association between these polymorphisms and longevity in a large combined group of Italian centenarians and octo/nonagenarians from Northern Ireland (NI). Materials and methods. Separated DNA was available from 1479 subjects from Italy and Northern Ireland (NI). In Italy 308 centenarians (males 67, females 241, mean age 100.8, SD2.1 years) and 579 young controls (males 347, females 232, mean age 40.7, SD 12.7 years) were included in the study. In NI, 296 octo/nonagenarians (males 92, females 204, mean age 89.8, SD 5.7 years) and 296 young sex-matched subjects (mean age 13.0, SD 1.4 years) had available DNA. PON1 55 (L/M) and 192 (Q/R) polymorphisms were studied using a PCR-RFLP approach. Results. There was a significant difference in PON1 192 genotypes in Italian centenarians compared to younger controls (X2=6.8, df=2, p=0.03) and a similar but non significant trend between octo/nonagenarian and young subjects in NI (X2=4.0, df=2, p=0.14). Using logistic regression analysis on the combined Italian and Irish datasets, there was a small survival advantage for centenarian and octo/nonagenarian subjects who were heterozygous for PON1 192 R allele, (OR 1.3, CI 1-1.6; p=0.04) with a stepwise increase for RR homozygous subjects (OR 1.7, CI 1.1-2.6; p=0.02), compared to QQ subjects. Comparing R and Q alleles there was a survival advantage for octo/nonagenarian/centenarian subjects who carried the R allele (OR 1.3, CI 1.1-1.5; p=0.007), but there was no sex-specific effect (p=0.77). LL, LM and MM genotypes of PON 55 polymorphisms showed similar frequencies in Italy (39.9, 47.0, 13.1%) and Ireland (39.5, 48.6, 11.9%) with no age or sex-related differences. The PON1 192R/Q and PON55L/M loci were in strong linkage disequilibrium with a Lewontin's D′ coefficient −0.928 (elderly) and −0.965 (young). There was a significant difference in haplotype frequency of these linked loci in older compared to younger subjects (Likelihood Ratio X2=9.60, df=3, p=0.02). Conclusion. These data suggest a modest association between the 192R allele and longevity in two very elderly populations in two European countries. Being homozygous for 192 RR further enhances survival advantage but this effect was not found to be sex specific. This finding is of interest because the 192R allele has previously been associated with increased risk of coronary heart disease. On the other hand, the 192R allele shows higher enzymatic activity, using paraoxon as substrate, and we postulate that its role in the metabolism of potentially toxic chemicals or other metabolic pathways may be important in survival to very old age.

The human forkhead box O1A (FOXO1A) gene belongs to the human forkhead gene family and acts downstream of the human insulin signalling pathway. In this study, polymorphisms of the Intron I of FOXO1A gene were studied in Italian healthy people and insulin resistant subjects. No significant association between the germ-line variability in the Intron I of FOXO1A and insulin resistance was observed. Interestingly, during the study, a new 39-bp sequence insertion polymorphism in Intron I of FOXO1A gene was described. The polymorphism was found to co-segregate in a co-dominant Mendelian fashion and to be present in an ethnically distinct population (Greeks). A BLAST search showed that the sequence shares 100% identity with a mtDNA (mitochondrial DNA) sequence coding for the ATP synthase 8 (ATPase8) and ATP synthase 6 (ATPase6) genes. Hence, FOXO1A Intron I is a polymorphic nuclear region involved in the exchange of DNA material between mitochondrial and genomic DNA, which is a well-established mechanism of evolutionary change in eukaryotes.

Current literature indicates that abrogation of the IGF-I response pathway affects longevity in Caenorhabditis elegans, and that the down-regulation of IGF-I gene expression is associated with an extension of the life span in mice. In this paper we tested the hypothesis that polymorphic variants of IGF-I response pathway genes, namely IGF-IR (IGF-I receptor; G/A, codon 1013), PI3KCB (phosphoinositol 3-kinase; T/C, -359 bp; A/G, -303 bp), IRS-1 (insulin receptor substrate-1; G/A, codon 972), and FOXO1A (T/C, +97347 bp), play a role in systemic IGF-I regulation and human longevity. The major finding of this investigation was that subjects carrying at least an A allele at IGF-IR have low levels of free plasma IGF-I and are more represented among long-lived people. Moreover, genotype combinations at IGF-IR and PI3KCB genes affect free IGF-I plasma levels and longevity. These findings represent the first indication that free IGF-I plasma levels and human longevity are coregulated by an overlapping set of genes, contributing to the hypothesis that the impact of the IGF-I/insulin pathway on longevity is a property that has been evolutionarily conserved throughout the animal kingdom.

Deregulation of the inflammatory response plays a major role in the age-related decline of physical performance. The causal pathway leading from inflammation to disability has not been fully clarified, but several researches suggest that interleukin-6 (IL-6) causes a reduction of physical performance in elderly through its effect on muscle function. In vitro studies demonstrated that IL-6 inhibits the secretion of insulin-like growth factor I (IGF-I) and its biological activity, suggesting that the negative effect of IL-6 on muscle function might be mediated through IGF-I. We evaluated the joint effect of IGF-I and IL-6 on muscle function in a population-based sample of 526 persons with a wide age range (20–102 yr). After adjusting for potential confounders, such as age, sex, body mass index, IL-6 receptor, and IL-6 promoter polymorphism, IL-6, IGF-I, and their interaction were significant predictors of handgrip and muscle power. In analyses stratified by IL-6 tertiles, IGF-I was an independent predictor of muscle function only in subjects in the lowest IL-6 tertile, suggesting that the effect of IGF-I on muscle function depends on IL-6 levels. This mechanism may explain why IL-6 is a strong risk factor for disability.

The LL genotype among subjects with paraoxonase (PON) polymorphism Met-Leu 54 has been shown to be associated with elevated risk of coronary heart disease. Indeed, insulin resistance (IR) is a well known cardiovascular risk factor that is likely attributable to a genetic background, lifestyle, and environmental factors such oxidative stress. Because subjects sharing the LL genotype have a more elevated degree of oxidative stress, one cannot rule out that in those subjects a more severe degree of IR can occur. Thus, the possible relationship between PON gene polymorphism and degree of IR was investigated. In 213 healthy subjects, the degree of IR was assessed by the homeostasis model assessment, and the Met-Leu 54 PON polymorphism was detected. The frequency was 0.366 for the LL genotype, 0.469 for the LM genotype, and 0.164 for the MM genotype. Comparing the three genotype groups, LL genotype had the more severe degree of IR, compared with LM (P < 0.01) and MM (P < 0.01) genotypes. No difference between LM and MM genotypes was found (P = 0.49). Subjects carrying the LL genotype were associated with the IR syndrome picture more than individuals carrying the M allele because they were more overweight and had the highest levels of triglycerides and blood pressure and the lowest values of plasma high-density lipoprotein cholesterol. In a multivariate stepwise regression analysis, LL genotype was a significant predictor of IR, independent of age, sex, body mass index, fasting plasma triglycerides, and high-density lipoprotein cholesterol (P < 0.001). In conclusion, the presence of LL PON genotype is associated with a more severe degree of IR. Thus, IR might be the possible missing link between Met-Leu 54 PON polymorphism and the increased cardiovascular risk.

Tyrosine Hydroxylase (TH) and Insulin (INS) genes lie extremely close in the 11p15.5 chromosomal region. An STR marker of the TH gene had revealed this locus associated with longevity. Thus, it seemed of interest to investigate the association between the TH-STR and INS gene variability (FokI-RFLP) with a phenotypic trait, such as the degree of insulin resistance (IR) and beta-cell function in centenarians (C). We analyzed age-related trajectories of IR and beta-cell function in a large sample (n=466) of individuals whose age ranged from 28 to more than 100 years; furthermore, allele average effects on IR and beta-cell function relevant to TH-STR and INS-FokI polymorphisms were estimated in C. Both IR and beta-cell function increased with advancing age and declined in subjects older than 90 years (p for trend0.001). C had lower IR (1.5+/-0.7 vs. 3.9+/-1.7, p0.001) and beta-cell function (26.1+/-8.5 vs. 55.4+/-16, p0.001) than nC. In nC, but not in C, IR and beta-cell function correlated with the main anthropometric and metabolic confounders. Nevertheless, significant allele average effects by TH-STR and INS-FokI polymorphisms on IR and beta-cell function were not observed in C. In conclusion, C has a lower degree of IR and a preserved beta-cell function in comparison to nC, but the cause of such metabolic differences, which are likely does not lie in this genomic region.

The p53 codon 72 polymorphism, which results in either an arginine or proline residue, plays a different role in vitro and in vivo in cell survival and drug resistance. We verified, in vitro, the impact of the arginine allele on cell survival under normoxia and hypoxia, and investigated in vivo the role of p53 codon 72 arginine homozygosity in the clinical outcome of advanced breast cancer patients.Tumors at advanced stages grow in vivo in a hypoxic environment, and we mimicked such conditions in vitro using p53 null breast cancer cells transfected with either the arginine or proline allele. We also analyzed in vivo the p53 codon 72 genotype status of advanced breast cancer patients.In vitro transfection of the arginine allele induced higher cell death under normoxia, whereas cell death was greater in proline-transfected cells under hypoxia. The arginine allele upregulated BCRP-I, a hypoxia response gene, which increases drug resistance. Metastatic breast cancer patients homozygous for arginine had a significantly shorter time to progression and overall survival than those with heterozygous arginine/proline tumors.We provide a molecular explanation for the association of the arginine allele with tumor aggressiveness and treatment resistance in advanced breast cancer.

The clinical use of endothelial progenitor cells is hampered by difficulties in obtaining an adequate number of functional progenitors. This study aimed to establish whether human thoracic aortas harvested from healthy multiorgan donors can be a valuable source of angiogenic progenitors. Immunohistochemical tissue studies showed that two distinct cell populations with putative stem cell capabilities, one composed of CD34+ cells and the other of c-kit+ cells, are present in between the media and adventitia of human thoracic aortas. Ki-67+ cells with high growth potential were located in an area corresponding to the site of CD34+ and c-kit+ cell residence. We thus isolated cells (0.5 approximately 2.0 x 10(4) aortic progenitors per 25 cm2) which, upon culturing, coexpressed molecules of mesenchymal stromal cells (i.e., CD44+, CD90+, CD105+) and showed a transcript expression of stem cell markers (e.g., OCT4, c-kit, BCRP-1, Interleukin-6) and BMI-1. Cell expansion was adequate for use in a clinical setting. A subset of cultured cells acquired the phenotype of endothelial cells in the presence of vascular endothelial growth factor (e.g., increased expression of KDR and von Willebrand factor positivity), as documented by flow cytometry, immunofluorescence, electron microscopy, and reverse transcription-polymerase chain reaction assays. An in vitro angiogenesis test kit revealed that cells were able to form capillary-like structures within 6 hours of seeding. This study demonstrates that thoracic aortas from multiorgan donors yield mesenchymal stromal cells with the ability to differentiate in vitro into endothelial cells. These cells can be used for the creation of an allogenic bank of angiogenic progenitors, thus providing new options for restoring vascularization at ischemic sites. Disclosure of potential conflicts of interest is found at the end of this article.

OBJECTIVES As is well known, acute myocardial infarction presents two electrocardiogram (EKG) patterns, ST-elevation (STEMI) and no ST-elevation (NSTEMI), characterized by different coronary artery thrombotic occlusion. Growing evidence shows that inflammation plays a central role in the pathogenesis of acute myocardial infarction. Among the factors that promote inflammation and arterial thrombosis, one of the most important is the proinflammatory cytokine tumor necrosis factor-alpha. The expression of this cytokine is modulated by a polymorphism located at nucleotide -308 of tumor necrosis factor-alpha promoter gene. The objective of our study is to verify whether tumor necrosis factor-alpha -308 polymorphism is associated with risk of acute myocardial infarction (STEMI and NSTEMI) or with biochemical myocardial ischemia markers, such as troponin I, creatine kinase-MB, lactate dehydrogenase and myoglobin. METHODS We analyzed tumor necrosis factor-alpha -308 polymorphism in a total of 603 study participants: 293 elderly patients affected by acute myocardial infarction (STEMI and NSTEMI) and 310 healthy controls. RESULTS We found that individuals carrying the tumor necrosis factor-alpha -308 AG+AA genotypes are significantly more represented among acute myocardial infarction patients affected by STEMI than among NSTEMI patients (OR = 1.86, 95% CI 1.08-3.21, p = 0.027) and healthy controls (OR = 1.64, 95% CI 1.03-2.64, p = 0.046). Furthermore, the patients carrying tumor necrosis factor-alpha -308 AG+AA genotypes displayed significant increased levels of biochemical myocardial ischemia markers. CONCLUSIONS Our study shows a significant association between the tumor necrosis factor-alpha -308 polymorphism and the occurrence of STEMI, and suggests that the tumor necrosis factor-alpha -308 polymorphism could play a role in the pathogenesis of cardiac ischemic damage, AA+AG genotype carrier individuals being likely to be affected by more severe ischemic damage than the rest of the population.

A common arginine to proline polymorphism is harboured at codon 72 of the human p53 gene. In this investigation, we found that fibroblasts and lymphocytes isolated from arginine allele homozygote centenarians and sexagenarians (Arg+) undergo an oxidative-stress-induced apoptosis at a higher extent than cells obtained from proline allele carriers (Pro+). At variance, the difference in apoptosis susceptibility between Arg+ and Pro+ is not significant when cells from 30-year-old people are studied. Further, we found that Arg+ and Pro+ cells from centenarians differ in the constitutive levels of p53 protein and p53/MDM2 complex, as well as in the levels of oxidative stress-induced p53/Bcl-xL complex and mitochondria-localised p53. Consistently, all these differences are less evident in cells from 30-year-old people. Finally, we investigated the in vivo functional relevance of the p53 codon 72 genotype in a group of old patients (66-99 years of age) affected by acute myocardial ischaemia, a clinical condition in which in vivo cell death occurs. We found that Arg+ patients show increased levels of Troponin I and CK-MB, two serum markers that correlate with the extent of the ischaemic damage in comparison to Pro+ patients. In conclusion, these data suggest that p53 codon 72 polymorphism contributes to a genetically determined variability in apoptotic susceptibility among old people, which has a potentially relevant role in the context of an age-related pathologic condition, such as myocardial ischaemia.

Previous studies have shown that a rise in blood pressure (BP) causes chronic inflammation of the endothelium which, in turn, may be responsible for further damage of endothelium and worsening of BP control. On the other hand, several metabolic abnormalities such as dyslipidemia, hyperinsulinemia/insulin-resistance, diabetes, and obesity causes inflammation followed by a later rise in arterial BP. We investigated the role of chronic inflammation in the modulation of BP independently of other traditional cardiovascular risk factors and atherosclerotic lesions.A total of 537 aged subjects, selected from the whole population of the INCHIANTI cohort, were enrolled. All subjects underwent plasma insulin, glucose, interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1ra), C-reactive protein, and tumor necrosis factor-alpha (TNF-alpha) levels determination. The IL-6-174 C/G promoter polymorphism was also evaluated.After adjusting for age, sex, insulin resistance syndrome score, and severity of carotid atherosclerosis, serum IL-1 beta (P.001), IL-1ra (P.005) concentration and the insulin resistance syndrome score (P.001) were the only predictors of diastolic BP. Indeed, age (P.001), insulin resistance syndrome score (P =.05), IL-1 beta (P.05), and severity of carotid atherosclerosis (P.05) were the only significant predictor of systolic BP.These results suggest that chronic inflammation may play a role in the modulation of arterial BP.

Current literature indicates that elevated IL-6 serum levels are associated with diseases, disability and mortality in the elderly. In this paper, we studied the IL-6 promoter genetic variability at -174 C/G locus and its effect on IL-6 serum levels in a total of 700 people from 60 to 110 years of age, including 323 centenarians. We found that the proportion of homozygotes for the G allele at -174 locus decreases in centenarian males, but not in centenarian females. Moreover, we found that, only among males, homozygotes for the G allele at -174 locus have higher IL-6 serum levels in comparison with carriers of the C allele. On the whole, our data suggest that those individuals who are genetically predisposed to produce high levels of IL-6 during aging, i.e. -174 locus GG homozygous men, are disadvantaged for longevity.