Age-related epigenetic drift deregulates SIRT6 expression and affects its downstream genes in human peripheral blood mononuclear cells.

Sirtuin 6 (SIRT6) exerts a protective effect on health and extends the lives of model organisms. We, therefore, aimed to clarify whether age-related epigenetic drift is responsible for differences in SIRT6 expression in peripheral blood mononuclear cells (PBMCs) of healthy young (n = 55, mean age 27.5 ± 4.4 years), middle-aged (n = 51, 65.4 ± 3.3 years), and long-lived (n = 51, 93.9 ± 3.6 years) humans. In silico analysis was performed using the STRING network. No age-related differences were observed in the percentage of SIRT6 CpG island methylation. However, the age affected the expression of miR-34a-5p, miR-125a-5p, miR-186-5p, miR-342-5p and miR-766-3p (all p < 0.0001), miR-181-2-3p and Let-7c (both p = 0.0003), and miR-103a-3p (p = 0.0069). A negative association was observed between SIRT6 mRNA and miR-186-5p (rs = -0.25, p = 0.026), and a positive association was observed with miR-34a-5p (rs = 0.31, p = 0.0055) and miR-181a-2-3p (rs = 0.39, p = 0.0002). SIRT6 mRNA also negatively correlated with the expression of TP53 (rs = -0.41, p = 0.0126) and MYC (rs = -0.35, p = 0.0448). Notably, the expression of several miRNAs and genes was similar in young and long-lived groups but different from the middle-aged group. We conclude that age-related epigenetic changes can affect the expression of SIRT6 in PBMCs and, in this way, possibly influence immunosenescence. Moreover, molecular events could differentiate 'normal' ageing from that of long-lived individuals.

Alterations in 5hmC level and genomic distribution in aging-related epigenetic drift in human adipose stem cells.

Aim: To clarify mechanisms affecting the level and distribution of 5-hydroxymethylcytosine (5hmC) during aging. Materials & methods: We examined levels and genomic distribution of 5hmC along with the expression of ten-eleven translocation methylcytosine dioxygenases (TETs) in adipose stem cells in young and age-advanced individuals. Results: 5hmC levels were higher in adipose stem cells of age-advanced than young individuals (p = 0.0003), but were not associated with age-related changes in expression of TETs. 5hmC levels correlated with population doubling time (r = 0.62; p = 0.01). We identified 58 differentially hydroxymethylated regions. Hypo-hydroxymethylated differentially hydroxymethylated regions were approximately twofold enriched in CCCTC-binding factor binding sites. Conclusion: Accumulation of 5hmC in aged cells can result from inefficient active demethylation due to altered TETs activity and reduced passive demethylation due to slower proliferation.

Glucocorticoid receptor (NR3C1) gene polymorphisms are associated with age and blood parameters in Polish Caucasian nonagenarians and centenarians.

INTRODUCTION: Polymorphism of the glucocorticoid receptor gene (NR3C1) may modify protein abundance or function and therefore disturb human homeostasis. METHODS: Variant frequencies of the three NR3C1 polymorphisms, rs2963154, rs10515522 and rs2918418, selected in silico as associated with longevity, was analyzed in 552 DNA samples from 95 to 106-year-old individuals and in 284 samples of cord blood DNA from newborns. RESULTS: Frequencies of the TT genotypes of rs2963154 and rs10515522, and of the rs291841 CC genotype, were higher in the long-lived study subjects (p = 0.002, p = 0.016 and p = 0.028, respectively). In the long-lived cohort, the rs2963154 CC genotype was associated with higher concentrations of total (p = 0.007) and high-density cholesterol (p = 0.039). The rs10515522 CC genotype was associated with a higher concentration of total cholesterol (p = 0.049). The rs2918418 GG genotype was associated with higher concentrations of total (p = 0.03) and low-density cholesterol (p = 0.03). None of the polymorphisms was associated with fasting glucose, C-reactive protein levels and white blood count, prevalence of diabetes, stroke, myocardial infarction, or cognitive function. However, carriers of the rs10515522 minor allele had significantly better survival rates than carriers of other genotypes. CONCLUSION: NR3C1 polymorphisms modify cholesterol levels, and may affect the survival rates of individuals in their tenth and eleventh decades of life.