Modulation of human longevity by SIRT3 single nucleotide polymorphisms in the prospective study “Treviso Longeva (TRELONG)”

Abstract

Human sirtuins are seven proteins with deacetylase activity that are emerging as key modulators of basic physiological functions. Some evidence links SIRT3 to longevity in mammals. This study aimed to investigate whether variants within SIRT3 gene were associated to human longevity. We analyzed 549 genomic DNA collected during the prospective study "Treviso Longeva," including elderly over 70 years of AGE (2014) age from the municipality of Treviso, a small city in the northeast of Italy. We genotyped SIRT3 rs3825075, rs4980329, and rs11555236 single nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction allelic discrimination assay. A cross-sectional analysis performed by comparing people over and under 85 years of age did not evidence association among the SIRT3 SNPs and longevity. However, when we performed a longitudinal analysis considering mortality as a dependent variable, we observed an association of SIRT3 rs11555236 and rs4980329 with longevity in the whole population (p values corrected for potential confounders=0.04 and 0.03, respectively). After stratification according to gender, the same SNPs were associated to female longevity only (p values corrected for potential confounders=0.03 and 0.02, respectively). Finally, as rs11555236 was reported to be in linkage disequilibrium with a putative functional enhancer within the SIRT3 gene, we assessed whether rs11555236 genotypes correlated with a different level of SIRT3 protein in peripheral blood mononuclear cells. We found an increased level of SIRT3 in subjects homozygous for the (T) allele. We suggest that SIRT3 genetic variability might be relevant for the modulation of human longevity in the Italian population.

Calorie restriction and sirtuins revisited

“…The failure of whole-body SIRT1 overexpression to extend the life span may be due to untoward effects on cancer, which counteract the observed slowing of aging in these mice (Herranz et al 2010). Finally, in humans, a link between SNPs at the SIRT3 locus and longevity has also been described (Albani et al 2013). All told, the above body of work strongly supports the proposal that sirtuins are conserved mediators of longevity.…”

Sirtuins and Accelerated Aging in Scleroderma

“…Multiple studies have shown declines in SIRT activity or levels with age in different organisms, tissues, and cells types [41, 48–52]. SIRT6 and SIRT7 knockout mice display progeroid phenotypes and have shorter lifespans than controls [53, 54], and SIRT3 polymorphisms have been associated with longevity in human populations [55]. Sirtuins play a protective role in multiple aging-related diseases including neurodegenerative disorders, hearing loss, cardiovascular disease, and disorders of glucose and lipid metabolism [21, 56, 57].…”

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

“…Interestingly, increased expression of SIRT3 may be linked with longevity in humans. The presence of SNP rs11555236 in linkage disequilibrium with the putative functional enhancer region of SIRT3, which is a part of variable number of tandem repeat (VNTR) element located within a SIRT3 intron (4,12), has been reported to be associated with increased longevity in some human populations (4,12,131). SIRT3 expression was higher in peripheral blood mononuclear cells from individuals homozygous for this variant (4).…”

“…The presence of SNP rs11555236 in linkage disequilibrium with the putative functional enhancer region of SIRT3, which is a part of variable number of tandem repeat (VNTR) element located within a SIRT3 intron (4,12), has been reported to be associated with increased longevity in some human populations (4,12,131). SIRT3 expression was higher in peripheral blood mononuclear cells from individuals homozygous for this variant (4). Conversely, SIRT3 expression and activity decline in response to high-fat feeding (9,59,77,111), in insulin resistance (174), and in human subjects with the metabolic syndrome (59).…”