Human longevity and 11p15.5: a study in 1321 centenarians

Abstract

The 11p15.5 chromosomal region (2.8 Mb) is of particular interest as it encloses five genes (HRAS1, SIRT3, TH, INS and IGF2), the variability of which was found to be associated with life extension by association studies. Mostly important, the above genes are homologous of genes that modulate lifespan in model organisms. We scanned the area in four European sample groups for a total of 1321 centenarians and 1140 younger subjects, who shared with centenarians ethnicity and geographical origin, with a set of 239 SNPs. No significant results (Po0.05) have been found on the earlier associated loci (ie, TH, IGF2, INS and HRAS1), and this study could not confirm the earlier findings on each of those genes. A meta-analysis was carried out on the SIRT3 SNP data; a total number of 2461 samples were included, but no positive association was found except for one SNP having a significant effect (rs939915). The same meta-analysis approach has been applied to the other 229 markers, and six SNPs have been found significant for the frequent genotype (rs4073591, DEAF1-rs4073590, KRTAP5-6-rs11040489, rs4930001, TSPAN32-rs800140 and rs16928120). This experience, although unable to confirm the earlier findings of the literature, highlights all the common difficulties of such studies in human longevity. Despite the rather negative findings presented here, the results derived from unprecedented studies involving such a large number of centenarians should be disseminated, thus contributing to set up adequate strategies to disentangle complex and likely heterogeneous phenotypes.

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

“…Most prior studies have found that increased SIRT1 is involved in healthful aging (Herranz et al., 2010; Sasaki et al., 2014; Satoh et al., 2013), whereas the results for SIRT3 are more controversial (Bellizzi et al., 2005; De Rango et al., 2008; Lescai et al., 2009; McDonnell, Peterson, Bomze & Hirschey, 2015; Rose et al., 2003). However, decreases in SIRT1 have been associated with cancer protection, which also is involved in healthful aging (Chen et al., 2014; Ohanna et al., 2014).…”

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

“…The SIRT3 single nucleotide polymorphism (SNP) rs11555236 minor allele (T) increased male survival in an Italian cohort from Calabria and was found in linkage disequilibrium with a putative enhancer located within SIRT3 intron 5 (Bellizzi et al 2005;Rose et al 2003). In a different multicentre study that recruited centenarians from Italy and Germany (for a total of 1,321 centenarians and 1,140 younger subjects), some SNPs in SIRT3 showed significant association with longevity in the Italian female and in the German male subgroups, although this result was not supported by a replication enrolling centenarians of French ancestry (Lescai et al 2009). Moreover, in a study analyzing genetic variants of the oldest old, a list of SIRT3 SNPs was detailed in longliving individuals of Caucasian ancestry (HalaschekWiener et al 2009).…”

Evidence from case–control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity

“…Furthermore, we expand the study to include the genetic variation of genes belonging to the same functional groups. Of the 16 genes included in this study, only SIRT1 and 3 have previously been investigated by a tagging single-nucleotide polymorphism (SNP) approach in a candidate association study (Flachsbart et al 2006;Kuningas et al 2007; Lescai et al 2009). …”

“…To more thoroughly examine as much of the known variation in each of these genes as possible, we here apply a tagging SNP approach using a total of 102 tagging SNPs covering the 16 gene regions. With the exception of SIRT 1 and 3 (Flachsbart et al 2006;Kuningas et al 2007;Lescai et al 2009), such an approach has, to our knowledge, not been applied before in a candidate gene study. Moreover, preceding studies have generally used a case-control study design, thus raising concerns of bias introduced by differences in characteristics of cases and controls, for example cohort effects.…”