Abstract
BackgroundSirtuin-6 (SIRT6) is involved in various crucial cellular pathways, being a key regulator of telomere structure, DNA repair, metabolism, transcriptional control and the NF-kappa B pathway. Sirt6 knock-out mice have been reported to develop typical features of aging and senescence at the age of 2–3 weeks and die within 4 weeks. The aim of this study was to investigate whether sequence variations of SIRT6 are associated with aging and longevity in Finnish men.MethodsThe sample of this study consisted of 43 longer-living and healthy males and 92 male control subjects who have died of natural causes at an average age of 66,6 (±4,1) years and who belonged to the Helsinki Birth Cohort Study (HBCS). Single nucleotide polymorphisms (SNPs) in the exons and their surroundings of the SIRT6 were studied using direct PCR sequencing.ResultsThe SNP rs117385980 (C > T), situated 23 bases downstream of the exon 2 exon/intron border was found in heterozygous form in 1/43 longer-living healthy men (Minor allele frequency (MAF) 0,0116) and in 9/92 controls (MAF 0,0489). To replicate this finding, we studied a group of 63 healthy men at an average age of 83 years from the Helsinki Businessmen Study (HBS)–cohort. The heterozygosity of the same SNP was seen in 2/63 men from the HBS–cohort (MAF 0,0159). Fisher exact test was performed in our two combined study samples. The P-value for all samples combined was 0.07 and the odds ratio 3.53 (95% confidence interval 0.96–13.4).ConclusionsThese results suggest an inverse association between the T allele of rs117385980 and longevity. The result needs to be confirmed in a larger study. It remains to be determined whether rs117385980 itself has an effect or if it is a mere genetic marker for some other yet undiscovered sequence variant causing a functional effect.
Highlights
Sirtuin-6 (SIRT6) is involved in various crucial cellular pathways, being a key regulator of telomere structure, DNA repair, metabolism, transcriptional control and the NF-kappa B pathway
Sirt6 overexpression had opposite results; lifespan of male mice was extended by 15% due to a reduction in insulin-like growth factor 1 receptor (IGF-1) signalling in white adipose tissue [7]
Sequencing SIRT6 exons and their boundaries resulted in the discovery of one single nucleotide polymorphism, which was more abundant in the controls than in the longer-living
Summary
Sirtuin-6 (SIRT6) is involved in various crucial cellular pathways, being a key regulator of telomere structure, DNA repair, metabolism, transcriptional control and the NF-kappa B pathway. Sirt knock-out mice have been reported to develop typical features of aging and senescence at the age of 2–3 weeks and die within 4 weeks. Aging is defined as an overall decline in the functional capacity of cells and organs caused by accumulated damage on the molecular level. It increases the risk for several unfavourable health outcomes including cardiovascular diseases, neurodegenerative disorders and cancer [1]. SIRT6 is involved in Hirvonen et al BMC Medical Genetics (2017) 18:41 the regulation of multiple cellular pathways that affect cell senescence at the molecular level. The sirt knockout mice develop features of aging at the age of 2–3 weeks and typically die within 4 weeks. Sirt overexpression had opposite results; lifespan of male mice was extended by 15% due to a reduction in IGF-1 signalling in white adipose tissue [7]
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