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The (Silent Information Regulator 2) Sir2 gene has been shown to regulate the life span of several model organisms. In mammals, the evolutionarily conserved homologue (Sirtuin 1) SIRT1 regulates neuroprotection, metabolism, and cell survival in response to stress. Based on these data, we hypothesized that SIRT1 might influence the prevalence of age-related diseases and modify the life span of humans. In order to test this, we genotyped five single nucleotide polymorphisms (SNPs) in 1245 participants of the population-based Leiden 85-plus Study. SIRT1 haplotypes were assessed and tested for association with the risks of mortality, metabolic profile, age-related diseases, and cognitive functioning. These analyses revealed a trend for lower cardiovascular mortality for haplotype 2 and rs3758391 SNP carriers. In further analyses, this trend was not supported by intermediate phenotypes, albeit the rs3758391 T-allele carriers had better cognitive functioning. In conclusion, our results indicate a role for SIRT1 in cognitive functioning, but the role in life span remains to be elucidated.

SIRT1 Gene, Age-Related Diseases, and Mortality: The Leiden 85-Plus Study