difference between centenarians and controls.

Experimental Gerontology 41 (2006) 98-102 www.elsevier.com/locate/expgero

Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity

Friederike Flachsbart, Peter JP. Croucher, Susanna Nikolaus, Jochen Hampe, Christina Cordes, Stefan Schreiber*

Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
Institute for Medical Informatics and Statistics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
Hospital for General Internal Medicine, University Hospital Schleswig-Holstein, 24105 Kiel, Germany

Received 19 August 2005; received in revised form 14 September 2005; accepted 20 September 2005
Available online 27 October 2005

Abstract:
The SIR2/Sirt1 gene has been demonstrated to regulate lifespan in many model organisms, including yeast, Caenorhabditis elegans and rodents. These findings render the human homologue, SIRT1, a very plausible candidate as a modifier of human life expectancy. We therefore sought to investigate whether common allelic variation in the SIRT1 gene was associated with human longevity. Five single nucleotide polymorphisms (SNPs), distributed across the entire gene, including the promoter region, were genotyped in our extensive DNA collections of 1573 long-lived individuals (centenarians and nonagenarians) and matched younger controls. Four of the markers were haplotype-tagging SNPs (htSNPs) that defined five common haplotypes. No evidence for an association was detected between any of the tested SNPs and the longevity phenotype at the allele, genotype or haplotype levels. These findings, based on an htSNP approach, suggest that there is no noteworthy influence of SIRT1 sequence variation on exceptional human longevity in the German population. However, this does not rule out the possibility that allelic variants in direct regulators or downstream substrates of SIRT1 could play critical roles in extending lifespan in humans.

Keywords: Case-control association design; Centenarians; Long-lived individuals; Aging; Single nucleotide polymorphism (SNP); Haplotype-tagging; Lifespan extension; Model organisms; Calorie restriction (CR)

The yeast SIR2 (silent mating type information regulator 2) gene was the first described member of a large gene family that encodes NADC-dependent protein deacetylases. These enzymes are involved in gene silencing, chromatin structure, DNA repair, and control of cellular survival (Guarente, 2000). Expression of extra copies of SIR2 and the nematode homologue sir-2.1 increases lifespan in yeast (Kaeberlein et al., 1999) and Caenorhabditis elegans (Tissenbaum and Guarente, 2001), respectively. The same effect - up-regulation of SIR2 with subsequent life extension - can also be achieved by exposing yeast cells to a low-calorie diet (Lin et al., 2000). The life-prolonging effects of calorie restriction (CR) have also been seen in more complex species, ranging from C. elegans to mammals (Masoro, 2000). Based on these observations, it has been suggested that the evolutionarily conserved SIR2 genes could play a similar role as modulators of lifespan in higher organisms (Guarente, 2000; Hekimi and Guarente, 2003).

1. Introduction
The human homologue SIRT1 is a plausible candidate as a modifier of human life expectancy as the SIR2/Sirt1 gene has been demonstrated to regulate lifespan in many model organisms, including yeast, Caenorhabditis elegans and rodents. Therefore, we investigated whether common allelic variation in the SIRT1 gene is associated with human longevity. We genotyped five single nucleotide polymorphisms (SNPs) distributed across the entire gene, including the promoter region, in our extensive DNA collections of 1573 long-lived individuals (centenarians and nonagenarians) and matched younger controls. Four of the markers were haplotype-tagging SNPs (htSNPs) that defined five common haplotypes. We found no evidence for an association between any of the tested SNPs and the longevity phenotype at the allele, genotype or haplotype levels. These findings suggest that there is no noteworthy influence of SIRT1 sequence variation on exceptional human longevity in the German population. However, this does not rule out the possibility that allelic variants in direct regulators or downstream substrates of SIRT1 could play critical roles in extending lifespan in humans.