Experimental Gerontology 41 (2006) 98–102

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

a b c a Friederike Flachsbart , Peter JP. Croucher , Susanna Nikolaus , Jochen Hampe , Christina Cordes c , Stefan Schreiber a,c,*, Almut Nebel a

a Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany b Institute for Medical Informatics and Statistics, University Hospital Schleswig-Holstein, 24105 Kiel, Germany c 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 as regulating 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. q 2005 Elsevier Inc. All rights reserved.

Keywords: Case–control association design; Centenarians; Long-lived individuals; Ageing; Single nucleotide polymorphism (SNP); Haplotype-tagging; Lifespan extension; Model organisms; 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 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 effects—up-regu- lation 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

‘sirtuins’ (Sirts), have been identified, of which Sirt1 is the most closely related to yeast SIR2 (Frye, 1999; 2000). There is indeed mounting evidence that the mammalian SIRT1 protein may also act as a potential modifier of longevity by slowing ageing during times of adversity. A recent study by Cohen et al. (2004) demonstrated that various tissues from rats on CR had increased amounts of SIRT1 protein compared to animals on a normal diet. The underlying mechanism leading to SIRT1 over-expression is still unknown but it may be mediated, in part, by the insulin-IGF1 signaling pathway (Cohen et al., 2004). SIRT1 protein upregulated through food withdrawal was found to bind and repress the fat regulator PPAR-gamma in murine adipocytes, thus stimulating fat breakdown (Picard et al., 2004). Because murine lifespan can be extended by reducing fat stores, these results suggest that activation of

* Corresponding author. Address: Institute for Clinical Molecular Biology, University Hospital Schleswig-Holstein, Campus Kiel, Schittenhelmstraße 12, 24105 Kiel, Germany. Tel.: C49 431 597 2350; fax: C49 431 597 1842. E-mail address: s.schreiber@mucosa.de (S. Schreiber).

0531-5565/$ - see front matter q 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.exger.2005.09.008

SIRT1 mediation by energy restriction could be a possible molecular mechanism of mammalian lifespan regulation (Picard et al., 2004). Interestingly, plant-derived polyphenols, such as the red-grape component resveratrol, induce SIR2/ SIRT1 gene activation and mimic the effects of CR in yeast, Drosophila and in human embryonic kidney 293 cell cultures

gene is associated with exceptional longevity in humans. To this end, we have analyzed five known single nucleotide polymorphisms (SNPs), which capture the majority of the variation in the SIRT1 gene via its common haplotypes, in our extensive collection of 1573 long-lived individuals (centenar- ians and nonagenarians) and appropriately matched younger controls.