SIRT1 Polymorphism, Long-Term Survival and Glucose Tolerance in the General Population

Sylwia M. Figarska, Judith M. Vonk, H. Marike Boezen*

Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Abstract

Mutations that increase activity of Sir2 (silent information regulator 2) are associated with extended lifespan of yeast, fruit flies and worms. SIRT1, the human homolog of Sir2, that controls numerous physiological processes including the glucose metabolism, is considered a candidate gene for predicting variation in human lifespan. Whereas the role of Sir2 has been extensively investigated in model organisms, less is known about the relation between SIRT1 and lifespan in humans. In the current study we included 1,390 subjects from a general population-based cohort with 18 years of follow-up to investigate associations between variation in single nucleotide polymorphisms (SNPs) in the SIRT1 gene and human survival. Additionally in 535 male subjects with available data we investigated associations between SIRT1 and glucose tolerance. Carriers of the minor allele of rs12778366 had a significantly reduced mortality risk compared to the wild types: Hazard Ratio 0.69 (95% CI 0.50 to 0.96; p = 0.025). The directions of the effect were the same in females and males, never and ever smokers and the effect was significantly protective in overweight/obese subjects. Carriers of the minor allele of SNP rs12778366 had better glucose tolerance indicated by 0.34 mmol/l lower glucose levels compared to wild type subjects (p= 0.03). This study shows that SIRT1 affects human long-term survival and therefore may be an important factor in modulating lifespan not only in lower organisms, but also in humans.

Funding: This work was supported by the Graduate School for Drug Exploration (GUIDE), University Medical Center Groningen, University of Groningen, the Netherlands. The Vlagtwedde\Vlaardingen study was supported by unrestricted grants of Stichting Astma Bestrijding (grant number 2005/020) and Netherlands Asthma Foundation (grant number 3.2.02.51). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

E-mail: h.m.boezen@umcg.nl

Introduction

of insulin resistance [8]. Overexpression of SIRT1 or using SIRT1 activators improves glucose homeostasis and insulin sensitivity in mice [8–11]. Therefore partly the effect of SIRT1 on longevity may be exerted via its association with insulin signaling, which has been proven to extend lifespan by 18% in fat-specific insulin receptor knockout (FIRKO) mice [12]. Furthermore, SIRT1 is required for a normal response to caloric restriction that causes many changes in glucose metabolism and increases lifespan [13].

In the ongoing quest to uncover factors that increase longevity, sirtuins have attracted scientific and public interest for the past decades [1]. Initially, overexpression of the silent information regulator Sir2, nicotinamide adenine dinucleotide (NAD+)-depen- dent histone deacetylase, has shown a beneficial effect on lifespan in budding yeast (Saccharomyces cerevisae) [2]. Subsequently, the experiments performed in worms (Caenorhabditis elegans) and flies (Drosophila melanogaster) [3,4] confirmed favorable properties of Sir2, signifying the importance of sirtuins as longevity genes. Since a more recent report showed an absence of effects of Sir2 overexpression on lifespan in C.elegans and Drosophila [5], a debate about the role of sirtuins in lifespan prolongation has arisen [1]. Therefore more studies are needed to elucidate the impact of sirtuins on lifespan, especially in humans. Out of seven identified mammalian homologues, sirtuin 1 (SIRT1) is the most closely related to Sir2 [6]. SIRT1 influences the activity of various transcription factors, including forkhead-box transcription factors (FOXOs), peroxisome proliferator-activated receptor c (PPAR c) and nuclear factor-kB (NF-kB) in target tissues resulting in enhanced gluconeogenesis and repressed glycolysis in the liver, reduction of adipogenesis in adipose tissue, and increased release of insulin in pancreatic beta cells [7]. SIRT1 controls adiponectin levels, inflammatory processes, gluconeogenesis, and levels of reactive oxygen species that together may lead to the development

In humans, during the last years polymorphisms in SIRT1 have been investigated in a context of metabolism and have been associated with BMI and risk of obesity [14–17], acute insulin response in Pima Indians [18], body fat and blood pressure in Japanese [19], basal energy expenditure and respiratory quotient [20], and with diabetes risk in interaction with prenatal exposure to famine [21]. The few studies that investigated SNPs in SIRT1 in relation to human lifespan or mortality did not find any associations [22–25].

expectancy is genetically determined [26] and the specific genetic determinants of human lifespan still remain largely unknown, SIRT1, as a metabolic master switch [7], may be considered a candidate gene for predicting variation in human lifespan. The Vlagtwedde/Vlaardingen cohort offers the unique opportunity to investigate the role of SIRT1 in long-term survival, because subjects included in the current study were followed up for 18 years. Since SIRT1 modulates a range of cellular processes

Table 1. Characteristics of participants at visit 1989/1990 by vital status on Dec 31st,