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variants are associated with aging in a healthy Han Chinese population

Wei-Guang Zhang a, Xiao-Juan Bai a, , Xiang-Mei Chen b

a Departments of Gerontology and Geriatrics, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China b Department of Kidney, General Hospital of Chinese PLA, Beijing, China

Background: Aging is by diverse environmental and genetic risk factors. The SIRT1 (silent information regulator 1) gene has been shown to regulate lifespan and aging in previous studies. We determined whether variation in the SIRT1 gene is associated with aging in healthy Chinese population. Methods: The study population comprised 482 healthy, unrelated Chinese subjects, of which 246 were aging individuals from 60 to 91 years old, and 236 younger individuals from 35 and 59 years old. All subjects were from Shenyang, China. Two single-nucleotide polymorphisms (SNP) were analyzed: rs3758391 near the 5′ end of the SIRT1 gene; and rs4746720, in the 3′ untranslated region. Results: Differences in allele and genotype frequency were seen between the groups, with rs3758391/C more common than rs3758391/T in the aging subjects (odds ratio=1.453, p=0.026), and with rs3758391/CC more common than rs3758391/CT and rs3758391/TT in the aging subjects (odds ratio=3.042, p=0.027). For the 3′ SNP, rs4746720/C was more common than rs4746720/T in the aging subjects (odds ratio=1.347, p=0.022), and rs4746720/CC was more common than rs4746720/CT and rs4746720/CT in the aging subjects (odds ratio=1.461, p=0.049). The haplotype frequency distribution was also different, with haplotype CC more common in the older group (odds ratio=1.63, p=0.01). Conclusion: These results suggest that SIRT1 gene polymorphisms may add a new factor on the multifactorial genetic contributions to aging.

© 2010 Elsevier B.V. All rights reserved.

1. Introduction

changes in a mouse model of genomic instability. A moderate increase in SIRT1 confers resistance to aging-related oxidative stress and apoptosis and appears to be beneficial for aging [8,9].

Aging is a progressive function decline process at the cellular and organism levels. The interaction of genetic and environmental factors contributes to the aging process. Genetic factors and life span correlate, implying a relatively strong genetic contribution to the human aging process [1,2]. Mammals possess seven sirtuins, encoded by SIRT1–SIRT7 [3,4]. The SIRT2 gene is the first gene discovered in the sirtuin family, and was associated with extended life span in several organisms. SIRT1 is a mammalian NAD+-dependent deacetylase homolog of yeast SIRT2. The SIRT1 gene has been shown to regulate lifespan and aging in model organisms that include yeast, C. elegans and rodents [5].

hasbeenconductedonhealthyagingpopulations,eventhoughSIRT1isan important candidate gene for retarding aging and forestalling the onset of age-associated diseases [10,11]. Recently, the Leiden 85 plus extremely aging Study found that the rs3758391 T-allele of the SIRT1 gene was associated with high cognitive function in Dutch people [12]. But the Leiden 85-plus Study, a study conducted on German subjects and a study in a Belgian Caucasian population did not find that the SIRT1 sequence variation influenced exceptional extremely aging in the German, Dutch and Belgian populations [12–14]. An association study of SIRT1 gene variation and visceral obesity in Belgian Caucasians found that the rs7069102 C-allele ofSIRT1 is associated with reduced risk of obesity [13]. Since obesity may accelerate the aging process [15], SIRT1 gene variability may contribute to changes in SIRT1 and correlate with the aging process.

SIRT1 antagonizes cellular senescence by activating ERK/S6K1 signaling in human diploid fibroblasts [6]. The SIRT1 activator resveratrol extends life span and improves glucose homeostasis in mice by stimulating SIRT1-mediated deacetylation of the transcrip- tional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 α) [7]. Increased SIRT1 expression promotes survival, and suppresses age-dependent transcriptional

Since the result obtained in other populations were not suitable Chinese people, in order to explore the potential role of variation in the SIRT1 gene in Chinese aging people, we conducted a study that uses a healthy Han Chinese population to investigate two functional single-nucleotide polymorphisms (SNPs) of SIRT1: rs3758391, which is near the 5′ end of the SIRT1 gene; and rs4746720, which is in the 3′ untranslated region (UTR).

⁎ Corresponding author. Tel.: +86 24 83282306; fax: +86 24 83282693. E-mail address: xjuanbai@yahoo.com.cn (X.-J. Bai).

0009-8981/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2010.06.030

2. Methods