Academic journal article Iranian Journal of Public Health

Association of SIRT6 Gene Polymorphisms with Human Longevity

Academic journal article Iranian Journal of Public Health

Association of SIRT6 Gene Polymorphisms with Human Longevity

Article excerpt

Introduction

Longevity and ageing are a complex and multifactorial process controlled by both environmental and genetic factors (1). Studies reported hundreds of genetic variants that played a role in extension of lifespan. Population studies of longevity in twins suggested that the genes contributed to 15% to 30% of the heritability to the human lifespan (2, 3). However, the mechanisms underlying the role of genetic factors in human longevity and successful ageing are unknown. Over the last decade, sirtuins attracted significant interests in ageing studies. The role of sirtuins has been studied in NAD-dependent lysine deacetylation and a related mono-ADP-ribosylation reaction (4). The histone deacetylase silent information regulator (Sir2) is a longevity control gene (5, 6). Sir2 activity depends on the levels of nicotinamide adenine dinucleotide (NAD) (7). Further, Sir2 increases longevity by suppressing ribosomal DNA homologous recombination and calorie restriction (6).

Mammalian genomes encode seven Sir2 homologs (SIRT1-7). The human SIRT6 gene is located on the minus strand of chromosome 19p13.3 and encodes a 355-amino-acid protein (8). It regulates the expression of several stress-responsive and metabolism related genes at the molecular level (9, 10). In addition, it plays an important biological role in heart disease, diabetes, obesity, inflammation and cancer. Therefore, SIRT6 activity is crucial in many chronic diseases and healthy longevity (11). SIRT6 knockout mice manifested kyphosis, cachexia, greying of fur, decreased bone mineral density, reduced weight and subcutaneous fat, hypoglycemia, and chronic inflammation. Their lifespan was reduced to about one month (12). SIRT6 plays an important role in maintaining normal retinal function and its deficiency causes major chromatin changes in the retina of mice (13). SIRT6 is a critical regulator of endothelial senescence. Oxidative stress-induced down regulation of SIRT6 probably mediates the pathogenesis of diabetic retinopathy (14).

However, SIRT6 overexpression extended the lifespan of male mice by 15%, related to decrease in serum insulin-like growth factor (IGF-1s) and increase in IGF-binding protein 1 (15). Transgenic mice overexpressing SIRT6 are protected from metabolic disorders associated with triglyceride and accumulation of serum cholesterol and decreased glucose tolerance (16). Therefore, SIRT6 not only extends lifespan but also improves health quality, which is a major anti-ageing breakthrough (17). Ageing is a normal process in any living mammal. SIRT6 is related to longevity and ageing in animal studies, with no reported connection between human SIRT6 and longevity.

The populations of Bama County located in the Hongshuihe River Basin, Guangxi Province, have prolonged lifespan (18, 19). Populations in Hongshuihe River Basin represent the typical groups for studying longevity in Guangxi, China (20, 21). Although studies investigated the relationships between longevity, environmental and genetic factors, the specific mechanisms are still not clear.

In this study, we studied the rs350846 polymorphism of SIRT6 in the longevity group and the controls in an effort to unravel the genetic basis of longevity.

Methods

Study population

Longevity was defined as survival to age 90 yr or more. Based on the sixth national population census of China in 2010, we selected the Bama County as the sample site, in which there was a higher proportion of the longevous people than other counties. There total of 169 unrelated longliving individuals who satisfied the conditions (43 males and 126 females aged 90-110 yr, the mean ages 94.90 ± 4.73) were randomly selected as longevity group, and 158 unrelated participants (59 males and 99 females aged 26-82 yr, the mean ages 70.59 ± 11.09) from Bama also were enrolled as the internal control group (environmentally matched). The external control group consisted of 176 subjects (56 males and 120 females aged 20-82 yr, the mean ages 49. …

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