A remarkable age-related increase in SIRT1 protein expression against oxidative stress in elderly: SIRT1 gene variants and longevity in human.

Ulkan Kilic,Mehmet Rusen Dundaroz,Omer Uysal,Ozlem Gok,Ufuk Erenberk,Tolga Dundar,Yasar Kucukardali,Emel Torun,Birsen Elibol-Can,Stephen E Alway

doi:10.1371/journal.pone.0117954

Abstract

Aging is defined as the accumulation of progressive organ dysfunction. Controlling the rate of aging by clarifying the complex pathways has a significant clinical importance. Nowadays, sirtuins have become famous molecules for slowing aging and decreasing age-related disorders. In the present study, we analyzed the SIRT1 gene polymorphisms (rs7895833 A>G, rs7069102 C>G and rs2273773 C>T) and its relation with levels of SIRT1, eNOS, PON-1, cholesterol, TAS, TOS, and OSI to demonstrate the association between genetic variation in SIRT1 and phenotype at different ages in humans. We observed a significant increase in the SIRT1 level in older people and found a significant positive correlation between SIRT1 level and age in the overall studied population. The oldest people carrying AG genotypes for rs7895833 have the highest SIRT1 level suggesting an association between rs7895833 SNP and lifespan longevity. Older people have lower PON-1 levels than those of adults and children which may explain the high levels of SIRT1 protein as a compensatory mechanism for oxidative stress in the elderly. The eNOS protein level was significantly decreased in older people as compared to adults. There was no significant difference in the eNOS level between older people and children. The current study is the first to demonstrate age-related changes in SIRT1 levels in humans and it is important for a much better molecular understanding of the role of the longevity gene SIRT1 and its protein product in aging. It is also the first study presenting the association between SIRT1 expression in older people and rs7895833 in SIRT1 gene.

Highlights

Sirtuin 1 (SIRT1), the longevity gene, is located on chromosome 10q21.3 and consists of 11 exons and 10 introns (PUBMED gene, updated on 30-Nov-2014)
SIRT1 protein expression level and its correlation with age, levels of eNOS and PON-1 proteins, total antioxidant status (TAS), total oxidant status (TOS) and oxidative stress index (OSI) were demonstrated in Fig. 2A and Table 3
We investigated how SIRT1 protein level, the product of longevity gene, changes with aging in response to the finding of one of our studies presenting a positive correlation with SIRT1 protein and age [15]

Summary

Introduction

Sirtuin 1 (SIRT1), the longevity gene, is located on chromosome 10q21.3 and consists of 11 exons and 10 introns (PUBMED gene, updated on 30-Nov-2014). SIRT1 protects cells against oxidative stress, regulates glucose/lipid metabolism, and promotes DNA stability by binding to and deacetylating several substrates [3]. Because of these protective roles against several age-related pathologies, SIRT1 is thought as one of the candidate molecules for promoting healthy aging. In previous lifespan studies done using yeast, worms and flies as model organisms, it was found that sirtuins are evolutionarily conserved mediators of longevity [5,6,7]. The effect of SIRT1 against age-related diseases for lifespan elongation may occur by increasing stress resistance and protecting cell death. Alcendor et al [9, 10] reported that the protective effects of SIRT1 are because of its inhibitory effect on p53 acetylation which stimulates cell death mechanisms and its stimulatory effect on cytoprotective- and stress resistancegenes activator FoxO1a which prevents oxidative stress by upregulating catalase activity

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