A Remarkable Age-Related Increase in SIRT1 Protein Expression against Oxidative Stress in Elderly: SIRT1 Gene Variants and Longevity in Human

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.

The influence of rs2273773 and rs7895833 SIRT1 gene polymorphisms on life expectancy in context of metabolic factors in Silesian population

“…Currently, there are only few works in world literature on the direct relationship between polymorphisms and prolonged life. Recent reports by Kilica et al [18] indicated a significant increase in sirtuin levels in the elderly (73.5 ± 1.0, 56-92 years) and a correlation between the incidence of the rs7895833 polymorphism AG genotype in individuals from this group and the control group, where the mean age was 46.9 ± 0.5 years. This genotype occurred in 33.3% of children (control group), in 27.0% of adults (control group) and in 45.6% of the elderly (study group) (p = 0.014) [18].…”

“…Therefore, currently, thanks to the rise of molecular biology, the importance of different variants of genes in the modification of ageing processes is increasingly pointed out as well as their impact on the prolongation of human life. One of the leading representatives is the SIRT1 gene, whose polymorphisms (rs7895833 A > G, rs2273773 C > T) are indirectly related to ageing by affecting cholesterol metabolism, body mass, obesity and atherosclerosis, as well as directly by causing cognitive impairment or increasing the amount and activity of sirtuins [18,21,22,23,24]. In our study, patients who had a BMI of 25 or more constituted the control group as scientific evidence indicates they live significantly shorter than those with a normal body mass.…”

“…W wątrobie aktywuje receptor LXR, co powoduje zahamowanie jelitowej absorpcji, i stymuluje odwrócony transport cholesterolu [17]. Biorąc pod uwagę związek przemian metabolicznych z procesami starzenia i rolę regulatorową sirtuin w obu vascular disease, and only few studies suggest their association with prolonged life [18].…”

“…Motywem wyboru tych konkretnych dwóch polimorfizmów (rs7895833 A > G, rs2273773 C > T) była chęć poszerzenia wiedzy na temat ich powiązań z dłu-gowiecznością. Dotychczasowa literatura wskazuje na ich rolę w patogenezie otyłości, cukrzycy typu 2 czy chorób sercowo-naczyniowych, a jedynie nieliczne prace wskazują na ich związek z wydłużeniem życia [18].…”

“…Dlatego obecnie, dzięki rozkwitowi biologii molekularnej, coraz częściej wskazuje się na znaczenie różnych wariantów genów w modyfikacji procesów starzenia i ich wpływ na wydłużenie życia człowieka. Jednym z czołowych przedstawicieli jest gen SIRT1, którego polimorfizmy (rs7895833 A > G, rs2273773 C > T) powiązane są pośrednio ze starzeniem poprzez wpływ na metabolizm cholesterolu, masę ciała, powstanie otyłości i miażdżycy oraz bezpośrednio przez upośledzenie procesów poznawczych czy wzrost ilości i aktywności sirtuin [18,21,22,23,24]. W naszym badaniu za próbę kontrolną przyjęto pacjentów, których BMI wynosi powyżej 25, gdyż jak dowodzą badania naukowe, osoby te żyją znacząco krócej od tych z prawidłową masą ciała.…”