Analysis of the association between SIRT6 gene polymorphisms with Lifespan in the Bushehr elderly health study
Aging is defined as the overall decline in the functional capacity of cells and organs due to accumulated damage at the molecular level, and increases the risk of several adverse health outcomes, including cardiovascular disease, neurological disorders, and cancer. The aging process involves all cells in the human body and can disrupt cellular homeostasis by increasing the dysregulation of some cellular components. These dysregulations can include: disruption of metabolic pathways, dysfunction of mitochondria, genomic instability, shortening of chromosome ends, epigenetic changes, disruption of protein homeostasis, dysfunction in the recognition and response to changing macronutrient concentrations, increased inflammation, and reduced regenerative capacity of stem cells, which are known as hallmarks of aging.
On the other hand, Sirtuin-6 is one of the mammalian sirtuins located in the nucleus and has ADP-ribosylation and NAD+-dependent deacetylation activities. The research background in this area indicates the potential impact of the SIRT6 gene on the hallmarks of aging (especially genomic stability and telomere stabilization) and, as a result, this gene is influential on longevity and health of life: SIRT6 maintains genomic stability by deacetylating telomeric amino acid residues. Deacetylation is required for chromatin compaction and responses to DNA damage and prevents cellular aging. Sirtuins play a critical role in maintaining genome integrity by helping to maintain the normal state of chromatin compaction and responses to DNA damage. In addition, SIRT6 is involved in several DNA repair systems, such as double-strand break repair. SIRT6 is known to regulate the expression of the enzyme TERT, which affects telomere length.
And the lack of SIRT6 leads to the formation of dysfunctional telomeres. Also, the absence or reduction of SIRT6 levels causes increased DNA damage and abnormal transcription, as well as instability in telomeres and centromeres and disruption of heterochromatin sustentation. At the molecular level, SIRT6 plays a role in DNA repair, telomere maintenance, silencing of repetitive elements including LINE1 retrotransposons, regulation of glucose homeostasis and inflammation. With this evidence, it can be concluded that:
SIRT6, as a gene whose effects on aging have been proven in terms of helping to maintain genome stability, is considered a potential candidate
for genetic studies in the field of longevity. Also, SIRT6 delays cellular senescence by increasing the degradation of p27Kip1 ubiquitin-proteasome. SIRT6 increases the expression of metallothionein 1/2 and Nrf2, and thus reduces oxidative stress. (Oxidative stress) is known as one of the factors affecting aging. SIRT6 also reduces inflammatory factors and increases anti-inflammatory factors by preventing the activity of c-jun, Notch1/4 signaling pathways and AKT signaling pathway. As a result, it will suppress inflammation. (Inflammation) is also known as one of the very important hallmarks involved in aging. SIRT6 also increases autophagy. The effect of (autophagy) on aging has also been proven previously. SIRT6 also activates PARP-dependent repair in single-strand and double-strand DNA breaks. SIRT6 also maintains the normal function of telomeres. As a result, it plays a broad role in genomic stability. (Genomic instability) is also known as the first hallmark of aging.
SIRT6 slows down cellular aging through its effects on NAD+ and glucose metabolic pathways.
Decreased SIRT gene expression increases FOXO gene expression, which encodes the forkhead box protein, which has also been shown to have an effect on aging. To better predict the variability in human lifespan and confirm the association between SIRT6 and lifespan in the Bushehr population, we considered SIRT6 gene polymorphisms as candidates and will conduct an association study to test whether SIRT6 polymorphisms are associated with lifespan in the Bushehr population. For this purpose, GWAS data from 3,000 elderly people in the Bushehr cohort will be used to determine the association between (three SIRT6 gene variants) and (individuals who died of natural death at the age of 60 to 70 years and healthy elderly who did not die).
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