SIRT6 is a nicotinamide adenine dinucleotide+ (NAD+) dependent enzyme with two enzymatic activity of deacylase (specifically deacetylase) and mono ADP-ribosyl transferase.  As a member of the sirtuin family, SIRT6 has diverse functions in cellular health, longevity, and age-related diseases. Overexpression of SIRT6 confers remarkable prolongation of lifespan in mice and flies.

Prolonged lifespan in mice is accompanied by significantly improved physical activity like that of younger mice, maintaining young liver metabolism, blood biochemistry and lipid profile of young mice, as well as improved memory, all consistent with maintenance of a younger phenotype.

Mechanistically SIRT6 affects the majority hallmarks of aging through its involvement in DNA repair including telomere and centrosome maintenance. It involves in maintaining metabolic homeostasis, and secretion of the senescence-associated secretory phenotype (SASP). In addition, SIRT6 can prevent the development of inflammation via inhibition of the production of inflammatory cytokines and promotion of polarization of immune cells to an immunosuppressive phenotype. SIRT6 plays a crucial role in metabolic homeostasis, particularly in glucose and fat metabolism and insulin sensitivity. It affects glucose metabolism by modulating gene expression and enhancing insulin secretion. Additionally, SIRT6 has been shown to maintain a hormonal profile similar to that observed in calorie-restricted diets, which are known to extend lifespan, emphasizing the significant role of SIRT6 in metabolic conditions and its potential implications for promoting overall health and longevity.

As we get older, SIRT6 levels decline in various cells and tissues. This decline in SIRT6 protein levels leads to the accumulation of DNA lesions, increasing the risk of genomic instability and compromising cellular integrity. It also results in the accumulation of cellular damage, making individuals more susceptible to age-related conditions. Furthermore, the decline in SIRT6 disrupts glucose homeostasis, contributing to impaired glucose tolerance, insulin resistance, and an elevated likelihood of developing metabolic disorders, such as type 2 diabetes. Moreover, SIRT6 deficiency contributes to chronic low-grade inflammation, which is associated with a range of age-related diseases, including cardiovascular diseases, neurodegenerative disorders, and autoimmune conditions. Lastly, the diminished presence of SIRT6 has implications for the development and progression of fatty liver disease, encompassing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

The decline in SIRT6 levels, also leads to an increased accumulation of senescent cells in tissues, which further exacerbates tissue dysfunction, promotes chronic inflammation, causes tissue damage, and ultimately contributes to a variety of age-related pathologies. On the other hand, SIRT6 levels have been found to be enriched in human centenarians, individuals who have surpassed the age of 100 years. The presence of a centenarian SIRT6 allele has been shown to enhance genome maintenance, including more efficient repair of DNA double strand breaks. These findings suggest that SIRT6 plays a significant role in contributing to the longevity and healthy aging observed in centenarian.

The importance of SIRT6 activity becomes particularly significant in the context of frailty, aging, neuronal and cardiovascular diseases, diabetes, and lipid disorders. SIRT6’s role in these conditions highlights its potential as a therapeutic target for mitigating the effects of aging and age-associated diseases, offering promising avenues for intervention, and improving overall health outcomes.