SIRT1

SIRT1 is a NAD-dependent deacetylase, which can regulate a number of processes by deacetylating key proteins, such as TP53. In yeast, the SIRT1 homologue sir2 has been linked to cellular senescence. Increasing the levels of SIRT1 homologues in fruit flies and roundworms extends lifespan, although these findings have been questioned by other studies. SIRT1-null mice are born smaller than controls with evidence of developmental retardation. Depending on their genetic background, SIRT1-null mice either die shortly after birth or reach adulthood, the latter being smaller than controls and sterile. Additionally, SIRT1-null mice utilize ingested food inefficiently, are hypermetabolic, contain inefficient liver mitochondria, have elevated rates of lipid oxidation and do not display an extended lifespan under caloric restriction. Heterozygous mice had a normal average lifespan. Mice with moderate overexpression of SIRT1 exhibit fat mass gain similar to controls exposed to a high-fat diet. Cardiac-specific low to moderate overexpression of SIRT1 attenuated age-dependent increases in cardiac hypertrophy, apoptosis, and expression of senescent biomarkers while a high level of overexpression had detrimental effects and induced cardiomyopathy. Overall, whole-body moderate overexpression of Sirt1 improves healthy ageing but does not increase mice lifespan. Brain-specific overexpression in mice results in moderately longer lifespan as females live 16% longer and males 9% longer. SIRT1 is overexpressed in calorie restricted rats, a response attenuated by insulin (INS) and IGF1. Increased dosage of SIRT1 in pancreatic beta cells enhanced INS secretion. In Cockayne syndrome, an accelerated ageing disease, activation of SIRT1 through a high-fat diet and NAD(+) supplementation results in the rescue the mice from the associated progeroid phenotypes. In murine induced pluripotent stem cells, SIRT1 is necessary for telomere elongation after reprogramming and is required to maintain genomic stability, telomeric transcription and remodeling of telomeric chromatin. SIRT1-deficient induced pluripotent stem cells accumulate chromosomal aberrations and show a derepression of telomeric heterochromatin. In humans, increased levels of SIRT1 and SIRT3 have been associated with frailty. Although SIRT1 could impact on age-related diseases, such as type 2 diabetes, further studies are needed to establish its role in human ageing.