The role of sirtuins (SIRT1-SIRT7) in cellular metabolism and aging: A molecular overview

Abstract

Sirtuins (SIRT1-SIRT7), a family of NAD⁺-dependent deacetylases and ADP-ribosyltransferases, have emerged as key regulators of metabolic homeostasis, stress responses, and the aging process in eukaryotic organisms. These highly conserved enzymes influence multiple biological pathways, including DNA repair, mitochondrial function, insulin sensitivity, and inflammation. Their dependence on NAD⁺ links their activity to the cell's metabolic state, positioning them as metabolic sensors. Sirtuins are localized in different cellular compartments-nucleus, cytoplasm, and mitochondria and each member exhibits unique substrate specificity and physiological roles. This review presents a comprehensive molecular overview of SIRT1 through SIRT7, highlighting their distinct and overlapping functions in cellular metabolism and aging. Furthermore, the potential of targeting sirtuins in age-related diseases and metabolic disorders is discussed, emphasizing the therapeutic promise of sirtuin modulation in promoting healthspan and longevity. Keywords: Sirtuins (SIRT1-SIRT7, ADP-ribosyltransferases, healthspan and longevity, insulin sensitivity 1. Introduction Aging is a complex biological process characterized by a gradual decline in physiological integrity, increased susceptibility to disease, and eventual death. Cellular metabolism plays a crucial role in determining the pace and quality of aging. Among the molecular regulators linking metabolism to aging, sirtuins have garnered significant attention for their conserved roles across species in modulating longevity and stress resistance. Sirtuins, initially discovered in yeast as silent information regulators (Sir2), are now recognized in mammals as a family of seven homologs (SIRT1-SIRT7). These proteins require nicotinamide adenine dinucleotide (NAD⁺) for their enzymatic activity, thereby directly coupling their function to the cellular redox state and energy availability. This dependency places sirtuins at the center of the metabolic-aging interface. Each sirtuin is compartmentalized in distinct cellular regions-SIRT1, SIRT6, and SIRT7 predominantly in the nucleus; SIRT2 in the cytoplasm; and SIRT3, SIRT4, and SIRT5 in the mitochondria. Their enzymatic functions extend beyond deacetylation to include ADP-ribosylation, demalonylation, and desuccinylation, with broad substrate specificity. Their roles in gene expression, mitochondrial biogenesis, glucose and lipid metabolism, and cell survival have been linked to age-related diseases such as diabetes, neurodegeneration, and cardiovascular disorders. This paper explores the molecular biology of each sirtuin and their integrative roles in metabolism and aging, setting the foundation for therapeutic strategies aimed at modulating sirtuin activity.