Chapter 5 - Sirtuins, healthspan, and longevity in mammals

Abstract

Aging, characterized by progressive deterioration of physiological function, leading to increased mortality, is associated with many major classes of diseases in humans: cancer, type II diabetes, and cardiovascular, and neurodegenerative diseases. The major goal of aging research is to develop interventions that can reduce the risk of age-related disease and prolong healthy lifespan. The seven mammalian sirtuins (SIRT1–SIRT7) are NAD+-dependent enzymes, which regulate a wide range of cellular processes, have emerged as promising candidates for new therapeutics to suppress a variety of age-associated pathologies to promote healthspan. While SIRT1 has been at the forefront of sirtuin research, functional insights regarding SIRT2–SIRT7 are rapidly accumulating. All mammalian sirtuins are implicated in influencing many common diseases of aging, serving as either disease promoters or suppressors in a context specific manner. Moreover, evidence reveals that increased expression of SIRT1 or SIRT6 extends mouse lifespan. Pharmacologic targeting of sirtuins—either directly with specific activators/inhibitors, or indirectly with interventions to boost cellular NAD+ levels—has been proposed as one means of treating or preventing age-associated disease. This chapter summarizes interactions between sirtuins and age-associated diseases, and the current status of development of small-molecule compounds to modulate sirtuin activities with high potency and specificity.