SIRT2 in metabolism, aging, and longevity

SIRT2, an NAD⁺-dependent deacetylase, is increasingly recognized as an important regulator of cellular metabolism and aging. By deacetylating diverse substrates, SIRT2 influences glucose metabolism, lipid metabolism, mitochondrial function, cytoskeletal dynamics, oxidative stress, and inflammatory responses, thereby contributing to cellular metabolic homeostasis and aging. Emerging evidence suggests that age-related alterations in NAD⁺ metabolism may affect SIRT2 activity and disrupt these processes, potentially promoting metabolic dysfunction, mitochondrial impairment, cellular senescence, and chronic inflammation. In addition, the effects of SIRT2 on aging appear to be highly context- and tissue-dependent, and its precise contribution to organismal longevity remains incompletely understood. In this review, we primarily focus on the role of SIRT2 in aging and longevity through the regulation of energy metabolism, with particular emphasis on the underlying molecular mechanisms and its interactions with metabolic and stress-responsive pathways. Understanding these mechanisms and regulations may provide new insights into SIRT2 biology and potential strategies for maintaining metabolic homeostasis and promoting healthy aging, even applications in clinic practice.