SIRT2 belongs to the class III histone deacetylase family, enzymes that remove chemical tags from proteins using nicotinamide adenine dinucleotide, or NAD+, as an essential cofactor. Its conserved catalytic core of roughly 275 amino acids contains a Rossmann-fold domain that grips NAD+ and a zinc-binding domain that stabilizes the protein’s structure. Because NAD+ levels inside cells fluctuate with nutritional status, mitochondrial function, and energy demand, SIRT2 effectively acts as a metabolic sensor: when the cellular energy landscape shifts, so does its deacetylase activity. By stripping acetyl groups from a broad range of non-histone substrates, SIRT2 alters the function, stability, and localization of metabolic enzymes, allowing cells to retune their metabolism in real time.

The clearest examples come from glucose metabolism. In the liver, SIRT2 deacetylates the glucokinase regulatory protein at lysine 126, which helps release glucokinase so the liver can take up glucose more efficiently. Overexpressing SIRT2 in the livers of obese diabetic mice improves glucose uptake and glucose tolerance, while reducing SIRT2 does the opposite. The enzyme also targets pyruvate kinase M2, a gatekeeper of glycolysis, in strikingly context-dependent ways. Deacetylation at lysine 305 promotes the formation of PKM2’s active tetramer and boosts glycolytic flux in cancer cells, whereas deacetylation at lysine 207 in inflamed microglial cells destabilizes the same protein and dampens glycolysis. SIRT2 further deacetylates phosphoglycerate mutase 2 and stabilizes the gluconeogenic enzyme PEPCK1, showing that it regulates multiple nodes of the glycolytic and gluconeogenic network rather than a single enzyme.

Lipid metabolism is another major arena. SIRT2 deacetylates ATP-citrate lyase, promoting its degradation and thereby limiting de novo fat synthesis. It stabilizes the transcription factor HNF4-alpha through deacetylation at lysine 458, a modification that protects the liver from insulin resistance, fatty infiltration, and inflammation. In the heart, SIRT2 deacetylates carnitine palmitoyltransferase 2 at lysine 239, restraining fatty acid oxidation and reactive oxygen species production in a way that protects against diabetic cardiomyopathy. In adipose tissue, SIRT2 deacetylates FOXO1, which strengthens FOXO1’s grip on PPAR-gamma and suppresses adipocyte differentiation while promoting fat breakdown. Hypoxia-inducible factor 1-alpha, elevated in obesity, suppresses SIRT2 in visceral fat cells, weakening fatty acid oxidation and mitochondrial gene expression and thereby promoting metabolic dysfunction.

Mitochondria, the cell’s power plants, are central to the aging process, and SIRT2 touches nearly every aspect of their biology. Oligodendrocytes package SIRT2 into exosomes and deliver it to neuronal axons, where it deacetylates the mitochondrial transporters ANT1 and ANT2 to boost ATP production. In vascular endothelial cells, loss of SIRT2 lowers mitochondrial membrane potential and ATP levels while increasing cell death. SIRT2 also guards the mitochondrial redox balance: its activity declines with age, and in aged mice its deficiency worsens vascular dysfunction by allowing abnormal activation of the p66Shc protein, which drives excess mitochondrial reactive oxygen species. During cellular senescence, reduced SIRT2 activity leaves tubulin excessively acetylated, disrupting microtubule dynamics and impairing the microtubule-dependent mitochondrial repair and mitophagy that aging cells desperately need.

Beyond direct metabolic control, SIRT2 plugs into the nutrient-sensing pathways that evolution has conserved as longevity regulators. In fruit flies, a tryptophan-derived microbial metabolite called indole-3-acetic acid extends lifespan through an AhR–SIRT2–TOR signaling axis, implicating SIRT2 in the gut-microbiome-to-longevity conversation. SIRT2 also activates AMPK, the cell’s fuel gauge, by deacetylating the kinase LKB1; when SIRT2 is missing, AMPK activity falls and cardiac hypertrophy worsens, even blunting the cardioprotective effects of metformin. Under amino acid starvation, SIRT2 is translationally upregulated through an upstream open reading frame and then suppresses global protein synthesis by stabilizing 4E-BP1, helping cells survive nutrient stress. Whether SIRT2 directly mediates the lifespan extension produced by dietary restriction remains unproven, but the circumstantial connections are compelling.

The review also connects SIRT2 to the classic hallmarks of aging. On oxidative stress, SIRT2 deacetylates FOXO3a to enhance antioxidant gene expression, activates PGAM2 to sustain NADPH production, and desuccinylates the glutathione-synthesis enzyme GCLC, all of which keep reactive oxygen species in check. In the Asian honeybee, age-related SIRT2 decline accompanies mitochondrial damage, while SIRT2 activation promotes PINK1/Parkin-dependent mitophagy and delays cellular aging. On inflammation, SIRT2 deacetylates the NF-kappa-B subunit p65 at lysine 310 to restrain inflammatory gene expression, suppresses the NLRP3 inflammasome to protect aging hematopoietic stem cells, and dismantles the cGAS–STING DNA-sensing pathway by deacetylating G3BP1, blunting a major driver of chronic age-related inflammation.

Genome integrity adds another layer. SIRT2-deficient mice show chromosomal instability and increased cancer susceptibility, partly because SIRT2 loss elevates H4K16 acetylation and disrupts mitotic deposition of H4K20 methylation. SIRT2 also maintains the expression and function of BubR1, a mitotic surveillance protein whose age-related decline is linked to multiple diseases. Perhaps most strikingly, SIRT2 expression drops in the hearts of aged macaques, and in human stem-cell-derived cardiomyocytes its loss hyperacetylates STAT3, activating the CDKN2B gene and imposing age-like characteristics; restoring SIRT2 in mice alleviates age-related cardiac dysfunction. In skeletal muscle, SIRT2 knockout in aged male mice worsens fat infiltration and impairs regeneration, pointing to a role in combating sarcopenia.

The authors are careful about the caveats. SIRT2’s effects are highly context- and tissue-dependent: the same deacetylation event can activate a metabolic enzyme under oxidative stress yet trigger its degradation in cancer cells, and inhibiting SIRT2 can actually improve the metabolic fitness of antitumor T cells. The enzyme also carries deacylase activities beyond deacetylation, including demyristoylation and delipoylation, whose physiological importance is only beginning to be explored, and age-accumulating isoforms such as SIRT2.3 may behave differently from the canonical protein. Its precise contribution to organismal longevity remains incompletely understood, and whether boosting NAD+ to enhance SIRT2 activity can translate into therapies for healthy aging is still an open question. What the evidence does establish is that SIRT2 functions as a molecular checkpoint linking cellular energy status to the adaptive responses that determine how tissues age, making it one of the most intriguing targets in the search for interventions that promote metabolic health across the lifespan.

Subject of Research: The role of the NAD+-dependent deacetylase SIRT2 in regulating energy metabolism, aging, and longevity

Article Title: SIRT2 in metabolism, aging, and longevity

Article References: Li, M., Dong, Y., Ren, W., Dong, W., & Ji, S. (2026). SIRT2 in metabolism, aging, and longevity. Frontiers in Molecular Biosciences, 13, Article 1990670. https://doi.org/10.3389/fmolb.2026.1990670

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1990670

Keywords: SIRT2, sirtuins, NAD+, aging, longevity, metabolism, mitochondria, inflammation, oxidative stress, glucose metabolism, lipid metabolism, cellular senescence