SIRT1 / SIRT3 / SIRT6 isoforms

Sirtuins are NAD⁺-dependent deacylases and ADP-ribosyltransferases; the three most studied longevity-relevant isoforms differ sharply in subcellular compartment and substrate specificity. SIRT1 is predominantly nuclear and cytosolic, deacetylating transcriptional regulators including p53, NF-κB, PGC-1α, and FOXO proteins to coordinate metabolism, stress response, and genome maintenance. SIRT3 localizes to the mitochondrial matrix, where its best-characterized substrates include SOD2 (K68; activating antioxidant defence) and components of the electron transport chain, directly linking NAD⁺ status to mitochondrial redox homeostasis. SIRT6 is a nuclear chromatin-associated sirtuin that removes H3K9ac and H3K56ac marks at sites of DNA damage and telomeres, and promotes genomic stability; overexpression of SIRT6 extends lifespan in male mice, and it was later shown to modulate IGF signalling and inflammation.