# SIRT1 / SIRT3 / SIRT6 isoforms

Sirtuins are a family of enzymes that depend on NAD⁺ to remove chemical tags from proteins. The three most studied for longevity differ sharply in where they work and what they target. SIRT1 is mostly in the nucleus and cytoplasm. It de-acetylates key regulators (like p53, NF-κB, PGC-1α, and FOXO proteins) to coordinate metabolism, stress response, and genome upkeep. SIRT3 lives in the mitochondria. Its best-known targets include the antioxidant enzyme SOD2 (which it activates) and parts of the electron transport chain, directly linking your NAD⁺ status to mitochondrial redox balance. SIRT6 sits on chromatin in the nucleus. It removes specific marks (H3K9ac and H3K56ac) at DNA-damage sites and telomeres, promoting genome stability. Overexpressing SIRT6 extends lifespan in male mice, and it was later shown to tune IGF signaling and inflammation.

## Sources

- Imai S, Guarente L. (2014). NAD+ and sirtuins in aging and disease. Trends in Cell Biology. https://doi.org/10.1016/j.tcb.2014.04.002
- Haigis MC, Sinclair DA. (2010). Mammalian sirtuins: biological insights and disease relevance. Annual Review of Pathology. https://doi.org/10.1146/annurev.pathol.4.110807.092250

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_Canonical: https://longevity-switzerland.com/en/glossary/sirt-isoforms · Part of Longevity Cities · Updated 2026-06-22_