Pathway

Sirtuins (SIRT1–SIRT7)

Last updated 2026-05-17· 1 min read

Reviewed by the Ultimate Longevity Bible editorial team. Educational reference — not medical advice. See disclaimer.

What they are

Sirtuins are seven (SIRT1–7) NAD⁺-dependent deacylase enzymes descended from the yeast Sir2 gene. They sit in different cellular compartments and act on different substrates:

SIRT1, SIRT6, SIRT7 — nucleus, chromatin.
SIRT3, SIRT4, SIRT5 — mitochondria.
SIRT2 — cytoplasm.

Why they matter

Sirtuin overexpression extends lifespan in worms, flies, and mice (in sex- and isoform-specific ways). They couple nutrient state (NAD⁺ availability) to chromatin remodelling, DNA repair, mitochondrial function, and metabolic flexibility.

SIRT6 stands out

SIRT6 knock-out mice show progeroid phenotype; SIRT6 transgenic males live longer. SIRT6 maintains telomere integrity and represses LINE-1 retrotransposons that accumulate with age.

Activators

NAD⁺ raising compounds: NR/NMN.
Sirtuin-activating compounds (STACs): resveratrol, pterostilbene (controversial mechanistic literature).
Caloric restriction and exercise (indirect via NAD⁺).

Longevity relevance

The sirtuins (SIRT1-SIRT7) are NAD+-dependent deacetylases and mono-ADP-ribosyltransferases central to metabolic sensing and stress-response biology. Their discovery in the yeast lifespan literature (Sir2) launched a wave of longevity interest and underpins the NAD+ precursor supplement category.

Family members

SIRT1 (nuclear): the most-studied; regulates PGC-1α, FOXO, p53, NF-κB. Central to caloric-restriction-response signalling.
SIRT3 (mitochondrial): regulates mitochondrial protein acetylation, metabolic enzymes, ROS management.
SIRT6 (nuclear): telomere maintenance, DNA repair, glucose homeostasis; SIRT6 overexpression extends mouse lifespan.
SIRT2, 4, 5, 7: various roles in cell-cycle regulation, metabolism, and stress response.

Interventions

NAD+ precursors (NR, NMN) aim to elevate sirtuin activity by increasing substrate availability.
Resveratrol and STAC (SIRT1-activating compound) programmes were once high-profile but the mechanistic story has been substantially revised.
Caloric restriction and exercise activate sirtuins indirectly.

References

Bonkowski, M. S. & Sinclair, D. A. Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat. Rev. Mol. Cell Biol. 17, 679–690 (2016).