What sirtuins are
Sirtuins are NAD+-dependent deacetylase enzymes, they remove acetyl groups from proteins, particularly histones (DNA-packaging proteins) and transcription factors. By altering protein acetylation, they regulate gene expression and protein function.
The seven sirtuins
- SIRT1, nuclear; major aging and metabolism regulator
- SIRT2, cytoplasmic; cell cycle
- SIRT3, mitochondrial; energy metabolism, oxidative stress
- SIRT4, mitochondrial; metabolism
- SIRT5, mitochondrial; metabolism, oxidative stress
- SIRT6, nuclear; DNA repair, glucose metabolism
- SIRT7, nucleolar; ribosomal biogenesis
What sirtuins do
- Regulate gene expression (deacetylate histones)
- Support DNA repair
- Activate PGC-1α (mitochondrial biogenesis)
- Regulate stress response
- Modulate inflammation
- Influence circadian biology
- Regulate metabolism (fasting state, glucose, lipids)
Sirtuin activators
- NAD+ adequacy (cofactor)
- Caloric restriction / fasting
- Exercise
- Cold exposure
- Resveratrol (modest direct activation)
- Pterostilbene
- Quercetin (some evidence)
The NAD+ link
Sirtuins use NAD+ as a substrate (consumed in their reactions). When NAD+ levels are low, sirtuin activity drops. This is the central reason NAD+ optimization is a longevity strategy, adequate NAD+ enables sirtuin function, which underlies many aging benefits.
Implications for aging
Sirtuins integrate:
- Metabolic state (fasting/feeding)
- Oxidative stress
- DNA damage signaling
- Inflammation
- Circadian biology
The integration is what makes sirtuin biology central to aging research. Activating them through lifestyle (exercise, fasting) and NAD+ adequacy is among the cleanest longevity interventions.
The clinical insight: Sirtuins are activated by metabolic stress (fasting, exercise) and require NAD+ as a cofactor. The combination of regular exercise, periodic fasting or time-restricted eating, and NAD+ adequacy supports sirtuin function, and through it, healthy aging.
Bottom line
Sirtuins are NAD+-dependent enzymes central to aging biology. Activated by metabolic stress and NAD+ adequacy. Their regulation of gene expression, DNA repair, and metabolism makes them key longevity targets. Lifestyle interventions plus NAD+ optimization activate them effectively.