Sirtuins

Sirtuins are a family of seven proteins (SIRT1–SIRT7) that regulate gene expression, mitochondrial function, DNA repair, and cellular stress resistance. They require NAD+ to function and are activated by fasting, caloric restriction, and exercise — placing them at the intersection of longevity science.

Sirtuins were discovered in the context of lifespan research in yeast, where activation of the sirtuin Sir2 extended replicative lifespan. In mammals, the seven sirtuins are distributed across different cellular compartments and perform distinct but related functions in longevity regulation.

SIRT1 is the most studied mammalian sirtuin: it deacetylates and regulates the activity of PGC-1α (the master regulator of mitochondrial biogenesis), p53 (a tumor suppressor), NF-κB (the master inflammatory transcription factor), and FOXO proteins (which regulate stress resistance and autophagy). SIRT1 activation therefore simultaneously promotes mitochondrial health, suppresses inflammation, enhances DNA repair, and activates cellular stress defenses.

SIRT3 regulates mitochondrial metabolism and is the primary sirtuin in that organelle. SIRT6 is critical for DNA double-strand break repair — mice with SIRT6 deletion die prematurely from a syndrome resembling accelerated aging.

All sirtuins require NAD+ as a substrate — they are NAD+-dependent deacylases. The decline in NAD+ with age consequently reduces sirtuin activity, and this is one mechanism through which preserving NAD+ supports longevity pathways.

Resveratrol, the polyphenol in red wine, was extensively studied as a sirtuin activator, but subsequent evidence suggests its direct sirtuin-activating effects in humans are modest. Caloric restriction, intermittent fasting, and aerobic exercise are the most reliable sirtuin activators available.

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