SIRT1 (sirtuin 1)
The NAD+-dependent metabolic sensor that resveratrol and pterostilbene activate to slow ageing
Definition
SIRT1 (sirtuin 1) is the most-studied of the seven human sirtuins: an NAD+-dependent deacetylase enzyme located in the nucleus and cytoplasm. It removes acetyl groups from key target proteins — PGC-1α, FOXO, p53, NF-κB — and thereby regulates mitochondrial biogenesis, glucose and lipid metabolism, DNA repair, inflammation, and autophagy. Because it consumes NAD+ in every reaction, its activity mirrors the cell's energy state, declining as NAD+ falls with age. It is the direct molecular target of resveratrol and pterostilbene.
Detailed explanation
SIRT1 acts as a switch that translates NAD+ availability into metabolic decisions. During fasting, caloric restriction, or exercise, the NAD+/NADH ratio rises and SIRT1 is activated; it then deacetylates and activates PGC-1α, the master regulator of mitochondrial biogenesis. Lagouge and Auwerx (Cell, 2006) showed that resveratrol, by activating SIRT1, improves mitochondrial function and protects against metabolic disease in mice, enhancing their endurance and aerobic capacity.
SIRT1 also deacetylates the FOXO family of transcription factors (Brunet, Science 2004), tilting the cellular response toward oxidative-stress resistance and repair rather than cell death, and it inhibits NF-κB (Yeung, 2004), dampening the chronic low-grade inflammation characteristic of ageing.
Therapeutic interest began with Howitz and Sinclair (Nature, 2003), who identified resveratrol as a sirtuin activator able to extend yeast lifespan by 70%. Pterostilbene — a dimethylated analogue of resveratrol with greater bioavailability — shares this pathway. Because SIRT1 requires NAD+, the most complete strategies pair an activator (pterostilbene, resveratrol) with NAD+ precursors (NMN, NR) so the enzyme never runs out of fuel.
Scientific sources
- PubMed — Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha (Lagouge, Auwerx, Cell 2006)
- PubMed — Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan (Howitz, Sinclair, Nature 2003)
- PubMed — Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase (Brunet, Science 2004)
- PubMed — Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase (Yeung, EMBO J 2004)
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