Resveratrol

Resveratrol is a natural polyphenol produced by several plants in response to stress, most notably found in the skin of red grapes, blueberries, and Japanese knotweed. It gained fame as the proposed explanation for the "French Paradox" — the observation that French populations had lower cardiovascular disease despite high-fat diets, potentially due to red wine consumption. Resveratrol's primary longevity mechanism is SIRT1 activation, which it achieves by lowering the Km of SIRT1 for both NAD+ and its acetylated substrate. SIRT1 activation triggers a cascade of beneficial effects: enhanced mitochondrial biogenesis (via PGC-1α deacetylation), improved insulin sensitivity, reduced inflammation, and activation of autophagy. Resveratrol also activates AMPK, inhibits NF-κB, and has direct antioxidant properties.

It works synergistically with NAD+ precursors — resveratrol activates SIRT1 while NMN/NR provides the NAD+ fuel that SIRT1 requires. Human studies show benefits for cardiovascular markers, glucose metabolism, and inflammation, though bioavailability remains a challenge that newer formulations aim to address.