Sirtuins

What sirtuins actually are — and aren't

Sirtuins are a family of seven enzymes (SIRT1 through SIRT7) that depend on NAD+ to function. They regulate DNA repair, inflammation, metabolism, and cellular stress responses. In the early 2010s, they were marketed as "longevity genes" — a claim that turned out to be partially overblown. The original studies showing dramatic lifespan extension in yeast and worms had confounding genetic backgrounds, and pharmaceutical efforts to develop sirtuin-activating drugs largely failed due to assay artifacts ^[1].

But the story didn't end there. More rigorous research has re-established specific sirtuins as genuine players in aging biology. SIRT6 overexpression extends mouse lifespan by about 14.5%, with improvements in healthspan markers across the board ^[2]. A 2025 human study found that SIRT1, SIRT3, and SIRT6 protein levels decline by 56-64% from young adulthood to old age ^[3]. The current scientific consensus is more nuanced than either the hype or the backlash: sirtuins matter for aging, but they're not a magic switch you can flip with a single supplement.

How sirtuins connect to NAD+ and caloric restriction

Sirtuins need NAD+ as a cofactor — they literally can't function without it. NAD+ levels decline roughly 50% by middle age, which means sirtuin activity drops in lockstep ^[4]. This is why NAD+ precursors like NMN and nicotinamide riboside have attracted so much attention: by replenishing NAD+, they indirectly reactivate sirtuins across the board.

Caloric restriction — the most consistently replicated lifespan-extending intervention in animal models — works partly through sirtuins. Fasting increases the NAD+/NADH ratio, directly activating SIRT1 and SIRT3. When researchers genetically deleted SIRT1 in mice, caloric restriction no longer extended lifespan ^[5]. The practical implication: time-restricted eating and periodic fasting activate sirtuins through the same pathway that caloric restriction does, without requiring permanent calorie reduction.

The seven sirtuins and what each one does

SIRT1 is the most studied. It operates in the nucleus and cytoplasm, regulating inflammation, mitochondrial biogenesis, glucose metabolism, and circadian rhythms. SIRT3, located in mitochondria, is the only sirtuin with a direct genetic link to human longevity — specific variants are associated with longer lifespan in centenarian studies. SIRT6 is the standout for anti-aging research: it maintains genomic stability by repairing DNA double-strand breaks, preserves telomere length, and is the only sirtuin whose overexpression has extended mammalian lifespan ^[2].

The remaining four (SIRT2, SIRT4, SIRT5, SIRT7) have specialized roles in cell cycle regulation, fatty acid metabolism, amino acid catabolism, and ribosomal function. They matter, but they don't grab headlines the way SIRT1, SIRT3, and SIRT6 do.

What actually activates sirtuins

Exercise is the most reliable sirtuin activator that costs nothing. A 2023 meta-analysis of 34 studies found that high-intensity and fasted exercise increase SIRT1 in skeletal muscle, while resistance training elevates circulating SIRT1, SIRT3, and SIRT6 ^[6]. Endurance athletes have higher baseline SIRT1 levels than sedentary individuals.

Resveratrol was once celebrated as the key sirtuin activator, but the clinical picture is complicated. It's the most potent natural SIRT1 activator in lab assays, but oral bioavailability is only about 20%, which limits real-world effects. A 2025 dose-response meta-analysis of randomized controlled trials found measurable SIRT1 increases with resveratrol supplementation, though effect sizes varied substantially ^[7]. Pterostilbene, a related compound with 80% bioavailability, may be a more practical alternative.

NAD+ precursors (NMN and NR) provide indirect sirtuin activation by restoring the cofactor sirtuins need to function. Human trials consistently show NAD+ elevation, with some evidence for improved muscle function in older adults. The metabolic and longevity endpoints are still being studied.

The honest bottom line

Sirtuins are real biology, not wellness marketing. But the most effective ways to activate them — exercise, fasting, adequate sleep, and avoiding chronic stress — aren't novel or expensive. NAD+ precursors and polyphenol-rich foods provide additional support, but they work best on top of lifestyle foundations, not as replacements for them.