Sirtuins: the NAD+-dependent enzymes behind the resveratrol and NMN claims

Before you read onResearch and educational information for adults, not medical advice. This entry explains one longevity term — what it means, why it matters and what the evidence says — and nothing here diagnoses, treats, cures or prevents any condition. Baseline labs come before anything, and your own physician has the final word. Longevity Bros offers coaching and written research protocols only — we do not sell, supply, source or ship any compound.

What it means

Sirtuins are a family of seven enzymes (SIRT1–SIRT7) that remove acetyl groups from proteins, altering their function. Their defining feature is that they need NAD+ as a co-substrate, which ties their activity to the cell's energy state: high NAD+ (fasting, exercise) means more sirtuin activity; low NAD+ (ageing, overfeeding) means less.

SIRT1 regulates metabolism, inflammation and circadian rhythm; SIRT3 lives in mitochondria and manages oxidative stress; SIRT6 is involved in DNA repair and glucose handling. Together they are a bridge between what you eat and how your cells maintain themselves.

Why it matters for longevity

Sirtuin activity falls with age, partly because NAD+ falls. Overexpressing SIRT6 extends lifespan in mice; sirtuin activation is one proposed mechanism for the benefits of calorie restriction and exercise. That is why raising NAD+ with NMN or NR, or activating SIRT1 with resveratrol, became the longevity-supplement thesis.

What the evidence says

The animal data are decent: SIRT6 overexpression extended lifespan in male mice (Kanfi 2012) and in both sexes in a 2021 follow-up; SIRT1 activation improves metabolic markers in rodent models. The original yeast lifespan results from the early 2000s have been contested but the mammalian mechanism work holds up.

In humans the chain breaks at the activator. Resveratrol trials show little consistent effect on metabolic markers, and oral bioavailability is poor. NAD+ precursors raise blood NAD+ reliably but trials have shown minor or no changes in the outcomes sirtuins are supposed to control (Martens 2018, Dollerup 2018, Yoshino 2021). No human trial has measured sirtuin activity change and linked it to an outcome.

How to measure or use it

Sirtuin activity is not measurable in a clinical lab. NAD+ levels can be measured in whole blood by some specialist labs, with wide reference ranges.
The activators with human evidence are the unglamorous ones: exercise, an overnight fast and keeping body fat in range, all of which raise the NAD+/NADH ratio.
If you take a precursor, judge it on the markers you can see — hs-CRP, HbA1c, performance — not on the mechanism.

Mitochondria and energy — the NAD+ trials, tabulated
NAD+ (research page) — what NAD+ is studied for
Supplements that have evidence — where resveratrol and NMN rank

Frequently asked questions

Does resveratrol activate sirtuins in humans?

In cells, at high concentrations, yes. In people, oral doses reach low blood levels and trials show little metabolic effect. The claim is mechanistic, not clinical.

Is raising NAD+ the same as activating sirtuins?

Not necessarily. NAD+ is required but not sufficient; trials that raised NAD+ have not shown the downstream changes the theory predicts.

Which sirtuin matters most for ageing?

SIRT1, SIRT3 and SIRT6 have the strongest animal data. In humans, none has been directly tested.

Your own protocol

Want this applied to your own numbers?

Fifteen minutes of intake, your labs, a human-reviewed protocol within about 24 hours, three documents, a free coach call and check-ins through the cycle. €399, follow-up included.

Build my protocol Book a 15-minute call