Sirtuins and NAD-Dependent Signaling

What sirtuins are

Sirtuins are a family of seven enzymes in mammals, called SIRT1 to SIRT7. They need a helper molecule, NAD+, to work. [1] NAD+ is a coenzyme central to energy metabolism, and it is also needed by non-redox enzymes including sirtuins. [2] Sirtuins have been linked to metabolism, stress response, DNA repair and inflammation. [1] This page is education only. It gives no amounts and no advice to take any supplement or drug. Aging is not an approved medical indication for any compound discussed.

The history, and why it became controversial

Early work found that sirtuins regulate lifespan in yeast, roundworms and fruit flies. Later, the role of sirtuins in worm and fly lifespan became controversial, and the role of the seven mammalian sirtuins in lifespan was unclear. [3] A 2012 commentary notes that this controversy was being re-examined, with a new fruit fly study reporting that the fly sirtuin was needed for lifespan extension on dietary restriction. [4] A 2012 drug-discovery review covers "the current status and controversies" around sirtuins as targets, with a focus on SIRT1. [5] A 2024 review states that overexpressing SIRT1 relatives extends lifespan in yeast, worms, flies and mice, [1] so the safest summary is: the animal story is real but not uniform, and it has been contested.

One mouse example: male, but not female, mice engineered to overproduce SIRT6 lived longer than normal mice. [3] Label: preclinical. A sex-specific result in engineered mice does not tell us what to expect in people.

Resveratrol and "sirtuin activators"

Resveratrol and a lab compound called SRT1720 have been shown to increase SIRT1 activity in some settings. [5] The 2024 review notes that this made resveratrol a candidate "calorie restriction mimetic" and led to many studies, including human clinical studies. [1] What those human studies found is covered in resveratrol and longevity and the Supplements guide to polyphenols, quercetin and resveratrol. Those guides own the human evidence; this page covers only the sirtuin idea behind the claims. Enzyme activation seen in the lab is preclinical evidence, not proof of benefit.

Human trials of sirtuin-targeting drugs

SRT2104 is an experimental drug designed to activate SIRT1.

• In a pilot trial in elderly volunteers, 28 days of SRT2104 was generally safe and well tolerated, cholesterol and triglycerides fell, and glucose responses did not change significantly. [6]
• In a phase II trial in people with type 2 diabetes, 28 days of SRT2104 did not improve glucose or insulin control, which the authors linked to uneven drug exposure between participants. [7]
• Several of the authors in the first trial worked for the companies developing the drug. [6]

Label: insufficient evidence. These were short trials of lab markers. SRT2104 is an unapproved investigational drug.

NAD+ and its precursors

NAD+ levels fall with age in rodents and humans, according to a 2021 review. The same review says much remains to be learned about whether raising NAD+ is safe or beneficial in aging people. [2] In a 2018 randomized crossover trial of healthy middle-aged and older adults, nicotinamide riboside raised NAD+ metabolism and was well tolerated over 6 weeks; the authors suggested that future trials look at blood pressure and arterial stiffness. [8] Raising a blood level of NAD+ is a biomarker change, not proof of a health benefit. For human trials and regulatory status, see NAD+, NMN and nicotinamide riboside, claim check: NAD+ boosters restore youthful energy and NAD+, NMN and longevity claims.

How to read sirtuin marketing

1. "Activates sirtuins" describes an enzyme, not a health result.
2. The lifespan findings come largely from yeast, worms, flies and mice, and parts of that story are contested. [3]
3. Human trials so far tested safety and markers, not lifespan. [6]
4. A product label that implies slowing or reversing aging is a marketing claim unless a human outcome trial supports it.