NAD+ and NMN: sirtuins, ageing and human trials

Nicotinamide adenine dinucleotide, NAD+, is one of the most important molecules in cellular metabolism. Its levels fall with age in several tissues, and restoring them in ageing animals has produced striking results. This has led to wide interest in NAD+ precursors, particularly nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). This article separates three questions that are often merged: whether raising NAD+ is biochemically plausible, whether precursors raise it in people, and whether that changes any clinical outcome.

This article summarises published research for scientific understanding. It is not dietary or medical advice, and it makes no claim that any compound slows ageing or extends lifespan in humans.

What NAD+ does

NAD+ has two broad roles. First, it is a coenzyme in redox reactions, carrying electrons between metabolic reactions, including those of energy production in mitochondria. Second, it is consumed as a co-substrate by several families of enzymes, notably the sirtuins and the poly(ADP-ribose) polymerases (PARPs)^[1]. Through these enzymes, NAD+ availability links cellular metabolism to DNA repair, gene regulation and stress responses^[2].

• Sirtuins are NAD+-dependent enzymes that remove chemical groups from proteins, including histones. Their activity is therefore sensitive to how much NAD+ is available.
• PARPs use NAD+ in DNA repair. In rodents, age-associated increases in DNA damage have been linked to PARP-driven depletion of NAD+^[3].
• CD38 is an enzyme that breaks down NAD+. In mice, its expression and activity increased with age, and it was required for the age-related decline in NAD+. It also degraded the precursor NMN in vivo^[4].

Does NAD+ decline with age in humans?

The evidence is observational. In human pelvic skin samples from 49 people aged from infancy to 77, NAD+ levels correlated negatively with age in both sexes. In men, PARP activity rose with age and correlated inversely with NAD+^[3]. A cross-sectional study of skeletal muscle found NAD+ among the metabolites most clearly lower in older adults. It was lower still in physically impaired older people, while exercise-trained older adults had levels closer to those of younger people^[5].

These studies show associations. They do not show that low NAD+ causes ageing or poor function. Physical activity, disease and other factors could influence both.

The precursors

Cells make NAD+ through several pathways, and supplements supply intermediates along them. NMN is the product of the enzyme NAMPT, which catalyses the rate-limiting step in mammalian NAD+ biosynthesis^[6]. NR is another precursor in the same family. In the first human pharmacokinetic trial of NR, single oral doses produced dose-dependent increases in the blood NAD+ metabolome. The study was sponsored by a supplier of NR^[7]. NMN and NR are therefore close relatives, and much of the human evidence discussed below involves one or the other.

Animal evidence

Studies in mice underpin much of the interest.

• Diabetes models. In mice with diabetes induced by diet or age, NMN improved glucose tolerance, partly by restoring NAD+ levels. Levels of NAD+ and of the enzyme NAMPT fell in several organs with age^[6].
• Long-term administration. In a 12-month study of normal ageing mice, oral NMN was rapidly used to make NAD+ in tissues. It suppressed age-associated weight gain, improved energy metabolism, physical activity, insulin sensitivity and plasma lipids, and improved eye function, without obvious toxicity^[8].

A 2018 review summarised evidence that restoring NAD+ in old or diseased animals can promote health and, in some models, extend lifespan^[9]. These are genuine findings in model organisms. They are the reason for human trials, not a substitute for them.

Human pharmacokinetic evidence

The first human NMN studies focused on safety and metabolism.

• Single doses. In 10 healthy Japanese men, single oral doses of NMN caused no significant clinical symptoms or changes in vital signs, and NMN breakdown products rose in plasma^[10].
• Repeated doses. In a 14-day randomised trial of 32 overweight or obese adults aged 55 to 80, an NMN formulation raised blood NMN and caused substantial dose-related increases in blood NAD+. Very little unchanged NMN appeared in urine^[11].

The consistent finding is that oral NMN and NR raise NAD+ and related metabolites in blood. That is the biomarker question answered. It is a necessary step, but it does not show that anything has changed in health or function.

Randomised trials of NMN

Several points temper these results. Primary outcomes were often biomarkers or were not met. Functional improvements were frequently secondary or nominal, and the authors of one trial stated that they should be confirmed in larger studies^[13]. The trials were small and short, and at least one included employees of a company producing NMN among its authors^[13]. The prediabetes trial is the most rigorous metabolic study. It used the reference-standard clamp method to measure insulin sensitivity in muscle, but it involved a specific group of women^[12].

Evidence from nicotinamide riboside

Trials of NR add useful context, because some tested metabolic outcomes directly and found no benefit.

• Obese, insulin-resistant men. In a 12-week randomised trial of 40 men, NR did not improve insulin sensitivity, glucose metabolism, energy expenditure or body composition^[16]. In the same trial, it did not change mitochondrial respiration, content or structure in skeletal muscle, or muscle NAD+ metabolite concentrations^[17].
• Healthy middle-aged and older adults. A six-week crossover trial found NR well tolerated and effective at raising NAD+ metabolism. It identified blood pressure and arterial stiffness as outcomes worth testing in future trials^[18].
• Aged muscle. In 12 older men, NR raised the NAD+ metabolome in muscle and lowered circulating inflammatory markers, but did not change mitochondrial bioenergetics^[19].

What the pooled evidence shows

A 2023 review found that NAD+-boosting compounds are safe and tolerable and raise NAD+ and related metabolites in several tissues. It concluded that clinical evidence that this improves physiological function is unclear. Small samples and widely varying doses and durations limit interpretation^[20]. A 2025 meta-analysis of randomised trials in adults over 60 found that NMN had no significant effect on muscle mass, grip strength, gait speed or chair-stand performance. It concluded that current evidence does not support NMN or NR for preserving muscle mass and function in this group^[21].

Three questions, three answers

Summary

NAD+ is central to redox metabolism and is consumed by sirtuins, PARPs and CD38. Observational studies show lower NAD+ in some older human tissues, and in mice NMN improves metabolic measures and mitigates aspects of age-associated decline. In people, NMN and NR reliably raise NAD+ in blood. Randomised trials have produced one well-measured improvement in muscle insulin sensitivity in a specific group, several small or secondary functional findings, and clear null results for insulin sensitivity, mitochondrial function and muscle outcomes. Biochemical plausibility and biomarker changes are established. Clinical benefit, and any effect on human ageing, are not.