What Is NAD+?

A redox carrier and a co-substrate

NAD+ and its reduced form NADH are coupled redox metabolites. A 2020 review describes them as mainly driving the cell's oxidative, energy-releasing reactions, which supports energy generation through glycolysis and mitochondrial respiration. The NAD+/NADH ratio is therefore a readout of the cell's redox state.Review · PMID 32573651

The same review describes a second role. Many enzymes that regulate gene expression, proteostasis and DNA repair need NAD+ as a co-substrate, including the sirtuin family of protein deacetylases and the PARP family of DNA repair enzymes. Their activity consumes NAD+, cleaving it to nicotinamide, and several pathways regenerate NAD+ to keep levels stable.Review · PMID 32573651

A study of the human plasma NAD+ metabolome lists the same set of consumers: CD38 glycohydrolases in second-messenger signaling, PARPs in DNA repair, and sirtuins as deacetylases. It also notes that the NADP+/NADPH ratio, a related pair, regulates the oxidative pentose phosphate pathway.Human observational · PMID 30124109

These two roles pull on the same pool. Every NAD+ molecule cleaved by a sirtuin, PARP or CD38 leaves the redox pair and has to be rebuilt from nicotinamide, so heavy consumption by one enzyme family can affect how much is available to the others and to energy metabolism. That is why the recycling pathway described next receives so much attention.Review · PMID 32573651

How cells make and recycle NAD+

Because the consuming enzymes turn NAD+ into nicotinamide, cells recycle it. A 2004 study in mouse fibroblasts measured the kinetics of the pathway that runs through nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (Nmnat). Nampt was the rate-limiting component of this pathway.In vitro · PMID 15381699

In the same study, raising Nampt, but not Nmnat, raised total cellular NAD and increased the transcriptional regulatory activity of Sir2alpha, the mouse counterpart of the sirtuin SIRT1. Gene expression profiles of Nampt-overexpressing and Sir2alpha-overexpressing cells correlated significantly, linking NAD+ supply directly to sirtuin function.In vitro · PMID 15381699

Nicotinamide mononucleotide (NMN) sits in this pathway as an intermediate. A 2016 study identified CD38 as the main enzyme degrading NMN in vivo in mice, which means CD38 affects both NAD+ itself and the precursors that feed it.Animal study · PMID 27304511

What happens to NAD+ with age

A 2012 study measured pelvic skin samples from 49 people aged between newborn and 77. NAD+ correlated negatively with age in both males (r = -0.706, p = 0.001) and females (r = -0.537, p = 0.01). In males, PARP activity rose with age (r = 0.768) and correlated inversely with tissue NAD+ (r = -0.639), and SIRT1 activity also fell with age.Human observational · PMID 22848760

A 2015 study used a magnetic resonance method to measure NAD+ and NADH in the living brains of healthy volunteers without sampling tissue. It found an age-dependent rise in intracellular NADH and age-dependent falls in NAD+, total NAD and the NAD+/NADH redox potential.Human observational · PMID 25730862

In blood, a 2019 study of healthy people across a wide age range found significant declines in plasma NAD+, NADP+ and NAAD with age, alongside rises in NADH, NADPH, nicotinamide, N-methyl-nicotinamide and ADP-ribose. Plasma NMN, nicotinic acid and NAMN did not change significantly across age groups.Human observational · PMID 30124109

The three studies measured different compartments: tissue from surgical samples, the living brain, and blood plasma. They agree on direction for NAD+ itself, but plasma is extracellular, and the plasma study frames its result as a change in the extracellular NAD+ metabolome that accompanies age-related impairment rather than as a measure of what happens inside cells.Human observational · PMID 22848760Human observational · PMID 25730862Human observational · PMID 30124109

Why levels fall: consumption by CD38 and PARP

The 2016 mouse study found that expression and activity of the NADase CD38 increase with aging, and that CD38 is required for the age-related NAD decline and the associated mitochondrial dysfunction, acting at least in part through regulation of SIRT3, a mitochondrial sirtuin.Animal study · PMID 27304511

The human skin study points to a second consumer. Its authors interpreted the PARP and NAD+ correlations as support for the hypothesis that oxidative DNA damage accumulating with age hyperactivates PARP, which then breaks down more NAD+. That is a correlation in tissue samples, not a direct test of cause.Human observational · PMID 22848760

NAD+, sirtuins and mitochondria in animal models

A 2013 mouse study traced one consequence of falling NAD+. During aging, mitochondrially encoded oxidative phosphorylation subunits were specifically lost, while nuclear-encoded ones were not. The authors linked this to a decline in nuclear NAD+ and accumulation of HIF-1α under normal oxygen, which they described as a pseudohypoxic state.Animal study · PMID 24360282

In that study, deleting SIRT1 accelerated the process, and raising NAD+ in old mice brought mitochondrial function back to that of young mice in a SIRT1-dependent manner. The finding ties the redox and co-substrate roles together: the same molecule that carries electrons also sets how active a sirtuin can be.Animal study · PMID 24360282

The authors noted parallels between this pseudohypoxic state and Warburg reprogramming and described the decline in mitochondrial function with age in their mice as apparently reversible. That conclusion rests on mouse tissue and has not been shown in people.Animal study · PMID 24360282

Precursors and the limits of the evidence

Human research mostly studies precursors rather than NAD+ itself. In a 2019 randomized, double-blind, placebo-controlled crossover trial in 12 older men over 21 days, the muscle NAD+ metabolome was higher with nicotinamide riboside (NR) than with placebo, shown by higher nicotinic acid adenine dinucleotide and nicotinamide clearance products. Muscle RNA sequencing showed downregulation of energy metabolism and mitochondrial pathways, mitochondrial bioenergetics did not change, and circulating inflammatory cytokines were lower.Human RCT · PMID 31412242

The age data are mostly cross-sectional: different people at different ages, measured once. The CD38 and sirtuin mechanisms come from mice and mouse cells. The 2020 review notes that dietary NAD+ precursors are being investigated, and that many cancers depend more heavily on NAD+, which complicates any simple view of raising it.Human observational · PMID 22848760Animal study · PMID 27304511Review · PMID 32573651

The studies at a glance

Key NAD+ studies by model. Results are as reported in each paper's abstract.

Frequently asked questions