What it is
NAD+ is the oxidized form of nicotinamide adenine dinucleotide (C21H27N7O14P2, MW 663.43 Da, CAS 53-84-9, PubChem CID 5893), a dinucleotide formed by pyrophosphate linkage of adenosine monophosphate to nicotinamide ribonucleotide. Every mammalian cell synthesizes NAD+ de novo from tryptophan via the kynurenine pathway and — supplying ~85% of the steady-state pool (Frontiers in Cell & Dev Biol 2024) — recycles it through the salvage pathway, in which nicotinamide (NAM) liberated by NAD+-consuming enzymes is converted to nicotinamide mononucleotide (NMN) by NAMPT and then to NAD+ by NMNAT1–3. Intracellular concentrations are 200–500 μM in most tissues, with 40–70% of the pool in mitochondria. The redox cycle (NAD+ + 2e⁻ + H⁺ ⇌ NADH) powers glycolysis, the TCA cycle, β-oxidation, and oxidative phosphorylation. The non-redox roles — sirtuin deacylation, PARP poly-ADP-ribosylation, CD38/CD157 hydrolysis to cyclic ADP-ribose — consume NAD+ stoichiometrically, which is why NAD+ is a flux metabolite, not an inert cofactor. Age-related decline in tissue NAD+ (Massudi 2012 in human skin; Zhu 2015 by 31P-MRS in brain; Camacho-Pereira 2016 implicating CD38) is well-documented and motivates the entire precursor-supplementation program. For grading purposes, 'NAD+' covers three distinct therapeutic classes: intravenous/subcutaneous NAD+ itself (longevity-clinic protocol, no FDA approval, minimal controlled human efficacy), oral NR (dietary supplement, best-characterized human PK), and oral NMN (drug-excluded by FDA in October 2022, Yoshino 2021 Science data). The evidence varies drastically by which one is being asked about.
In plain English
NAD+ is a small molecule your body makes and uses in every cell. It helps turn food into energy, and it's needed by several families of enzymes including one called "sirtuins" that's been tied to aging research. Your cells store a lot of it — most of it sits in the mitochondria (the cell's power plants). Your body makes new NAD+ two ways: from the amino acid tryptophan (found in food), and by recycling it. The recycling path uses NMN and NR as stepping stones back to NAD+. Older people and stressed tissues have less NAD+ than younger, healthier ones — that's a well-documented finding and is the whole reason anyone started selling "NAD+ boosters." When people talk about "taking NAD+," they might mean three totally different things: IV NAD+ (injected at clinics — not FDA approved), oral NR (a legal supplement with the best human research), and oral NMN (banned as a supplement by FDA in October 2022). How strong the evidence is depends entirely on which one you're asking about.
How it works
- 01
Sirtuin cofactor function (SIRT1–7)
NAD+ is the obligate co-substrate of the seven mammalian sirtuin NAD+-dependent deacylases (Imai 2000 first characterized SIRT1 as the NAD+-dependent enzyme). Each deacetylation consumes one NAD+ and releases nicotinamide and 2'-O-acetyl-ADP-ribose. SIRT1 activity scales with NAD+/NADH ratio; its IC50 for inhibition by released nicotinamide is ~175 μM (Guarente 2016, npj Aging Mech Dis). SIRT1 deacetylates PGC-1α, p53, FOXO3a, and NF-κB p65, which is the molecular basis of the longevity / caloric-restriction-mimetic narrative. SIRT3 (mitochondrial) deacetylates MnSOD, OPA1, and multiple TCA-cycle enzymes; SIRT6 (nuclear) regulates telomere maintenance and base-excision repair. This mechanism is well-characterized in biochemistry — but sirtuin activation is necessary, not sufficient, for any clinical outcome.
In plain English
It fuels the "longevity" enzymes (sirtuins)
You have 7 "sirtuin" enzymes (named SIRT1 through SIRT7) that many aging researchers have studied for decades. They need NAD+ to do their job. Each time a sirtuin works, it uses up one NAD+ molecule. SIRT1 turns off several other proteins connected to aging, metabolism, and inflammation — that's where the "NAD+ is the longevity molecule" story comes from. SIRT3 lives inside mitochondria (cell power plants) and helps them work. Important caveat: sirtuins NEEDING NAD+ doesn't mean giving more NAD+ to a person will make their sirtuins do more good things. The connection is required, but not enough.
- 02
PARP and CD38 NAD+-consumption economy
PARP1 (Alano 2010, J Neurosci) and CD38 (Camacho-Pereira 2016, Cell Metab; Chini 2020) are the two dominant NAD+-consuming enzymes in aging tissue. CD38 expression rises with age in multiple tissues and is the proposed molecular explanation for age-related NAD+ decline. CD38 inhibitors (78c, Chini 2018) raise tissue NAD+ in mice without exogenous precursors — an alternative therapeutic axis to precursor supplementation that has not yet been tested in humans. PARP overactivation under chronic DNA damage can deplete cellular NAD+ and trigger parthanatos; this is the molecular rationale for NAD+ precursor therapy in PARP-inhibitor-induced toxicity (EBioMedicine 2025) and in chemotherapy adjuncts.
In plain English
Two enzymes "eat" NAD+ faster as you age
Two enzymes, CD38 and PARP1, use up NAD+ faster as you get older. CD38 especially: its levels go UP with age in many tissues, and some scientists think that's the main reason NAD+ levels drop with age. In mice, blocking CD38 raises NAD+ without needing any supplement — but that's never been tested in humans. PARP1 activates when your DNA gets damaged and can drain NAD+ — which is why some researchers are testing NAD+ precursors to protect against chemotherapy side effects.
- 03
Salvage pathway — NAMPT is rate-limiting
The salvage pathway converts nicotinamide (released by sirtuin, PARP, and CD38 reactions) back into NAD+ in two steps: NAMPT (nicotinamide phosphoribosyltransferase) adds PRPP to yield NMN; NMNAT1/2/3 add AMP to yield NAD+. Revollo 2004 (J Biol Chem) and the Imai lab established NAMPT as rate-limiting. NAMPT expression oscillates circadianly under CLOCK/BMAL1 control (Ramsey 2009, Science; Nakahata 2009, Science) — so plasma and hepatic NAD+ oscillate with ~24-h periodicity, which is the mechanistic rationale for timed NAD+-precursor dosing. NAMPT declines with age in most tissues (Frontiers Mol Biosci 2024 review), which is part of why older adults have the biggest NAD+ rise from precursor supplementation.
In plain English
How your body recycles NAD+ (and why it slows with age)
Most of your NAD+ comes from recycling — not from eating more. The broken-down pieces get rebuilt into NAD+ in two steps, and the first step (done by an enzyme called NAMPT) is the bottleneck. NAMPT follows a 24-hour rhythm, which is why NAD+ levels rise and fall over the day. NAMPT also drops as you age, which partly explains why NAD+ goes down with age — and why older adults get the biggest NAD+ boost from supplements.
- 04
Oral NR pharmacokinetics — why the biomarker grade is earned
Trammell 2016 (Nat Commun) administered single oral NR doses of 100, 300, and 1,000 mg to 12 healthy adults, showed dose-proportional whole-blood NAD+ elevation, and identified a distinct NR-specific metabolic signature (the NAD+ metabolome) that distinguished NR from equivalent doses of niacin or niacinamide. Airhart 2017 (PLoS ONE) showed NR 1 g/day × 8 days doubled whole-blood NAD+ in healthy middle-aged volunteers. Conze 2019 (Sci Rep) confirmed chronic safety and continued NAD+ elevation over 8 weeks at 1 g/day. Multiple labs, multiple cohorts, consistent direction and magnitude — this is the strongest part of the NAD+ literature.
In plain English
Why oral NR reliably raises blood NAD+
A 2016 study gave 12 healthy adults single doses of NR and showed: more NR = more NAD+ in the blood, reliably. Other studies showed that taking 1 gram of NR a day for 8 days doubles NAD+ in the blood, and the effect keeps going for at least 8 weeks. Multiple labs, multiple groups of people, same answer. This is why "NR raises NAD+ in your blood" is the one claim in this whole field that's actually solid.
- 05
Intravenous NAD+ pharmacokinetics — why the IV grade is low
Grant 2019 (Front Aging Neurosci) infused 750 mg NAD+ over 6 hours in three healthy adults and sampled plasma at 0, 2, 4, 6, and 8 hours. Plasma NAD+ rose, but parallel plasma nicotinamide rose far more sharply — most of the infused NAD+ was being hydrolyzed in the circulation (plausibly by cell-surface CD38 and plasma NAD+-glycohydrolases) and entering tissues as nicotinamide rather than as intact NAD+. By Grant's estimates only ~3% of the infused dose remained as NAD+ in the systemic pool at 2 hours. This undermines the 'direct NAD+ repletion' story for commercial clinic protocols, which typically run 500–1,000 mg over 2–4 hours (faster than Grant's 6-hour infusion, which was selected because faster infusions cause severe 'chest pressure' side effects — a known tolerability issue of clinic IV NAD+).
In plain English
Why IV NAD+ drips score badly
A 2019 pilot study gave 3 healthy adults 750 mg of NAD+ through an IV over 6 hours. They checked their blood regularly. What they found: most of the NAD+ broke apart in the bloodstream almost as soon as it went in — only about 3% was still intact NAD+ after 2 hours. The rest turned into a smaller building block (nicotinamide) that the body then has to rebuild. So the marketing claim that IV NAD+ "directly restores your NAD+" doesn't match the pharmacology. Also, clinics run this faster than the study did (2–4 hours instead of 6) because faster = even more chest-pressure, flushing, and nausea. That tells you how poorly your body tolerates getting NAD+ directly into a vein.
- 06
What the mechanism does not explain
The mechanism is strong enough to motivate the program but does not explain the biomarker-to-outcome gap. Oral NR reliably raises whole-blood and skeletal-muscle NAD+ by 1.5–2.7× (Martens 2018, Elhassan 2019), but does not improve insulin sensitivity (Dollerup 2018), VO2max (Stocks 2021), or grip strength / SPPB (Dolopikou 2020) in placebo-controlled trials. The hypothesis that NAD+ rise in whole blood corresponds to NAD+ rise in the tissues that actually perform the claimed function (e.g., hepatocyte nuclear NAD+ for insulin signaling, mitochondrial NAD+ for oxidative phosphorylation) is not directly tested in most trials. Compartmentalization — the mitochondrial SLC25A51 NAD+ transporter, identified only in 2020 (Luongo 2020, Nature; Kory 2020, Nature) — is likely why increasing systemic NAD+ does not automatically raise the functional pool in the tissue of interest.
In plain English
What the science doesn't explain — the "biomarker-to-outcome gap"
The mechanism makes good sense, but it doesn't explain the central letdown of this research: oral NR reliably raises NAD+ in blood and muscle, but doesn't actually make people stronger, faster, or healthier on the measures scientists test. One probable reason: "NAD+ in the blood" isn't the same as "NAD+ in the exact little compartment of the exact cell where you need it." Scientists only discovered the gate that lets NAD+ into mitochondria (called SLC25A51) in 2020. You may have to get NAD+ INTO mitochondria for it to do anything useful — and just having more in your blood doesn't automatically do that.