Curated summaries of peer-reviewed NAD+ research. Each entry links the original paper via PMID and DOI, plus a plain-language key-finding for fast scanning.
Grozio A, Mills KF, Yoshino J, et al.
Key finding: Oral NMN reaches tissues intact via a dedicated intestinal transporter.
Identified Slc12a8 as a dedicated NMN transporter in the small intestine. Established a pharmacological basis for oral NMN bioavailability distinct from the Nam-salvage route.
Yoshino M, Yoshino J, Kayser BD, et al.
Key finding: NMN improved skeletal muscle insulin sensitivity and gene expression in postmenopausal women.
Randomized, placebo-controlled 10-week trial of 250 mg/day NMN in postmenopausal women with prediabetes. The first human trial to show a concrete mechanistic metabolic benefit.
Trammell SAJ, Schmidt MS, Weidemann BJ, et al.
Key finding: NR is orally bioavailable in humans and raises blood NAD+ without flushing.
First human pharmacokinetic data for NR. Single oral doses of 100-1,000 mg raised blood NAD+ in a dose-dependent fashion without flushing or adverse events.
Elhassan YS, Kluckova K, Fletcher RS, et al.
Key finding: NR raises tissue NAD+ in aged muscle and shifts mitochondrial transcription.
21-day NR supplementation at 1 g/day in aged men raised skeletal muscle NAD+ and shifted mitochondrial gene expression — the first mechanistic human data on tissue-level NAD+ response.
Pirinen E, Auranen M, Khan NA, et al.
Key finding: Niacin restored NAD+ and improved muscle function in mitochondrial myopathy patients.
10-month niacin titration in patients with mitochondrial myopathy restored muscle NAD+ and improved strength and muscle mass — the clearest clinical efficacy result for any NAD+ precursor.
Conze D, Brenner C, Kruger CL
Key finding: NR is well tolerated at doses up to 1 g/day over 8 weeks in healthy adults.
8-week, randomized controlled trial of NR at 100, 300, 1,000 mg/day vs. placebo. No clinically meaningful safety signals across the dose range.
Covarrubias AJ, Perrone R, Grozio A, et al.
Key finding: Tissue NAD+ decline is a shared mechanism across the hallmarks of aging.
The canonical recent review of NAD+ biology and aging — covers biosynthesis, degradation, sirtuin/PARP/CD38 signaling, and the translation gap from rodent models to human therapy.
Martens CR, Denman BA, Mazzo MR, et al.
Key finding: NR at 1 g/day raises NAD+ ~60% and may reduce systolic BP in adults with Stage 1 hypertension.
6-week crossover trial of 1 g/day NR in middle-aged and older adults. Raised NAD+ ~60% and reduced systolic blood pressure in a subgroup with elevated baseline BP.
Imai S, Armstrong CM, Kaeberlein M, Guarente L
Key finding: Sir2 deacetylase activity consumes NAD+, establishing a direct biochemical link between cellular NAD+ levels and gene silencing.
Foundational biochemistry paper establishing that yeast Sir2 — the founding member of the sirtuin family — is an NAD+-dependent histone deacetylase rather than a conventional deacetylase. Using purified recombinant Sir2 and reconstituted acetylated histone substrates, Imai and colleagues showed that deacetylase activity was strictly dependent on NAD+ as a cosubstrate, with nicotinamide and O-acetyl-ADP-ribose as reaction products. This mechanistic finding linked cellular NAD+ concentration directly to chromatin silencing and, by extension, to gene regulation, genomic stability, and lifespan. The paper reframed NAD+ from a simple redox cofactor into a signaling molecule coupling metabolic state to transcriptional output. It launched two decades of sirtuin biology across seven mammalian homologs (SIRT1-7) and provided the theoretical basis for why NAD+ decline with age would impair deacetylase-dependent stress responses, mitochondrial function, and DNA damage repair. Nearly every subsequent NAD+-aging hypothesis cites this work as the mechanistic anchor.
Lin SJ, Defossez PA, Guarente L
Key finding: Calorie-restriction-induced lifespan extension requires intact NAD+ biosynthesis and Sir2, linking nutrient sensing to sirtuin-mediated longevity.
Genetic demonstration in budding yeast that calorie restriction extends replicative lifespan through an NAD+/Sir2-dependent pathway. Lin and colleagues showed that reducing glucose from 2% to 0.5% extended mean lifespan by roughly 30%, and that this extension was completely abolished in sir2 deletion mutants and in strains with impaired NAD+ biosynthesis (npt1 mutants). Glucose restriction increased Sir2 silencing activity at rDNA and telomeric loci, consistent with elevated cellular NAD+ availability. The paper established the conceptual framework that underlies modern NAD+-boosting therapeutics: metabolic state sets NAD+ levels, NAD+ levels gate sirtuin activity, and sirtuin activity modulates lifespan and stress resistance. It also implicated the NAD+ salvage pathway (via Npt1/Pnc1) as rate-limiting for this effect. Though yeast replicative lifespan is not mammalian aging, the molecular logic — NAD+ as the metabolic sensor linking nutrient intake to longevity-regulating enzymes — translated to flies, worms, and mammals in subsequent decades.
Bieganowski P, Brenner C
Key finding: NR is a distinct NAD+ precursor in humans, converted via the conserved NRK1/NRK2 kinases — a route independent of the Preiss-Handler pathway.
Seminal paper identifying nicotinamide riboside (NR) as a bona fide NAD+ precursor vitamin and defining the nicotinamide riboside kinase (NRK1/NRK2) pathway that converts it to NMN and then NAD+ independently of the classical Preiss-Handler route. Using yeast genetics, Bieganowski and Brenner screened for suppressors of a qns1 NAD+ auxotroph and recovered NR as a salvageable precursor. They cloned the NRK1 gene, then identified the human orthologs NRK1 (NMRK1) and NRK2 (NMRK2), showing both possessed kinase activity on NR. This established a third route to NAD+ in mammals, alongside the de novo tryptophan pathway and the Preiss-Handler route from nicotinic acid. The discovery directly enabled the development of NR as an oral supplement — because the NRK pathway is present in humans, dietary NR could be converted to NAD+ in tissues without requiring deamidation. Every subsequent NR clinical trial traces to this mechanistic foundation.
Massudi H, Grant R, Braidy N, Guest J, Farnsworth B, Guillemin GJ, Sabharwal P
Key finding: Skin NAD+ declines with age in humans, correlating with rising oxidative stress and poly-ADP-ribose accumulation — direct human evidence of the age-related NAD+ deficit.
One of the earliest and most-cited demonstrations that tissue NAD+ declines with chronological age in humans. Massudi and colleagues analyzed skin biopsy samples from healthy male and female donors spanning a wide age range and quantified NAD+, NADH, and markers of oxidative stress by HPLC and biochemical assays. Total NAD+ content declined significantly with age in both sexes, with concurrent increases in oxidative stress markers (lipid peroxidation, protein carbonyls) and in poly-ADP-ribose accumulation — consistent with PARP hyperactivation consuming NAD+ in response to accumulating DNA damage. The study cohort was modest (n ≈ 30) and tissue-specific (dermal), but it provided the first direct human evidence for the age-associated NAD+ decline that had been documented in rodents. The findings anchored the hypothesis that PARP-driven NAD+ consumption is a causal contributor to the aging phenotype and motivated subsequent CD38- and PARP-inhibitor investigations.
Camacho-Pereira J, Tarragó MG, Chini CCS, et al.
Key finding: CD38 upregulation with age is the primary driver of tissue NAD+ decline; CD38 loss preserves NAD+ and mitochondrial function via SIRT3.
Landmark paper identifying CD38 — an NAD+-consuming ecto-enzyme — as the principal driver of age-related NAD+ decline in mammalian tissues. Using CD38-knockout mice, Camacho-Pereira and colleagues showed that old CD38-/- animals retained youthful NAD+ levels across liver, muscle, and adipose tissue, whereas wild-type tissues exhibited the canonical 50-70% drop by 24 months of age. CD38 protein expression increased with age in multiple tissues, and pharmacological CD38 inhibition (78c and related compounds) was sufficient to rescue tissue NAD+ in aged wild-type mice. The NAD+ restoration in CD38-/- animals reversed mitochondrial dysfunction in a SIRT3-dependent fashion, normalizing oxygen consumption, membrane potential, and metabolic flexibility. This established CD38 as the dominant NADase in aging mammals, reframed the NAD+ decline as an enzymatic consumption problem rather than a biosynthetic deficit, and opened CD38 inhibition as a therapeutic axis distinct from precursor supplementation.
Gomes AP, Price NL, Ling AJY, et al.
Key finding: Short-term NMN restores aged-mouse muscle NAD+ and reverses pseudohypoxic mitochondrial dysfunction, implicating NAD+ decline as a causal aging driver.
Mechanistic mouse study from the Sinclair lab showing that age-related NAD+ decline induces a pseudohypoxic state in which HIF-1α stabilizes under normoxia, disrupting SIRT1-mediated signaling from nucleus to mitochondria and causing mitochondrial-encoded OXPHOS gene expression to fall. Aged (22-month) C57BL/6 mice had ~50% lower muscle NAD+ than young (6-month) controls, paired with reduced mitochondrial respiratory capacity and impaired PGC-1α/β signaling. Critically, one week of intraperitoneal NMN at 500 mg/kg/day restored muscle NAD+ to youthful levels, normalized the nuclear-mitochondrial communication axis, and reversed key features of mitochondrial dysfunction — effectively making 22-month-old muscle resemble that of 6-month-old animals at the transcriptomic and respirometric level. The work cemented NAD+ as a causal, reversible mediator of mitochondrial aging and served as the experimental foundation for subsequent NMN trials in humans. The rapid rescue also demonstrated that NAD+ deficit, not accumulated damage, drives a meaningful portion of the aged phenotype.
Dollerup OL, Christensen B, Svart M, et al.
Key finding: 12 weeks of 2 g/day NR in obese but otherwise healthy men did not improve insulin sensitivity, ectopic lipid, or body composition vs. placebo.
Randomized, double-blind, placebo-controlled trial of NR in 40 sedentary obese but otherwise healthy men (BMI 30-40). Participants received 1 g NR twice daily (2 g/day total) or placebo for 12 weeks. Primary endpoint was insulin sensitivity measured by hyperinsulinemic-euglycemic clamp. Secondary endpoints included body composition (DXA), hepatic and intramyocellular lipid content (MRS), and muscle mitochondrial function (ex vivo respirometry). Contrary to preclinical expectations based on rodent high-fat-diet studies, NR at this dose produced no statistically significant improvement in insulin sensitivity, ectopic lipid, body composition, or resting energy expenditure vs. placebo. Safety was excellent with no serious adverse events. The trial is an important counterpoint to optimistic rodent extrapolations: even at doubled doses for three times the duration of early NR safety studies, metabolic endpoints in otherwise-healthy obese men did not improve. The study highlighted the rodent-to-human translation gap and sharpened focus on populations with greater baseline NAD+ deficit as more likely responders.
Brakedal B, Dölle C, Riemer F, et al.
Key finding: Oral NR at 1 g/day for 30 days raises cerebral NAD+ in newly diagnosed Parkinson's patients, with transcriptomic and motor-symptom trends favoring treatment.
Randomized, double-blind, placebo-controlled phase I trial of NR in 30 newly diagnosed, drug-naïve Parkinson's disease patients. Participants received 1 g/day NR or placebo for 30 days. Primary outcome was brain NAD+ measured by 31P-MRS. NR supplementation produced a significant increase in cerebral NAD+ and NAD+-related metabolites, with 10 of 13 NR-treated patients classified as biochemical responders. Responders showed upregulation of mitochondrial and metabolic gene programs in peripheral blood mononuclear cells and skeletal muscle, as well as a trend toward clinical symptom improvement on the MDS-UPDRS motor scale. The trial provided the first human evidence that an oral NAD+ precursor can raise NAD+ in the living human brain, directly addressing skepticism about whether NR crosses the blood-brain barrier or its metabolites reach central tissue. Safety was excellent. NADPARK motivated larger follow-up trials (NR-SAFE, NOPARK) and established Parkinson's disease as a leading neurodegeneration indication for NAD+ therapeutics.
Katayoshi T, Uehata S, Nakashima N, et al.
Key finding: 12 weeks of 250 mg/day NMN in middle-aged adults raised blood NAD+ and was associated with reduced arterial stiffness (CAVI) vs. placebo.
Long-duration, placebo-controlled trial of oral NMN in healthy middle-aged Japanese adults. Participants received 125 mg NMN twice daily (250 mg/day) or placebo for 12 weeks, with cardiovascular and NAD+-metabolome endpoints measured at baseline and end of treatment. NMN supplementation significantly elevated whole-blood NAD+ and related metabolites (NMN, NAM, MeNAM) relative to placebo. A secondary analysis showed reduction in cardio-ankle vascular index (CAVI) — a measure of arterial stiffness — in the NMN group compared with placebo, with effect magnitude correlating with baseline CAVI. Safety was good; no serious adverse events and no clinically significant changes in liver or kidney function panels. The study is one of the few human NMN trials published in a peer-reviewed journal, extends prior short-term PK studies, and provides early signal for vascular-aging endpoints that will inform larger cardiovascular-focused trials. Cohort size and single-country sample limit generalizability.
Mouchiroud L, Houtkooper RH, Moullan N, et al.
Key finding: NAD+ repletion extends C. elegans lifespan through SIR-2.1/DAF-16 and mitochondrial UPR, a conserved NAD+-sirtuin-proteostasis longevity axis.
C. elegans genetic and pharmacologic study demonstrating that NAD+ augmentation — via precursor supplementation (NR, NAM) or PARP inhibition — extends lifespan through a conserved SIR-2.1/DAF-16/mitochondrial unfolded protein response (UPR-mt) axis. Raising worm NAD+ by any of the tested interventions extended mean lifespan by 12-25% in wild-type animals, with lifespan extension abolished in sir-2.1, daf-16/FOXO, or ubl-5 (UPR-mt) loss-of-function backgrounds. Transcriptomic profiling showed activation of mitochondrial chaperones (hsp-6, hsp-60) and canonical FOXO targets. Parallel experiments in mammalian cells and mouse muscle confirmed conservation of the NAD+ → SIRT1 → UPR-mt program. This paper is central to the mechanistic rationale for NAD+ boosters as geroprotectors: it ties together three disparate literatures (NAD+ metabolism, sirtuin signaling, mitochondrial proteostasis) into a single longevity-regulating pathway and provides the first unambiguous genetic demonstration that NAD+ repletion extends lifespan in a metazoan.
Zhang H, Ryu D, Wu Y, et al.
Key finding: Oral NR at 400 mg/kg/day extends aged-mouse lifespan and restores stem cell function through SIRT1 and mitochondrial UPR.
Mouse study from the Auwerx laboratory showing that oral NR supplementation extends lifespan and rescues adult stem cell function in aged animals. 24-month-old C57BL/6J mice given 400 mg/kg/day NR in drinking water for six weeks exhibited increased muscle stem cell (satellite cell) number and myogenic capacity, improved neural stem cell function, and restored intestinal stem cell compartment integrity. NR-treated aged mice showed improved mitochondrial function (membrane potential, respiration, mtDNA copy number), reduced senescence markers, and extended median lifespan by approximately 5%. Mechanistically, the improvements depended on SIRT1-mediated mitochondrial UPR activation and were blunted in SIRT1 knockouts. The study is one of the few published mouse lifespan experiments for an oral NAD+ precursor and paired the longevity outcome with mechanistic stem-cell biology — strengthening the translational case for NAD+-boosting interventions as systemic gerotherapeutics. Dose translates to approximately 1.9 g/day human-equivalent via standard allometric scaling.
Mills KF, Yoshida S, Stein LR, et al.
Key finding: 12 months of oral NMN at 100-300 mg/kg/day prevents multi-system age-associated physiological decline in mice without adverse effects.
12-month chronic-administration study of oral NMN in wild-type C57BL/6N mice, from the Imai laboratory. Animals received 100 or 300 mg/kg/day NMN in drinking water starting at 5 months of age and continuing through 17 months. NMN supplementation significantly mitigated age-associated declines in insulin sensitivity, plasma lipids, body composition (retained lean mass and reduced fat mass), energy expenditure, physical activity, and mitochondrial function in skeletal muscle. Eye function and bone density were also preserved. Importantly, long-term NMN raised tissue NAD+ without adverse effects on liver or kidney function across a full year of continuous exposure, addressing safety concerns that had limited chronic rodent studies up to that point. The study is the most frequently cited preclinical justification for human NMN trials, both in magnitude of tissue effect and in demonstrating durable multi-system benefit over near-lifespan timescales. Dose-response was evident, with 300 mg/kg/day producing larger effects than 100 mg/kg/day.
Bertoldo MJ, Listijono DR, Ho WHJ, et al.
Key finding: Oral NMN rescues oocyte quality, meiotic fidelity, and fertility in reproductively aged mice through restoration of ovarian NAD+.
Mouse study showing that oral NMN supplementation restores oocyte quality and fertility in reproductively aged females. Aged (12-14 month) C57BL/6 mice — a model of human perimenopausal decline — given 2 g/L NMN in drinking water for four weeks showed restored NAD+ in ovarian tissue, reversal of age-associated oocyte meiotic defects (aneuploidy, spindle disorganization), improved fertilization rates, and recovery of litter sizes to near young-adult levels. Mitochondrial function in oocytes normalized, as did the NAD+/NADH ratio. Single-cell metabolomics confirmed that older oocytes from NMN-treated animals resembled those of young controls. The effects were oocyte-specific and did not restore cycle regularity, implicating the NAD+ deficit as an intrinsic gamete problem rather than a whole-reproductive-axis issue. The study is the principal preclinical evidence for ongoing human reproductive-aging trials with NAD+ precursors and is frequently cited in fertility-clinic white-paper claims that run ahead of the human evidence.
Cantó C, Houtkooper RH, Pirinen E, et al.
Key finding: Oral NR at 400 mg/kg/day prevents high-fat-diet-induced obesity and insulin resistance in mice via SIRT1/SIRT3 activation and mitochondrial biogenesis.
The first preclinical demonstration that oral NR protects against diet-induced metabolic disease in mice, from the Auwerx laboratory. C57BL/6J mice fed a high-fat diet supplemented with 400 mg/kg/day NR showed markedly reduced weight gain, improved insulin sensitivity, and preserved glucose tolerance compared with high-fat-diet controls. NR-treated animals exhibited enhanced oxidative metabolism in skeletal muscle and brown adipose tissue, with increased mitochondrial biogenesis and activation of SIRT1 and SIRT3 signaling. Whole-body energy expenditure was elevated without changes in food intake or activity, consistent with increased thermogenic capacity. The effects mirrored those of resveratrol and PPAR-δ agonists but through the upstream mechanism of cosubstrate (NAD+) availability. The study directly motivated human NR trials in metabolic populations — obesity, prediabetes, NAFLD — and is the most-cited preclinical paper on NR's metabolic benefits. It also established the 400 mg/kg/day mouse dose (≈2 g/day human-equivalent) that shaped subsequent clinical trial dose selection.
Fang EF, Scheibye-Knudsen M, Brace LE, et al.
Key finding: PARP-1 hyperactivation depletes NAD+ and disables SIRT1-dependent mitophagy; NAD+ precursors rescue mitochondrial quality control in DNA-repair-deficient progeria.
Mechanistic paper linking NAD+ depletion to mitophagy failure in the premature-aging disease xeroderma pigmentosum group A (XPA). XPA patient fibroblasts and Xpa-/- mouse tissues accumulate unrepaired DNA damage, which chronically activates PARP-1 and drains cellular NAD+ to roughly half of control levels. The resulting NAD+ deficit suppresses SIRT1 activity, impairing its deacetylation of PGC-1α and downstream mitochondrial quality-control programs — with defective mitophagy and accumulation of damaged mitochondria as the terminal phenotype. Critically, restoring NAD+ by supplementation with NR or NMN — or by PARP-1 inhibition — rescued mitophagy, mitochondrial function, and cellular viability in both patient cells and Xpa-/- mice. The work generalized to other DNA-repair-deficiency progeroid syndromes (Cockayne syndrome, ataxia telangiectasia) in follow-up papers and established the PARP-1 → NAD+ → SIRT1 → mitophagy cascade as a unifying mechanism for segmental progerias. It also provided the strongest mechanistic rationale for NAD+ repletion in neurodegenerative disease where DNA damage accumulates.
Irie J, Inagaki E, Fujita M, et al.
Key finding: Single oral NMN doses up to 500 mg are safe and well-tolerated in healthy men, with dose-dependent rises in downstream NAD+ metabolites.
The first published single-dose pharmacokinetic and safety study of oral NMN in humans. Ten healthy Japanese men (ages 40-60) received a single oral dose of NMN at 100, 250, or 500 mg, with serial blood sampling over five hours and clinical chemistry monitoring. NMN was well tolerated at all three doses, with no serious adverse events and no clinically significant changes in vital signs, sleep quality, or laboratory panels (liver enzymes, kidney function, glucose, lipids). Plasma concentrations of NMN itself remained largely undetectable by LC-MS, but downstream NAD+ metabolites — particularly N-methyl-nicotinamide (MeNAM) and N-methyl-2-pyridone-5-carboxamide (2PY) — rose dose-dependently within 30 minutes, consistent with rapid conversion of NMN to NAD+ and subsequent metabolic processing. Bilirubin rose slightly and uric acid fell slightly at higher doses, both within clinical reference ranges. The study established acute safety at single doses up to 500 mg and is the foundational human PK data underpinning all subsequent NMN trial dose selection. Limitations include small cohort, single-dose design, and indirect readout of NAD+ via downstream metabolites rather than direct tissue measurement.
Rajman L, Chwalek K, Sinclair DA
Key finding: NAD+-boosting interventions show robust rodent efficacy across aging and disease phenotypes, but translation to human clinical endpoints remains the principal open question.
Comprehensive review covering the in vivo preclinical and emerging clinical evidence for NAD+-boosting interventions — NR, NMN, nicotinic acid, nicotinamide, PARP inhibitors, and CD38 inhibitors. Rajman, Chwalek, and Sinclair systematically summarize rodent evidence across aging, metabolic disease, neurodegeneration, cardiovascular disease, and inflammatory conditions, and compare mechanistic coverage (sirtuins, PARPs, CD38, cADPR signaling). The paper distinguishes what is firmly established (tissue NAD+ decline with age, precursor supplementation raises NAD+ in most tissues, SIRT1/SIRT3 activation rescues multiple hallmarks in mice) from what remains speculative (lifespan extension in mammals, human clinical efficacy, tissue-selective delivery). It provides a structured framework for evaluating NAD+ claims by intervention class and organ system and remains one of the most-cited single entry points into the field for clinicians and translational researchers. Published at the inflection point between early mouse data and the first wave of human RCTs, the review set expectations for what subsequent trials would need to demonstrate.