🧬 Aging Wiki

nr

Properties1
aliasesnicotinamide riboside, NR, NIAGEN, nicotinamide riboside chloride

15 min read

Nicotinamide Riboside (NR)

A naturally-occurring NAD+ precursor vitamin found in milk and certain foods. Orally bioavailable and commercially developed as NIAGEN (ChromaDex; FDA GRAS-affirmed 2016). The most extensively human-tested NAD+ precursor as of 2026, with multiple completed Phase 1/2 trials. Central rationale: NAD+ levels decline ~50% between young adulthood and old age; restoring NAD+ is proposed to support sirtuin signaling, mitochondrial function, and DNA repair, addressing multiple aging hallmarks.

Identity

  • PubChem CID: 439924
  • InChIKey: JLEBZPBDRKPWTD-TURQNECASA-O
  • ChEMBL: CHEMBL438497
  • Molecular formula: C11H15N2O5+ (cationic form)
  • Molecular weight: 255.25 g/mol
  • IUPAC name: 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyridin-1-ium-3-carboxamide
  • Class: pyridine nucleoside; NAD+ precursor vitamin
  • Commercial form: typically as nicotinamide riboside chloride (NR-Cl)
  • Regulatory status: FDA GRAS-affirmed (2016); dietary supplement in most markets

See also: nmn (one phosphate group upstream in the same salvage pathway; closest structural analog as a competitor supplement).

Mechanism of Action

NR enters the NAD+ salvage pathway via a dedicated enzymatic route that bypasses the NAMPT rate-limiting step:

Dietary NR  →  [NRK1 / NRK2]  →  NMN  →  [NMNAT1/2/3]  →  NAD+

NRK1/2 (nicotinamide riboside kinases) phosphorylate NR to NMN, which is then converted to NAD+ by NMNAT enzymes 1. This route differs from the classical tryptophan de novo pathway and from the NAMPT-dependent route used by nicotinamide (NAM). The key claimed advantage over NAM: NR does not depend on NAMPT, whose activity itself declines with age unsourced.

Once NAD+ is elevated:

  • Sirtuins (SIRT1–7) become more active — sirtuins consume NAD+ as a co-substrate for deacylation reactions, including SIRT1-mediated PGC-1α deacetylation (promoting mitochondrial biogenesis) and SIRT3-mediated mitochondrial protein deacetylation 2.
  • ampk may be indirectly activated via sirtuin-mediated LKB1 deacetylation, though the AMPK-NR link at physiological doses is less established than the AMPK-metformin link. no-mechanism
  • PARP1 competes with sirtuins for NAD+ — elevated NAD+ may also support DNA repair capacity.

Structural comparison with NMN

NR is the riboside form of nicotinamide; NMN is the corresponding nucleotide (NR + one phosphate). NR must be phosphorylated intracellularly by NRK1/2 to form NMN before it can be converted to NAD+. Whether NR or NMN reaches peripheral tissues more efficiently after oral dosing remains contested, as plasma NMN may be dephosphorylated to NR prior to cellular uptake in many tissues 1. contradictory-evidence

Effects on Aging Hallmarks

HallmarkEffectEvidence level
deregulated-nutrient-sensingRestores NAD+-dependent sirtuin activity; may re-sensitize nutrient-sensing networksLimited (human); strong (rodent)
mitochondrial-dysfunctionNR increased mitochondrial function markers and extended lifespan in mice; muscle mitochondrial biogenesis observedPreclinical strong; human limited
genomic-instabilityNAD+ supports PARP1-mediated DNA repair; NR may partially restore repair capacity in aged tissuePreclinical; no direct human evidence

Pharmacokinetics

Oral bioavailability is the most important practical constraint. Trammell et al. 2016 showed that NR is uniquely and orally bioavailable in both mice and humans — a significant distinction from some other NAD+ precursors — with dose-dependent elevation of whole-blood NAD+ metabolome 3.

Key PK findings from human studies:

ParameterValueSource
PBMC NAD+ elevation vs placebo~60% (median: 12.2 vs 7.7 pmol/mg protein; p=0.048 one-sided) at 1000 mg/dayMartens 2018 4
Dose1000 mg/day oral (typical trial dose)Martens 2018 4; Brakedal 2022 5
Duration to steady-stateNot formally characterized; inferred within 6-week trial windowMartens 2018 4
Brain NAD+ elevation (31P-MRS)Confirmed in 10/13 Parkinson’s patients with data at 1000 mg/day × 30 days (p=0.016)Brakedal 2022 5
SafetyWell-tolerated; no serious adverse events at 1000 mg/day × 6 weeks in healthy older adults; no AEs in PD patients × 30 daysMartens 2018 4; Brakedal 2022 5

dose-response-unclear — The dose-response relationship across the 250–2000 mg range in humans has not been fully characterized. Most trials use 1000 mg/day; whether lower doses produce proportionally lower NAD+ elevation, and whether higher doses are more effective or merely accelerate catabolism, is not established.

Dose-Response and Human Trial Evidence

Trammell 2016 — Human PK / bioavailability

Single-dose oral NR (100, 300, and 1000 mg) raised whole-blood NAD+ and NAD+ metabolome in a dose-dependent manner in n=12 healthy subjects 3. A separate preliminary experiment in one 52-year-old male at 1000 mg/day for 7 days showed blood NAD+ could rise as much as 2.7-fold; this n=1 observation motivated the clinical trial. First published evidence of oral bioavailability in humans. Open-label design; ChromaDex co-authors (two employees) on the paper 3.

Martens 2018 — Safety and NAD+ elevation in healthy older adults

Randomized double-blind placebo-controlled crossover (2 × 6 weeks): 1000 mg NR/day (500 mg twice daily, NIAGEN) in n=30 randomized (n=24 completed) healthy middle-aged and older adults (55–79 years). Whole-blood PBMC NAD+ elevated ~60% vs placebo (median NR: 12.2 vs placebo: 7.7 pmol/mg protein; p=0.048 one-sided). No statistically significant difference in adverse events between NR and placebo conditions. Exploratory finding: mean SBP −3.9 mmHg overall (not statistically significant after correction for multiple comparisons); among the 13 subjects with above-normal baseline BP (120–139 mmHg) mean SBP was ~9 mmHg lower after NR — exploratory, no formal inference 4. Most frequently cited human NR safety study.

Freeberg 2022 — Cardiovascular RCT protocol (phase IIa)

Study protocol paper, not results. Freeberg et al. published the protocol for a randomized, double-blind, placebo-controlled, parallel-group phase IIa trial (NCT03821623) designed to evaluate 3 months of NR (500 mg × 2/day) on casual systolic BP and aortic stiffness in n=94 midlife and older adults (age ≥50 years) with above-normal baseline SBP (120–159 mmHg). The protocol was motivated by the exploratory BP signal in Martens 2018 6. Results of this trial are not reported in this paper. needs-replication — Cardiovascular benefit not yet published from this powered trial.

2024–2026 RCT wave (recency refresh, R34)

A burst of moderate-quality NR RCTs in disease-specific populations published 2024–2026 — most show NAD+ elevation with selective clinical signals. Findings below are from PubMed abstracts + Crossref metadata; PDFs verified locally for Heggelund 2024 and McDermott 2024 only. needs-replication on remaining.

  • Heggelund 2024 (Nat Aging) — COPD airway inflammation 7: n=40 stable COPD patients, NR for 6 weeks. Sputum IL-8 reduced −52.6% vs placebo at week 6 (95% CI −75.7% to −7.6%, p=0.030); effect persisted 12 weeks post-treatment (−63.7%, p=0.034). Whole-blood NAD+ rose >2-fold; plasma IL-6 unchanged. Exploratory: gene-pathway upregulation related to genomic integrity in airway tissue; reduced epigenetic-age signal in airway biopsies. NCT04990869. First disease-specific NR RCT to hit a primary inflammatory endpoint.
  • McDermott 2024 (Nat Commun) NICE — peripheral artery disease 8: n=90 PAD patients, NR ± resveratrol vs placebo for 6 months. NR improved 6-min walk distance vs placebo by +17.6 m (90% CI +1.8, +∞; primary endpoint met). Per-protocol (≥75% adherence) NR alone improved 6-min walk by +31.0 m; NR+resveratrol +26.9 m — resveratrol added no benefit. First positive functional-outcome RCT in NR.
  • Brody 2024 (GeroScience) — MCI cognition pilot 9: n=20 mild cognitive impairment, NR 1 g/day × 10 weeks. NAD+ rose 2.6-fold (p<0.001). Cognition (MoCA) stable, no improvement. Default-mode network cerebral blood flow reduced (p=0.013). Pilot — not powered for cognition. needs-replication
  • Takeda 2025 (Aging Cell) — Werner syndrome crossover 10: progeroid disorder; NR 1 g/day × 26 weeks crossover, n small. CAVI (cardio-ankle vascular index, arterial stiffness) improved; skin ulcer area decreased; heel pad thinning trend; blood creatinine decreased. Safety profile unchanged. First positive RCT in a progeroid disease.
  • Caldo-Silva 2025 (J Cachexia Sarcopenia Muscle) meta-analysis 11: NMN/NR RCTs vs placebo in older adults (mean age 60.9–83). NMN: no significant effect on skeletal muscle index (MD −0.42), handgrip strength, gait speed, or 5-time chair stand test. NR data sparser. Class-level null on muscle-functional endpoints in older adults.
  • Schloesser 2026 (Nat Metab) — direct human comparison NR vs NMN vs NAM 12: n=65 healthy adults, 14-day randomized open-label. NR and NMN (but NOT NAM) comparably raise circulatory NAD+. Ex vivo with human gut microbiota: both NR and NMN are converted to nicotinic acid (NA) by gut microbes, and ex-vivo NA (not NR/NMN/NAM directly) is the potent NAD+ booster in whole blood. Authors propose a gut-dependent model where NR/NMN act as systemic NAD+ boosters via microbial NA conversion. Reframes mechanism debate; superiority of NMN’s Slc12a8 route (Grozio 2019) further questioned. needs-replication

Brakedal 2022 (NADPARK) — Phase 1 in Parkinson’s disease

Randomized double-blind Phase 1 trial; n=30 newly diagnosed, treatment-naive Parkinson’s disease patients (15 NR, 15 placebo); 1000 mg NR/day × 30 days. Key findings: (1) brain NAD+ confirmed elevated via 31P-MRS in the NR group (paired t-test p=0.016), though response was heterogeneous — 10/13 NR patients with available MRS data showed an increase — first in-human demonstration of CNS NAD+ elevation by oral NR; (2) in MRS-responders (n=10) a trend toward decreased MDS-UPDRS was seen (mean decrease 2.33 points, paired t-test p=0.017); no significant UPDRS change in the overall NR group; (3) NR altered cerebral metabolism (FDG-PET network pattern) 5. Not powered for efficacy (Phase 1 safety + target engagement; primary outcome was cerebral NAD+ penetration and metabolic response).

StudynDesignDoseDurationPrimary finding
Trammell 2016 312 (clinical trial arm; plus n=1 pilot)open-label PK100, 300, 1000 mg single dosesingle doseDose-dependent NAD+ metabolome elevation in blood; NAD+ rose up to 2.7-fold (n=1 pilot at 1000 mg/day × 7 days)
Martens 2018 430 randomized; 24 completedrandomized crossover1000 mg/day (500 mg × 2)6 weeksPBMC NAD+ elevated ~60% vs placebo (p=0.048 one-sided); well-tolerated; exploratory BP signal not significant overall
Freeberg 2022 694 planned (protocol only)rct phase-IIa (protocol)1000 mg/day (500 mg × 2)3 monthsStudy protocol — no results reported at publication
Brakedal 2022 530 (15 NR, 15 placebo)rct phase-11000 mg/day30 daysBrain NAD+ elevated by 31P-MRS (p=0.016); mild UPDRS trend in MRS-responders only

Evidence Quality: Non-Human Studies

Zhang et al. 2016 (Science) showed NR supplementation to aged mice (C57BL/6) improved mitochondrial and stem cell function and extended lifespan 2. This is the most-cited mechanistic NR study in rodents (1173 citations as of DOI lookup, 2026-05-04). Exact lifespan percentages and sex breakdown not verified — the PDF failed to download (green OA via EPFL repository inaccessible to archive); the seeder’s claim of “+4.6% in females” cannot be confirmed from the source. no-fulltext-access for lifespan figures; recommend verification when PDF becomes available.

DimensionStatus
Pathway (NAD+/sirtuin/AMPK) conserved in humans?yes
Phenotype (NAD+ decline with age) conserved in humans?yes
Lifespan extension replicated in humans?no — not yet testable in primary endpoint trials

needs-human-replication — Lifespan and healthspan endpoint results in mice have not been replicated in human randomized trials. Human trials to date have used surrogate endpoints (NAD+ levels, BP, physical function) not hard aging endpoints.

Comparison with NMN

FeatureNRnmn
StructureRiboside (no phosphate)Nucleotide (+ one phosphate)
Salvage entryNRK1/2 → NMN → NAD+NMNAT directly → NAD+
Bypasses NAMPT?YesYes
Oral bioavailability in humansEstablished (Trammell 2016)Debated; rapidly converted to NR in gut per some data
Human trial depthLarger — multiple completed RCTsGrowing; fewer completed at this dose range
Commercial developmentNIAGEN (ChromaDex); GRAS 2016Multiple suppliers; GRAS petition filed separately
Head-to-head vs NRNo completed published RCTNo completed published RCT

contradictory-evidence — No published head-to-head RCT compares NR and NMN pharmacodynamics (NAD+ AUC, tissue distribution) at equivalent molar doses in humans. Claims of superiority of either compound are not yet evidence-based.

Safety and Tolerability

Based on completed trials at 1000 mg/day up to 6 weeks (Martens 2018) and 30 days (Brakedal 2022):

  • Well-tolerated; no serious adverse events 4 5
  • Common adverse events: mild GI symptoms (nausea, flushing, leg cramps, headache) — in Martens 2018 two subjects on placebo (not NR) dropped out for side effects; no subject dropped out during the NR phase. In Brakedal 2022, seven NR patients and three placebo patients reported minor AEs, all unrelated to NR
  • No liver toxicity signals in reported biochemistry (Martens 2018)

long-term-unknown — No trial has evaluated NR beyond 6 weeks in a healthy population or 30 days in a disease population. Long-term effects on cancer risk (PARP1 competition; sirtuin modulation of tumor suppressor networks), autoimmunity, or other systems are not established. Animal data does not suggest harm, but dedicated long-term safety studies are absent.

Limitations and Gaps

  • No hard aging endpoint in humans. All human trials use surrogate endpoints. The effect of NR on healthspan, frailty, or survival in humans is unknown.
  • The “restore age-related NAD+ deficit” rationale is undermined at the blood level (2026). Trętowicz et al. 2026 (n=303 across 7 cohorts) found whole-blood NAD+ is stable with age in humans — there is no age-related blood NAD+ deficit to correct in healthy adults. NR still raises blood NAD+ above baseline (confirmed by Trętowicz’s twin-pair NR positive-control arm itself), but the supplementation is making “high” higher rather than restoring “low” to normal. The field’s strongest remaining rationales for NR in aging are (a) tissue-level NAD+ decline (muscle/skin) and (b) pathological NAD+ deficit in specific disease contexts (COPD, PAD, Werner — where Heggelund 2024, McDermott 2024, Takeda 2025 RCTs met primary endpoints). contradictory-evidence 13
  • Modest effect sizes. The exploratory BP signal in Martens 2018 (−3.9 mmHg SBP overall, not significant after correction; ~−9 mmHg in elevated-BP subgroup, exploratory) is promising but unconfirmed. Freeberg 2022 is a protocol paper for a powered trial (NCT03821623) designed to test this — results not yet published.
  • Tissue-specific NAD+ dynamics. Whole-blood NAD+ is a convenient biomarker but may not reflect tissue-specific (muscle, brain, liver) NAD+ adequately. Brakedal 2022 addresses CNS only. As of 2026, blood NAD+ is not a useful aging biomarker (Trętowicz 2026); whether it remains a useful pharmacodynamic biomarker for NR engagement is also weakened — the assay can detect NR-induced rise, but the baseline against which to interpret the rise is no longer “age-depressed.”
  • NR vs NMN debate unresolved. Mechanism of peripheral absorption and interconversion (NR ↔ NMN in the gut/plasma) is not fully mapped in humans. contradictory-evidence
  • Mouse lifespan data unverified. Zhang 2016 lifespan extension claim cannot be confirmed from the source — PDF download failed (green OA via EPFL inaccessible). Seeder-claimed figure of “+4.6% in females” is unverified. needs-human-replication no-fulltext-access
  • ChromaDex commercial interest. ChromaDex funded or co-funded several early NR trials (including Trammell 2016). Independent academic replication is growing but conflicts of interest should be noted.
  • needs-canonical-id — CAS number for NR-Cl (commercial supplement form) was not retrieved; PubChem entry 439924 represents the cation. The chloride salt (NIAGEN) may carry a distinct CID.

Classification

  • SENS strategy: None directly — NR addresses upstream metabolic function rather than a discrete SENS damage category. Relates most closely to mitochondrial maintenance (MitoSENS context if NAD+ supports mitochondrial protein quality).
  • Hallmark targets: deregulated-nutrient-sensing, mitochondrial-dysfunction
  • Intervention category: nad-precursors (R23d class page) — NMN/NR/niacin/NAM class context.

Footnotes

Footnotes

  1. ratajczak-2016-nrk1-nad-metabolism · doi:10.1038/ncomms13103 · in-vitro + in-vivo · model: mammalian cell lines (NIH/3T3, HepG2, AML12) + mouse IP injection · archive: verified ↩ ↩2

  2. zhang-2016-nad-repletion-lifespan-mice · doi:10.1126/science.aaf2693 · n=not verified · in-vivo · model: aged C57BL/6 mice · archive: download failed (green OA via EPFL; inaccessible) no-fulltext-access ↩ ↩2

  3. trammell-2016-nr-bioavailable-humans · doi:10.1038/ncomms12948 · n=12 (clinical trial arm) + n=1 (pilot) · open-label PK · model: healthy humans (single dose, 100/300/1000 mg) · ChromaDex co-authors (2 employees) · archive: verified ↩ ↩2 ↩3 ↩4

  4. martens-2018-nr-older-adults · doi:10.1038/s41467-018-03421-7 · n=30 randomized; 24 completed · randomized double-blind crossover · model: healthy middle-aged and older adults (55–79 yr) · archive: verified ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7

  5. brakedal-2022-nadpark-parkinsons · doi:10.1016/j.cmet.2022.02.001 · n=30 (15 NR, 15 placebo) · rct phase-1 · model: newly diagnosed treatment-naive Parkinson’s disease patients · 30 days · archive: verified ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  6. freeberg-2022-nr-blood-pressure · doi:10.3389/fcvm.2022.881703 · n=94 planned · rct phase-IIa protocol (NCT03821623) · model: midlife and older adults (age ≥50 yr) with above-normal SBP (120–159 mmHg) · no results reported at publication · archive: verified ↩ ↩2

  7. heggelund-2024-nr-copd-airway-inflammation · doi:10.1038/s43587-024-00758-1 · n=40 · rct (randomized double-blind placebo-controlled) · p=0.030 (primary endpoint, sputum IL-8 −52.6%) · model: stable COPD patients · NR 6 weeks · NCT04990869 · archive: local PDF available · Nature Aging 2024 · integrated from abstract + Crossref metadata pending full PDF verification ↩

  8. mcdermott-2024-nice-nr-pad · doi:10.1038/s41467-024-49092-5 · n=90 · rct (randomized double-blind placebo-controlled, NR ± resveratrol vs placebo) · primary endpoint met (6MWD +17.6 m, 90% CI +1.8, +∞) · model: peripheral artery disease patients · 6 months · Nature Communications 2024 · archive: local PDF available · integrated from abstract + Crossref metadata pending full PDF verification ↩

  9. brody-2024-nr-mci-cognition · doi:10.1007/s11357-023-00999-9 · n=20 · rct pilot (placebo-controlled) · NAD+ 2.6-fold rise (p<0.001) · cognition stable · model: mild cognitive impairment older adults · NR 1 g/day × 10 weeks · GeroScience 2024 · archive: pending download · integrated from abstract pending PDF verification ↩

  10. takeda-2025-nr-werner-syndrome · doi:10.1111/acel.70093 · n small · rct (double-blind randomized crossover placebo-controlled) · CAVI improved; skin ulcer area decreased · model: Werner syndrome (progeroid) patients · NR 1 g/day × 26 weeks crossover · Aging Cell 2025 · archive: pending download · integrated from abstract pending PDF verification ↩

  11. caldosilva-2025-nmn-nr-muscle-meta-analysis · doi:10.1002/jcsm.13799 · meta-analysis · NMN: no significant effect on SMI, HGS, gait speed, 5CST in older adults · model: middle-aged to elderly (60.9–83 y) · Journal of Cachexia, Sarcopenia and Muscle 2025 · archive: pending · integrated from abstract pending PDF verification ↩

  12. schloesser-2026-nad-precursors-comparison · doi:10.1038/s42255-025-01421-8 · n=65 · rct (open-label, placebo-controlled, three-arm comparison NR vs NMN vs NAM) · NR and NMN comparably raise circulatory NAD+; NAM does not · ex-vivo: gut microbes convert NR/NMN to nicotinic acid; NA is the potent NAD+ booster · 14 days · Nature Metabolism 2026 · archive: pending download · integrated from abstract pending PDF verification — substantively reframes mechanism debate ↩

  13. tretowicz-2026-blood-nad-stable-aging · doi:10.1038/s42255-026-01537-5 · observational + intervention pooled · n=303 across 7 independent cohorts (Netherlands, Spain, Finland) · whole-blood NAD+ stable with age (all 6 age-comparison analyses null: P 0.24–0.62, R² 0.012–0.051) and stable across exercise/protein interventions in older adults; positive control: 5-month NR supplementation in twin-pair cohort (NCT03951285) raises whole-blood NAD+ as expected — confirms NR’s pharmacodynamic effect is detectable on this validated UHPLC-HRMS assay · prior conflicting blood-NAD+/aging literature attributed to pre-analytical handling artifacts (frozen-without-methanol loses 30–80% of NAD+) · Nature Metabolism 2026-05-14 · Trętowicz MM et al. (Houtkooper laboratory, Amsterdam UMC) · archive: not yet in archive · verified: false (Results/Discussion paywalled; Abstract + Reporting Summary + 8 source-data XLSX directly verified) ↩

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