NAD+ (and its precursors NMN / NR)
NAD+ / NMN / NR — the longevity coenzyme: elegant theory, real biomarker rise, unproven human benefit

Class: small_molecule
Synonyms: NAD⁺ (nicotinamide adenine dinucleotide)
Function tags: longevity / healthy-aging (claimed)
cellular energy / mitochondrial
DNA repair / sirtuins
metabolic
Overall evidence grade: A
WADA prohibited: no
Last updated: 2026-07-13

In brief: NAD⁺ is a fundamental coenzyme (not a peptide) that powers energy metabolism, DNA repair, and the sirtuin "longevity" enzymes — and declines with age, which is the basis of a very elegant theory: top NAD⁺ back up (via precursors like NMN or NR) and you might slow aging. That theory, and Harvard scientist David Sinclair's public NMN use, helped build a multi-hundred-million-dollar supplement industry. The science is honest but sobering: NMN/NR reliably and safely raise blood NAD⁺, and the animal data are genuinely impressive — but in humans, a 2025 meta-analysis of 10 RCTs found no benefit for muscle, strength, or physical function, and metabolic trials mostly haven't reproduced the mouse results (promising signals exist in specific patient groups — prediabetes, Parkinson's, PAD — not healthy people). Add a female-only mouse-lifespan effect and a shaky resveratrol pairing, and the picture is: a real, important molecule with a reliable biomarker effect and a real evidence gap on the outcomes that matter. Whether that gap is "doesn't work" or "trials too short" (Sinclair's view) is genuinely unresolved. It anchors this register's NAD⁺ biology — the pathway that MOTS-c (#10), 5-Amino-1MQ (#59), and SLU-PP-332 (#60) all feed into.

## Identity NAD⁺ is a **coenzyme** — not a peptide — present in every cell and required for **hundreds of enzymatic reactions**: the **electron-transport chain** (ATP/energy), the **sirtuins (SIRT1–SIRT7)** ("longevity" deacylases), **PARPs** (DNA repair), and **CD38** (immune signalling). Because oral NAD⁺ itself is poorly absorbed, the market sells **precursors — mainly NMN and NR** — that cells convert into NAD⁺, plus **IV NAD⁺** infusions. It's included in this (mostly peptide) register because it is the **biochemical hub** that several register compounds act through. ## Mechanism (as proposed) NAD⁺ cycles between oxidized (NAD⁺) and reduced (NADH) forms to shuttle electrons in **energy metabolism (ATP production)**. It's also the **required substrate** for three big consumer classes: **sirtuins** (SIRT1–7, which deacetylate histones/proteins to regulate metabolism, stress resistance, and gene expression — the "longevity" link), **PARPs** (DNA-damage repair), and **CD38** (whose age-related rise *consumes* NAD⁺). With age, NAD⁺ falls (more consumption, less synthesis), so **sirtuin and repair capacity drop** — the rationale for precursor supplementation. NMN and NR feed the **salvage pathway** to regenerate NAD⁺. All of this biochemistry is **solid and non-controversial**; what's unresolved is whether **pushing NAD⁺ back up in humans actually restores youthful function** — the biomarker moves reliably, the clinical outcomes so far mostly don't.

Evidence grades by outcome:
outcome: Raising NAD⁺ levels (the biomarker)
grade: A
base: Multiple RCTs: NMN/NR reliably ↑ blood NAD⁺ (~40–59% at modest doses), safely
caveat: This grades "does it raise NAD⁺" — YES. It does not mean the downstream health claims are proven
outcome: Physical function / muscle / strength (healthy older adults)
grade: F
base: 2025 meta-analysis, 10 RCTs: no benefit
caveat: The clearest negative: marker up, function unchanged
outcome: Metabolic health (general)
grade: D
base: Human trials mostly failed to reproduce animal results
caveat: Some signals; overall "iffy" per researchers
outcome: Specific clinical populations (prediabetes ♀, early Parkinson's, PAD)
grade: C
base: Small trials with some promising results
caveat: Population-specific, preliminary, needs replication in large trials
outcome: Longevity / lifespan (humans)
grade: F
base: No human lifespan data; mouse data (female-biased)
caveat: Untestable short-term; the core claim is unproven in people
outcome: Safety
grade: B
base: Extensive human exposure
caveat: Generally well-tolerated and safe short-term (a genuine plus); long-term/high-dose and IV-specific safety less characterised; NMN regulatory status contested

Legal status:
region: EU
status: sold as a dietary supplement (NMN, NR, niacin/nicotinamide) 
note: sold as a dietary supplement (NMN, NR, niacin/nicotinamide) and as IV NAD⁺ in wellness clinics. Note: NMN's US supplement status has been contested by the FDA (a regulatory grey area after NMN was investigated as a drug); NR is broadly sold. Not an approved anti-aging therapy anywhere.

Cosmetic claims:

Note: The longevity supplement everyone's heard of — where the biomarker reliably moves but the human benefits don't (yet). This is the register's most mainstream, most commercially enormous entry, and a textbook "elegant theory, iffy human data" case. Three threads: (1) it's not a peptide — a fundamental coenzyme — and anchors the biology that several register peptides (#10, #59, #60) converge on; (2) its theory is genuinely elegant (NAD+ falls with age → sirtuins/DNA-repair suffer → restore it → slow aging), championed by Harvard's David Sinclair; (3) the honest catch — supplements (NMN/NR) reliably raise blood NAD+, but a 2025 meta-analysis of 10 RCTs found no benefit for muscle, strength, or physical function in older adults. The gap between "moves the marker" and "changes outcomes" is the whole story.
Status note: watch: longer/larger RCTs and the disease-specific trials — neurodegeneration, metabolic — that could finally close or confirm the biomarker-vs-outcome gap

Sources:
2025 meta-analysis (10 RCTs) — NMN/NR: no benefit for muscle mass/strength/physical function in older adults.
Human NMN/NR trials showing reliable NAD⁺ elevation (~40–59%) and good tolerability; NPR/expert commentary ("pretty iffy" on functional benefits; promising in specific populations — prediabetes, Parkinson's, PAD).
Sinclair et al. 2013 (NAD⁺ decline ↔ aging, the landmark); reviews of NAD⁺/sirtuin/PARP/CD38 biology (MDPI 2025).
Mouse data: NMN lifespan extension female-biased; resveratrol reproducibility/lifespan controversies.
FDA NMN supplement-status dispute (regulatory context). (No human lifespan data; healthy-population functional benefit unproven as of 2026.)