NAD+ vs MOTS-C
Nicotinamide adenine dinucleotide is a redox cofactor and the substrate consumed by sirtuins, PARPs and CD38, and because the molecule itself is not orally bioavailable, its human literature is really a literature about precursors, principally nicotinamide riboside and nicotinamide mononucleotide. MOTS-c is a 16-amino-acid microprotein encoded within the mitochondrial 12S rRNA gene that signals from mitochondria to the nucleus, and its interventional data come almost entirely from rodents and cell culture. The two are set side by side because both are sold as mitochondrial interventions, and the recurring claim in vendor material is that they are complementary because MOTS-c raises cellular NAD+. No study has compared them. Searches restricted to titles and abstracts return two observational biomarker papers in which NAD-related enzymes and MOTS-c were measured in the same samples, and neither administered anything. The remaining publications engaging both are reviews that discuss them as separate members of the same therapeutic category.
No study has compared them directly.
Everything below is drawn from separate studies that used different models, endpoints and species. That is a real limit on what can be concluded, not a formality.
No experiment has administered NAD+ or an NAD+ precursor and MOTS-c within the same design, in any species, and no study has compared them on a shared endpoint. A title and abstract search pairing MOTS-c with NAD, NAD+ or nicotinamide returns exactly two records, both observational extracellular-vesicle biomarker studies from the same group, in which MOTS-c was quantified as one of several mitochondrial proteins while NAD appeared only as a measured NAD-handling enzyme or as assay chemistry. Neither compound was given to anyone. Beyond those, the publications that engage both are reviews of mitochondrial-targeted interventions, which place NAD+ precursors and mitochondrial-derived peptides in adjacent sections of the same catalogue rather than testing one against the other. Several of those reviews do assert a link, describing MOTS-c administration in aged mice as raising NAD+ availability and modulating sirtuin signalling, and one review of mitochondria-derived peptides states plainly that MOTS-c can increase NAD+ levels. That proposed relationship is a claim carried in review text about rodent work, not a measured comparison, and no human study has tested it.
The 9 publications that cover both
- 01Human clinical2021
Neural cell-derived plasma exosome protein abnormalities implicate mitochondrial impairment in first episodes of psychosis
Goetzl EJ, Srihari VH, Guloksuz S, et al. · The FASEB Journal · observational case-control study, 10 patients with a first episode of psychosis and 10 matched controls, mitochondrial proteins quantified by immunoassay in neural cell-derived plasma exosomes
MOTS-c and humanin were measured as endogenous constituents of neural-derived exosomes and differed between patients and controls, supporting mitochondrial impairment as a feature of first-episode psychosis. NAD entered the study only as assay chemistry, through the conversion of NADH to NAD+ used to measure ATP synthase activity. Neither MOTS-c nor any NAD+ precursor was administered.
- 02Human clinical2021
Abnormal levels of mitochondrial proteins in plasma neuronal extracellular vesicles in major depressive disorder
Goetzl EJ, Wolkowitz OM, Srihari VH, et al. · Molecular Psychiatry · observational biomarker study, 20 participants with major depressive disorder sampled before and after eight weeks of antidepressant treatment, mitochondrial proteins quantified in plasma neuron-derived extracellular vesicles
Endogenous MOTS-c and humanin levels were quantified alongside other mitochondrial proteins and were abnormal relative to controls. The NAD-generating enzyme NMNAT2 and the NAD-consuming enzyme SARM1 were among the proteins measured, so the study engaged NAD metabolism only through its enzymes. Neither MOTS-c nor an NAD+ precursor was administered.
- 03Review2024
Beneficial Effects of Low-Grade Mitochondrial Stress on Metabolic Diseases and Aging
Min SH, et al. · Yonsei Medical Journal · narrative review of mitohormesis and the mitochondrial unfolded protein response in metabolic disease and ageing
The review covered both compounds as consequences of the same signalling system. MOTS-c was described as inhibiting the folate cycle, raising the AMPK activator AICAR in skeletal muscle cells and improving glucose and fatty-acid metabolism. NAD+ was described as an obligate cofactor for sirtuins and poly-ADP-ribose polymerase, with reversal of NAD+ depletion reported to improve mitochondrial and stem-cell function and extend lifespan in mice. The two were discussed in separate sections and not compared.
- 04Review2024
Mitochondria as Nutritional Targets to Maintain Muscle Health and Physical Function During Ageing
Broome SC, Whitfield J, Karagounis LG, Hawley JA · Sports Medicine · narrative review of ageing, exercise training and supplements with a mechanistic basis for acting on human skeletal muscle mitochondria
The review reported that while some NAD+ precursors improved physical function in older individuals, the improvement appeared unrelated to and independent of changes in skeletal muscle mitochondrial function. Mitochondrial-derived peptides were placed in a different category, identified as compounds whose safety and efficacy should be investigated in preclinical models rather than as an established intervention.
- 05Systematic review2025
Exercise Mimetics in Aging: Suggestions from a Systematic Review
Giacomello E, Nicoletti C, Canato M, Toniolo L · Nutrients · systematic search of PubMed and Scopus for exercise mimetics, 97 research articles selected and discussed
Both compounds appeared in the catalogue of exercise-mimetic strategies. Nicotinamide mononucleotide was described as an NAD+ precursor interacting with the sirtuin pathway, with animal work reporting restored capillary density and improved treadmill endurance. MOTS-c was described as a mitochondrially encoded hormone whose plasma levels correlated with insulin resistance and whose administration to obese mice promoted metabolic homeostasis. The review did not compare them or rank them.
- 06Review2025
Mitochondria-derived peptides: Promising microproteins in cardiovascular diseases (Review)
Ran Y, et al. · Molecular Medicine Reports · narrative review of mitochondria-derived peptides, principally humanin and MOTS-c, in cardiovascular disease
The review stated that MOTS-c can increase NAD+ levels and that NAD+ acts as an activator of sirtuins with a role in ageing, presenting the relationship as a mechanistic link between the peptide and NAD+ biology. The supporting citations were preclinical, and no experiment described in the review administered an NAD+ precursor alongside the peptide.
- 07Review2025
Mitochondrial Dysfunction in the Development and Progression of Cardiometabolic Diseases: A Narrative Review
Pliouta L, et al. · Journal of Clinical Medicine · narrative review of mitochondrial dysfunction in cardiometabolic disease and of the interventions proposed to address it
The review described nicotinamide riboside and nicotinamide mononucleotide as NAD+ precursors that improve mitochondrial function by enhancing sirtuin activity, promoting mitochondrial biogenesis and supporting antioxidant defence, and noted protein hyperacetylation in diastolic heart failure as reversible with nicotinamide riboside. MOTS-c was covered separately as a 16-amino-acid peptide reported in animal models to enhance skeletal muscle insulin sensitivity and protect against diet-induced obesity.
- 08Review2025
Exercise-Induced Muscle-Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging
Tero-Vescan A, Degens H, Matsakas A, et al. · Pharmaceuticals · narrative review of myokine and adipokine signalling in ageing, with a proposed treatment algorithm stratified by age-related comorbidity
This review made the link between the two explicit, stating that exogenous MOTS-c administration in aged mice improved physical performance and metabolic profiles partly through an ability to increase NAD+ availability and modulate sirtuin pathways including SIRT1 and SIRT3. Nicotinamide riboside and nicotinamide mononucleotide were listed among the NAD+-related mediators discussed. The statement summarised rodent work and no comparative experiment was reported.
- 09Review2026
An integrated anti-aging framework targeting NAD(+) homeostasis, mitochondrial quality control, and redox stability: Roles of NMN/NR, PQQ, and EGT
Sun Y, Han JC, Tran K, et al. · Redox Biology · narrative review proposing a three-compound anti-ageing framework built on nicotinamide mononucleotide and nicotinamide riboside, pyrroloquinoline quinone and l-ergothioneine, synthesising preclinical and early clinical evidence
The framework treated NAD+ precursors as the central regulator of mitochondrial homeostasis, with the most immediate effects on metabolic activation. MOTS-c entered as a mediator rather than as an intervention: the review described a companion compound maintaining mitochondrial function and reducing radiation-induced lung injury through a MOTS-c-dependent mechanism. The peptide was not proposed as a therapeutic in its own right and was not compared with the NAD+ precursors.
Side by side.
| NAD+ | MOTS-C | |
|---|---|---|
| Evidence maturity | Early clinical | Preclinical only |
| Studies cited here | 15 | 15 |
| Published 2023 or later | 11 | 12 |
| Newest paper | 2026 | 2026 |
| Molecular class and origin | A dinucleotide redox cofactor present in every cell, not a peptide. It is consumed as a substrate by sirtuins, PARPs and CD38, and preclinical work reports that tissue concentrations fall with age. | A 16-amino-acid microprotein encoded inside the mitochondrial 12S rRNA gene, translated from mitochondrial DNA and released into circulation, described as a retrograde signal from mitochondria to the nucleus. |
| Mechanism as described in the literature | Substrate availability. Raising the precursor pool is reported to support sirtuin and PARP activity, mitochondrial respiration and antioxidant defence, and reversal of depletion improved mitochondrial and stem-cell function in aged mice. | Signalling. The peptide targets the folate-methionine one-carbon cycle, raises the AMPK activator AICAR, activates AMPK, binds and activates casein kinase 2 in muscle, and regulates nuclear stress-response gene expression. Several reviews additionally describe it as raising cellular NAD+. |
| Size of the evidence base | Substantial in humans. Randomised placebo-controlled trials span prediabetes, peripheral artery disease, hypertension, long COVID, Friedreich's ataxia, mild cognitive impairment and immune thrombocytopenia, alongside meta-analyses of 15 parallel randomised trials on safety and of muscle outcomes across trials in older adults. | Substantial in animals and absent in humans for administration. Rodent and cell studies cover insulin sensitivity, exercise capacity, islet senescence and muscle bioenergetics, while the human record is observational biomarker work and one mitochondrial genotype association across cohorts totalling more than 27,000 participants. |
| Best-characterised finding | That oral precursors reliably raise circulating NAD+, two- to threefold in trial after trial, and are well tolerated for weeks to months. What that elevation delivers is far less consistent, with meta-analyses of muscle, glucose and lipid outcomes returning null results. | That administered MOTS-c improved metabolic and physical outcomes in mice: prevention of age-dependent and diet-induced insulin resistance, improved physical performance in young, middle-aged and old animals, and improved intrinsic muscle mitochondrial bioenergetics dependent on PGC-1 alpha and AMPK signalling. |
| Human data | Interventional. Trials have given nicotinamide riboside or nicotinamide mononucleotide by mouth and measured walking distance, insulin sensitivity, cognition, blood pressure and platelet response, with results ranging from positive on individual secondary endpoints to null on primary ones. | Observational only. No controlled trial has administered exogenous MOTS-c to humans. Human studies measured endogenous levels in metabolic, cardiovascular, renal and reproductive conditions, in trained versus sedentary participants, and after heat treatment during limb immobilisation. |
| Evidence maturity | Early clinical. The pharmacokinetics are settled and the safety record over periods up to about six months is reassuring, but no trial has shown durable improvement in muscle mass, cognition, glycaemic control or blood pressure, and lifespan and stem-cell rejuvenation findings remain rodent results. | Preclinical. Everything known about administering the peptide comes from animals and cell culture, so dosing, pharmacokinetics, long-term safety and any functional benefit in people are unestablished. |
| Consistency of the human measurements | Consistent on the biomarker and inconsistent on outcomes. Precursors raise blood NAD+ in essentially every trial that measures it, yet trials of the same precursor in different populations have reported improvement, no change and worse scores on physical-function measures. | Inconsistent in direction. Circulating MOTS-c has been reported lower in diabetes and in polycystic ovary syndrome but higher in obesity and in acute coronary syndrome, and levels did not change after surgical weight loss despite other metabolic improvements. Assay methods differ between studies. |
| Basis of most marketing claims | Extrapolation from the reliable rise in blood NAD+ and from rodent lifespan and stem-cell work to human ageing outcomes that the controlled trials and meta-analyses have not confirmed. | Extrapolation from rodent administration studies and from human observational associations to an effect of injecting the peptide into people, which no trial has tested. The proposed synergy with NAD+ rests on review statements about preclinical work rather than on any combined experiment. |
And what it does not.
The two are not competing answers to one question, and the literature does not let them be ranked. What the combined evidence supports is narrow: oral NAD+ precursors raise circulating NAD+ dependably and appear well tolerated for periods up to roughly six months, and MOTS-c administration improves metabolic and physical measures in rodents through AMPK-linked signalling. What it does not support is more consequential. No trial has shown that raising NAD+ produces durable gains in muscle mass, cognition, glycaemic control or blood pressure, and pooled analyses of those endpoints have been null, while one review of nutritional mitochondrial targets noted that where physical function did improve with precursors, the improvement appeared independent of skeletal muscle mitochondrial function. On the other side, nothing has been administered to a human at all, and the circulating peptide moves in opposite directions across conditions, so even its use as a marker is unsettled. The claim that the two are synergistic because the peptide raises NAD+ appears only in review text describing rodent work, and no experiment has given both.
Common questions.
- Has any study given both an NAD+ precursor and MOTS-c in the same experiment?
No. A title and abstract search pairing MOTS-c with NAD, NAD+ or nicotinamide returns two records, both observational extracellular-vesicle biomarker studies in which MOTS-c was measured as one protein among several and NAD appeared only through NAD-handling enzymes or as assay chemistry. Neither administered anything. Full-text searching adds reviews that discuss the two as separate members of the same category, but no combined or comparative experiment has been published in any species.
- Where does the claim that MOTS-c raises NAD+ come from?
From review literature summarising rodent work. One review of mitochondria-derived peptides states that MOTS-c can increase NAD+ levels and that NAD+ activates sirtuins; another states that MOTS-c administration in aged mice improved physical performance partly through increased NAD+ availability and modulation of SIRT1 and SIRT3. Those are secondary descriptions of animal experiments rather than measurements from a trial, and no human study has tested whether administering the peptide changes NAD+ status in people.
- Why is the human literature about precursors rather than about NAD+ itself?
Because the cofactor is poorly absorbed when taken orally, so human trials have used nicotinamide riboside and nicotinamide mononucleotide instead. A 2016 study established that nicotinamide riboside raised blood NAD+ in a dose-dependent way and more effectively than equivalent molar amounts of nicotinamide or nicotinic acid. A 2026 randomised study comparing three boosters found that riboside and mononucleotide raised circulatory NAD+ comparably over 14 days while nicotinamide did not.
- What has human research on MOTS-c actually measured?
Endogenous levels, not administered peptide. Studies have compared circulating MOTS-c across diabetes, obesity, acute coronary syndrome, polycystic ovary syndrome and cerebral palsy, tracked it after exercise, heat treatment during limb immobilisation and bariatric surgery, and linked a mitochondrial variant in the coding region to type 2 diabetes risk in East Asian men. A meta-analysis of seven studies covering 602 participants found the direction of change differed between diabetes and obesity.
- Do the trials show that raising NAD+ improves physical function in older adults?
Not consistently. A systematic review and meta-analysis in older participants found no significant effect of nicotinamide mononucleotide on skeletal muscle index, handgrip strength, gait speed or chair-stand performance, and reported nicotinamide riboside associated with longer six-minute walk distance in peripheral artery disease but poorer physical-battery and chair-stand scores in mild cognitive impairment. The authors concluded that current evidence does not support these precursors for preserving muscle mass.
For research purposes only. Not for human consumption, diagnosis, treatment, or prevention of any condition. Nothing on this page is medical advice, and no comparison here should be read as a recommendation of either compound.