MOTS-c vs NAD+: What the Published Research Compares

MOTS-c and NAD+ are often grouped as "mitochondrial" longevity compounds, but they are different kinds of molecule: MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA, first described in 2015, while NAD+ (nicotinamide adenine dinucleotide) is a coenzyme, not a peptide, that every cell uses in energy metabolism. Their evidence also differs in kind: MOTS-c rests almost entirely on cell and mouse studies, while the human research on NAD+ mostly tested oral precursors and measured NAD+ levels as the main outcome.

We found no study that compares the two directly. Below are their published records side by side, with the model behind each finding.

At a glance

	MOTS-c	NAD+
What it is	16-amino-acid peptide encoded in the mitochondrial 12S rRNA gene region	Coenzyme (a dinucleotide), not a peptide
First described	Lee et al., Cell Metabolism, 2015	Long-established coenzyme; the precursor trials cited here date from 2018 on
Proposed role	Signaling peptide acting on metabolism, with AMPK activation reported in cells and mice	Cofactor in energy metabolism and co-substrate for other enzymes
Main research model	Cell culture and mice	Human trials of oral precursors (NR, NMN), plus extensive animal work
Human data	We found no published randomized trial of MOTS-c itself; a small company-run trial tested an analog	Several randomized trials of precursors measuring NAD+ and metabolic markers
FDA status	Not approved; FDA staff proposed against compounding listing; advisory committee recommended it in July 2026	NAD+ not approved as a drug; NMN confirmed by FDA in 2025 as not excluded from dietary supplements
Sport	Prohibited by name under WADA S4 since the 2025 List	Not named on the List; large-volume intravenous infusions are a prohibited method outside hospital care

What each one is

MOTS-c stands for mitochondrial open reading frame of the 12S rRNA type-c. Changhan Lee and colleagues at the University of Southern California reported it in Cell Metabolism in 2015 as a short peptide encoded within mitochondrial DNA. The paper builds on the earlier discovery of humanin, another peptide encoded in mitochondrial DNA.

NAD+ is an established piece of biochemistry. It carries electrons in the reactions that extract energy from food and serves as a co-substrate for other enzymes. Interest in it as an aging target comes from reports, mostly in rodents, that NAD+ levels fall with age; Elhassan and colleagues described the human data on that decline as sparse. Most human research has used precursors that cells convert into NAD+: nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).

The evidence for MOTS-c

Cell and mouse work. In the 2015 paper, Lee and colleagues reported that MOTS-c acted mainly on skeletal muscle, inhibited the folate cycle and its linked purine synthesis, and activated AMPK, a cellular energy sensor. In mice, MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance and diet-induced obesity.

Reynolds and colleagues (Nature Communications, 2021), from the same research group and collaborators in New Zealand, reported that MOTS-c improved physical performance in young, middle-aged and old mice, and that treatment started late in life increased physical capacity in old mice. The same paper is also the main human data point: in people, exercise increased endogenous MOTS-c in skeletal muscle and in the circulation. That is an observation about the body's own peptide during exercise, not a test of MOTS-c given to anyone.

Human trials. We found no published randomized trial of MOTS-c itself. The company CohBar ran a phase 1a/1b trial of CB4211, a modified analog of MOTS-c, and in 2021 reported topline results from 20 people with obesity and fatty liver disease over four weeks. The company reported that the analog was well tolerated and that liver enzymes fell more than with placebo, while liver fat fell substantially in both the treatment and placebo groups. An analog is not the native peptide, and a four-week, 20-person safety study is not efficacy evidence.

The FDA's reading. In its briefing document for the July 2026 advisory meeting, FDA staff wrote that the pharmacology studies of MOTS-c were limited to in vitro and rodent models, that its molecular targets remain unknown, and that neither the nomination nor the agency's own search identified information on MOTS-c given to humans.

The evidence for NAD+

The NAD+ literature has the human trials that MOTS-c lacks, with a limit worth stating at the outset: most measured whether a precursor raises NAD+ or related metabolites, which is a biochemical outcome rather than a clinical one.

Martens and colleagues (Nature Communications, 2018) ran a randomized, placebo-controlled crossover trial of NR in healthy middle-aged and older adults, two six-week periods. NR was well tolerated and stimulated NAD+ metabolism. Effects on blood pressure and arterial stiffness were flagged as worth testing in future trials.
Elhassan and colleagues (Cell Reports, 2019) gave NR or placebo to 12 aged men for 21 days in a randomized crossover design. NR raised the NAD+ metabolome in muscle and lowered some circulating inflammatory markers, without changing mitochondrial energy output.
Yoshino and colleagues (Science, 2021) ran a 10-week randomized, placebo-controlled trial of NMN in postmenopausal women with prediabetes who were overweight or obese. They reported improved muscle insulin sensitivity and signaling.
The NADPARK study (Brakedal and colleagues, Cell Metabolism, 2022) was a phase 1 trial in 30 people newly diagnosed with Parkinson's disease. NR was well tolerated and raised brain NAD levels, though variably between participants.

NAD+ given directly into a vein has a much thinner record. Grant and colleagues (Frontiers in Aging Neuroscience, 2019) published a pilot study of a six-hour intravenous infusion and reported that plasma NAD+ did not change for the first two hours, consistent with rapid removal from the blood. Oral precursor studies do not describe infused NAD+.

Regulatory status

MOTS-c is not FDA-approved for any use. The FDA had placed it in Category 2 of its compounding policy, for substances that may present significant safety risks, and removed it in April 2026 after its nominator withdrew. At the July 23 and 24, 2026 meeting of the Pharmacy Compounding Advisory Committee, FDA staff proposed against adding it to the 503A bulks list, and the committee voted to recommend it, 7 to 5 with two abstentions according to Pharmacy Times. The vote is not binding, and we found no proposed rule as of this writing. An interim access policy for some peptides is now under White House review, with its covered substances not yet public.

NAD+ is not an FDA-approved drug either. Its precursors sit mostly in the dietary supplement category. For NMN, that position was contested: the FDA said in 2022 that NMN was excluded from the supplement definition because it had been studied as a drug, then, in letters dated September 29, 2025, concluded that it is not excluded, according to the law firm Venable. Lawful as a supplement is not the same as shown to work.

Sport

MOTS-c was added to the World Anti-Doping Agency's Prohibited List in 2025, named under S4 as an example of an AMP-activated protein kinase activator, according to the US Anti-Doping Agency. NAD+ is not named on the List. Separately, USADA states that intravenous infusions above a set volume are a prohibited method outside hospital care, surgery or clinical investigation, whatever the substance.

For the rest of this class, see our review of the longevity peptides and our evidence review of epitalon.

Frequently asked questions

Is NAD+ a peptide?

No. NAD+ is a coenzyme made of two nucleotides. It is often sold and discussed alongside peptides, but it is a different class of molecule.

Has MOTS-c been tested in humans?

We found no published randomized trial of MOTS-c itself. A small company-run trial tested a modified analog, CB4211, for four weeks, and a 2021 study measured the body's own MOTS-c rising during exercise.

Which has more human evidence, MOTS-c or NAD+?

NAD+, through its precursors. Randomized trials of NR and NMN have measured NAD+ levels and some metabolic markers in people. Whether raising NAD+ changes how people age has not been shown.

Is MOTS-c banned in sport?

Yes. It has been named on the WADA Prohibited List under hormone and metabolic modulators since 2025.

Sources:

No compound discussed in this review is FDA-approved as a drug. Nothing above is dosing guidance or a treatment claim. Research use only.

For research use only · Not for human or veterinary use · No research compound discussed here is FDA-approved for any indication