MOTS-c vs NAD+: a peptide and a coenzyme compared

MOTS-c and NAD+ are often mentioned together because both sit at the center of mitochondrial and metabolic research, but they are different kinds of molecule. MOTS-c is a 16-amino-acid peptide encoded in mitochondrial DNA and studied mostly in mice and cell lines as a signal that acts on skeletal muscle. NAD+ (nicotinamide adenine dinucleotide) is not a peptide at all: it is a coenzyme present in every living cell, used in hundreds of redox reactions and consumed by enzymes such as sirtuins and PARPs. Here is how they compare.

Side-by-side comparison

What MOTS-c is

MOTS-c stands for "mitochondrial open reading frame of the 12S rRNA-c." It was described in Cell Metabolism in March 2015 by Lee and colleagues. The researchers found a 51-base-pair open reading frame inside the mitochondrial 12S rRNA gene, a region already known for the related peptide humanin. The sequence is read using the standard cytoplasmic genetic code, which led the authors to conclude the transcript is exported from mitochondria and translated in the cytoplasm.

In that first paper, MOTS-c acted mainly on skeletal muscle. In cells it slowed the folate-methionine pathway and de novo purine synthesis, which caused the metabolite AICAR to build up more than 20-fold and switched on AMPK, a central energy sensor. In mice it prevented diet-induced obesity and insulin resistance and restored muscle glucose uptake in older animals. The sirtuin SIRT1 was partly required for some of these effects.

Later work added two themes. A 2018 Cell Metabolism paper showed that under glucose restriction, serum deprivation or oxidative stress, MOTS-c moves into the cell nucleus in an AMPK-dependent way and binds stress-response genes alongside the transcription factor NRF2. A 2021 Nature Communications paper reported that MOTS-c improved physical performance in young, middle-aged and old mice, and that exercise raised MOTS-c levels in human skeletal muscle and blood. These human data describe natural MOTS-c levels only.

What NAD+ is

NAD+ is the oxidized form of nicotinamide adenine dinucleotide, a molecule found in every cell. It has two broad jobs. First, it carries electrons: it is reduced to NADH during glycolysis, fatty acid oxidation and the citric acid pathway, which feeds energy production in mitochondria. Second, it is used up as a substrate by several enzyme families, including the sirtuin deacetylases, PARPs involved in DNA repair signaling, and the CD38/CD157 enzymes.

Cells make NAD+ in three ways: from the amino acid tryptophan, from nicotinic acid, and, most importantly in mammals, through a salvage route in which the enzyme NAMPT turns nicotinamide into NMN, which is then converted to NAD+. Nicotinamide riboside (NR) feeds into the same route. A 2018 review from Washington University describes NAD+ falling with age at the cell, tissue and organism level, linked to lower NAMPT and higher NAD+ consumption by PARPs and CD38. Most of that evidence comes from mice.

Where the two overlap

The link between MOTS-c and NAD+ is pathways, not structure. MOTS-c's effects run largely through AMPK and partly through SIRT1, and SIRT1 needs NAD+ to work. That shared connection to cellular energy sensing is why the two appear together in aging and metabolism research. It does not mean one can stand in for the other, and no study we found tested them head to head.

What the human evidence shows

• MOTS-c: a published review of MOTS-c research lists human studies that are observational, measuring MOTS-c levels in groups such as people with obesity, type 2 diabetes or kidney disease. A 2023 Frontiers in Endocrinology review noted that no effective clinical use of MOTS-c had been developed. The closest interventional data are for CB4211, a modified analog from CohBar. Its Phase 1a/1b study, announced in August 2021, met its safety goal with no serious adverse events in a small group (20 people with fatty liver in the Phase 1b part), with mild to moderate local skin reactions reported. An analog is a different molecule, and the study was short and small.
• NAD+: a 2019 pilot study in Frontiers in Aging Neuroscience followed plasma and urine during a six-hour intravenous NAD+ infusion and found that NAD+ was removed from plasma rapidly for at least the first two hours.

Neither molecule has controlled trial evidence showing a health benefit in people.

Regulatory status in October 2026

Neither MOTS-c nor NAD+ is an FDA-, EMA- or MHRA-approved medicine. On 28 October 2026, HHS filed an enforcement-discretion policy that lets 503A compounding pharmacies prepare several peptides, including MOTS-c; that is not an approval, and it does not cover research-grade material. See our HHS compounding policy explainer. For NAD+'s precursor NMN, the FDA said in letters dated 29 September 2025 that NMN is not excluded from the dietary supplement definition, reversing its earlier position; that decision concerns NMN, not NAD+. For the wider picture, see are peptides legal?

Notes for the lab bench

Because one is a peptide and the other a small nucleotide, they are characterized differently. For MOTS-c, purity by HPLC and identity by mass spectrometry are the key results to look for; and our guide to how to verify a peptide COA covers checking the paperwork. When preparing in-vitro stock solutions, use the molecular weight on the certificate, including any counterion, and the peptide calculator for molarity math.

Frequently asked questions

Sources

1. Lee et al., The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis, Cell Metabolism (3 March 2015)
2. Lee et al., Cell Metabolism 2015, full text (PDF)
3. Kim et al., MOTS-c translocates to the nucleus under metabolic stress, Cell Metabolism (September 2018)
4. Reynolds et al., MOTS-c as an exercise-induced regulator of age-related physical decline, Nature Communications (20 January 2021)
5. Review: Mitochondria-derived peptide MOTS-c, effects and mechanisms related to stress, metabolism and aging (PubMed Central)
6. Zheng et al., MOTS-c: a promising mitochondrial-derived peptide, Frontiers in Endocrinology (25 January 2023)
7. CohBar: CB4211 Phase 1a/1b topline results (10 August 2021)
8. RCSB Protein Data Bank: NAD ligand record
9. Johnson and Imai, NAD+ biosynthesis, aging, and disease, F1000Research (2018)
10. Pilot study: plasma and urine NAD+ metabolome during a 6-hour IV infusion, Frontiers in Aging Neuroscience (12 September 2019)
11. Venable LLP: FDA declares NMN is a dietary supplement (October 2025)