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Humanin vs MOTS-c

Last updated: October 3, 2026 · 5 min read · By the Grey Peptides Editorial Board

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Grey Peptides
Grey Peptides Editorial Board
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Key takeaways
  • Humanin and MOTS-c are both short peptides encoded in mitochondrial DNA, a class discovered only this century.
  • Their evidence comes from cells and animals; human studies only measure their levels in blood or tissue.
  • No published trial has given either peptide to people. Neither is approved anywhere.
  • WADA names MOTS-c as prohibited; humanin falls under the catch-all S0 section in our reading.

Side by side

Humanin Low and MOTS-c Low are the two most studied members of a new class, the mitochondrial-derived peptides 1. The table is read from our encyclopedia entries.

FieldHumaninMOTS-c
Encyclopedia entryHumanin Full entryMOTS-c Full entry
Molecule classPeptidePeptide
CategoryLongevityLongevity
FDA statusResearch ChemicalResearch Chemical
Approved elsewhereNone recordedNone recorded
Evidence gradeLowLow
Half-lifeNot measured in the abstracts we holdUndetermined in humans
FormulaC119H204N34O32S2C101H152N28O22S2
Molecular weight2,687.3 g/mol2,174.7 g/mol
WADA 2026Prohibited (S0 catch-all)Prohibited at all times (S4.4.1)
WADA 2027Prohibited (S0 catch-all)Prohibited at all times (S4.4.1)
In one lineA 24-amino-acid peptide encoded in mitochondrial DNA: protective in cells and animals, measured but never given in human studies.A mitochondrially encoded peptide studied for its effects on metabolic homeostasis, insulin sensitivity, and exercise capacity.
MechanismInteracts with pro-apoptotic BAX and Bid proteins, preventing their activation and inhibiting apoptosis. Activates STAT3 signaling through a membrane receptor complex. Demonstrates insulin-sensitizing activity via effects on IRS-1 and AMPK. Crosses the blood-brain barrier and shows neuroprotective activity against amyloid-β and prion toxicity in neuronal cultures.Acts via AMPK activation to regulate glucose and fatty acid metabolism. In mouse models, MOTS-c administration prevents diet-induced obesity, improves insulin sensitivity, and enhances exercise capacity, in part through effects on skeletal muscle metabolic gene expression. Circulating MOTS-c declines with age in humans and has been proposed as a longevity-associated peptide.
Sources in the entry2012
Study cards1912
Dosage pageNoneDosage page

A new class of signals

Mitochondria carry their own small genome, long thought to encode only a handful of proteins for energy production. Humanin changed that view: a 2013 review presents it as the first small peptide found to be encoded in mitochondrial DNA and the founder of a new class of mitochondrial-derived peptides (review) 2. A 2022 review describes it as first identified in 2001 in surviving neurons from a person with Alzheimer's disease, and as the most studied of the class, alongside MOTS-c and the SHLP peptides (review) 3. MOTS-c was named in 2015 (animal study) 4.

Humanin: neuroprotection and metabolism in the lab

Humanin's early work focused on the brain. A 2004 review describes it suppressing neuronal death from Alzheimer's-related insults, including amyloid-beta and familial Alzheimer's genes, in laboratory models (review) 5. Later rodent work moved to metabolism: humanin infused into the brain improved whole-body insulin sensitivity through a signalling pathway in the hypothalamus, an effect reproduced by potent analogues given intravenously (animal study) 6. In cells and mice, it induced autophagy, the cell's recycling system, and reduced misfolded protein build-up in muscle (animal study) 7.

Human evidence is observational. Humanin protein in thigh muscle rose by 35% after 12 weeks of resistance training in men with impaired glucose regulation (randomised exercise trial measuring humanin) 8, and plasma humanin was lower in people with macular degeneration than in controls (observational study) 9.

MOTS-c: insulin sensitivity and exercise in mice

The 2015 paper that named MOTS-c showed it regulates insulin sensitivity and metabolic balance, acting mainly on skeletal muscle (animal study) 4. In mice it enhanced physical performance at young, middle and old ages, and treatment started late in life improved physical capacity (animal study) 10. In humans, a MOTS-c gene variant found in East Asian populations was linked to type 2 diabetes in men across 27,527 people (genetic association) 11.

How they compare

The two peptides are often marketed together, but they act differently in the lab. Humanin is described as working through a cell-surface receptor complex and by binding apoptosis proteins, with a long research history in neuroprotection 5. MOTS-c is described as a metabolic regulator that moves to the cell nucleus under stress 4. Both influence insulin sensitivity in rodents 6 4, which is why both appear in longevity marketing.

Both also share the same evidence gap. Human studies measure their levels: in a 2025 case-control study, blood transcripts of both were lower in Alzheimer's disease than in people with subjective cognitive decline, but plasma protein levels did not distinguish Alzheimer's from mild cognitive impairment (observational study) 12. Measuring a peptide in blood says nothing about what happens when it is injected, any more than measuring insulin levels shows what an insulin injection would do to someone who does not need it. No published trial has given either peptide to people 1, so dose, safety and benefit in humans are all unknown, not merely unproven.

Questions to ask before choosing either

  • Has either been tested in people for what I want? As of October 3, 2026, neither has a published treatment trial.
  • Is the product humanin itself or an analogue such as HNG, which much of the animal work used?
  • What is in the vial, and has it been tested for identity and impurities?
  • Am I an athlete? MOTS-c is named on the WADA list 1.

How the differences add up (as of October 3, 2026)

Humanin has the longer laboratory history and a neuroprotection focus; MOTS-c has a cleaner metabolic story in mice. Neither has moved beyond cells, animals and observational human data, and neither is approved anywhere. For sport, WADA names MOTS-c under S4.4.1, and humanin falls under S0 by our reading 1. Our MOTS-c vs SS-31 page compares MOTS-c with a mitochondrial peptide that did reach approval. Doses on this page are those in our entries' sources, not recommendations.

Frequently asked questions

What is the difference between humanin and MOTS-c?

Both are peptides encoded in mitochondrial DNA. Humanin was studied first, mainly for neuroprotection; MOTS-c mainly for metabolism and exercise in mice.

Has humanin been tested in humans?

No published study has given humanin to people; human studies only measure its levels.

Is MOTS-c banned in sport?

Yes. WADA names MOTS-c under S4.4.1. Humanin falls under S0 as an unapproved substance by our reading.

Sources

  1. Grey Peptides dataset records for humanin and MOTS-c (not approved; WADA: humanin S0 inferred, MOTS-c named under S4.4.1; studied doses as sourced on each entry); read October 3, 2026.
  2. Lee, C., et al. (2013). Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol Metab, 24(5), 222-8. PMID: 23402768
  3. Gong, Z., et al. (2022). Cardio-protective role of Humanin in myocardial ischemia-reperfusion. Biochim Biophys Acta Gen Subj, 1866(2), 130066. PMID: 34896254
  4. Lee, C., et al. (2015). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab, 21(3), 443-54. PMID: 25738459
  5. Niikura, T., et al. (2004). Humanin: after the discovery. Mol Neurobiol, 30(3), 327-40. PMID: 15655255
  6. Muzumdar, R. H., et al. (2009). Humanin: a novel central regulator of peripheral insulin action. PLoS One, 4(7), e6334. PMID: 19623253
  7. Kim, S. J., et al. (2022). Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension. Biochim Biophys Acta Gen Subj, 1866(1), 130017. PMID: 34624450
  8. Gidlund, E. K., et al. (2016). Humanin skeletal muscle protein levels increase after resistance training in men with impaired glucose metabolism. Physiol Rep, 4(23). PMID: 27923980
  9. Nashine, S., et al. (2022). Effect of Humanin G (HNG) on inflammation in age-related macular degeneration (AMD). Aging (Albany NY), 14(10), 4247-4269. PMID: 35576057
  10. Reynolds, J. C., et al. (2021). MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nat Commun, 12(1), 470. PMID: 33473109
  11. Zempo, H., et al. (2021). A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c. Aging (Albany NY), 13(2), 1692-1717. PMID: 33468709
  12. Rodríguez-Esparragón, F., et al. (2025). Insights into the Biomarker Potential of Humanin and Mots-c Expression and Telomere Length in Alzheimer's Disease. Int J Mol Sci, 26(22). PMID: 41303353

Educational information, not medical advice. Each dose in this guide names its source, an approved label or a published study. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose.

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