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Humanin & MOTS-c: Mitochondrial Peptide Research

For decades, scientists treated mitochondrial DNA like a one-trick genome — 37 genes devoted almost entirely to energy production.

For decades, scientists treated mitochondrial DNA like a one-trick genome — 37 genes devoted almost entirely to energy production. Then, in 2001, a Japanese research team screening brain tissue from an Alzheimer's patient stumbled onto something unexpected: a tiny peptide, just 24 amino acids long, encoded by a previously overlooked open reading frame in the mitochondrial 16S rRNA gene. They named it humanin.

Fourteen years later, Pinchas Cohen's lab at USC identified a second mitochondrial-derived peptide (MDP) — MOTS-c, a 16-amino-acid chain hidden in the 12S rRNA gene — that turned out to be a potent metabolic regulator. Together, humanin and MOTS-c have rewritten our understanding of what mitochondria actually do: not just burn fuel, but send molecular signals that influence aging, brain health, metabolism, and survival across the entire body.

This article reviews the current evidence on both peptides, from their molecular mechanisms to their implications for age-related disease.

Table of Contents

  1. The Discovery of Mitochondrial-Derived Peptides
  2. Humanin: Mechanisms and Research
  3. MOTS-c: Mechanisms and Research
  4. Head-to-Head Comparison
  5. The Aging Connection
  6. Clinical Translation: Where Things Stand
  7. The Bottom Line
  8. References

The Discovery of Mitochondrial-Derived Peptides

The human mitochondrial genome is compact — just 16,569 base pairs compared to the nuclear genome's 3.2 billion. For years, researchers assumed it had been fully mapped. But the discovery of humanin revealed something hiding in plain sight: short open reading frames (sORFs) within ribosomal RNA genes that encode small, bioactive peptides.

After humanin came a cascade of related discoveries. Cohen's group at USC identified six additional peptides from the 16S rRNA gene — the small humanin-like peptides (SHLPs 1 through 6) — in 2016. MOTS-c, from the 12S rRNA gene, was first described in a landmark 2015 paper in Cell Metabolism (Lee et al., 2015). A ninth MDP, SHMOOSE, was later identified through mitochondrial genome-wide association studies.

These peptides share a defining characteristic: they are secreted from cells, circulate in blood plasma, and act on distant tissues like hormones. They represent a form of retrograde signaling — messages sent from the mitochondrial genome to the rest of the organism.

For deeper profiles of each peptide, see our dedicated pages on humanin and MOTS-c.

Humanin: Mechanisms and Research

How Humanin Works

Humanin (amino acid sequence: MAPRGFSCLLLLTSEIDLPVKRRA, molecular weight ~2,687 Da) signals through a trimeric cell-surface receptor complex made up of three subunits: CNTFR-alpha, WSX-1, and gp130 — the same shared receptor subunit used by the interleukin-6 cytokine family (Hashimoto et al., 2009).

When humanin binds this receptor, it triggers three downstream signaling cascades:

  • JAK/STAT3 — the primary pathway for neuroprotection and cell survival
  • PI3K/AKT — involved in anti-apoptotic signaling
  • ERK1/2 (MAPK) — supports cell growth and differentiation

Blocking gp130 with antibodies eliminates humanin's protective effects on all three pathways, confirming the receptor as the critical gateway (Kim et al., 2016). Humanin also binds directly to the pro-apoptotic protein Bax, preventing it from triggering mitochondrial-mediated cell death, and interacts with IGFBP-3 to modulate insulin-like growth factor signaling.

Neuroprotection and Alzheimer's Disease

Humanin's original claim to fame remains its strongest area of evidence. In cell culture, humanin protects neurons against toxicity from amyloid-beta (the protein that aggregates in Alzheimer's plaques), mutant presenilin, and mutant amyloid precursor protein — covering the three major genetic causes of familial Alzheimer's disease.

In rodent models, the results are equally compelling:

  • Rats treated with humanin showed increased dendritic branching, greater spine density, and higher levels of both pre- and post-synaptic proteins — all translating to improved long-term potentiation and recovery of memory deficits caused by Aβ1-42 injection (Zhang et al., 2017).
  • Humanin reduced Aβ-induced tau hyperphosphorylation by activating protein phosphatase 2A (PP2A), addressing both hallmark pathologies of Alzheimer's simultaneously.
  • Triple-transgenic AD mice treated with humanin showed reduced plaque burden and preserved cognitive function.

In humans, a mitochondrial genome-wide association study identified a SNP (rs2854128) in the humanin-coding region associated with lower circulating humanin and accelerated cognitive aging in a large, nationally representative cohort of older adults (Yen et al., 2018).

For more on peptide research in neurodegeneration, see Peptides for Alzheimer's Disease Research.

Cardiovascular Protection

The humanin analogue S14G-humanin (HNG), which is roughly 1,000 times more potent than native humanin, has generated strong preclinical cardiovascular data:

  • Atherosclerosis: In apolipoprotein E-deficient mice fed a high-cholesterol diet, 16 weeks of daily HNGF6A (another analogue) injections decreased atherosclerotic plaque size in the proximal aorta and prevented endothelial dysfunction — without directly lowering cholesterol (Widmer et al., 2013).
  • Heart failure: HNG delayed the onset of cardiac dysfunction in isoproterenol-induced heart failure mice, reduced inflammatory cell infiltration, attenuated fibrosis, and decreased cardiomyocyte apoptosis (S14G study, 2023).
  • Ischemia-reperfusion injury: In rats, HNG administered during ischemia reduced infarct size by 47% and improved left ventricular ejection fraction by activating AKT survival pathways.
  • Diabetic heart damage: HNG attenuated cardiac hypertrophy and improved heart function in streptozotocin-induced diabetic rats by suppressing the p38/NF-kB inflammatory cascade (Kamal et al., 2021).
  • Thrombosis: HNG inhibited platelet aggregation and cremaster arterial thrombus formation in mice without prolonging bleeding time — a meaningful distinction from conventional antiplatelet drugs (Qin et al., 2020).

MOTS-c: Mechanisms and Research

How MOTS-c Works

MOTS-c operates through a different mechanism than humanin. Rather than binding a cell-surface receptor, MOTS-c exerts its effects primarily by entering cells and disrupting the folate cycle — specifically, it inhibits de novo purine biosynthesis, which causes the metabolic intermediate AICAR to accumulate. AICAR is a well-known activator of AMP-activated protein kinase (AMPK), the cell's master energy sensor (Lee et al., 2015).

The downstream consequences of AMPK activation include:

  • Upregulation of glucose transporter GLUT4 in skeletal muscle
  • Increased fatty acid oxidation
  • Improved mitochondrial biogenesis
  • Improved insulin sensitivity

But MOTS-c does something no other known mitochondrial factor does. Under metabolic stress — glucose deprivation, serum starvation, oxidative damage — MOTS-c physically moves from the cytoplasm into the nucleus within 30 minutes. Once there, it interacts with stress-responsive transcription factors including NRF2 (the master regulator of antioxidant genes), ATF1, and ATF7, binding directly to antioxidant response elements (AREs) in their promoter regions (Kim et al., 2018).

This makes MOTS-c the first known mitochondrial-encoded factor that directly regulates nuclear gene expression — a genuine retrograde signal from the mitochondrial genome to the nuclear genome. A 2024 study in iScience added another layer: MOTS-c directly binds and activates casein kinase 2 (CK2) in skeletal muscle, stimulating glucose uptake through a tissue-specific mechanism (Yoon et al., 2024).

Metabolic Effects and Insulin Sensitivity

MOTS-c's metabolic profile is its most extensively studied feature:

  • Mice on a high-fat diet treated with MOTS-c were dramatically leaner than controls, with lower weight gain despite equal food intake — suggesting increased metabolic rate rather than appetite suppression.
  • In aged mice (32 months), MOTS-c injection reversed age-related skeletal muscle insulin resistance and restored circulating MOTS-c to youthful levels.
  • Plasma MOTS-c levels in human males correlate inversely with fasting insulin, HbA1c, and BMI — the classic triad of metabolic dysfunction.
  • A genetic variant in MOTS-c (m.1382A>C, resulting in K14Q) that nullifies peptide activity was linked to a 50% increased diabetes risk in Japanese males, with nearly double the risk among sedentary carriers (Fuku et al., 2015).
  • A 2025 study in Nature's Experimental & Molecular Medicine found MOTS-c treatment reduced senescence in aged mouse pancreatic islet cells and improved glucose intolerance — pointing to direct effects on insulin-producing beta cells (Kim et al., 2025).

Exercise Mimetic Properties

MOTS-c has earned the label "exercise mimetic" based on convergent evidence:

  • In healthy young men, a single bout of cycling increased skeletal muscle MOTS-c levels 11.9-fold, with circulating plasma levels rising 1.6-fold. Four hours post-exercise, muscle levels were still 18.9-fold above baseline (Reynolds et al., 2021).
  • Old mice treated with MOTS-c showed substantially improved treadmill endurance — with older animals showing the most dramatic gains.
  • MOTS-c reduces circulating myostatin (the protein that inhibits muscle growth), and human plasma levels of MOTS-c are inversely correlated with myostatin levels.
  • A 2024 study demonstrated that MOTS-c prevented immobilization-induced muscle atrophy in mice by suppressing lipid infiltration into muscle tissue.

These findings position MOTS-c at the intersection of exercise biology and aging research. For related reading, see our guide on peptides for mitochondrial health.

Emerging Research Areas

Recent studies have expanded MOTS-c's profile beyond metabolism:

  • Cancer: A 2024 study in Advanced Science found MOTS-c suppressed ovarian cancer progression by targeting USP7-mediated LARS1 deubiquitination, adding tumor-suppressive properties to its resume (Yin et al., 2024).
  • Immune regulation: MOTS-c prevented activation of T cells from type 1 diabetes patients, suggesting immunomodulatory potential in autoimmune disease.
  • Host defense: Research from Changhan Lee's lab at USC demonstrated MOTS-c acts as a host-defense peptide, directly combating bacteria — a function that may reflect mitochondria's ancient bacterial origins.
  • Cardiac protection: A 2025 study in Frontiers in Physiology showed MOTS-c restored mitochondrial respiration in diabetic rat hearts by improving glucose metabolism and upregulating antioxidant defenses (Kesherwani et al., 2025).

Head-to-Head Comparison

FeatureHumaninMOTS-c
Discovery2001 (Hashimoto et al.)2015 (Lee, Cohen et al.)
Size24 amino acids16 amino acids
Gene location16S rRNA (MT-RNR2)12S rRNA (MT-RNR1)
Primary receptor/targetTrimeric receptor (CNTFR/WSX-1/gp130)Folate cycle / AMPK pathway
Key signalingSTAT3, AKT, ERK1/2AMPK, NRF2, CK2
Primary tissue targetsBrain, heart, retinaSkeletal muscle, fat, pancreas
Strongest evidenceNeuroprotection, cardiovascularInsulin sensitivity, exercise biology
Nuclear translocationNoYes (under metabolic stress)
Decline with ageYes (plasma and tissue)Yes (plasma and tissue)
Link to centenariansChildren of centenarians have higher levelsK14Q variant increases diabetes risk
Potent analoguesHNG (S14G-humanin), colivelinCB4211 (discontinued clinical trial)
Human clinical dataObservational cohort studies onlyOne Phase 1a/1b trial of CB4211 analog
WADA statusNot listedBanned substance

Both peptides decline with age, are associated with age-related disease when levels drop, and show broad protective effects in preclinical models. But they work through fundamentally different mechanisms — humanin as a circulating cytokine-like factor acting through cell-surface receptors, MOTS-c as an intracellular metabolic regulator that physically enters the nucleus.

The Aging Connection

The link between MDPs and aging may be the most consequential finding in this field. Several lines of evidence converge:

Circulating levels drop with age. In mice, humanin levels decline steadily over the first 16 months of life. In monkeys, levels fall between ages 19 and 25. MOTS-c follows the same pattern — levels in 32-month-old mice are significantly lower than in young animals (Cobb et al., 2016).

Long-lived species maintain higher levels. The naked mole rat — which can live over 30 years, roughly ten times longer than a similarly sized mouse — maintains stable humanin levels over two decades. Mice, by contrast, show rapid decline.

Centenarian offspring have elevated humanin. In a study of 18 children of centenarians compared with 19 age-matched controls, centenarian offspring had significantly higher circulating humanin. Since these individuals carry a genetic predisposition for exceptional longevity, this suggests humanin levels may be both a marker and a mediator of healthy aging (Yen et al., 2020).

Supplementation extends lifespan. In C. elegans, overexpressing humanin increases lifespan through a daf-16/FOXO-dependent mechanism. MOTS-c supplementation in aged mice increases both median and maximum lifespan. Treating middle-aged mice twice weekly with HNG improved metabolic parameters and reduced inflammatory markers.

These findings position MDPs alongside other mitochondria-targeted approaches, including SS-31 (elamipretide) and epitalon, as candidates in the growing peptide-based longevity research pipeline.

Clinical Translation: Where Things Stand

Despite two decades of preclinical promise, mitochondrial-derived peptides have been slow to reach human testing.

The only clinical trial of an MDP-based drug involved CB4211, a synthetic MOTS-c analog developed by CohBar, Inc. — a company co-founded by Pinchas Cohen. The Phase 1a/1b trial enrolled 65 healthy adults in the safety phase and 20 obese participants with fatty liver disease (at least 10% liver fat) in the efficacy phase. Over 28 days, the 11 subjects receiving 25 mg daily subcutaneous CB4211 showed:

  • Significant reductions in ALT and AST (liver damage markers)
  • Significant improvements in glucose metabolism
  • A trend toward weight loss versus placebo
  • Generally mild injection site reactions as the primary side effect

The results were encouraging but limited — a 4-week study of 20 subjects cannot establish long-term efficacy or safety. CohBar subsequently discontinued CB4211's clinical development, though next-generation analogs remain in the pipeline.

Key obstacles include poor bioavailability, short half-lives, high synthesis costs, and the challenge of delivering small peptides to target tissues. The FDA has placed MOTS-c on its list of bulk drug substances with "potential significant safety risks," prohibiting its use in compounded medications. WADA has banned MOTS-c in competitive sport.

No human clinical trials of native humanin or native MOTS-c have been conducted. All therapeutic use remains investigational. Current humanin data in humans is limited to observational cohort studies examining correlations between circulating levels and disease outcomes.

The Bottom Line

Humanin and MOTS-c have fundamentally changed how scientists think about mitochondria. These organelles are not just cellular power plants — they are signaling hubs that communicate with the nucleus, influence gene expression, and help regulate aging across the entire organism.

The preclinical evidence is substantial. Humanin protects neurons, preserves cardiac function, and appears to be a genuine biomarker (and possibly a driver) of exceptional longevity. MOTS-c mimics exercise at the molecular level, reverses insulin resistance in aged muscle, and represents the first known example of a mitochondrial gene product that directly regulates the nuclear genome.

But preclinical promise and clinical proof are different things. The only human trial of an MDP-based drug was small, short, and has since been discontinued. Native forms of both peptides have never been tested in clinical trials. Major pharmacological hurdles — stability, delivery, cost — remain unresolved.

What the science does make clear: mitochondrial-derived peptides are real biological signals with measurable effects on metabolism, neuronal survival, cardiovascular function, and lifespan in animal models. As the field matures, the gap between laboratory findings and clinical application will determine whether humanin and MOTS-c fulfill their early promise — or remain fascinating biology without a therapeutic home.

References

  1. Hashimoto, Y., et al. (2001). "A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ." Proceedings of the National Academy of Sciences, 98(11), 6336-6341. PubMed

  2. Lee, C., Zeng, J., Drew, B.G., et al. (2015). "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance." Cell Metabolism, 21(3), 443-454. PMC

  3. Kim, S.J., Xiao, J., Wan, J., Cohen, P., Yen, K. (2017). "Mitochondrially derived peptides as novel regulators of metabolism." Journal of Physiology, 595(21), 6613-6621. PMC

  4. Kim, K.H., Son, J.M., Benayoun, B.A., Lee, C. (2018). "The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress." Cell Metabolism, 28(3), 516-524. PMC

  5. Hashimoto, Y., et al. (2009). "Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor α/WSX-1/gp130." Molecular Biology of the Cell, 20(12), 2864-2873. PMC

  6. Yen, K., et al. (2018). "Humanin prevents age-related cognitive decline in mice and is associated with improved cognitive age in humans." Scientific Reports, 8, 14212. Nature

  7. Yen, K., et al. (2020). "The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan." Aging, 12(12), 11185-11199. Aging

  8. Zhang, W., et al. (2017). "Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats." Neuroscience Bulletin, 33(5), 501-514. PMC

  9. Kim, S.J., et al. (2016). "The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus." Oncotarget, 7(29), 46899-46912. Oncotarget

  10. Qin, Q., et al. (2020). "Humanin analogue, HNG, inhibits platelet activation and thrombus formation by stabilizing platelet microtubules." Journal of Cellular and Molecular Medicine, 24(8), 4773-4783. PMC

  11. CohBar, Inc. (2021). "CohBar announces positive topline results from the Phase 1a/1b study of CB4211." GlobeNewsWire

  12. Yoon, J.S., et al. (2024). "MOTS-c modulates skeletal muscle function by directly binding and activating CK2." iScience, 27(12), 111212. Cell

  13. Yin, L., et al. (2024). "Mitochondrial-derived peptide MOTS-c suppresses ovarian cancer progression by attenuating USP7-mediated LARS1 deubiquitination." Advanced Science, 11(48). Wiley

  14. Kesherwani, V., et al. (2025). "Mitochondria-derived peptide MOTS-c restores mitochondrial respiration in type 2 diabetic heart." Frontiers in Physiology, 16, 1602271. Frontiers

  15. Kim, S.J., et al. (2025). "Mitochondrial-encoded peptide MOTS-c prevents pancreatic islet cell senescence to delay diabetes." Experimental & Molecular Medicine. Nature

  16. Cobb, L.J., et al. (2016). "Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers." Aging, 8(4), 796-809. PMC

  17. El-Kott, A.F., et al. (2023). "S14G-humanin confers cardioprotective effects against chronic adrenergic and pressure overload-induced heart failure in mice." Heliyon, 9(12). PMC

  18. Kamal, N.N., et al. (2021). "The protective effects of S14G-humanin (HNG) against streptozotocin (STZ)-induced cardiac dysfunction." Bioengineered, 12(1), 12299-12313. PMC