Other compounds

Humanin

Updated · 28 sources · Editorial policy

Humanin is a small peptide of 24 amino acids encoded in mitochondrial DNA, inside the gene for the mitochondrial 16S ribosomal RNA (MT-RNR2). A Japanese group found it in 2001 while screening for genes that kept nerve cells alive when exposed to Alzheimer’s disease-related toxins (Hashimoto et al., PNAS 2001). It was the first known mitochondrial-derived peptide (MDP), the family that later came to include MOTS-c (Lee et al., Trends Endocrinol Metab 2013).

In cells and animals, humanin and its more potent lab-made analogs protect many tissues from stress and cell death, and they improve insulin sensitivity in rodents. The single most important fact is that no trial has given humanin or any of its analogs to people. Human studies only measure the body’s own humanin levels, which fall with age in some studies and rise with exercise. Humanin is not an approved drug anywhere.

This page summarizes what the published laboratory, animal and human observational studies report. It is for education only and is not medical advice.

Property Detail
Class Mitochondrial-derived peptide (MDP); endogenous cytoprotective (cell-protecting) peptide
Structure 24 amino acids; C₁₁₉H₂₀₄N₃₄O₃₂S₂, 2,687.2 g/mol (PubChem)
Origin 75-base-pair open reading frame inside the mitochondrial 16S rRNA gene (MT-RNR2)
Main lab analog HNG (S14G-humanin), one amino-acid swap; reported to be ≈1,000 times more potent
Doses studied Animals only, mostly the analog HNG, e.g. 4 mg/kg by intraperitoneal injection twice weekly in aging mice. No human dosing data
Half-life No human data. HNG in mice: ≈30 minutes after injection; in rats: over 4 h
Known binding partners FPRL1 (FPR2) receptor; a CNTFR/WSX-1/gp130 receptor complex; Bax and IGFBP-3 inside or outside cells
US status Not FDA-approved; no registered trial giving it to people; not a controlled substance
WADA status Not named on the 2026 list; unapproved substances fall under S0, prohibited at all times

What it is

Humanin was found by “rescue” screening. Researchers put a library of genes from the brain of a person with Alzheimer’s disease (the occipital cortex) into nerve cells programmed to die from a mutant Alzheimer’s gene, then recovered the genes from the cells that survived (Hashimoto et al., PNAS 2001). The protective clone encoded a short peptide that cells secreted into the culture medium and that worked from outside the cell.

The gene sits in a 75-base-pair stretch of the mitochondrial 16S rRNA gene. Mitochondria read genetic code slightly differently from the rest of the cell, so the same stretch can yield slightly different peptides depending on where it is translated. Both versions were biologically active, and where humanin is actually made in the cell is still unresolved (Lee et al., 2013). Similar sequences also exist in the nuclear genome as copies of mitochondrial DNA, which complicates the picture (Guo et al., Nature 2003; Lee et al., 2013).

PubChem lists humanin as a 24-residue peptide with the formula C₁₁₉H₂₀₄N₃₄O₃₂S₂ and a molecular weight of 2,687.2 g/mol (PubChem CID 16131438). Six further peptides encoded in the same region, named small humanin-like peptides (SHLP1–6), were described in 2016 (Cobb et al., Aging 2016).

Analogs

Most animal studies use modified versions rather than native humanin. Each is named by the position that was changed:

Analog Change Reported effect
HNG (S14G-humanin) Serine at position 14 replaced by glycine Fully protected cultured nerve cells at 10 nM, where native humanin needed 1–10 μM (Hashimoto et al., PNAS 2001); described as ≈1,000-fold more potent (Muzumdar et al., PLoS One 2009)
F6A-humanin Phenylalanine at position 6 replaced by alanine No longer binds IGFBP-3 (Ikonen et al., PNAS 2003)
HNGF6A Both changes combined Potent and does not bind IGFBP-3; used in rat insulin studies (Muzumdar et al., 2009)

Swapping the same serine for alanine instead of glycine abolished activity, and a cysteine at position 8 was also essential (Hashimoto et al., J Neurosci 2001).

How it is thought to work

Humanin appears to act both outside and inside cells. These findings come from cell culture and isolated proteins:

  • Cell-surface receptors. Humanin activates the formyl-peptide receptor FPRL1 (FPR2 in mice), the same receptor used by amyloid-beta, and may block amyloid-beta’s access to it (Ying et al., J Immunol 2004). It also binds a cytokine receptor complex made of CNTFR, WSX-1 and gp130, which switches on STAT3 signaling in nerve cells (Hashimoto et al., Mol Biol Cell 2009).
  • Blocking a cell-death protein. Inside cells, humanin binds Bax, a protein that triggers programmed cell death (apoptosis), and stops it from moving to mitochondria and releasing cytochrome c (Guo et al., Nature 2003).
  • IGFBP-3. Humanin binds insulin-like growth factor-binding protein 3 with high affinity, at a site that does not compete with IGF-1 binding, and blocked IGFBP-3-induced cell death in some cell types but not others (Ikonen et al., PNAS 2003).

Humanin levels move opposite to the growth hormone (GH) and IGF-1 axis (Lee et al., Aging Cell 2014):

  • In mice, 20 days of GH or IGF-1 injections lowered plasma humanin by ≈30%. Mice engineered to make excess GH had 70% lower humanin.
  • In 11 GH-deficient children, humanin was strongly inversely correlated with IGF-1 (r = −0.69). Four weeks of clinical GH treatment at 50 μg/kg/day lowered plasma humanin by ≈20%.
  • People with GH receptor deficiency (Laron syndrome), who have very low IGF-1, had 80% higher humanin than matched relatives (6 per group).

These are small studies, and what the change in humanin means for health is not known. Related library pages: HGH and IGF-1.

Pharmacokinetics

No pharmacokinetic study of humanin or its analogs in people has been published.

The only dedicated study measured HNG in rodents after a single intraperitoneal injection, using an ELISA (Chin et al., Endocrinology 2013):

Species and dose Finding
Normal mice, HNG 2 mg/kg Rapid clearance; half-life ≈30 minutes (under 1 h)
Mice given HNGF6A, or mice lacking IGFBP-3 Longer half-life than normal mice given HNG, showing that IGFBP-3 binding affects clearance
Rats, HNG 5 mg/kg Half-life over 4 h; highest levels in plasma, lower in liver, undetectable in brain and heart

The authors noted that the rats received a higher dose and that the reason for the species difference was unclear. Because native humanin, HNG and HNGF6A behave differently, none of these numbers can be applied to people.

Regulatory status

  • Approval. Humanin and its analogs are not approved as medicines by the FDA or any other regulator.
  • Trials. A search of ClinicalTrials.gov found only observational studies that measure humanin levels (for example after heart surgery or in kidney injury) and exercise or anesthesia studies that use humanin as a lab marker. None gives humanin to participants (ClinicalTrials.gov).
  • FDA compounding review. Humanin does not appear on FDA’s list of bulk drug substances that may present significant safety risks in compounding, as updated April 22, 2026 (FDA). That absence is not an approval; it means FDA has not published a review.
  • Controlled substances. Humanin is not named in the US Schedule III list that covers the anabolic steroids (21 CFR 1308.13).
  • Sport. The 2026 WADA Prohibited List does not name humanin. Its S0 class prohibits at all times any pharmacological substance not covered elsewhere on the list “with no current approval by any governmental regulatory health authority for human therapeutic use,” such as drugs in pre-clinical development (WADA 2026 Prohibited List). As an unapproved peptide, humanin and its analogs appear to fall within that wording. By contrast, MOTS-c is named explicitly under S4.4.1.

What the research shows

Nerve cells and the brain (cell culture and animals)

Humanin was discovered for its effect against Alzheimer’s-related toxicity. In cultured nerve cells, it blocked cell death caused by many mutant Alzheimer’s genes and by amyloid-beta, but not by unrelated insults such as glutamate or a prion fragment (Hashimoto et al., J Neurosci 2001).

In animals:

  • Stroke model. In mice with a blocked brain artery, 0.1 μg HNG injected into the brain 30 minutes beforehand cut infarct (damaged tissue) volume from 56.2% to 26.1%. HNG given into the abdomen also reduced infarct size (Xu et al., Stroke 2006).
  • Cognitive aging. Female mice given HNG 4 mg/kg by intraperitoneal injection twice weekly from 18 months of age performed better on some balance and memory tests than untreated mice (Yen et al., Sci Rep 2018).

None of these effects has been tested in people.

Insulin sensitivity (rats)

The main metabolic study used clamp tests, the reference method for measuring insulin sensitivity, in rats (Muzumdar et al., PLoS One 2009):

Model Treatment Main finding
Normal rats Humanin infused into the brain Higher glucose infusion rate, lower liver glucose output and higher muscle glucose uptake; effect required hypothalamic STAT3
Normal rats The analog HNGF6A infused into a vein, 0.05 mg/kg/h Reproduced the same effects; blocking hypothalamic STAT3 removed the liver effect entirely
Zucker diabetic fatty rats (a diabetes model) Single intravenous dose of 100 μg HNGF6A (n = 5) vs saline (n = 4) Blood glucose fell by nearly 50% from a mean of 293 mg/dL, starting at ≈90 minutes and lasting through 4 h

The same paper reported that humanin had no direct effect on glucose production in isolated liver cells, which is why the authors concluded the liver effect is routed through the brain. A version of humanin that cannot pair up with itself had no metabolic effect at all.

Related peptides from the same mitochondrial region behave similarly in rodents: SHLP2 infused into the brain also acted as an insulin sensitizer, and its blood levels fell with age (Cobb et al., Aging 2016).

Heart and blood vessels (animals and observation)

In female mice given an HNG analog by intraperitoneal injection for 14 months from 18 months of age, hearts showed less collagen buildup (fibrosis) and fewer dying cells than untreated old mice (Qin et al., Am J Physiol Heart Circ Physiol 2018).

In people, the data are correlational. Among 40 patients having coronary angiography, those with poor coronary endothelial function had lower plasma humanin than those with normal function (1.3 ± 1.1 vs 2.2 ± 1.5 ng/mL, p = 0.03) (Widmer et al., Am J Physiol Heart Circ Physiol 2013). An association like this does not show that raising humanin protects arteries.

Exercise and humanin in people

Human exercise studies measure the body’s own humanin, not an injected peptide:

Study Design Finding
Woodhead et al., J Appl Physiol 2020 10 untrained young men, one high-intensity interval session, then 6 sessions over 2 weeks Humanin rose in muscle and plasma right after a session. Two weeks of training trended toward lower resting plasma humanin (p = 0.063)
Gidlund et al., Physiol Rep 2016 55 men with impaired glucose regulation randomized to resistance training, Nordic walking or control for 12 weeks Muscle humanin protein rose 35% with resistance training; serum humanin did not change in any group

Aging and longevity

The most direct longevity data come from worms and mice (Yen et al., Aging 2020):

  • Worms. Overexpressing humanin raised average lifespan from 17.7 to 19.0 days. The gain disappeared in worms lacking daf-16, the FOXO gene, so it depends on that pathway.
  • Mice. Twice-weekly HNG at 4 mg/kg started at 18 months and continued for 14 months produced no significant lifespan difference. Treated mice did have less visceral fat, more lean mass and lower circulating IGF-1 at 28 months, in groups of 5 per measurement.
  • Across species. Humanin fell with age in mice and rhesus macaques but stayed stable for two decades in naked mole-rats, a long-lived rodent.
  • Centenarian families. Offspring of centenarians (n = 18) had higher circulating humanin than age-matched controls (n = 19).

Human level data conflict. Several studies report a decline with age (Muzumdar et al., 2009; Lee et al., 2013), but another study found plasma humanin positively correlated with age in healthy subjects, with lower levels in Alzheimer’s disease and no difference in type 2 diabetes (Conte et al., Geroscience 2021). Measurements rely on different ELISA assays, which limits comparison between studies.

Genetic variants

Two natural variants in the humanin reading frame have been linked to outcomes in people:

  • A mitochondrial variant (rs2854128) was associated with lower circulating humanin, and in over 10,000 participants of the US Health and Retirement Study with a higher calculated “cognitive age” (beta 0.195; 95% CI 0.056–0.333; p = 0.006) (Yen et al., Sci Rep 2018).
  • A rare variant called P3S, enriched among Ashkenazi centenarians carrying the APOE4 Alzheimer’s risk allele, bound APOE4 and reduced amyloid buildup more than normal humanin in a mouse model (Miller et al., Aging Cell 2024).

Associations with a natural variant say nothing about the safety or effect of injecting the peptide.

Side effects and risks

No human safety data

No published study has given humanin or an analog to a person, so its side effects, tolerated dose range, immune reactions and long-term effects in people are unknown. Material sold as a “research peptide” is not made to pharmaceutical standards, so identity, purity and sterility are unverified.

Tumor biology cuts both ways

Humanin blocks apoptosis, the controlled cell-death program that also removes damaged and cancerous cells, so its effect in cancer is uncertain and may be harmful.

  • In mice carrying triple-negative breast cancer, systemic humanin reduced tumor cell death, blunted the effect of chemotherapy, and accelerated tumor growth and the development of lung metastases. The authors wrote that caution is needed when considering humanin for degenerative diseases (Moreno Ayala et al., Sci Rep 2020).
  • A separate mouse study pointed the other way: HNG protected sperm-producing cells and white blood cells from cyclophosphamide chemotherapy while leaving, and even adding to, the drug’s suppression of melanoma metastases (Lue et al., Endocrinology 2015).

A 2019 review of humanin as a drug target concluded that this controversy over cancer progression and chemoresistance needs to be resolved before any clinical translation (Zuccato et al., Expert Opin Ther Targets 2019).

Effects on the GH/IGF-1 axis

In mice, HNG lowered plasma IGF-1 with or without chemotherapy (Lue et al., 2015), and long-term HNG lowered circulating IGF-1 in aging mice (Yen et al., 2020). Lower IGF-1 is linked to longer life in rodents, but it is not an obvious goal for anyone seeking muscle growth, and the direction of this interaction in people has not been tested.

Anti-doping

Although humanin is not named on the WADA list, the S0 class prohibits substances with no regulatory approval for human therapeutic use at all times (WADA 2026 Prohibited List). Athletes in tested sports should assume an unapproved peptide of this kind is covered.

Key takeaways

  • The first mitochondrial-derived peptide. Humanin is 24 amino acids encoded in the mitochondrial 16S rRNA gene, found in 2001 in a screen for genes that protect nerve cells. MOTS-c came from the same family.
  • No human trials of any kind. Every treatment result comes from cells, worms, mice or rats, usually with the lab analog HNG rather than native humanin.
  • Animal effects are broad but not longevity-proven. HNG reduced stroke damage and heart fibrosis in mice and improved insulin sensitivity in rats, yet twice-weekly treatment from middle age did not significantly extend mouse lifespan.
  • Human studies only measure natural levels. Exercise raises muscle humanin, and low levels track with Alzheimer’s disease and poor coronary endothelial function, but studies disagree on whether levels fall with age.
  • A real cancer concern. Because humanin blocks apoptosis, it accelerated tumor growth and metastasis in a mouse breast cancer model, and reviewers call this unresolved.
  • No approval, no safety profile. It is not an approved drug and is not FDA-reviewed for compounding; as an unapproved substance it falls under WADA’s S0 class.

Sources

  1. Hashimoto Y, Niikura T, Tajima H, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A. 2001;98(11):6336–6341. PubMed.
  2. Hashimoto Y, Niikura T, Ito Y, et al. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer’s disease-relevant insults. J Neurosci. 2001;21(23):9235–9245. PubMed.
  3. Guo B, Zhai D, Cabezas E, et al. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003;423(6938):456–461. PubMed.
  4. Ikonen M, Liu B, Hashimoto Y, et al. Interaction between the Alzheimer’s survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci U S A. 2003;100(22):13042–13047. PubMed.
  5. Ying G, Iribarren P, Zhou Y, et al. Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. J Immunol. 2004;172(11):7078–7085. PubMed.
  6. Hashimoto Y, Kurita M, Aiso S, et al. Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130. Mol Biol Cell. 2009;20(12):2864–2873. PubMed.
  7. Xu X, Chua CC, Gao J, et al. Humanin is a novel neuroprotective agent against stroke. Stroke. 2006;37(10):2613–2619. PubMed.
  8. Muzumdar RH, Huffman DM, Atzmon G, et al. Humanin: a novel central regulator of peripheral insulin action. PLoS One. 2009;4(7):e6334. PubMed.
  9. Lee C, Yen K, Cohen P. Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol Metab. 2013;24(5):222–228. PubMed.
  10. Chin YP, Keni J, Wan J, et al. Pharmacokinetics and tissue distribution of humanin and its analogues in male rodents. Endocrinology. 2013;154(10):3739–3744. PubMed.
  11. Widmer RJ, Flammer AJ, Herrmann J, et al. Circulating humanin levels are associated with preserved coronary endothelial function. Am J Physiol Heart Circ Physiol. 2013;304(3):H393–H397. PubMed.
  12. Lee C, Wan J, Miyazaki B, et al. IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell. 2014;13(5):958–961. PubMed.
  13. Lue Y, Swerdloff R, Wan J, et al. The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice. Endocrinology. 2015;156(12):4511–4521. PubMed.
  14. Cobb LJ, Lee C, Xiao J, et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging (Albany NY). 2016;8(4):796–809. PubMed.
  15. Gidlund EK, von Walden F, Venojärvi M, et al. Humanin skeletal muscle protein levels increase after resistance training in men with impaired glucose metabolism. Physiol Rep. 2016;4(23):e13063. PubMed.
  16. Qin Q, Mehta H, Yen K, et al. Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice. Am J Physiol Heart Circ Physiol. 2018;315(5):H1127–H1136. PubMed.
  17. Yen K, Wan J, Mehta HH, et al. Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans. Sci Rep. 2018;8(1):14212. PubMed.
  18. Zuccato CF, Asad AS, Nicola Candia AJ, et al. Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases. Expert Opin Ther Targets. 2019;23(2):117–126. PubMed.
  19. Woodhead JST, D’Souza RF, Hedges CP, et al. High-intensity interval exercise increases humanin, a mitochondrial encoded peptide, in the plasma and muscle of men. J Appl Physiol (1985). 2020;128(5):1346–1354. PubMed.
  20. Moreno Ayala MA, Gottardo MF, Zuccato CF, et al. Humanin Promotes Tumor Progression in Experimental Triple Negative Breast Cancer. Sci Rep. 2020;10(1):8542. PubMed.
  21. Yen K, Mehta HH, Kim SJ, et al. The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Aging (Albany NY). 2020;12(12):11185–11199. PubMed.
  22. Conte M, Sabbatinelli J, Chiariello A, et al. Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer’s disease in comparison with healthy aging. Geroscience. 2021;43(2):985–1001. PubMed.
  23. Miller B, Kim SJ, Cao K, et al. Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology. Aging Cell. 2024;23(7):e14153. PubMed.
  24. National Center for Biotechnology Information. Humanin, PubChem Compound CID 16131438. PubChem.
  25. ClinicalTrials.gov. Studies matching “humanin” (searched October 2026). ClinicalTrials.gov.
  26. Food and Drug Administration. Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks (content current as of April 22, 2026). FDA.
  27. Code of Federal Regulations. 21 CFR 1308.13, Schedule III. 21 CFR 1308.13.
  28. World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. WADA 2026 Prohibited List.