Humanin
A 24-amino-acid peptide encoded in mitochondrial DNA: it protects cells in the lab and improves insulin action and survival signals in animals, but no human has been given humanin in a published trial.
Humanin was found in 2001 in surviving brain cells from a person with Alzheimer's disease, and it turned out to be encoded by the mitochondria's own genome, the first of a family of mitochondrial-derived peptides. Laboratory and animal studies report protection against cell death, better insulin sensitivity and longer life in worms. In people it has only been measured, never tested as a treatment.
What is it?
Humanin was identified in 2001 by functional expression screening for genes that stop neurons dying from Alzheimer's-type insults, in the surviving neurons of a person with Alzheimer's disease. The hit was a 24-amino-acid peptide whose code sits inside the mitochondrial gene for 16S ribosomal RNA. That made it the first of what are now called mitochondrial-derived peptides, a family that includes MOTS-c and the small humanin-like peptides, and it changed how researchers think about mitochondria: not only as power plants but as a source of signals to the rest of the cell and body.
In the laboratory humanin protects many cell types. Early reviews describe it blocking neuronal death from amyloid-beta and familial Alzheimer's genes through a cell-surface receptor complex that switches on the JAK2/STAT3 pathway, and inside cells by binding the pro-death protein Bax. Later studies found it raises the survival protein Apollon/Bruce, induces autophagy, reduces inflammation in retinal cells carrying mitochondria from people with macular degeneration, protects blood-vessel cells from high-glucose ageing through SIRT6, and is released by human macrophages as they clear dead cells. Researchers mostly use HNG, a variant with glycine at position 14 that is far more potent.
In animals humanin acts on metabolism as well as the brain. Infused into the brains of rats it improved whole-body insulin sensitivity through hypothalamic STAT3, and intravenous analogues lowered blood sugar in diabetic rats; an analogue also reduced weight gain and changed liver fat secretion through the brain. It improved testicular ageing in old rats, enhanced neurotransmitter release in the hippocampus, and extended lifespan in the worm C. elegans in a way that needed autophagy.
The human evidence is observational. Blood levels of humanin fall with age, are lower in people with macular degeneration and, as gene transcripts, in Alzheimer's disease, and rise in muscle after resistance training in men with prediabetes. None of that shows that giving humanin helps anyone, and no published study has given it to people. It is not approved anywhere, and what is sold online is an unregulated research chemical.
Mechanism of Action
Humanin acts both outside cells, through surface receptors, and inside them, on the machinery of cell death. Most of what is known comes from cell culture and rodents, often with the potent analogue HNG.
Surface receptor and STAT3
Binding a heterotrimeric humanin receptor activates JAK2 and STAT3, which protected neurons from Alzheimer's-linked insults and raised the anti-apoptosis protein Apollon/Bruce. In rats, hypothalamic STAT3 carried its insulin-sensitising effect.
Blocking Bax inside the cell
Inside cells humanin binds Bax, a protein that punctures mitochondria to trigger apoptosis. A 2025 structural study found humanin variants form fibrils and that beta-sheet structure matters for binding BCL-2 family proteins.
Autophagy
Humanin increased autophagy in several cell lines and mouse muscle, and its lifespan extension in C. elegans depended on autophagy (2022).
Inflammation and oxidative stress
HNG lowered inflammatory proteins in retinal cells carrying macular-degeneration mitochondria, and protected blood-vessel cells from high-glucose senescence through SIRT6.
Published Research
Our evidence set holds 46 papers that name humanin. Twenty-six name it in their titles and have an abstract; 19 are carded below: 5 in people (all measuring humanin, none giving it), 5 in animals, 5 in cells or structural studies and 4 reviews. The 2001 discovery paper is listed under References because its title does not use the name.
Humanin after its discovery
Humanin, a 24-residue neuroprotective factor, suppressed neuronal death from Alzheimer's-specific insults, including amyloid-beta and familial Alzheimer's genes, and protected cerebrovascular smooth muscle cells. It acts through putative cell-surface receptors and a signalling cascade that interferes with JNK activation, and intracellular humanin suppressed mitochondrial apoptosis by inhibiting Bax.
Two routes to blocking cell death
Humanin works through at least two mechanisms: in a glioblastoma cell line it binds the apoptosis protein Bax, and in neurons it acts through a putative cell-surface receptor, which carries its neuroprotective effect. Because it is also made in normal tissues such as the testis, the authors raised a possible role in cancer development.
Insulin action through the brain, rats
Humanin infused into the brain improved whole-body insulin sensitivity through hypothalamic STAT3; intravenous potent analogues reproduced the effect, which was blocked when hypothalamic STAT3 was inhibited. A single dose of an analogue lowered blood glucose in diabetic Zucker rats, and circulating humanin fell with age in people and mice.
The first mitochondrial-derived peptide
A review of mitochondria as senders of retrograde signals to the cell, presenting humanin as the first small peptide encoded in mitochondrial DNA and the founder of a new class of mitochondrial-derived peptides.
Raising the survival protein Apollon
Humanin binding its heterotrimeric receptor activated JAK2 and STAT3 and raised the level of Apollon/Bruce, an inhibitor-of-apoptosis protein; overexpressing Apollon alone protected neurons against a familial Alzheimer's mutant of amyloid precursor protein.
Liver fat secretion through the brain, rodents
The analogue HNG given into the abdomen reduced body weight gain, and given intravenously or into the brain it acutely increased triglyceride secretion from the liver. Cutting the vagus nerve blocked the effect, so HNG's action on liver lipid output is centrally mediated.
Heart tissue after an hour of pure oxygen
Patients about to have bypass surgery were ventilated with 40% or 100% oxygen for 60 minutes. High oxygen changed the expression of 20 genes in heart muscle, including two humanin-like genes (MTRNR2L2 and MTRNR2L8), and activated a cell-survival network. Humanin was measured, not given.
Muscle humanin after resistance training
Fifty-five men with impaired glucose regulation were randomised to resistance training, Nordic walking or no training three times a week for 12 weeks. Humanin protein in thigh muscle rose by 35% after resistance training, while serum humanin did not change.
Retinal cells with macular-degeneration mitochondria
In retinal pigment epithelium cells carrying mitochondria from people with age-related macular degeneration, HNG protected against mitochondrial damage and cell death, which the authors propose as a route to treating dry macular degeneration.
Autophagy and lifespan
A screen of mitochondrial-derived peptides identified humanin as an autophagy inducer in three cell lines. In mice it raised autophagy genes and reduced misfolded protein build-up in muscle, and in C. elegans its lifespan extension required autophagy.
Neurotransmitter release in the hippocampus
HNG, which had improved cognition in Alzheimer's mouse models, increased regulated exocytosis: it raised neurotransmitter release in the hippocampus and enlarged secretory events and vesicle size in primary neuroendocrine cells.
Macular degeneration and inflammation
Humanin protein levels were lower in plasma from people with macular degeneration than in controls, and HNG reduced inflammation-associated proteins such as IL-17A in retinal cells carrying macular-degeneration mitochondria.
Ageing testes in rats
In aged male rats with low testosterone, humanin improved testicular structure, hormone levels and antioxidant defences, lowered active caspase-3 and BAX and raised BCL2 and a proliferation marker, possibly through the Nrf2 pathway.
Humanin and the heart
Humanin, first identified in 2001 in surviving neurons from a person with Alzheimer's disease, is the first and most studied of the mitochondrial-derived peptides, alongside MOTS-c and SHLP1-6. The review summarises its protection against myocardial ischaemia-reperfusion injury and its reported roles in ageing, metabolic, cardiovascular and autoimmune disease.
Children in septic shock
In 140 children with septic shock, serum humanin was higher on day 1 than day 3 and higher in the 39 with thrombocytopenia-associated multiple organ failure, but the association did not hold after adjusting for age and illness severity.
Blood-vessel cells and high glucose
In human umbilical vein endothelial cells, high glucose lowered SIRT6, raised reactive oxygen species and drove senescence; [Gly14]-humanin restored SIRT6 and reduced both oxidative stress and senescence.
Made by macrophages clearing dead cells
Human macrophages that had engulfed apoptotic neutrophils produced humanin, which promoted the resolution of inflammation; humanin was also detected in gum fluid from people with periodontitis after inflammation began.
Humanin forms fibrils
Biophysical studies showed humanin and its variants form amyloid-like beta-sheet fibrils with different shapes. Variants known to be poorly secreted differed in this behaviour, and beta-sheet transitions were needed for binding BCL-2 family proteins, which the authors note matters for how humanin is administered.
Blood markers in Alzheimer's disease
In a case-control study, humanin and MOTS-c gene transcripts in blood 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.
Dosing Data
Humanin has no approved dose and no human dose from any study. Animal studies gave humanin or HNG into the brain, a vein or the abdomen at doses chosen for rodents, which do not translate into a human dose.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. 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. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
No human safety data exist; no published study has given humanin to people.
Contraindications & Cautions
With no human studies, these cautions follow from what is known.
Legal Status
Humanin is not approved as a medicine anywhere.
Frequently Asked Questions
?Has humanin been tested in people?
Not as a treatment. Human studies have measured humanin levels in blood or muscle, in ageing, macular degeneration, Alzheimer's disease, sepsis and exercise, but no published study has given it to people.
?What is HNG?
S14G-humanin, a version with glycine in place of serine at position 14. It is much more potent than natural humanin and is what most animal and cell studies use.
?Does humanin extend lifespan?
In the worm C. elegans it did, through autophagy (2022). No study has tested lifespan in mammals or people.
?Why does humanin decline with age?
Circulating humanin was lower in older people and mice in a 2009 study, and lower in people with macular degeneration. Whether the decline causes disease or just accompanies it is not known.
?Does exercise raise humanin?
In one trial, 12 weeks of resistance training raised humanin protein in thigh muscle by 35% in men with prediabetes, but not in blood.
?How is humanin related to MOTS-c?
Both are mitochondrial-derived peptides, encoded by mitochondrial DNA. Humanin was the first found; MOTS-c came later. Both decline with age and both are sold online as research chemicals.
References
- [Review] Niikura T, et al. "Humanin: after the discovery." Mol Neurobiol, 2004;30(3):327-40. PMID: 15655255.
- [Review] Nishimoto I, et al. "Unravelling the role of Humanin." Trends Mol Med, 2004;10(3):102-5. PMID: 15106598.
- [Animal] Muzumdar RH, et al. "Humanin: a novel central regulator of peripheral insulin action." PLoS One, 2009;4(7):e6334. PMID: 19623253.
- [Review] Lee C, et al. "Humanin: a harbinger of mitochondrial-derived peptides?." Trends Endocrinol Metab, 2013;24(5):222-8. PMID: 23402768.
- [In Vitro] Hashimoto Y, et al. "Apollon/Bruce is upregulated by Humanin." Mol Cell Biochem, 2014;397(1-2):147-55. PMID: 25138702.
- [Animal] Gong Z, et al. "Central effects of humanin on hepatic triglyceride secretion." Am J Physiol Endocrinol Metab, 2015;309(3):E283-92. PMID: 26058861.
- [Human] Karu I, et al. "Exposure to sixty minutes of hyperoxia upregulates myocardial humanins in patients with coronary artery disease - a pilot study." J Physiol Pharmacol, 2015;66(6):899-906. PMID: 26769839.
- [Human] Gidlund EK, et al. "Humanin skeletal muscle protein levels increase after resistance training in men with impaired glucose metabolism." Physiol Rep, 2016;4(23). PMID: 27923980.
- [In Vitro] Nashine S, et al. "Humanin G (HNG) protects age-related macular degeneration (AMD) transmitochondrial ARPE-19 cybrids from mitochondrial and cellular damage." Cell Death Dis, 2017;8(7):e2951. PMID: 28726777.
- [Animal] Kim SJ, et al. "Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension." Biochim Biophys Acta Gen Subj, 2022;1866(1):130017. PMID: 34624450.
- [Animal] Ikegawa N, et al. "Humanin derivative, HNG, enhances neurotransmitter release." Biochim Biophys Acta Gen Subj, 2022;1866(10):130204. PMID: 35843407.
- [Human] Nashine S, et al. "Effect of Humanin G (HNG) on inflammation in age-related macular degeneration (AMD)." Aging (Albany NY), 2022;14(10):4247-4269. PMID: 35576057.
- [Animal] El Kattawy HA, et al. "Humanin Ameliorates Late-onset Hypogonadism in Aged Male Rats." Curr Mol Pharmacol, 2022;15(7):996-1008. PMID: 35086467.
- [Review] Gong Z, et al. "Cardio-protective role of Humanin in myocardial ischemia-reperfusion." Biochim Biophys Acta Gen Subj, 2022;1866(2):130066. PMID: 34896254.
- [Human] Atreya MR, et al. "SERUM HUMANIN IN PEDIATRIC SEPTIC SHOCK-ASSOCIATED MULTIPLE-ORGAN DYSFUNCTION SYNDROME." Shock, 2024;61(1):83-88. PMID: 37917869.
- [In Vitro] Li M, et al. "[Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6." Sci Rep, 2024;14(1):30924. PMID: 39730568.
- [In Vitro] Maraux M, et al. "HUMANIN produced by human efferocytic macrophages promotes the resolution of inflammation." Cell Death Dis, 2025;16(1):656. PMID: 40877234.
- [In Vitro] Morris DL, et al. "Humanin variants aggregate to produce different fibril morphologies." J Biol Chem, 2025;301(7):110403. PMID: 40543583.
- [Human] Rodríguez-Esparragón F, et al. "Insights into the Biomarker Potential of Humanin and Mots-c Expression and Telomere Length in Alzheimer's Disease." Int J Mol Sci, 2025;26(22). PMID: 41303353.
- [pubmed] Hashimoto Y, 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):6336-41. PMID: 11371646.
Sources & Citations
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