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Peptide Atlas
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Humanin

Tier 2 · Preclinical
Also known as HNG · MT-RNR2 · Humanin peptide

The strongest evidence present is Tier 1: the ADEX randomized controlled trial (NCT01681602, 95 participants, 16 weeks) measured humanin in neuron-derived extracellular vesicles as a biomarker of exercise response in Alzheimer's disease patients. However, multiple sources agree there are no published randomized or interventional human trials of *exogenous* humanin or its HNG analog, no Phase 1 first-in-human safety study, and no FDA approval; a June 2026 ClinicalTrials.gov query returned six humanin-related studies, all observational biomarker work. A tier-2 database assigns humanin an evidence score of 2/5, noting substantial mechanistic and preclinical evidence but no human therapy trials. Efficacy claims therefore rest on cell, animal and observational human biomarker data.

Half-life
~0.5 h
Routes
Subcutaneous injection · Intraperitoneal injection (animal studies) · Intravenous (animal protocols only) · Intracerebroventricular (animal protocols only)
Goals
Longevity / healthspan · Neuroprotection / cognitive health · Metabolic health / insulin sensitivity · Cardiovascular protection · Anti-inflammatory
Cost / mg
Not recorded

How it works

Vendor and review sources describe humanin as a small peptide encoded within the mitochondrial genome that acts as a 'mitokine'(vendor claim) — a signal that mitochondria send to the rest of the body when under stress. Sources report it works by latching onto cell-surface receptors and by blocking proteins inside the cell that would otherwise trigger cell death, and that its levels naturally decline with age. In cell and animal studies it is reported to protect neurons, heart and other cells from damage and to improve how the body handles insulin and glucose. A widely studied engineered version called HNG (the S14G analog) is reported to be about 1,000-fold more potent than the natural peptide in cell culture. Importantly, no human trials of giving humanin as a drug have been published.

Overview

Overview

Vendor and review sources describe humanin (aliases HNG, MT-RNR2, Humanin peptide) as a 24-amino-acid mitochondrial-derived peptide encoded by a short open reading frame within the mitochondrial 16S ribosomal RNA gene (MT-RNR2), with the sequence MAPRGFSCLLLLTSEIDLPVKRRA(vendor claim). A review states it is encoded by a 75-bp open reading frame, and vendor profiles give its molecular weight as approximately 2,687 Da (cited formulas C119H204N34O32S2 and C118H200N32O35S)(vendor claim). The AlzDiscovery review notes the peptide is 21 amino acids when translated in mitochondria and 24 amino acids when translated in the cytoplasm, and that there are 13 humanin-like open reading frames (MTRNR2L#) in the nuclear genome.

Discovery

Sources attribute the discovery of humanin to 2001, though they differ on the investigator. One vendor guide credits the Nishimoto group in Tokyo, working through a functional screen for factors that rescue neurons from familial Alzheimer's disease toxicity(vendor claim); a review instead credits Hashimoto, using a cDNA library from the brain tissue of an Alzheimer's patient. Several sources report it was discovered through functional expression screening of a cDNA library from the occipital lobe of an Alzheimer's disease patient, identified in neurons that resisted Alzheimer's-related cell death. A review describes humanin as the first newly discovered peptide encoded in the mitochondrial genome in over three decades and the first member of a novel class of mitochondrial-derived peptides (MDPs). A community source states it is one of the three major MDPs alongside MOTS-c and the SHLP peptides; a review reports eight MDPs identified to date, with the 12S rRNA harboring MOTS-c and the 16S rRNA gene encoding humanin and SHLP 1-6.

Mechanism

Sources report humanin engages two cell-surface receptor systems — the formyl peptide receptors FPR2/FPR3 (FPRL1) and the heterotrimeric CNTFR-alpha/WSX-1/gp130 cytokine receptor complex — with activation triggering JAK2/STAT3 signaling and STAT3 phosphorylation. One vendor states gp130 is essential for humanin-induced neuroprotection and that STAT3 activation mediates its neuroprotective effects(vendor claim). A murine study reports humanin inhibits neuronal cell death by binding an IL-6-receptor-related complex involving CNTFRalpha, WSX-1 and gp130 and is effective against Alzheimer's-related neuronal dysfunction in transgenic mice. Sources also report humanin binds the carrier protein IGFBP-3 and binds the pro-apoptotic Bcl-2 family proteins Bax and tBid directly inside the cell to prevent mitochondrial outer membrane permeabilization and cytochrome c release. In vitro reports indicate its protective effect is strictly dependent on primary structure and that it is secreted to act in autocrine and paracrine fashion; in one study it abolished cell death caused by familial Alzheimer's genes and by amyloid-beta.

Reviews describe humanin functioning as a mitokine — communicating mitochondrial stress to distant tissues — influencing JAK2, STAT3, MAPKs and JNK signaling and altering mitochondrial bioenergetics. One vendor states it activates PI3K/Akt and enhances mitochondrial biogenesis, and reports it is found naturally in brain, heart, liver and skeletal muscle(vendor claim). A review reports it binds IGFBP-3, decreases circulating IGF-I, is itself regulated by IGF-I, and is a new player in IGF-I signaling; a review of human observational data reports plasma humanin levels are inversely correlated with growth hormone and IGF-1 expression.

Analogs

Sources describe the S14G analog (HNG) — serine-14 replaced by glycine — as approximately 1,000-fold more potent than native humanin at activating the heterotrimeric receptor in cell culture. The AlzDiscovery review describes HNGF6A (adding an alanine-for-phenylalanine substitution at position 6) as having superior stability and pharmacokinetics and being more potent at modulating insulin action, and describes colivelin as the most potent derivative developed to date, with neuroprotective activity in the femtomolar range and 10^3-10^7 times the potency of humanin. One source notes native humanin has poor stability and bioavailability, so S14G-HN and AGA-HNG are used in preclinical models. Vendor material describes HNG (S14G-humanin) as the analog most commonly sold by research-peptide suppliers rather than the wild-type 24-mer(vendor claim).

Preclinical and observational findings

Across rodent models, one vendor guide summarizes that humanin or HNG protects neurons from amyloid-beta toxicity, attenuates myocardial ischemia-reperfusion injury, slows atherosclerotic plaque progression in ApoE-knockout mice, improves central regulation of peripheral insulin sensitivity, and preserves cognition in aged mice(vendor claim). A study reports that in C. elegans, humanin overexpression increases lifespan dependent on daf-16/Foxo, and that humanin transgenic mice show overlapping phenotypes; another reports treating middle-aged mice twice weekly with HNG improved metabolic healthspan and reduced inflammatory markers. Reviews report protection against diabetes, cardiovascular and neurodegenerative disease, suppression of apoptosis in osteoporosis models, and benefit in stroke and cancer models. A rat study reports HNG at 5 mg/kg/day IP for 21 days attenuated endometrial fibrosis and intrauterine adhesions and improved fertility (mating rate rising from 40% to 80% versus 100% in controls), attributed to inhibition of endometrial ferroptosis; the same study found humanin downregulated in human IUA endometria. A study reports HNG ameliorated cognitive impairment in Alzheimer's mouse models and increased hippocampal acetylcholine, and one reports S14G-HNG exerted anti-inflammatory effects in a gout model via SIRT1 (with the authors noting colchicine showed a better effect). An AMD study reports Humanin G protected RPE cybrid cells and reduced inflammatory markers.

Multiple sources report endogenous circulating humanin levels decline with age in humans and rodents and are lower in type 2 diabetes, Alzheimer's disease, coronary artery disease and MELAS, while children of centenarians have higher levels and higher humanin is associated with longevity. One vendor states levels decline approximately 40% between ages 20 and 80(vendor claim). A review reports humanin is stable in the naked mole-rat, a model of negligible senescence, and that exercise and mitochondrial stress upregulate muscle MDP expression. In the ADEX randomized trial (NCT01681602, 95 participants, 16 weeks), humanin in neuron-derived extracellular vesicles increased in the exercise group of Alzheimer's patients — especially APOE ε4 carriers — while remaining unchanged in controls, which the authors suggest may mediate cognitive benefits of exercise.

One low-tier vendor page attributes specific preclinical percentages to humanin (e.g., 30% increase in mitochondrial respiration and ATP, 30-40% reduction in neuronal death, 12% median lifespan increase); these figures appear only in that single source and are not corroborated by the peer-reviewed literature.

Evidence status

Multiple sources state there are no published randomized controlled or interventional human trials of exogenous humanin or its HNG analog for any indication, no published Phase 1 first-in-human safety study, and no FDA approval; a June 2026 ClinicalTrials.gov query returned six registered humanin studies, all observational biomarker work. A tier-2 database assigns humanin an evidence score of 2/5, citing substantial mechanistic and preclinical evidence but no human therapy trials.

What the research shows

149 findings extracted from the 20 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 3 human trial findings, 10 human study findings, 18 animal findings, 1 in vitro finding, 2 expert opinion findings and 1 theoretical finding.

  • human trialHumanin levels in neuron-derived extracellular vesicles (NDEVs) increased in the exercise group in Alzheimer's disease patients3

  • human trialHumanin levels in NDEVs increased especially in APOE ε4 carriers participating in exercise intervention3

  • human trialHumanin levels remained unchanged in the control group after 16 weeks3

  • human studyIn children of centenarians, circulating humanin levels are much greater than age-matched control subjects1

  • human studyHumanin levels are decreased in human diseases such as Alzheimer's disease and MELAS1

  • human studyHumanin signaling mediates exercise-derived and dietary strategy-related molecular and systemic health benefits, including healthy aging2

  • human studyAlterations of humanin levels are associated with general aging processes and could influence the development of age-related chronic metabolic, cardiovascular and neurological diseases2

  • human studyCirculating humanin levels decline with age in both humans and animal models6

Show 27 more findings

  • human studyHigher humanin levels have been associated with longevity in observational studies6

  • human studyHumanin expression levels were downregulated in the endometria of patients with IUAs relative to controls9

  • human studyAMD plasma showed reduced Humanin protein levels compared to control plasma samples10

  • human studyAMD plasma showed higher protein levels of inflammation markers compared to control plasma samples10

  • human studyMetabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs in humans13

  • animalIn C. elegans, overexpression of humanin is sufficient to increase lifespan, dependent on daf-16/Foxo1

  • animalHumanin transgenic mice have many phenotypes that overlap with the worm phenotypes and have increased protection against toxic insults1

  • animalTreating middle-aged mice twice weekly with the potent humanin analogue HNG improves metabolic healthspan parameters and reduces inflammatory markers1

  • animalHNG (HN with substitution of Gly for Ser14) ameliorated cognitive impairment in AD mouse models4

  • animalHNG did not affect the physical activities of the mice but modestly improved their object memory4

  • animalBased on in vitro and in vivo studies, HN significantly suppressed apoptosis during treatment of bone osteoporosis, cardiovascular diseases, diabetes mellitus, and neurodegenerative diseases5

  • animalGBM mouse models recapitulating intratumoral humanin release show accelerated blood-tumor barrier (BTB) formation7

  • animalBoth systemic and intracerebroventricular (ICV) administrations of SHLP2 protected male mice from high-fat diet (HFD)-induced obesity8

  • animalSHLP2 improved insulin sensitivity in mice8

  • animalHumanin analogue (HNG) supplementation attenuated the development of endometrial fibrosis and intrauterine adhesions (IUAs)9

  • animalHNG improved fertility in rats with IUAs9

  • animalThe elevated Gait score promoted synovitis score and activated myeloperoxidase (MPO) observed in MSU crystals-treated mice were significantly reversed by colchicine and S14G-HNG11

  • animalTreatment of rodents with humanin can enhance insulin sensitivity13

  • animalTreatment of rodents with humanin can offer protection against a range of age-associated metabolic disorders13

  • animalHumanin preserves endothelial cell function in a mouse model of atherosclerosis14

  • animalHumanin improves insulin sensitivity in mouse models of type 2 diabetes14

  • animalA potent analogue of humanin blocks cardiac fibrosis in aging mice14

  • animalHumanin is effective against AD-related neuronal dysfunction in vivo in murine AD models including familial AD gene-expressing transgenic mice16

  • in vitroHumanin has been shown to protect cells from beta amyloid toxicity14

  • expert opinionS14G-HNG has been reported to exert great anti-inflammatory effects11

  • expert opinionHumanin was initially discovered to have neuroprotective effects15

  • theoreticalNo clinical applications have been validated through controlled trials6

How it works

Based on 2 human trial findings, 6 human study findings, 16 animal findings, 27 in vitro findings, 32 expert opinion findings and 9 theoretical findings.

  • human trialHumanin is a neuroprotective protein present in neuron-derived extracellular vesicles3

  • human trialUpregulation of humanin in NDEVs may mediate cognitive benefits of exercise in Alzheimer's disease3

  • human studyHumanin is a member of a new family of peptides encoded by short open reading frames within the mitochondrial genome1

  • human studyHumanin is conserved in animals and is both neuroprotective and cytoprotective1

  • human studyIn multiple species, humanin levels generally decline with age1

  • human studyHumanin (HN) is an endogenous 24-residue peptide that was first identified as a protective factor against neuronal death in Alzheimer's disease (AD)4

  • human studyIn humans, muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging13

  • human studyHumanin plasma levels are inversely correlated with growth hormone and insulin-like growth factor 1 expression, which may promote accelerated aging14

Show 84 more findings

  • animalHumanin levels are surprisingly stable in the naked mole-rat, a model of negligible senescence1

  • animalThe hippocampal acetylcholine (ACh) levels were increased by intraperitoneal injection of HNG4

  • animalHN directly enhances regulated exocytosis in neurons, which can contribute to the improvement of cognitive functions4

  • animalHumanin administration has improved metabolic parameters, reduced inflammation, and extended healthspan in animal models6

  • animalGP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy7

  • animalSHLP2 is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress8

  • animalActivation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake8

  • animalSHLP2 promotes thermogenesis via POMC neuron activation8

  • animalSHLP2 binds to and activates chemokine receptor 7 (CXCR7)8

  • animalHNG contributed to regulation of endometrial fibrosis by inhibiting endometrial ferroptosis in rats with IUAs9

  • animalHumanin is a mitochondrial-derived peptide widely expressed in multiple tissues9

  • animalS14G-humanin (HNG) has a protective effect against myocardial fibrosis9

  • animalHNG significantly attenuated altered expression levels of ferroptosis-related proteins in endometria of rats with IUAs9

  • animalHumanin has cyto- or metaboloprotective properties13

  • animalHumanin protects neurons from AD-related neuronal death16

  • animalHumanin inhibits neuronal cell death and dysfunction by binding to a novel IL-6-receptor-related receptor(s) on the cell surface involving CNTFRalpha, WSX-1, and gp13016

  • in vitroHNG enhanced ACh-induced dopamine release in rat pheochromocytoma PC12 cells4

  • in vitroHNG increased ACh-induced secretory events and vesicular quantal size in primary neuroendocrine cells4

  • in vitroHumanin was first identified in 2001 for its ability to protect neurons from amyloid-beta (Aβ) toxicity6

  • in vitroHumanin has demonstrated protective effects against apoptosis triggered by amyloid-beta toxicity, oxidative stress, serum starvation, and various chemical stressors in neuronal cells, cardiac cells, pancreatic beta cells, and other tissue types6

  • in vitroHumanin interacts with FPRL1 (Formyl Peptide Receptor Like-1), a G-protein coupled receptor involved in inflammatory regulation and immune cell signaling6

  • in vitroHumanin binds to a heterotrimeric receptor composed of ciliary neurotrophic factor receptor (CNTFR), WSX-1 (IL-27 receptor alpha), and gp130 (glycoprotein 130), with activation triggering JAK-STAT signaling and STAT3 phosphorylation6

  • in vitroNanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation7

  • in vitroHumanin interaction with GBM and myeloid cells induces chemoresistance by activating GP130 receptor signaling7

  • in vitroHNG significantly attenuated erastin-induced decrease in viability of Ishikawa cell line9

  • in vitroHNG attenuated increase in reactive oxygen species production in Ishikawa cells9

  • in vitroHNG attenuated downregulation of GPX4 in Ishikawa cells9

  • in vitroHumanin G (HNG) is a Mitochondrial Derived Peptide (MDP) that is cytoprotective in AMD10

  • in vitroHumanin G can protect against mitochondrial and cellular stress induced by damaged AMD mitochondria10

  • in vitroHumanin G reduced CD62E/E-Selectin protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G reduced CD62P/P-Selectin protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G reduced ICAM-1 protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G reduced TNF-α protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G reduced MIP-1α protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G reduced IFN-γ protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G reduced IL-1β protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G reduced IL-13 protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G reduced IL-17A protein levels in AMD RPE cybrid cells10

  • in vitroHumanin G may rescue from mtDNA-mediated inflammation in AMD cybrids10

  • in vitroS14G-HNG treatment increased mitochondrial reactive oxygen species (ROS) and Malondialdehyde (MDA) levels, upregulated NADPH oxidase-4 (NOX-4), activated NLRP3 inflammasome, and elevated production of inflammatory factors in MSU crystals-treated BMDMs were dramatically reversed by S14G-HNG11

  • in vitroS14G-HNG treatment was accompanied by the upregulation of sirtuin type-1 (SIRT1)11

  • in vitroThe protective effects of S14G-HNG against MSU crystals-induced NLRP3 inflammasome activation were significantly abolished by the knockdown of SIRT111

  • in vitroHumanin and MOTS-c both exacerbate the senescence-associated-secretory-phenotype (SASP) in senescent cells by stimulating the secretion of IL-6, IL-1β, IL-8, IL-10 and tumor necrosis factor α14

  • expert opinionHumanin is a mitochondrial-derived peptide that functions as a mitokine, enabling communication of mitochondrial stress to distant cells and tissues2

  • expert opinionHumanin is a mitochondrial-derived peptide comprising 24 amino acids and encoded by a 75-bp ORF5

  • expert opinionHN exerts pro-apoptotic activity of TNF-α in cancer5

  • expert opinionHN exhibits anti-apoptotic activity by binding through extracellular CNTFR-α/gp130/WSX-1 trimeric receptors5

  • expert opinionHN is a small mitochondrial-derived cytoprotective polypeptide encoded by mtDNA5

  • expert opinionHN regulates mitochondrial functions under stress conditions through JAK/STAT pathway and interaction with BCL-2 family of proteins5

  • expert opinionHumanin is the first newly discovered peptide encoded in the mitochondrial genome in over three decades15

  • expert opinionHumanin is the first member of a novel class of mitochondrial derived peptides15

  • expert opinionHumanin is a small, 24 amino acid peptide15

  • expert opinionHumanin binds IGFBP-315

  • expert opinionHumanin decreases circulating IGF-I levels15

  • expert opinionIGF-I regulates humanin levels15

  • expert opinionHumanin is a new player in IGF-I signaling15

  • expert opinionHumanin is a mitochondrial derived peptide that has cytoprotective properties17

  • expert opinionHumanin and analogs protect neurons by increasing their resilience to a variety of cell stressors and can inhibit toxic Aβ oligomerization17

  • expert opinionHumanin promotes insulin sensitivity and metabolic adaptions following exercise17

  • expert opinionHumanin is encoded by a small open reading frame within the 16S rRNA (MT-RNR2)17

  • expert opinionWhen translated in the mitochondria, the peptide is 21 amino acids long, and 24 amino acids long when translated in the cytoplasm17

  • expert opinionThere are 13 humanin-like open reading frames found in the nuclear genome (MTRNR2L#)17

  • expert opinionHumanin is produced in response to cellular stress and has cytoprotective activities both intracellularly and extracellularly17

  • expert opinionHumanin can influence a variety of signaling pathways including JAK2, STAT3, MAPKs, and JNK17

  • expert opinionCytoprotective effects are largely mediated through the humanin heterotrimeric receptor complex, which consists of ciliary neurotrophic factor receptor α (CNTFR), the cytokine receptor WSX-1, and the transmembrane glycoprotein gp13017

  • expert opinionHumanin can influence cellular bioenergetics by altering mitochondrial activity17

  • expert opinionS14G-HN (HNG) is a humanin analog where the serine at position 14 is substituted for a glycine17

  • expert opinionHNG is 1000 times more potent than humanin in activating the humanin heterotrimeric receptor17

  • expert opinionHNGF6A contains the S14G substitution to increase potency as well as a substitution of an alanine in place of the phenylalanine at position 617

  • expert opinionHNGF6A is more potent at modulating insulin action17

  • expert opinionColivelin is the most potent humanin derivative developed to date and shows neuroprotective activity at the fM range17

  • expert opinionColivelin is 10^3 to 10^7 more potent than humanin and other humanin analogs17

  • expert opinionHumanin is a mitochondria-derived peptide18

  • expert opinionHumanin exerts protective function in many tissues, especially in nervous tissues18

  • expert opinionHumanin plays an important role in regulating the response of the cell to oxidative stress and apoptosis in ovaries and testes via modulation of several signaling pathways18

  • theoreticalCompensatory increase in humanin synthesis and secretion could preserve mitochondrial function and overall cellular vitality2

  • theoreticalHumanin is a 24-amino-acid peptide encoded by mitochondrial DNA, specifically the MT-RNR2 gene within the 16S ribosomal RNA region6

  • theoreticalHumanin belongs to a class of molecules known as mitochondria-derived peptides (MDPs)6

  • theoreticalS14G-humanin (S14G-HNG) is a modified peptide of HNG with higher inhibitory activity on the accumulation and deposition of Aβ11

  • theoreticalHumanin is a mitochondrial-derived peptide encoded by the 16S ribosomal RNA gene13

  • theoreticalMDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell and to distal tissues to modulate adaptative responses to metabolic stress13

  • theoreticalHumanin and its homologs and MOTS-c are mitochondrial-derived peptides (MDPs) encoded by mitochondrial DNA that play a cytoprotective role by helping preserve mitochondrial function and cell viability under stressful conditions14

  • theoreticalThe cytoprotective activity of MDPs may be permissive for increased expression of a set of proinflammatory cytokines14

  • theoreticalEndogenous Humanin may suppress the onset of AD-related dementia by inhibiting both AD-related neuronal cell death and dysfunction16

Dosing

Based on 1 expert opinion finding.

  • expert opinionClinical human testing has not been conducted, and therapeutic dosing has not been established17

How the body handles it

Based on 1 expert opinion finding.

  • expert opinionHNGF6A has superior stability and pharmacokinetics relative to IGFBP-3 binding analogs17

Safety and side effects

Based on 1 human study finding, 1 expert opinion finding and 1 theoretical finding.

  • human studyExcessive humanin concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure2

  • expert opinionEndogenous humanin is a safe peptide, but its effects can be context dependent, and may be sex dependent17

  • theoreticalNo human intervention trials have been completed6

What people use it for

Based on 3 human study findings, 3 animal findings and 9 expert opinion findings.

  • human studyHumanin responsiveness to mitochondrial stress is induced in response to exercise and mitochondrial challenges in skeletal muscle2

  • human studyRegular exercise increases humanin levels and is associated with increased lifespan2

  • human studyHumanin levels decline with age17

  • animalSHLP2 has therapeutic potential in metabolic disorders8

  • animalS14G-HNG could possess potential benefits against MSU crystals-induced gout arthritis, with colchicine displaying a better effect11

  • animalHumanin has shown beneficial effects in diverse disease models including stroke, cardiovascular disease, and cancer15

  • expert opinionHN protects cells against various diseases, including diabetes mellitus, cardiovascular, and neurodegenerative diseases5

  • expert opinionHN exhibits protective effects in leukocytes, germ cells, neurons, and tissues against cellular stress conditions and apoptosis5

Show 7 more findings

  • expert opinionHumanin influences metabolism, promotes insulin sensitivity, and prolongs healthspan17

  • expert opinionMaintenance of humanin levels may prolong healthspan17

  • expert opinionHumanin may protect against ischemic cardiovascular damage17

  • expert opinionHumanin has potential as a novel therapeutic approach for male infertility18

  • expert opinionHumanin has potential as a novel therapeutic approach for male contraception18

  • expert opinionHumanin has potential as a novel therapeutic approach for female infertility18

  • expert opinionHumanin has potential for glucose metabolism in polycystic ovary syndrome18

Other findings

Based on 1 expert opinion finding and 1 theoretical finding.

  • expert opinionHN was initially discovered in 2001 by Hashimoto using a cDNA library from healthy brain tissue of an Alzheimer's patient5

  • theoreticalHumanin is a 24-amino-acid bioactive peptide16

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Limited evidence

No human trials of exogenous humanin exist; all human data is observational.

Multiple sources (including tier-1 and tier-2) agree there are no published randomized or interventional human trials of exogenous humanin/HNG, no Phase 1 safety study, and no FDA approval. A June 2026 ClinicalTrials.gov query returned six humanin studies, all observational. Efficacy claims rest on cell, animal and observational human biomarker data only.

Contested

Humanin's cytoprotection may be harmful in cancer and at high levels.

While most sources emphasize protective anti-apoptotic effects, others report a dual/harmful role: humanin can protect cancer cells from apoptosis and promote tumor survival, promotes temozolomide resistance in glioblastoma via GP130, exerts pro-apoptotic TNF-α activity in cancer, and excessive concentrations are associated with cancer and heart failure. It can also exacerbate the pro-inflammatory SASP in senescent cells.

Contested

Reported half-life varies widely across sources.

The AlzDiscovery review cites a 30-minute half-life in mice; a database says clearance is rapid and half-life is not characterized in humans; a low-tier vendor page claims a 2-4 hour subcutaneous half-life with detectability up to 12 hours. Native humanin is also described as having poor stability.

Single source

Precise preclinical efficacy percentages come from one low-tier vendor page.

The specific figures (30% mitochondrial respiration increase, 30-40% neuronal death reduction, 12% lifespan increase, etc.) appear only in a single tier-3 sports-medicine vendor page and are not corroborated by the peer-reviewed sources; unusual precision without cited studies.

Limited evidence

Human dosing is entirely extrapolated, and vendor/community protocols vary.

No validated human dose exists. Vendor and community guidance ranges widely — from 0.5 mg daily starting doses to 2-10 mg subcutaneously, to allometric estimates of ~21 mg per dose — all derived from animal data, in vitro concentrations and anecdotal community use rather than trials.

Single source

One vendor internally contradicts itself on whether trials exist.

The peptide science institute source states both that 'controlled interventional trials are in early stages' and that 'controlled interventional trials giving exogenous humanin to humans are absent'; the balance of all other sources supports that no interventional human trials exist.

Using it with other compounds

Check a stack
  • MOTS-cComplementary

    May be complementary

    Both humanin and MOTS-c are mitochondrial-derived peptides ('mitokines') that signal cellular stress and improve metabolism, but they work through different downstream routes — humanin is chiefly cytoprotective/anti-apoptotic (Bax inhibition, STAT3, PI3K/Akt) while MOTS-c drives AMPK activation and Nrf2 antioxidant responses. Together they cover complementary arms of the same mitochondrial-stress response, which is why they are often discussed as a metabolic/longevity pairing.

    Tier 4Theoretical — not established

    Shares mitochondrial function · anti inflammatory

  • KlothoComplementary

    No documented conflict

    Both are endogenous 'longevity-associated' factors that reduce inflammation (NF-kB/NLRP3), improve insulin sensitivity, and modulate IGF-1/insulin signaling, but through unrelated mechanisms — klotho works via FGF23/Wnt/Nrf2 regulation while humanin acts as a mitochondrial-derived cytoprotective signal. They target overlapping healthspan endpoints from different directions.

    Tier 4Theoretical — not established

    Shares anti inflammatory · IGF1 signaling

  • SS-31Complementary

    May be complementary

    Both aim to protect mitochondria and reduce oxidative/ischemic injury, but by different means: SS-31 physically stabilizes the inner-membrane cardiolipin and electron-transport supercomplexes to preserve ATP output and cut ROS, whereas humanin signals through receptors to trigger anti-apoptotic and anti-inflammatory programs. One protects mitochondrial machinery directly, the other signals survival — a genuinely complementary combination.

    Tier 4Theoretical — not established

    Shares mitochondrial function · anti inflammatory

  • LL-37Same mechanism

    Worth caution

    Both LL-37 and humanin act on the formyl peptide receptor FPR2 and share anti-inflammatory, cytoprotective signaling. Because they engage the same receptor, combining them is more likely to be redundant (competing for the same target) than additive, so it makes more sense to choose one FPR2-directed agent rather than stack the two.

    Tier 4Theoretical — not established

    Shares anti inflammatory

  • VilonComplementary

    No documented conflict

    Humanin is a mitochondrial-derived cytoprotective 'mitokine' with anti-inflammatory and IGF-1-related signaling; Vilon is a gene-regulatory geroprotector supporting immune and metabolic function in aged tissue. They target aging through distinct mechanisms (mitochondrial stress signaling vs. chromatin/gene reactivation) that can complement each other in a longevity-oriented approach.

    Tier 4Theoretical — not established

    Shares anti inflammatory · IGF1 signaling

  • SemaglutideSame downstream effect

    Worth caution

    Both improve glucose handling and insulin sensitivity but by completely different upstream mechanisms — semaglutide is a GLP-1 receptor agonist boosting glucose-dependent insulin secretion and appetite suppression, whereas humanin is reported to improve insulin sensitivity via mitochondrial/IGF signaling. They converge on the same metabolic endpoint, which is worth monitoring if combined (watch glucose).

    Tier 4Theoretical — not established
    What the research doesn't establish
    Humanin's effects on insulin sensitivity are documented through mitochondrial biogenesis and PI3K/Akt signaling, but semaglutide's glucose-lowering action is attributed to GLP-1 receptor–driven insulin secretion; its only mitochondrial and PI3K/AKT signals come from an animal cardiotoxicity model, not its metabolic effects. A shared downstream pathway between the two has not been demonstrated.

    Shares mitochondrial function · mTOR PI3K

  • P21Same mechanism

    Worth caution

    This is a real overlap worth understanding: humanin's reported neuroprotection depends on the CNTFR-alpha/WSX-1/gp130 cytokine receptor complex acting through JAK2/STAT3 and PI3K/Akt, and P21 is a CNTF-fragment that engages the same CNTF/LIFR/gp130 receptor family and STAT3/Akt signaling. Because they converge on the same gp130/JAK-STAT machinery, combining them is more likely to be redundant than additive at that receptor, though their broader effects differ.

    Tier 4Theoretical — not established

    Shares mTOR PI3K

  • EpithalonComplementary

    No documented conflict

    Both are studied as geroprotective peptides that reduce oxidative stress and are reported to extend healthspan in animal models, but epithalon acts on telomerase/hTERT and circadian-melatonin gene regulation while humanin works through mitochondrial cytoprotection. Distinct anti-aging mechanisms with a shared longevity goal.

    Tier 4Theoretical — not established

    Shares mitochondrial function

  • HexarelinComplementary

    Worth caution

    Both peptides report cardioprotection against ischemia-reperfusion injury and anti-apoptotic effects, but by different means: hexarelin through CD36/PI3K-Akt and (theoretical) MDM2 anti-apoptotic docking, humanin as a mitochondrial 'mitokine' acting via gp130/STAT3 and PI3K/Akt survival signaling. Overlapping IGF-1 and PI3K/Akt survival pathways make them mechanistically complementary for cytoprotective goals.

    Tier 4Theoretical — not established

    Shares IGF1 signaling · anti inflammatory · mTOR PI3K

  • CerebrolysinComplementary

    No documented conflict

    Both support neuronal survival through anti-apoptotic Bcl-2-family and PI3K/Akt survival signaling, reduced neuroinflammation, and improved neuronal energy metabolism, but via different entry points — cerebrolysin supplies neurotrophic peptide fragments acting on Trk receptors, while humanin acts as a mitokine through its gp130/STAT3 cytoprotective pathway. They target overlapping neuroprotective endpoints by distinct upstream routes.

    Tier 4Theoretical — not established

    Shares mitochondrial function · anti inflammatory · mTOR PI3K · IGF1 signaling

  • DavunetideComplementary

    No documented conflict

    Both are reported neuroprotective, anti-apoptotic peptides that recruit PI-3K/Akt survival signaling, but davunetide works by stabilizing microtubules and lowering tau phosphorylation while humanin works through mitochondrial/cytokine-receptor cytoprotection. Different molecular handles converging on neuronal survival.

    Tier 4Theoretical — not established

    Shares anti inflammatory · mTOR PI3K

  • FOXO4-DRIStack with caution

    Worth caution

    FOXO4-DRI kills senescent cells specifically by activating the p53/BAX/caspase intrinsic apoptosis pathway. Humanin is a broadly cytoprotective, anti-apoptotic peptide that directly inhibits BAX and related pro-apoptotic Bcl-2 family proteins — the very machinery FOXO4-DRI relies on. In theory humanin could blunt the senolytic (apoptosis-inducing) effect, so co-dosing may reduce senescent-cell clearance.

    Tier 4Theoretical — not established

    Timing If combined, consider separating so senolytic pulses of FOXO4-DRI are not overlapped by anti-apoptotic humanin dosing.

    Shares anti inflammatory

Safety and side effects

Safety and Cautions

No human trials of exogenous humanin have been conducted, so a human safety profile has not been established. The AlzDiscovery review states endogenous humanin is a safe peptide, but that its effects can be context-dependent and may be sex-dependent, and that because clinical human testing has not been conducted, therapeutic dosing has not been established.

Cancer and dose-dependent concerns

Several sources describe a dual or potentially harmful role:

  • A review warns that excessive humanin concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure.
  • One source cautions that humanin's cytoprotective effects may protect cancer cells from apoptosis, potentially promoting tumor survival, and notes it is not FDA-approved for any medical use.
  • A study reports that nanomolar concentrations of humanin promote temozolomide resistance in glioblastoma through DNA-damage-response activation, that GBM mouse models with humanin release show accelerated blood-tumor-barrier formation via GP130 signaling, and that GP130 blockade improved chemotherapeutic efficacy.
  • A review notes humanin exerts pro-apoptotic activity of TNF-α in cancer, in contrast to its anti-apoptotic activity in other tissues.

Inflammation and senescence

A review reports that humanin and MOTS-c can exacerbate the senescence-associated secretory phenotype (SASP) in senescent cells by stimulating secretion of IL-6, IL-1β, IL-8, IL-10 and TNF-α, and that MDP cytoprotective activity may be permissive for increased proinflammatory cytokine expression.

Regulatory status

Sources state humanin is not FDA-approved for any medical use and that no interventional human safety data exist. One vendor source internally contradicts itself on whether trials exist (stating both that interventional trials are 'in early stages' and that they are 'absent'); the balance of all other sources supports that no interventional human trials exist.

Reconstitution and handling

Dosing

No dose has been established for this compound. No regulatory label or FDA approval exists for humanin, and a database and dosing guides state no validated or approved human dose exists — dosing is entirely extrapolated from animal pharmacokinetic data, in vitro bioactive concentrations, the peptide's natural age-related decline, and community experience. The figures below are what sources report, not guidance.

Preclinical / animal figures

  • A database notes preclinical studies typically use the potent analog HNG in animal models at microgram-to-milligram-per-kg doses by intermittent injection.
  • A community source reports published studies use HNG at 0.5-4 mg/kg in mice (IP or subcutaneous), typically 2-4 mg/kg IP twice weekly.
  • A rat fertility study used HNG at 5 mg/kg/day intraperitoneally for 21 days.
  • A study treated middle-aged mice with HNG twice weekly.

Extrapolated / community human figures (not from trials)

  • A community source states allometric scaling for a 70 kg human suggests roughly 0.3 mg/kg human-equivalent dose (~21 mg per dose), while community members report using 1-5 mg per injection.
  • One vendor states research studies have used doses of 2-10 mg subcutaneously and that practitioners recommend starting at 2-5 mg administered 2-3 times per week(vendor claim).
  • One vendor guide describes community protocols beginning at 0.5 mg HNG daily during Week 1, advancing to 1-2 mg if tolerated, with an 8-12 week on / 4-8 week off cycling approach and subcutaneous administration(vendor claim); it notes IV and ICV routes appear only in animal protocols.

No human trial has tested any of these regimens. Vendor material notes the analog actually sold and used is generally HNG (S14G-humanin) rather than the wild-type 24-mer(vendor claim).

Reconstitution and storage

Vendor sources describe standard peptide handling(vendor claim):

  • One vendor guide gives practical figures for a 5 mg vial reconstituted with 2 mL bacteriostatic water, yielding 2,500 mcg/mL(vendor claim) — on a U-100 insulin syringe this is 40 units for a 1 mg dose, with an injection volume of about 0.1-0.3 mL.
  • The same guide reports 28 days of storage stability after reconstitution.
  • One vendor recommends reconstituting with bacteriostatic water using insulin syringes and storing the lyophilized peptide at -20°C or colder(vendor claim).

These are calculations about vial concentration and handling, not dosing recommendations.

Sources

Ordered by evidence quality — the strongest first.

  1. The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan - PubMed(opens in a new tab)
    Tier 1Web · pubmed.ncbi.nlm.nih.gov
  2. Mitochondrial stress and mitokines in aging.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  3. Neuron-derived extracellular vesicles in blood reveal effects of exercise in Alzheimer's disease.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  4. Humanin derivative, HNG, enhances neurotransmitter release.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  5. Review article Humanin: A mitochondrial-derived peptide in the treatment of apoptosis-related diseases(opens in a new tab)
    Tier 2Web · sciencedirect.com
  6. Humanin: The Complete Guide - GLPbase(opens in a new tab)
    Tier 2Web · glpbase.com · 2026
  7. Myeloid cells coordinately induce glioma cell-intrinsic and cell-extrinsic pathways for chemoresistance via GP130 signaling.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  8. Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  9. The humanin analogue (HNG) alleviates intrauterine adhesions by inhibiting endometrial epithelial cells ferroptosis: a rat model-based study.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  10. Effect of Humanin G (HNG) on inflammation in age-related macular degeneration (AMD).(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  11. The protective effects of S14G-humanin (HNG) against mono-sodium urate (MSU) crystals- induced gouty arthritis.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  12. Humanin: A mitochondria-derived peptide with emerging properties.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  13. Mitochondrial-derived peptides in energy metabolism.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  14. Mitochondrial-Derived Peptides Exacerbate Senescence.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  15. Humanin: Functional Interfaces with IGF-I.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2016
  16. Humanin and the receptors for humanin.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2010
  17. Humanin and Humanin Analogs(opens in a new tab)
    Tier 3Web · alzdiscovery.org
  18. The role of humanin in the regulation of reproduction.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  19. The mitochondrial derived peptide humanin is a regulator of ...(opens in a new tab)
    Tier 4Web · pmc.ncbi.nlm.nih.gov
  20. Aging-associated mitochondrial circular RNAs.(opens in a new tab)
    Tier 4PubMed · pubmed.ncbi.nlm.nih.gov · 2026

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