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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' — 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. 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). 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; 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. 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. 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.

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. 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. 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

277 findings extracted from the 30 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 4 human trial findings, 19 human study findings, 29 animal findings, 2 in vitro findings, 14 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 trialAfamelanotide (Scenesse) is the FDA-approved pharmaceutical formulation with proven safety and efficacy from Phase 3 clinical trials, delivered as a controlled-release subcutaneous implant26

  • 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

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  • human studyRodent and primate data plus human observational associations indicate circulating humanin declines with age and correlates with longevity5

  • human studyCirculating humanin levels decline with age in both rodents and humans7

  • human studyHumanin levels are reduced in Alzheimer's disease and coronary artery disease7

  • human studyHumanin levels are elevated in children of centenarians7

  • human studyCirculating humanin levels decline with age in both humans and animal models8

  • human studyHigher humanin levels have been associated with longevity in observational studies8

  • human studyHumanin expression levels were downregulated in the endometria of patients with IUAs relative to controls11

  • human studyAMD plasma showed reduced Humanin protein levels compared to control plasma samples12

  • human studyAMD plasma showed higher protein levels of inflammation markers compared to control plasma samples12

  • human studyMetabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs in humans15

  • human studyResearch is limited to cell culture, animal models, and observational studies showing correlation between endogenous humanin levels and longevity in centenarian studies20

  • human studyCentenarians' offspring have higher circulating humanin levels20

  • human studyCirculating levels decline approximately 40% between ages 20 and 8025

  • human studyHuman data documents the age-related decline in circulating levels and correlations with metabolic and cognitive health25

  • human studyEndogenous circulating humanin levels decline with age, are lower in type 2 diabetes, and differ between healthy aging, Alzheimer's disease, and metabolic disease cohorts27

  • 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

  • animalOriginal 2001 PNAS discovery showed rescue of neuronal death from familial Alzheimer's mutations and amyloid-beta5

  • animalBased on in vitro and in vivo studies, HN significantly suppressed apoptosis during treatment of bone osteoporosis, cardiovascular diseases, diabetes mellitus, and neurodegenerative diseases6

  • animalHumanin levels remain stable in exceptionally long-lived naked mole-rats7

  • animalGBM mouse models recapitulating intratumoral humanin release show accelerated blood-tumor barrier (BTB) formation9

  • animalBoth systemic and intracerebroventricular (ICV) administrations of SHLP2 protected male mice from high-fat diet (HFD)-induced obesity10

  • animalSHLP2 improved insulin sensitivity in mice10

  • animalHumanin analogue (HNG) supplementation attenuated the development of endometrial fibrosis and intrauterine adhesions (IUAs)11

  • animalHNG improved fertility in rats with IUAs11

  • animalThe elevated Gait score promoted synovitis score and activated myeloperoxidase (MPO) observed in MSU crystals-treated mice were significantly reversed by colchicine and S14G-HNG13

  • animalTreatment of rodents with humanin can enhance insulin sensitivity15

  • animalTreatment of rodents with humanin can offer protection against a range of age-associated metabolic disorders15

  • animalHumanin preserves endothelial cell function in a mouse model of atherosclerosis16

  • animalHumanin improves insulin sensitivity in mouse models of type 2 diabetes16

  • animalA potent analogue of humanin blocks cardiac fibrosis in aging mice16

  • animalHumanin is effective against AD-related neuronal dysfunction in vivo in murine AD models including familial AD gene-expressing transgenic mice18

  • animalHNG improves insulin sensitivity and enhances glucose-stimulated insulin secretion21

  • animalPreclinical studies demonstrate 12% increase in median lifespan in animal models23

  • animalPreclinical studies demonstrate 25% reduction in age-related pathologies and disease burden23

  • animalMouse and rat studies show neuroprotection with reduced neuronal death in stroke and Alzheimer's models24

  • animalMouse and rat studies show improved glucose tolerance and insulin sensitivity in some studies24

  • animalMouse and rat studies show reduced ischemia-reperfusion injury24

  • animalModest lifespan increase observed in certain mouse models24

  • animalNeuroprotective effects are consistently demonstrated across multiple Alzheimer's and neurodegenerative disease animal models25

  • animalAcross rodent models, humanin or its more potent S14G analog 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 cognitive function in aged mice27

  • in vitroHumanin abolished cell death caused by familial Alzheimer's disease genes (V642I-APP, M146L-PS1, N141I-PS2) and amyloid-beta7

  • in vitroHumanin has been shown to protect cells from beta amyloid toxicity16

  • expert opinionThere are no published randomized controlled human trials of humanin or its HNG analog as a therapy5

  • expert opinionS14G-HNG has been reported to exert great anti-inflammatory effects13

  • expert opinionHumanin was initially discovered to have neuroprotective effects17

  • expert opinionNo human clinical trials exist for humanin20

  • expert opinionHumanin protects neurons from oxidative stress, inflammation, and accumulation of toxic proteins associated with neurodegenerative diseases22

  • expert opinionHumanin may protect the heart and vascular system from ischemia-reperfusion injury22

  • expert opinionHumanin improves endothelial function and reduces inflammatory markers within blood vessels22

  • expert opinionHumanin improves insulin sensitivity, glucose utilization, and lipid profiles22

  • expert opinionEndogenous Humanin has been studied as a biomarker for aging and disease, but exogenous administration has not been tested in human clinical trials24

  • expert opinionNo human clinical trials exist for exogenous administration of Humanin24

  • expert opinionControlled interventional trials are in early stages25

  • expert opinionControlled interventional trials giving exogenous humanin to humans are absent25

  • expert opinionApitegromab is positioned as the most clinically advanced selective myostatin inhibitor currently in development with an active Phase 3 program and FDA Fast Track designation26

  • expert opinionThe clinical literature on exogenous humanin in humans is nonexistent. A direct ClinicalTrials.gov query in June 2026 returned six humanin-related registered studies. All six are observational biomarker work. Zero are interventional trials of exogenous synthetic humanin or HNG at any dose, by any route, for any indication.27

  • theoreticalNo clinical applications have been validated through controlled trials8

How it works

Based on 2 human trial findings, 6 human study findings, 26 animal findings, 41 in vitro findings, 49 expert opinion findings, 2 anecdotal findings and 19 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 aging15

  • human studyHumanin plasma levels are inversely correlated with growth hormone and insulin-like growth factor 1 expression, which may promote accelerated aging16

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  • 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 has substantial mechanistic and preclinical evidence for cytoprotection, anti-apoptosis, neuroprotection and metabolic effects in cell and animal models5

  • animalHumanin administration has improved metabolic parameters, reduced inflammation, and extended healthspan in animal models8

  • animalGP130 blockade attenuates both DDR activity and BTB formation, resulting in improved preclinical chemotherapeutic efficacy9

  • animalSHLP2 is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress10

  • animalActivation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake10

  • animalSHLP2 promotes thermogenesis via POMC neuron activation10

  • animalSHLP2 binds to and activates chemokine receptor 7 (CXCR7)10

  • animalHNG contributed to regulation of endometrial fibrosis by inhibiting endometrial ferroptosis in rats with IUAs11

  • animalHumanin is a mitochondrial-derived peptide widely expressed in multiple tissues11

  • animalS14G-humanin (HNG) has a protective effect against myocardial fibrosis11

  • animalHNG significantly attenuated altered expression levels of ferroptosis-related proteins in endometria of rats with IUAs11

  • animalHumanin has cyto- or metaboloprotective properties15

  • animalHumanin protects neurons from AD-related neuronal death18

  • 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 gp13018

  • animalHumanin overexpression extends lifespan in C. elegans through daf-16/FOXO-dependent mechanisms21

  • animalHumanin provides 30-40% reduction in neuronal cell death in neurodegenerative disease models23

  • animalHumanin provides 30% reduction in synaptic loss in hippocampal neurons23

  • animalHumanin provides 40% increase in pro-survival Akt signaling pathway activation23

  • animalHumanin provides 20-30% enhancement in glucose uptake and insulin sensitivity23

  • animalHumanin demonstrates 25-50% reduction in pro-inflammatory cytokines (IL-6, TNF-α)23

  • animalHumanin demonstrates 20-35% decrease in systemic inflammatory markers23

  • animalSome preclinical experiments demonstrate insulin-sensitizing effects24

  • animalOther studies show activation of IGF-1 pathway24

  • 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 limits stress-induced apoptosis by binding pro-apoptotic proteins (BAX, Bid/Bim) and IGFBP-3 intracellularly5

  • in vitroHumanin signals extracellularly through FPR2/FPRL1 and the CNTFR/WSX-1/gp130 complex to activate JAK2/STAT3, ERK1/2 and AKT survival pathways5

  • in vitroHumanin protective effect was strictly dependent on primary structure and was found to be secreted extracellularly, acting in autocrine and paracrine fashion7

  • in vitroHumanin operates through humanin binding to trimeric cell-surface receptor complex composed of CNTFR, WSX-1, and gp1307

  • in vitroHumanin binding triggers JAK2/STAT3 signaling cascade7

  • in vitrogp130 is essential for humanin-induced neuroprotection7

  • in vitroSTAT3 activation mediates humanin's neuroprotective effects7

  • in vitroHumanin was first identified in 2001 for its ability to protect neurons from amyloid-beta (Aβ) toxicity8

  • 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 types8

  • in vitroHumanin interacts with FPRL1 (Formyl Peptide Receptor Like-1), a G-protein coupled receptor involved in inflammatory regulation and immune cell signaling8

  • 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 phosphorylation8

  • in vitroNanomolar concentrations of the signaling peptide humanin promote temozolomide (TMZ) resistance through DDR activation9

  • in vitroHumanin interaction with GBM and myeloid cells induces chemoresistance by activating GP130 receptor signaling9

  • in vitroHNG significantly attenuated erastin-induced decrease in viability of Ishikawa cell line11

  • in vitroHNG attenuated increase in reactive oxygen species production in Ishikawa cells11

  • in vitroHNG attenuated downregulation of GPX4 in Ishikawa cells11

  • in vitroHumanin G (HNG) is a Mitochondrial Derived Peptide (MDP) that is cytoprotective in AMD12

  • in vitroHumanin G can protect against mitochondrial and cellular stress induced by damaged AMD mitochondria12

  • in vitroHumanin G reduced CD62E/E-Selectin protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G reduced CD62P/P-Selectin protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G reduced ICAM-1 protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G reduced TNF-α protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G reduced MIP-1α protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G reduced IFN-γ protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G reduced IL-1β protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G reduced IL-13 protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G reduced IL-17A protein levels in AMD RPE cybrid cells12

  • in vitroHumanin G may rescue from mtDNA-mediated inflammation in AMD cybrids12

  • 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-HNG13

  • in vitroS14G-HNG treatment was accompanied by the upregulation of sirtuin type-1 (SIRT1)13

  • in vitroThe protective effects of S14G-HNG against MSU crystals-induced NLRP3 inflammasome activation were significantly abolished by the knockdown of SIRT113

  • 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 α16

  • in vitroHumanin directly prevents mitochondrial membrane permeabilization by inhibiting Bax and Bid oligomerization21

  • in vitroHumanin has demonstrated cytoprotective effects in cultured cells including protection against oxidative stress-induced cell death24

  • in vitroHumanin inhibits apoptosis in neurons in Alzheimer's disease models24

  • in vitroHumanin preserves mitochondrial function under stress conditions24

  • in vitroHumanin modulates insulin/IGF-1 signaling pathways24

  • in vitroHumanin interacts with insulin receptor and IGF-1 receptor signaling24

  • in vitroThe S14G analog (HNG) is approximately 1,000-fold more potent in cell culture models25

  • 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 ORF6

  • expert opinionHN exerts pro-apoptotic activity of TNF-α in cancer6

  • expert opinionHN exhibits anti-apoptotic activity by binding through extracellular CNTFR-α/gp130/WSX-1 trimeric receptors6

  • expert opinionHN is a small mitochondrial-derived cytoprotective polypeptide encoded by mtDNA6

  • expert opinionHN regulates mitochondrial functions under stress conditions through JAK/STAT pathway and interaction with BCL-2 family of proteins6

  • expert opinionHumanin is the first newly discovered peptide encoded in the mitochondrial genome in over three decades17

  • expert opinionHumanin is the first member of a novel class of mitochondrial derived peptides17

  • expert opinionHumanin is a small, 24 amino acid peptide17

  • expert opinionHumanin binds IGFBP-317

  • expert opinionHumanin decreases circulating IGF-I levels17

  • expert opinionIGF-I regulates humanin levels17

  • expert opinionHumanin is a new player in IGF-I signaling17

  • expert opinionHumanin is a mitochondrial derived peptide that has cytoprotective properties19

  • expert opinionHumanin and analogs protect neurons by increasing their resilience to a variety of cell stressors and can inhibit toxic Aβ oligomerization19

  • expert opinionHumanin promotes insulin sensitivity and metabolic adaptions following exercise19

  • expert opinionHumanin is encoded by a small open reading frame within the 16S rRNA (MT-RNR2)19

  • expert opinionWhen translated in the mitochondria, the peptide is 21 amino acids long, and 24 amino acids long when translated in the cytoplasm19

  • expert opinionThere are 13 humanin-like open reading frames found in the nuclear genome (MTRNR2L#)19

  • expert opinionHumanin is produced in response to cellular stress and has cytoprotective activities both intracellularly and extracellularly19

  • expert opinionHumanin can influence a variety of signaling pathways including JAK2, STAT3, MAPKs, and JNK19

  • 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 gp13019

  • expert opinionHumanin can influence cellular bioenergetics by altering mitochondrial activity19

  • expert opinionS14G-HN (HNG) is a humanin analog where the serine at position 14 is substituted for a glycine19

  • expert opinionHNG is 1000 times more potent than humanin in activating the humanin heterotrimeric receptor19

  • expert opinionHNGF6A contains the S14G substitution to increase potency as well as a substitution of an alanine in place of the phenylalanine at position 619

  • expert opinionHNGF6A is more potent at modulating insulin action19

  • expert opinionColivelin is the most potent humanin derivative developed to date and shows neuroprotective activity at the fM range19

  • expert opinionColivelin is 10^3 to 10^7 more potent than humanin and other humanin analogs19

  • expert opinionHumanin is one of the three major mitochondrial-derived peptides along with MOTS-c and SHLP peptides20

  • expert opinionHumanin is a 24-amino acid mitochondrial-derived peptide originally discovered in 2001 as a factor protecting neurons from Alzheimer's disease-related cell death21

  • expert opinionHumanin is a mitochondrial-derived peptide encoded by a short open reading frame in the mitochondrial 16S ribosomal RNA gene22

  • expert opinionHumanin-G (HNG) contains a glycine substitution that enhances its stability and biological activity22

  • expert opinionHumanin inhibits pro-apoptotic proteins, particularly those in the Bcl-2 family22

  • expert opinionHumanin activates the PI3K/Akt pathway to promote cell survival and growth22

  • expert opinionHumanin enhances mitochondrial biogenesis and improves energy metabolism22

  • expert opinionHumanin is encoded by mitochondrial DNA (16S rRNA gene) and represents the first identified mitochondrial-derived peptide with systemic biological activity23

  • expert opinionHumanin is a 24-amino acid peptide encoded in the mitochondrial genome (specifically in the 16S rRNA region) and naturally produced in human cells24

  • expert opinionHumanin is a 24-amino-acid cytoprotective peptide encoded by the mitochondrial 16S rRNA gene25

  • expert opinionApitegromab represents a clear advancement over ACE-031 in myostatin pathway therapeutics with selective targeting that addresses vascular toxicity issues26

  • expert opinionAfamelanotide and melanotan-1 are the same molecule (Nle4-D-Phe7-alpha-MSH) with different names, regulatory statuses, and delivery systems26

  • expert opinionHumanin is a 24-amino-acid peptide encoded inside the mitochondrial 16S ribosomal RNA gene (MT-RNR2)27

  • expert opinionHumanin was discovered in 2001 by the Nishimoto group in Tokyo through a functional screen for factors that rescue neurons from familial Alzheimer's disease toxicity27

  • expert opinionHumanin engages two separate cell-surface receptor systems (FPR2/FPR3 and the heterotrimeric CNTFR-alpha/WSX-1/gp130 cytokine receptor complex)27

  • expert opinionHumanin 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 permeabilization27

  • expert opinionHumanin sequence: M-A-P-R-G-F-S-C-L-L-L-L-T-S-E-I-D-L-P-V-K-R-R-A27

  • expert opinionHumanin is a mitochondria-derived peptide28

  • expert opinionHumanin exerts protective function in many tissues, especially in nervous tissues28

  • 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 pathways28

  • anecdotalS14G-humanin (HNG) analog is approximately 1000-fold more potent than native humanin20

  • anecdotalNative humanin is 1,000x weaker than HNG (S14G-humanin)21

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

  • theoreticalHumanin is a 24-amino-acid mitochondrial-derived peptide5

  • theoreticalEngineered analogs such as HNG were developed for greater stability and potency5

  • theoreticalHumanin is a 24-amino acid mitochondrial-derived peptide with sequence MAPRGFSCLLLLTSEIDLPVKRRA and molecular weight of approximately 2,687 Da7

  • theoreticalHumanin is encoded by short open reading frame within mitochondrial 16S ribosomal RNA gene (MT-RNR2)7

  • theoreticalHumanin is a 24-amino-acid peptide encoded by mitochondrial DNA, specifically the MT-RNR2 gene within the 16S ribosomal RNA region8

  • theoreticalHumanin belongs to a class of molecules known as mitochondria-derived peptides (MDPs)8

  • theoreticalS14G-humanin (S14G-HNG) is a modified peptide of HNG with higher inhibitory activity on the accumulation and deposition of Aβ13

  • theoreticalHumanin is a mitochondrial-derived peptide encoded by the 16S ribosomal RNA gene15

  • 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 stress15

  • 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 conditions16

  • theoreticalThe cytoprotective activity of MDPs may be permissive for increased expression of a set of proinflammatory cytokines16

  • theoreticalEndogenous Humanin may suppress the onset of AD-related dementia by inhibiting both AD-related neuronal cell death and dysfunction18

  • theoreticalHumanin activates mitochondrial optimization pathways, leading to 30% increase in mitochondrial respiration rates and ATP production23

  • theoreticalHumanin provides cytoprotection through STAT3 receptor signaling25

  • theoreticalHumanin provides cytoprotection through IGFBP-3 binding25

  • theoreticalHumanin provides cytoprotection through direct Bax interaction25

  • theoreticalHumanin binds the CNTFR/WSX-1/gp130 trimeric receptor complex, activating STAT3 signaling25

  • theoreticalHumanin binds Bax itself, preventing mitochondrial outer membrane permeabilization and cytochrome c release25

Dosing

Based on 3 animal findings, 8 expert opinion findings, 2 anecdotal findings and 1 theoretical finding.

  • animalPreclinical studies typically use the potent analog HNG (S14G-humanin) in animal models (e.g., microgram-to-milligram-per-kg, intermittent injection)5

  • animalPublished studies use HNG at doses of 0.5-4 mg/kg in mice, administered IP or SubQ20

  • animalMouse studies typically use HNG at 2-4 mg/kg IP twice weekly20

  • expert opinionNo validated or approved human dose exists for humanin5

  • expert opinionClinical human testing has not been conducted, and therapeutic dosing has not been established19

  • expert opinionDosing is entirely extrapolated from animal pharmacokinetic data, in vitro bioactive concentrations, the peptide's natural age-related decline, and community experience21

  • expert opinion8-12 week on / 4-8 week off cycling approach is conservative given the complete absence of human clinical trial data21

  • expert opinionResearch studies have typically used doses ranging from 2-10 mg administered subcutaneously22

Show the remaining 6

  • expert opinionFor general health optimization, practitioners recommend starting with 2-5 mg administered 2-3 times per week22

  • expert opinionHumanin can be administered subcutaneously using insulin syringes22

  • expert opinionHumanin should be reconstituted with bacteriostatic water22

  • anecdotalCommunity uses 1-5 mg per injection20

  • anecdotalCommunity protocols typically begin at 0.5 mg HNG daily during Week 1, advancing to 1–2 mg if well-tolerated21

  • theoreticalFor a 70 kg human, allometric scaling suggests approximately 0.3 mg/kg HED, or roughly 21 mg per dose20

How the body handles it

Based on 1 animal finding, 1 in vitro finding, 5 expert opinion findings and 1 theoretical finding.

  • animalS14G-HN and AGA-HNG are analogs studied in preclinical models24

  • in vitroS14G-humanin analog (HNG) exhibits approximately 1,000-fold greater potency than native humanin7

  • expert opinionHumanin half-life not formally characterized in humans5

  • expert opinionHNGF6A has superior stability and pharmacokinetics relative to IGFBP-3 binding analogs19

  • expert opinionHumanin is metabolized through standard peptide degradation pathways with excellent tissue distribution, and demonstrates detectability up to 12 hours post-administration using specialized analytical methods23

  • expert opinionNative Humanin is a 24-amino acid peptide with poor stability and bioavailability24

  • expert opinionHNG (Humanin-G) is an analog with better stability from Gly substitution24

  • theoreticalNative humanin is reported to clear rapidly5

Safety and side effects

Based on 1 human study finding, 5 expert opinion findings, 1 anecdotal finding and 2 theoretical findings.

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

  • expert opinionHumanin has no regulatory approval5

  • expert opinionEndogenous humanin is a safe peptide, but its effects can be context dependent, and may be sex dependent19

  • expert opinionNo human clinical trials exist for exogenous humanin/HNG supplementation21

  • expert opinionHumanin is not FDA-approved for any medical use24

  • expert opinionThere is no published Phase 1 first-in-human safety study. There is no FDA approval.27

  • anecdotalThe first public dataset of anecdotal peptide side-effect reports, aggregated from Reddit, research forums, and anonymous user submissions26

  • theoreticalNo human intervention trials have been completed8

Show the remaining 1

  • theoreticalHumanin's cytoprotective effects may protect cancer cells from apoptosis, potentially promoting tumor survival24

What people use it for

Based on 4 human study findings, 4 animal findings, 11 expert opinion findings and 2 anecdotal 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 studyObservational human biomarker associations link endogenous humanin levels to aging and longevity in centenarian offspring and cognitive aging5

  • human studyHumanin levels decline with age19

  • animalSHLP2 has therapeutic potential in metabolic disorders10

  • animalS14G-HNG could possess potential benefits against MSU crystals-induced gout arthritis, with colchicine displaying a better effect13

  • animalHumanin has shown beneficial effects in diverse disease models including stroke, cardiovascular disease, and cancer17

  • animalIV and ICV routes appear only in animal study protocols21

Show the remaining 13

  • expert opinionHN protects cells against various diseases, including diabetes mellitus, cardiovascular, and neurodegenerative diseases6

  • expert opinionHN exhibits protective effects in leukocytes, germ cells, neurons, and tissues against cellular stress conditions and apoptosis6

  • expert opinionHumanin influences metabolism, promotes insulin sensitivity, and prolongs healthspan19

  • expert opinionMaintenance of humanin levels may prolong healthspan19

  • expert opinionHumanin may protect against ischemic cardiovascular damage19

  • expert opinionHumanin was discovered in neurons that survived Alzheimer's disease pathology25

  • expert opinionHumanin was discovered in 2001 in a functional screen for survival factors in neurons that resisted Alzheimer's disease-related cell death25

  • expert opinionHumanin has potential as a novel therapeutic approach for male infertility28

  • expert opinionHumanin has potential as a novel therapeutic approach for male contraception28

  • expert opinionHumanin has potential as a novel therapeutic approach for female infertility28

  • expert opinionHumanin has potential for glucose metabolism in polycystic ovary syndrome28

  • anecdotalHNG (S14G-humanin) is most commonly used analog21

  • anecdotalSubcutaneous administration is the route documented in community sources21

Other findings

Based on 1 human study finding, 9 expert opinion findings and 1 theoretical finding.

  • human studyHumanin was discovered in 2001 through functional expression screening of cDNA library from Alzheimer's disease patient occipital lobe7

  • expert opinionHN was initially discovered in 2001 by Hashimoto using a cDNA library from healthy brain tissue of an Alzheimer's patient6

  • expert opinionHumanin is a 24-amino acid peptide that was first discovered in the brain tissue of patients with Alzheimer's disease22

  • expert opinionHumanin shows a natural decline with age22

  • expert opinionHumanin is found naturally in various tissues including the brain, heart, liver, and skeletal muscle22

  • expert opinionIn lyophilized form, Humanin should be stored at -20°C or colder22

  • expert opinionHumanin is a naturally occurring 24-amino acid mitochondrial-derived peptide (MDP) first identified in the brains of Alzheimer's disease patients as a survival factor against amyloid-beta toxicity23

  • expert opinion255 published studies including 17 human studies and 137 animal studies25

Show the remaining 3

  • expert opinionPeptide Protocol Wiki is a comprehensive peptide research database featuring 133+ evidence-based peptide profiles with dosing protocols, mechanism of action breakdowns, and clinical research summaries26

  • expert opinionHumanin is sold by research-peptide suppliers, almost always as the more potent S14G analog (HNG) rather than the wild-type 24-mer27

  • theoreticalHumanin is a 24-amino-acid bioactive peptide18

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

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish them as mitochondrial-derived peptides (mitokines) with distinct but complementary pathways. Humanin targets anti-apoptotic Bcl-2 family members and activates JAK2/STAT3 and PI3K/Akt, while MOTS-c activates AMPK and the Keap1-Nrf2 antioxidant axis. Both are explicitly tagged with mitochondrial_function and anti_inflammatory in their approved tags. The mechanisms support the claim of complementary action: humanin's cytoprotection via apoptosis inhibition and STAT3 signaling differs from MOTS-c's AMPK-driven metabolic remodeling and Nrf2-mediated antioxidant stress response. Both improve insulin sensitivity and glucose metabolism through different routes, and both are described as mitokines signaling cellular/mitochondrial stress. The shared dimensions (mitochondrial_function, anti_inflammatory) are directly supported by the tagged attributes and mechanism descriptions, and the explanation accurately reflects the distinct downstream pathways documented in each peptide's mechanism material.

    Shares mitochondrial function · anti inflammatory

  • 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 fully establish

    While both peptides have approved tags for 'mitochondrial_function' and 'mTOR_PI3K', the mechanism descriptions do not establish that they share these downstream pathways. For humanin, mitochondrial_function and mTOR_PI3K are explicitly documented (enhanced mitochondrial biogenesis, PI3K/Akt pathway). For semaglutide, the mechanisms show only BNIP3-mediated mitochondrial signaling in an animal cardiotoxicity model and PI3K/AKT in that same context—neither is presented as a primary or established pathway for semaglutide's glucose/metabolic effects. The explanation correctly identifies different upstream mechanisms (GLP-1 receptor vs. mitochondrial/IGF signaling) but does not demonstrate convergence on the same documented downstream pathways. The shared tags alone do not justify 'same_downstream' without explicit mechanistic overlap in the descriptions provided.

    Shares mitochondrial function · mTOR PI3K

  • 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

    What the research doesn't fully establish

    Both peptides' mechanisms clearly support the complementary relationship with the claimed shared dimensions. The mechanism material explicitly establishes: (1) Both target mitochondrial_function—SS-31 directly stabilizes cardiolipin, cristae, and ETC supercomplexes to preserve ATP and reduce ROS; humanin enhances mitochondrial biogenesis and bioenergetics. (2) Both target anti_inflammatory—SS-31 modulates inflammation/pyroptosis; humanin reduces pro-inflammatory cytokines via JAK2/STAT3 and SIRT1. (3) The explanation accurately characterizes their distinct mechanisms: SS-31 acts through direct physical stabilization of inner-membrane structures and oxidative phosphorylation, while humanin acts through receptor signaling (FPR2/FPR3, gp130) to trigger cytoprotection and anti-apoptotic programs. These are genuinely different mechanistic approaches (direct structural vs. signaling-mediated) that converge on shared protective outcomes, meeting the definition of complementarity. The mechanisms do not contradict this relationship; they substantiate it.

    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

    What the research doesn't fully establish

    The mechanism descriptions clearly establish that both LL-37 and humanin target FPR2 (formyl peptide receptor 2). LL-37 is described as targeting 'FPR2 (formyl peptide receptor 2)' and humanin targets 'Formyl peptide receptors FPR2/FPR3 (FPRL1)'. Both peptides are also documented to have anti-inflammatory effects: LL-37 shows 'Immunomodulation (both anti- and pro-inflammatory)' with anti_inflammatory tag, and humanin shows 'Anti-inflammatory / reduced pro-inflammatory cytokines (reported)' with anti_inflammatory tag. The shared dimension of anti-inflammatory activity combined with the documented shared FPR2 receptor target justifies the 'same_mechanism' relationship type and the reasoning that they may compete for the same receptor, making them potentially redundant rather than additive.

    Shares anti inflammatory

  • 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

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish convergence on shared signaling pathways. Humanin targets the CNTFR-alpha/WSX-1/gp130 heterotrimeric complex and activates JAK2/STAT3 and PI3K/Akt pathways. P21, as a CNTF fragment, targets the CNTF receptor complex (CNTFR-alpha/LIFR/gp130) and activates JAK/STAT (STAT3) and PI3K/Akt pathways. Both mechanisms explicitly document gp130 engagement and both activate PI3K/Akt signaling. The proposed shared dimension (mTOR_PI3K) is directly supported by both peptides' documented PI3K/Akt pathway activation. The explanation correctly identifies the convergence on gp130/JAK-STAT machinery as a basis for potential redundancy. This is a mechanistically justified relationship based on the provided descriptions.

    Shares mTOR PI3K

  • 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

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish the claimed shared dimensions. Anti-inflammatory: Humanin shows anti-inflammatory/reduced pro-inflammatory cytokines effects; Klotho explicitly targets NLRP3 inflammasome and NF-κB signaling with anti-inflammatory activity. IGF1_signaling: Both mechanisms explicitly list IGF-1/insulin signaling as a pathway (humanin: IGF-I signaling; klotho: IGF-1/insulin signaling axis). The proposed relationship as 'complementary' is well-justified by the mechanisms: they share these two functional dimensions but achieve them through distinct molecular pathways (humanin via mitochondrial stress signaling/JAK2/STAT3/PI3K-Akt; klotho via FGF23/FGFR1c/TGF-β/Wnt/Nrf2). Both are described as endogenous longevity-associated factors with overlapping healthspan effects (insulin sensitivity, anti-inflammatory, anti-oxidative stress), supporting the 'complementary' characterization of targeting similar endpoints through different mechanisms.

    Shares anti inflammatory · IGF1 signaling

  • 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

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish the two claimed shared dimensions: (1) Anti-inflammatory: Vilon suppresses IL-1β/IL-6/TNF-α cytokines in vitro and is tagged anti_inflammatory; Humanin reduces pro-inflammatory cytokines and is tagged anti_inflammatory. (2) IGF1_signaling: Vilon modulates IGF1/FOXO1 gene expression and is tagged IGF1_signaling; Humanin engages IGF-I signaling and is tagged IGF1_signaling. The proposed relationship type (complementary) is justified: the mechanisms describe distinct pathways—Vilon acts via chromatin remodeling and gene reactivation (receptor-independent, DNA-binding), while Humanin acts via cell-surface receptors (FPR2/FPR3, gp130) and intracellular anti-apoptotic targets (Bax, Bid/Bim)—that converge on shared anti-inflammatory and IGF1 outcomes relevant to aging. The explanation accurately reflects both mechanisms' descriptions and their potential synergy in addressing age-related dysfunction.

    Shares anti inflammatory · IGF1 signaling

  • 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

    What the research doesn't fully establish

    Both peptides' mechanisms support a complementary relationship focused on mitochondrial_function and geroprotection. Humanin is explicitly described as a 'mitokine' encoded in the mitochondrial genome that enhances mitochondrial biogenesis/bioenergetics and has approved tag 'mitochondrial_function.' Epithalon has the same approved tag 'mitochondrial_function' and includes antioxidant/mitochondrial ROS modulation in its pathways. Both are reported to extend lifespan/healthspan in animal models through distinct mechanisms—humanin via direct mitochondrial cytoprotection and anti-apoptosis, epithalon via telomerase activation and circadian-melatonin restoration. The explanation accurately characterizes these as complementary (non-overlapping but synergistic) approaches to geroprotection that both address mitochondrial function and oxidative stress, justifying the proposed relationship and shared dimension.

    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

    What the research doesn't fully establish

    Both peptides' mechanisms clearly establish the three claimed shared dimensions: (1) IGF1_signaling is explicitly listed in approved tags for both; (2) anti_inflammatory is documented for both (hexarelin via NLRP3/NF-κB suppression, humanin via reduced pro-inflammatory cytokines); (3) mTOR_PI3K is approved for both. The explanation correctly identifies mechanistic complementarity: hexarelin activates PI3K/Akt via CD36 and theoretical MDM2 anti-apoptotic pathways, while humanin activates PI3K/Akt via gp130/STAT3 and mitochondrial signaling. Both demonstrate cardioprotection against ischemia-reperfusion injury and anti-apoptotic effects through distinct upstream mechanisms converging on shared survival pathways (PI3K/Akt, IGF-1 signaling). The proposed relationship type 'complementary' is well-justified by the mechanisms: they achieve overlapping cytoprotective outcomes through different receptor systems and upstream pathways, making them mechanistically distinct but functionally aligned.

    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

    What the research doesn't fully establish

    The mechanisms clearly establish complementary action on shared dimensions. Both peptides demonstrate: (1) mitochondrial_function—humanin explicitly acts as a 'mitokine' enhancing mitochondrial biogenesis/bioenergetics, cerebrolysin improves neuronal energy metabolism; (2) anti_inflammatory—humanin reduces pro-inflammatory cytokines via JAK2/STAT3, cerebrolysin modulates microglia and downregulates TNF-α; (3) mTOR_PI3K—both activate PI3K/Akt survival signaling (humanin directly, cerebrolysin via NTF pathway); (4) IGF1_signaling—humanin engages IGF-I signaling and IGFBP-3, cerebrolysin upregulates IGF-1. The proposed explanation accurately reflects the mechanisms: both converge on anti-apoptotic Bcl-2 family modulation and neuronal survival but via distinct upstream routes (humanin through gp130/STAT3 cytoprotection as a mitokine; cerebrolysin through Trk receptor-mediated neurotrophic factor mimicry). The shared dimensions are explicitly supported by the provided mechanism material, and the complementary relationship is justified by their different entry points achieving overlapping neuroprotective endpoints.

    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

    What the research doesn't fully establish

    Both peptides' mechanisms clearly support the proposed complementary relationship with the shared dimensions of anti_inflammatory and mTOR_PI3K. Humanin is explicitly tagged with both dimensions and described as activating PI3K/Akt signaling with anti-inflammatory effects. Davunetide is also explicitly tagged with both dimensions and described as recruiting PI3K/Akt pathway signaling with anti-inflammatory activity. The explanation accurately characterizes their distinct molecular mechanisms (humanin via mitochondrial/cytokine signaling; davunetide via microtubule stabilization and tau regulation) that converge on shared downstream survival pathways. Both are reported as neuroprotective and anti-apoptotic. The mechanisms do not contradict this relationship—they support it as complementary approaches to neuronal protection through different upstream targets but overlapping downstream signaling (PI3K/Akt, anti-inflammatory effects).

    Shares anti inflammatory · mTOR PI3K

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.
  • 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; 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.

Reconstitution and storage

Vendor sources describe standard peptide handling:

  • One vendor guide gives practical figures for a 5 mg vial reconstituted with 2 mL bacteriostatic water, yielding 2,500 mcg/mL — 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.

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. Humanin: Mechanism, Status, Dose Reference & Half-Life | PeptideStat(opens in a new tab)
    Tier 2Web · peptidestat.com
  6. Review article Humanin: A mitochondrial-derived peptide in the treatment of apoptosis-related diseases(opens in a new tab)
    Tier 2Web · sciencedirect.com
  7. Humanin: Research Evidence & Safety Profile | PeptideInsight(opens in a new tab)
    Tier 2Web · peptideinsight.com · 2026
  8. Humanin: The Complete Guide - GLPbase(opens in a new tab)
    Tier 2Web · glpbase.com · 2026
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. Humanin: A mitochondria-derived peptide with emerging properties.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  15. Mitochondrial-derived peptides in energy metabolism.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  16. Mitochondrial-Derived Peptides Exacerbate Senescence.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  17. Humanin: Functional Interfaces with IGF-I.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2016
  18. Humanin and the receptors for humanin.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2010
  19. Humanin and Humanin Analogs(opens in a new tab)
    Tier 3Web · alzdiscovery.org
  20. Humanin Community Protocols & Anecdotal Reports | Peptide Protocol Wiki(opens in a new tab)
    Tier 3Web · peptideprotocolwiki.com
  21. Humanin Dosage Chart: 0.5-2mg HNG Daily Protocol (2026)(opens in a new tab)
    Tier 3Web · thepeptidecatalog.com
  22. Humanin Dosage, Mechanism & Benefits - Online Peptide Calculator(opens in a new tab)
    Tier 3Web · peptidecalculatorapp.com
  23. Humanin Peptide | Energy & Healthy Aging(opens in a new tab)
    Tier 3Web · paragonsportsmedicine.com
  24. Humanin Safety: Side Effects & Risks (2026 Review) | PepCodex(opens in a new tab)
    Tier 3Web · pepcodex.com
  25. Humanin: Research Overview, Evidence & Mechanism | PSI(opens in a new tab)
    Tier 3Web · peptidescienceinstitute.org
  26. Peptide Protocol Wiki — Evidence-Based Peptide Research Database(opens in a new tab)
    Tier 3Web · peptideprotocolwiki.com
  27. Humanin Peptide Guide 2026: Mitochondrial Cytoprotection(opens in a new tab)
    Tier 3Web · thepeptidetoolkit.com · 2026
  28. The role of humanin in the regulation of reproduction.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  29. The mitochondrial derived peptide humanin is a regulator of ...(opens in a new tab)
    Tier 4Web · pmc.ncbi.nlm.nih.gov
  30. Aging-associated mitochondrial circular RNAs.(opens in a new tab)
    Tier 4PubMed · pubmed.ncbi.nlm.nih.gov · 2026