Humanin is a mitochondrial-derived peptide (MDP). In 2001, Hashimoto et al. pulled a short open reading frame from an Alzheimer's disease occipital-lobe cDNA library and showed that the encoded peptide could stop neuronal death from familial Alzheimer's genes and from amyloid-beta in culture. Later rodent papers tested insulin-clamp pharmacology and age-related cognition. Human data in the papers used here are circulating-level associations and a mitochondrial SNP correlation. They are not a human efficacy trial of exogenous Humanin.
That is the whole claim. A dish rescue, a mouse rotarod, a rat clamp, and a plasma ELISA are not a treatment result in people. Research-vendor vials are not the peptides used in those papers.
PeptidePrices already tracks Humanin listings and a short research profile. This explainer is the evidence map those pages do not carry: what the peptide is, which study designs exist, what the numbers actually measured, and where the human gap still sits.
What Humanin is
Hashimoto, Niikura, Tajima, and colleagues (PNAS, 22 May 2001, PMID 11371646) named the molecule Humanin after a 75-base ORF that encodes a 24-residue peptide, MAPRGFSCLLLLTSEIDLPVKRRA. The library came from the occipital cortex of an Alzheimer's disease patient. NCBI title lookup matches that record.
Muzumdar et al. (PLoS ONE, 2009) describe Humanin as transcribed from an open reading frame within mitochondrial 16S ribosomal RNA (MT-RNR2) and give the same 24-residue sequence at 2656.3 Da. They also report a rodent homolog (rattin) in muscle, liver, and hypothalamus, not epididymal fat. Those are sequence and tissue-detection statements. They are not a drug label.
HNG is the S14G analog. In Hashimoto's F11-cell titration, synthetic Humanin reached complete suppression of V642I-APP death at 1 to 10 μM, while S14G (sHNG) was fully protective at 10 nM. Muzumdar et al. later wrote that the S14G change increases biologic potency by about 1,000-fold. C8A (sHNA) failed at 100 μM in the discovery paper. Those concentration gaps are culture pharmacology. They are not an approved potency claim.
Humanin is not SS-31 (elamipretide) and not MOTS-c. Sharing a mitochondria conversation is not sharing a molecule. Yen et al. 2018 mention a MOTS-c longevity SNP only as MDP-genetics background. That is not a Humanin result.
| Thing | What it is | What a paper can show |
|---|---|---|
| Endogenous Humanin | A short peptide from a mitochondrial 16S rRNA ORF | Tissue or plasma detection, age or ancestry associations |
| Synthetic Humanin / HNG / HNGF6A | Laboratory analogs, including S14G and F6A substitutions | Culture death assays, rodent clamps, rodent cognition |
| Research-vendor vial | A catalog chemical sold as Humanin | Paperwork and listed milligrams, not a trial product |
A COA check can test whether a certificate names a real lab. It cannot turn a catalog vial into the Hashimoto peptide or the HNG used in Yen 2018. Humanin is not FDA-approved for any indication. It is not a consumer protocol.
How the proposed mechanism works, and where it stops
The discovery paper is a death-trap screen. Hashimoto et al. transfected F11/EcR cells with an occipital-cortex cDNA library, challenged them with inducible V642I-APP, and recovered surviving plasmids. The 24-residue ORF was the active fragment. Transfected Humanin was secreted. Synthetic peptide reproduced the rescue.
In that system, 10 μM synthetic Humanin and 10 nM sHNG blocked cytotoxicity from V642I-APP, M146L-PS1, and N141I-PS2 without changing expression of those products. In primary cortical neurons, 25 μM Aβ1-43 caused death and dystrophic neurites. 10 μM synthetic Humanin returned mortality and LDH toward baseline. 10 nM sHNG protected. 10 nM wild-type peptide and 10 μM C8A did not. Humanin did not block death from Q79, SOD1 mutants, etoposide, or Fas. The authors argued against simple Aβ binding: effective HNG was three to four orders of magnitude below toxic Aβ, and Humanin still blocked FAD-gene death in F11 cells that Aβ peptides do not kill. That is a culture-mechanism limit, not proof of an Alzheimer's drug.
Gong et al. (Journal of Cell Biology, 2018, PMID 29187525) added an autophagy path. Humanin localized to the cytosolic face of lysosomes, interacted with HSP90, and stabilized HSP90 binding to chaperone-mediated autophagy (CMA) substrates. 20 μM HNG raised long-lived protein degradation. CMA reporter puncta rose at or below 10 μM HNG. The increase disappeared in LAMP-2A knockdown cells. Macroautophagy (LC3-II) did not explain the effect. This is a dish mechanism, not an in-vivo efficacy trial.
Price et al. (Biochemistry, 2020, PMID 32383868) showed Humanin blocked acetylcholinesterase-induced Aβ aggregation in vitro, and that IGFBP-3 abolished that block. Muzumdar et al. put IGFBP-3 on the metabolic side. F6A reduces IGFBP-3 binding. HNGF6A (S14G plus F6A) was the IV-active clamp peptide.
What the studies actually tested
Four independent primary papers define the public map. Three supporting papers add rat Aβ behavior, astrocyte release, and in-vitro aggregation.
Hashimoto et al., PNAS, 2001. Discovery and culture rescue: occipital AD cDNA, 24-residue ORF, FAD-gene and Aβ1-43 protection, S14G gain of potency, C8A loss of function, no rescue of Q79, SOD1, etoposide, or Fas. Human material was a cDNA library, not a treated patient.
Muzumdar et al., PLoS ONE, 2009. Independent rat pharmacology plus observational circulating-level work. 92 three-month male Sprague-Dawley rats and 9 Zucker diabetic fatty (ZDF) rats. Intracerebroventricular Humanin (20 μg total; 0.16 μg/kg/min in the basal-clamp figure) raised glucose infusion rate by lowering hepatic glucose production and, under hyperinsulinemic clamps, raising peripheral glucose uptake. Dimerization-deficient Humanin did nothing. Hypothalamic STAT-3 phosphorylation rose about 10-fold within an hour. A STAT-3 inhibitor abolished the clamp effect. Native Humanin or F6AHN at 0.375 mg/kg/hr IV did not significantly change insulin action at that dose. HNGF6A at 0.05 mg/kg/hr IV did. A 100 μg HNGF6A IV bolus in ZDF rats (baseline glucose 293.1 ± 18.7 mg/dL, n = 4) lowered glucose by nearly 50% over 4 hours, from about 90 minutes. Plasma Humanin fell with age in mice and in humans (ELISA, p < 0.05). Skeletal-muscle rattin was lower in old rats. Hypothalamic rattin only trended down (p = 0.12). Rodent pharmacology plus an age association is not a human trial of exogenous Humanin.
Yen et al., Scientific Reports, 2018 (PMID 30242290, DOI 10.1038/s41598-018-32616-7, article 14212). NCBI title lookup matches that record. The DOI is not 10.1038/s41598-018-32418-x, an unrelated paraspinal-muscle myotonometer paper (PMID 30254233). Eighteen-month female C57BL/6N mice received HNG 4 mg/kg intraperitoneal twice weekly or vehicle (100 mice at start). At 24 months, HNG mice stayed on a rotarod longer (N = 24 control, 23 HNG). At 28 months the rotarod gap was not significant. Barnes maze improved in a subset (N = 7 control, 8 HNG). Y-maze spontaneous alternation improved (N = 10/group). Dentate gyrus BrdU and doublecortin counts at about 32 months did not differ (n = 6 control, 8 HNG). Activated Iba1 microglia fell. Mouse HNG treatment is not human efficacy.
The same paper's human arms are associations. In BVAIT, 71 African-American and 75 Caucasian-American participants (age ≥40) had plasma Humanin measured. Mean circulating Humanin was nearly 20% lower in the African-American group (p < 0.05). Mitochondrial SNP rs2854128, a synonymous stop-codon change (TAA to TAG), was associated with a 14% decrease in circulating Humanin (p < 0.05). In the Health and Retirement Study, the alternate allele was associated with older cognitive age (p < 0.05) after adjustment for sex, education, and race. The race-by-SNP interaction was significant (p = 0.005): about two years older cognitive age among African-American carriers and about 0.2 years among Caucasian-American carriers. The authors called the human findings correlative.
Gong et al., Journal of Cell Biology, 2018. CMA activation through HSP90 in fibroblasts, cardiomyoblasts, neuronal cells, and primary cardiomyocytes. Protective effects against stressors were lost in CMA-deficient cells.
Chai et al., Neuroscience Bulletin, 2014 (PMID 25391447). The fetched PMC record is abstract-complete. Humanin increased dendritic branches and spine density, raised synaptic proteins, enhanced LTP, and improved Aβ1-42 memory deficits, with less tau hyperphosphorylation via PP2A. Rat Aβ-injection phenotypes. The dose is not restated because the fetched HTML omitted the methods table.
Zárate et al., Frontiers in Aging Neuroscience, 2019 (PMID 31214013). Ovariectomized rats had lower CA1 Humanin immunoreactivity. Estradiol plus progesterone doubled Humanin in astrocyte-conditioned media. After a 3-minute 5 μM glutamate pulse, 0.01 to 1 μM Humanin for 24 hours prevented dendritic atrophy and synaptophysin puncta loss without changing MTT viability.
| Paper | Design | Human exogenous Humanin |
|---|---|---|
| Hashimoto 2001, PNAS | Culture rescue of FAD genes and Aβ1-43 | None. Human material was a cDNA library. |
| Muzumdar 2009, PLoS ONE | Rat clamps, ZDF bolus, age ELISA | None as a drug. Human arm is circulating HN vs age. |
| Yen 2018, Sci Rep | Aged-mouse HNG; plasma HN; rs2854128 | None as a drug. Human arms are associations. |
| Gong 2018, J Cell Biol | Culture CMA | None |
| Chai 2014, Neurosci Bull | Rat Aβ1-42 (abstract) | None |
| Zárate 2019, Front Aging Neurosci | OVX rats; glutamate synapses | None |
| Price 2020, Biochemistry | In-vitro Aβ aggregation | None |
A registered interventional human efficacy trial of exogenous Humanin was not identified in the evidence review for this article.
Research doses reported in animals and culture
Humanin and HNG are not approved for human use. The table reports what laboratories used. It is not a dosage guide and it is not a consumer protocol.
| Setting | Reported exposure | Source |
|---|---|---|
| F11 cells, FAD-gene death | Synthetic HN complete at 1-10 μM; sHNG complete at 10 nM; C8A failed at 100 μM | Hashimoto et al., 2001 |
| Primary cortical neurons, Aβ1-43 | 10 μM sHN; 10 nM sHNG | Hashimoto et al., 2001 |
| Rat ICV clamp | 20 μg HN or F6AHN; 0.16 μg/kg/min in the basal-clamp figure | Muzumdar et al., 2009 |
| Rat IV clamp | HN or F6AHN 0.375 mg/kg/hr (no significant insulin-action change at that dose); HNGF6A 0.05 mg/kg/hr | Muzumdar et al., 2009 |
| ZDF rats | Single 100 μg HNGF6A IV bolus | Muzumdar et al., 2009 |
| Aged female mice | HNG 4 mg/kg intraperitoneal, twice weekly, from 18 months | Yen et al., 2018 |
| CMA assays | HNG 10-20 μM in culture | Gong et al., 2018 |
| Hippocampal neurons after glutamate | Humanin 0.01-1 μM for 24 hours | Zárate et al., 2019 |
That does not make 4 mg/kg, 100 μg, 0.05 mg/kg/hr, 10 nM, or 10 μM an approved dose. Mouse intraperitoneal HNG and rat IV HNGF6A are different analogs. A catalog vial is not the Hashimoto peptide, not Yen's HNG, and not a protocol. No reconstitution instructions or human-equivalent milligram translation appear here.
What this does not mean
- It is not human efficacy. No identified trial gave exogenous Humanin or HNG to people and measured a clinical endpoint.
- It is not an approved neuroprotective or metabolic drug. FDA has not approved Humanin, HNG, or HNGF6A for Alzheimer's disease, cognitive aging, diabetes, or longevity.
- A culture rescue is not a patient result. Hashimoto's neurons and F11 cells are dishes.
- Mouse rotarod and Y-maze are not a human cognition claim. Yen's HNG arm is aged female C57BL/6N mice. The 28-month rotarod difference was not significant.
- A plasma decline or a SNP is not a treatment. Muzumdar's age ELISA and Yen's rs2854128 findings are observational.
- A rat clamp is not a human insulin-sensitizer trial. ZDF glucose falling after 100 μg HNGF6A is four diabetic rats over four hours.
- CMA activation is not proof that Humanin clears damaged proteins in a human brain.
- Humanin is not MOTS-c and not SS-31. Other mitochondrial stories do not transfer.
- A research-vendor listing is not the study product. Identity, amount, and sterility can differ.
- This is not medical advice, and it is not a consumer dosing protocol.
This week's other maps stay on their own molecules: FOXO4-DRI remains preclinical, and NAD+ IV is a metabolome study. This is not the morning Survodutide SYNCHRONIZE post. Humanin is not an incretin.
Limitations
The human gap is first. The only human measurements here are Hashimoto's cDNA/RNA work, Muzumdar's circulating-HN-by-age ELISA, and Yen's plasma levels plus rs2854128. Nobody in those papers received Humanin as a drug.
Sample sizes are small where treatment happened. Yen's late cognitive tests used 7 to 10 mice per arm. The ZDF bolus used 4 rats.
Analogs are not interchangeable. HNG (S14G) and HNGF6A (S14G plus F6A) were built to raise potency or drop IGFBP-3 binding. A catalog vial is not either analog unless the certificate says so.
Yen 2020 (Aging, PMID 32575074) is a review. A review is context, not primary efficacy.
What to watch
- A first registered interventional human protocol. Until one exists, exogenous Humanin stays preclinical plus biomarker association.
- Peer-reviewed human pharmacodynamics after a defined analog. Plasma ELISA without dosing is not pharmacokinetics.
- Independent aged-mouse cognition replication. Yen 2018 is one NIA-colony HNG schedule. The late rotarod loss of significance is already in that paper.
- Whether later metabolic papers keep HNGF6A IV or return to native Humanin. Muzumdar's native IV dose did not move insulin action.
- Ancestry-stratified Humanin assays that name the immunoassay. Yen's 20% BVAIT gap and 14% SNP gap are that assay, those cohorts, and that SNP.
- How vendors describe the peptide. PNAS 2001 language is not a sterility claim.
FAQs
What is Humanin?
A mitochondrial 16S rRNA ORF peptide. Hashimoto 2001 reported a 24-residue secreted peptide that rescued neurons from familial Alzheimer's genes and Aβ in culture. Not FDA-approved.
Has Humanin been tested as a drug in humans?
No interventional efficacy trial was identified. Human data here are circulating-level ELISA work and a SNP association, not patient dosing.
Did HNG reverse aging or Alzheimer's in people?
No. Yen 2018 treated aged mice, then measured human plasma Humanin and rs2854128. That is not a human Alzheimer's or aging result.
What dose was used?
Papers reported 4 mg/kg HNG intraperitoneal twice weekly in aged mice and 100 μg HNGF6A IV in ZDF rats. Humanin and HNG are not approved for human use. That does not make those figures an approved dose.
Is a research-vendor vial the same peptide used in these papers?
No. The papers used defined synthetic Humanin or HNG. Catalog listings are a different market.
Is this a MOTS-c, SS-31, NAD+, or GLP-1 story?
No. Those molecules have separate evidence maps. This is not an incretin or Survodutide article.
This article is for general informational purposes only and is not medical advice. Talk to a licensed clinician about personal medical decisions. Humanin is an endogenous mitochondrial-derived peptide. Exogenous Humanin and HNG are not FDA-approved. Nothing here is a dosing protocol, an availability claim, or a recommendation to obtain an unapproved product.
Continue your research
- Humanin price and vendor comparison
- Humanin research profile
- SS-31 (elamipretide)
- What is MOTS-c?
- FOXO4-DRI preclinical evidence
- NAD+ IV metabolome evidence
- COA Authenticity Checker
Sources
- Hashimoto et al. PNAS 2001. PMID 11371646
- Yen et al. Sci Rep 2018;8:14212. PMID 30242290. DOI 10.1038/s41598-018-32616-7
- Muzumdar et al. PLoS One 2009;4(7):e6334. PMID 19623253
- Gong et al. J Cell Biol 2018. PMID 29187525
- Zárate et al. Front Aging Neurosci 2019. PMID 31214013
- Chai et al. Neurosci Bull 2014. PMID 25391447
- Price et al. Biochemistry 2020. PMID 32383868