Section 01
What it's used for
Alzheimer's: Cell and Animal Research
In cell and animal studies, humanin protects brain cells from damage caused by amyloid-beta, reducing cell death, oxidative stress, and neuron connection loss. In rats, it eased amyloid-beta-related memory problems, but didn't clear plaque.
▸Clinical wording
In cell-culture and animal studies, humanin protects neurons from amyloid-beta toxicity, reducing neuronal death and downstream effects such as oxidative stress, tau hyperphosphorylation, and synaptic loss. In a rat model, humanin also attenuated amyloid-beta-induced cognitive deficits. No study was found showing that humanin reduces amyloid-beta plaque burden itself.
Heart and Blood Vessel Research
Research shows humanin reduces heart damage from blocked-then-restored blood flow, slows artery hardening, and improves blood-vessel-lining function. People with higher blood humanin levels tend to have lower cardiovascular disease risk.
▸Clinical wording
Research shows humanin reduces cardiac ischemia/reperfusion injury, inhibits atherosclerosis, and improves endothelial function. Circulating humanin levels inversely correlate with cardiovascular disease risk.
Metabolic Health in Aging
Researchers observed that humanin improves how the body responds to insulin, reduces fatty liver buildup, and supports mitochondrial cell-energy function. It may help counter the metabolic decline linked to aging cell-energy systems.
▸Clinical wording
Humanin improves insulin sensitivity, reduces hepatic steatosis, and enhances mitochondrial function. It may counteract metabolic decline associated with aging mitochondrial dysfunction.
Mitochondrial Signaling Research Tool
Humanin is a key research tool for understanding mitochondrial-derived peptides — a newly discovered class of signals sent from mitochondria, the cell's energy factories, back to the nucleus and other parts of the cell.
▸Clinical wording
Humanin serves as a key research tool for understanding mitochondrial-derived peptide signaling — a new class of retrograde signals from mitochondria to the nucleus and other cellular compartments.
Section 02
Mechanism of Action
A tiny protein made by mitochondria
- Researchers found it while screening for genes that rescue nerve cells from death.
- Those cells had been damaged by Alzheimer's-linked genes and by amyloid-beta, the plaque protein.
- It failed to rescue cells dying from two other genetic causes, so the effect is selective.
- Its 24-unit sequence sits inside a gene of mitochondrial DNA, the cell's own power-plant genome.
▸Clinical wording
A short open reading frame inside the mitochondrial 16S rRNA gene
Humanin was found by functional expression screening for cDNAs that rescue neuronal cells from death caused by several familial Alzheimer's disease genes and by amyloid-beta. The clone encoded a 24-amino-acid polypeptide that was transcribed and then secreted into the culture medium, and the rescue depended on its primary structure, with no effect on death caused by Q79 or SOD1 mutants. The identical sequence is present in mitochondrial DNA, inside the MT-RNR2 16S rRNA gene, which places humanin in the mitochondrial-derived peptide family.
Blocking the cell's self-destruct proteins
- It grabs a protein called Bax and stops it reaching mitochondria to start cell death.
- Silencing the peptide made cells more vulnerable and let more Bax move to membranes.
- It also binds one long form of a related killer protein, but not the shorter forms.
- All of these results come from cell lines and isolated mitochondria, not from animals.
▸Clinical wording
Bax and BimEL sequestration at the outer mitochondrial membrane
Humanin binds Bax and prevents its translocation from cytosol to mitochondria; reducing humanin with siRNA sensitises cells to Bax and increases Bax movement to membranes. Humanin also binds the extra-long isoform BimEL, but not BimL or BimS, and protects against BimEL-induced apoptosis, while humanin mutants unable to bind BimEL lose that protection. On mitochondria isolated from bax-null cells humanin still blocked BimEL-driven SMAC and cytochrome c release and prevented Bak oligomerisation. Cell lines and isolated organelles.
A three-part receptor on nerve cells
- In two nerve cell lines the peptide made three receptor pieces clump together.
- Treatment switched on STAT3, a messenger carrying survival signals towards the nucleus.
- Silencing two of the receptor pieces cut the protective effect to roughly a fifth.
- Injected into mice, it raised survival signalling in the hippocampus of old but not young animals.
▸Clinical wording
CNTFR-alpha/WSX-1/gp130 receptor complex and STAT3
In F11 neurohybrid and SH-SY5Y cells, humanin induced hetero-oligomerisation of the recombinant extracellular domains of CNTFR-alpha, WSX-1 and gp130, and immunoprecipitation showed humanin-dependent association of endogenous WSX-1 with gp130. Treatment raised STAT3 Tyr705 phosphorylation, and siRNA against CNTFR-alpha or WSX-1 cut humanin and HNG cytoprotection to roughly 20% of control. Acting through GP130/IL6ST, humanin also raises AKT, ERK1/2 and STAT3 phosphorylation via PI3K, MEK and JAK respectively, and injected humanin raised hippocampal AKT and ERK1/2 phosphorylation in old but not young mice.
Competing with the Alzheimer's plaque protein
- It attracts immune scavenger cells through a receptor also used by amyloid-beta 42.
- In nerve precursor cells both molecules switched that receptor on, but only amyloid-beta killed cells.
- The peptide blocked that killing, consistent with the two competing for the same receptor.
- Later high-resolution structures showed exactly where each molecule sits inside the receptor.
▸Clinical wording
FPR2/FPRL1, a receptor shared with amyloid-beta 42
Synthetic humanin induced chemotaxis of mononuclear phagocytes through human FPRL1 and its mouse counterpart FPR2, the same receptors amyloid-beta 42 uses. In neuroblast cells both peptides activated FPRL1, but only amyloid-beta 42 caused apoptotic death, and humanin blocked it, consistent with competition for receptor access. Cryo-EM structures of FPR2 bound to Gi with either amyloid-beta 42 or N-formyl humanin later localised recognition to a polar cavity inside the receptor helical bundle and a hydrophobic groove in the extracellular region.
Effects on blood sugar in rodents
- A screening method identified a carrier protein (IGFBP-3) that binds the peptide directly.
- Injected into rat brains, it lowered sugar output by the liver and raised uptake elsewhere.
- That effect ran through a brain messenger, and blocking the messenger abolished it.
- In mice with interrupted heart blood flow, a modified version raised two protective signals.
▸Clinical wording
IGFBP-3 binding and metabolic signalling in rodents
A yeast two-hybrid screen identified humanin as an IGFBP-3 binding partner; binding maps to the 18-amino-acid heparin-binding domain of IGFBP-3, does not compete with IGF-I, and is lost in the F6A variant. In rats, intracerebroventricular humanin during a hyperinsulinaemic-euglycaemic clamp lowered hepatic glucose production and raised peripheral glucose uptake, with an approximately tenfold rise in hypothalamic STAT3 phosphorylation that STAT3 inhibition abolished; the non-IGFBP-3-binding analogue was more potent. In mouse myocardial ischaemia-reperfusion the analogue HNG raised AMPK and eNOS phosphorylation.
Section 03
Biological Pathways
- STAT3 via tripartite receptorHumanin drives hetero-oligomerization of CNTFR-alpha, WSX-1 and gp130, raising STAT3 Tyr705 phosphorylation; silencing CNTFR-alpha or WSX-1 cut cytoprotection to roughly 20% of control.
- Bax and BimEL sequestrationHumanin binds Bax, preventing its translocation to mitochondria, and separately binds BimEL to block BimEL-induced apoptosis, still blocking cytochrome c release in bax-null cell lines and isolated organelles.
- FPR2/FPRL1 shared with amyloid-betaHumanin activates FPRL1/FPR2, the same receptors used by amyloid-beta 42, driving phagocyte chemotaxis; in neuroblast cells amyloid-beta 42 caused apoptosis through this receptor, and humanin blocked it.
- IGFBP-3 binding and AMPK/eNOSHumanin binds the heparin-binding domain of IGFBP-3 without competing with IGF-I; in rats this lowered hepatic glucose output via hypothalamic STAT3, while HNG raised AMPK and eNOS phosphorylation.
Section 04
Dosage Information
MAPRGFSCLLLLTSEIDLPVKRRA| Route / system | Context | Range studied | Limitation |
|---|---|---|---|
| Endogenous — measured, not administered | Observational human studies; nobody was given it | Median 774 pg/mL in sedentary people vs 1258 pg/mL in athletes; 2.2 ± 1.5 ng/mL with healthy heart vessels vs 1.3 ± 1.1 ng/mL without | Levels the body keeps on its own and nobody changed, only compared with fitness and vessel health. They say nothing about injecting milligrams. |
| Into the abdomen — mouse studies | Old mice; HNG, a stronger lab-made version | HNG 4 mg/kg twice weekly from 18 months of age for 14 months; heart and metabolism models used 0.1–4 mg/kg a day | HNG is a strengthened humanin, injected into the belly of mice. 4 mg/kg would be 280–360 mg in a 70–90 kg adult — never scaled, measured or given to anyone. |
| Subcutaneous — self-administration | Research-chemical vendors and community practice | 1–5 mg a day, or about 1 mg per session three times weekly in 4–12 week cycles — roughly 11–71 µg/kg for a 70–90 kg adult | Vendors say outright the numbers are scaled from mouse mg/kg. No registered trial has ever given humanin or HNG to a person, so nothing has tested them. |
Results
Syringe Fill Level (100u syringe)
Set positive values for: Recommended dose per kg.
Research Use Only. This information is for educational and research purposes only. Not intended for medical advice or self-medication.
Section 05
Protocols
No protocols featuring this peptide yet. Browse All Protocols
Section 06
Stability & Storage
Lyophilised powder
Stored at −20 °C and shielded from air and light. The methionine at position 1 makes the peptide prone to oxidation, and the exact retention time depends on the batch and manufacturer.
After reconstitution
Reconstituted with sterile water shortly before use. Because the peptide oxidises easily, the solution is kept cold and used promptly, with the exact holding time following the manufacturer's instructions.
Section 07
Side Effects & Precautions
Limited human safety data as humanin remains largely in preclinical research. No significant toxicity observed in animal studies at therapeutic doses. Theoretical concern that anti-apoptotic activity could promote survival of damaged or pre-malignant cells.
Section 08
Regulatory Status
It remains a preclinical research peptide: no approved label, indication, dose or established human safety profile exists for it.
FDA / United States
Not approved
Humanin has never been nominated for the 503A bulk-substances process and is not on the 503A Bulks List, so section 503A opens no lawful route for a pharmacy to compound it for human use.
EU / EMA
Not approved
Humanin has no EU marketing authorisation and does not appear among medicines evaluated by the CHMP.
WADA
Prohibited under S0
Humanin is not individually named on the Prohibited List, but as a mitochondria-derived peptide outside the growth-hormone/IGF-1 pathway covered by S2, it falls under the S0 catch-all for non-approved substances — banned at all times, with no therapeutic-use exemption.
Clinical trials
No completed human trial exists
Evidence for humanin's cytoprotective and metabolic effects comes from cell cultures and rodent models; no Phase 1 safety or pharmacokinetic study in humans has been published.
A «research use only» label does not turn humanin into an approved medicine and says nothing about its purity. Regulatory status differs between jurisdictions and changes over time — check the current documents of your own regulator before relying on any of this.
Section 09
Research Studies
- [1]A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and AbetaHashimoto Y, Niikura T, Tajima H, et al. · Proceedings of the National Academy of Sciences · 2001
- [2]Humanin peptide suppresses apoptosis by interfering with Bax activationGuo B, Zhai D, Cabezas E, et al. · Nature · 2003
- [3]Cytoprotective peptide humanin binds and inhibits proapoptotic Bcl-2/Bax family protein BimELLuciano F, Zhai D, Zhu X, et al. · Journal of Biological Chemistry · 2005
- [4]Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M. · Molecular Biology of the Cell · 2009
- [5]The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampusKim SJ, Guerrero N, Wassef G, et al. · Oncotarget · 2016
- [6]Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptorYing G, Iribarren P, Zhou Y, et al. · The Journal of Immunology · 2004
- [7]Structural basis of FPR2 in recognition of Abeta42 and neuroprotection by humaninZhu Y, Lin X, Zong X, et al. · Nature Communications · 2022
- [8]Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosisIkonen M, Liu B, Hashimoto Y, et al. · Proceedings of the National Academy of Sciences · 2003
- [9]Humanin: a novel central regulator of peripheral insulin actionMuzumdar RH, Huffman DM, Atzmon G, et al. · PLoS ONE · 2009
- [10]Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in miceMuzumdar RH, Huffman DM, Calvert JW, et al. · Arteriosclerosis, Thrombosis, and Vascular Biology · 2010
- [11]Peptides derived from small mitochondrial open reading frames: genomic, biological, and therapeutic implicationsMiller B, Kim SJ, Kumagai H, et al. · Experimental Cell Research · 2020
Section 10
Frequently Asked Questions
Humanin is a 24-amino-acid peptide encoded inside mitochondrial DNA — inside the 16S ribosomal RNA gene, not a standard protein-coding gene — discovered in 2001 while screening for factors that protect neurons from Alzheimer's-related toxicity. In cell and animal studies it blocks programmed cell death by binding pro-apoptotic proteins like Bax and BimEL, and activates survival signalling (STAT3, AKT, ERK) through cell-surface receptors including a CNTFR-alpha/WSX-1/gp130 complex and FPR2 — the same receptor amyloid-beta 42 uses. It is classed as a mitochondrial-derived peptide, a signalling role for mitochondrial DNA identified only in the past two decades.
No. The only human data are observational: circulating humanin levels were measured and compared between groups — for example, a median of 774 pg/mL in sedentary people versus 1258 pg/mL in athletes, and higher levels in people with healthy coronary vessels than those without. Nobody was given humanin in these studies; everything about administering it, including the stronger synthetic analog HNG, comes from mouse experiments.
The only interventional dosing is in mice: old mice received the enhanced analog HNG at 4 mg/kg injected into the abdomen twice weekly for 14 months, with other mouse metabolic and cardiac studies using 0.1–4 mg/kg a day. Self-administration practice circulating outside any trial — roughly 1–5 mg a day — is a direct scale-up of that mouse mg/kg figure, something vendors state outright; no human dose-finding study of humanin or HNG has ever been conducted.
Animal studies at the doses tested showed no significant toxicity, but human safety data barely exist because humanin has never gone through a human trial. There is a specific theoretical concern rather than a measured one: humanin's core mechanism is blocking programmed cell death, and the same anti-apoptotic action that protects healthy neurons could in principle help damaged or pre-malignant cells survive. This has not been tested either way.
Humanin has no regulatory approval anywhere and remains an investigational compound in preclinical and early translational research. It is not on WADA's prohibited list, unlike many growth-factor peptides, since it has no established performance-enhancing use — that absence of prohibition reflects its research status, not a safety clearance.
As lyophilised powder it is kept at −20 °C, shielded from air and light — the methionine at position 1 makes it prone to oxidation, and how long it holds up varies by batch and manufacturer. Once reconstituted, the solution is kept cold and used promptly rather than stored, again because of that oxidation sensitivity.