Humanin: The Complete Guide

Humanin is a 24-amino-acid mitochondrial-derived peptide (MDP) — sequence MAPRGFSCLLLLTSEIDLPVKRRA — encoded within the 16S rRNA region of the mitochondrial genome. It was the first member of the MDP family identified.

Discovery (2001, not 2003):

Hashimoto Y, Niikura T, et al. Proc Natl Acad Sci U S A 2001. PMID 11371646. “A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta.” Identified through a functional cDNA-library screen for clones that protected neuronal cells from familial-AD-gene-induced and Aβ-induced death — the source library was the occipital lobe of an AD patient (relatively spared by disease).

Date correction worth noting: some references list humanin’s discovery as 2003. That’s the year the IGFBP-3 binding partner was identified (Ikonen et al., PMID 14561895). The peptide itself was first described in 2001.

Lineage and lab provenance:

• Discovery lab: Ikuo Nishimoto’s group at Keio University (Tokyo). Nishimoto died in 2003; subsequent Japanese work continued under Yuichi Hashimoto and Masaaki Matsuoka.
• Major Western lab: Pinchas Cohen (now at USC Leonard Davis School of Gerontology) — who later led the discovery of MOTS-c (2015) and the broader MDP family (SHLPs, etc.).
• Family: humanin is the founding member of the mitochondrial-derived peptide family. MOTS-c, SHLP1–6, and other MDPs were discovered later, modeled on humanin’s discovery template.

Regulatory status:

• FDA (US): not approved for any indication. No NDA, no IND on file. Sold as research chemical only.
• EMA (EU): not approved.
• WADA 2026: not explicitly named on the 2026 Prohibited List. Likely covered by the S2 catch-all language (peptide hormones, growth factors, related substances and mimetics) since humanin signals via cytokine-receptor complexes (CNTFR / WSX-1 / gp130). Note that MOTS-c, the sister MDP, was explicitly added to the WADA list in recent years — humanin has not received the same explicit treatment, likely because its performance-enhancement profile is less obvious.

Humanin acts through multiple intersecting cellular survival pathways. The mechanism story is unusually well-mapped for a research peptide because the molecule has been studied for two decades by both the Japanese discovery group and the Cohen lab in the US.

1. Anti-apoptotic via Bax inhibition (the most-cited mechanism)

Humanin binds Bax (a pro-apoptotic Bcl-2-family protein) and prevents its translocation from cytosol to mitochondria, blocking the mitochondrial apoptosis pathway.

Source: Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC. Nature 2003. PMID 12732850.

2. IGFBP-3 partnership

Humanin binds insulin-like growth factor binding protein-3 (IGFBP-3) and modulates IGFBP-3-dependent cell survival. This was the bridge to Cohen-lab humanin work.

Source: Ikonen M, Liu B, Hashimoto Y, et al. PNAS 2003. PMID 14561895.

3. Cytokine-receptor complex (CNTFR / WSX-1 / gp130)

Humanin activates a heterotrimeric receptor complex composed of ciliary neurotrophic factor receptor α (CNTFR), WSX-1, and gp130, driving intracellular STAT3 phosphorylation.

Source: Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M. Mol Biol Cell 2009. PMID 19386761.

4. Central regulation of insulin action

Hypothalamic / intracerebroventricular humanin in rodents improves peripheral insulin sensitivity and glucose homeostasis.

Source: Muzumdar RH, Huffman DM, Atzmon G, et al. PLoS One 2009. PMID 19623253.

Caveat: the “TRIM5α inhibition” mechanism that appears in some encyclopedia entries and vendor copy has zero PubMed support. Skip it.

Most preclinical humanin literature uses analogs, not wild-type peptide. Vendor copy that says “humanin protects against X in mouse models” is technically correct but is leaning on analog data more than wild-type data.

Analog	Modification	Notes
HNG (S14G-Humanin)	Single substitution: serine → glycine at position 14	Most-studied analog. ~1000-fold more potent than wild-type in some neuroprotection assays. Workhorse of Alzheimer’s mouse studies (PMID 15678515 Tajima 2005; PMID 21993310 Zhang 2012).
HNGF6A	Combines S14G and F6A	Cohen-lab work; further-stabilized analog with improved metabolic activity. Specific primary PMID not cleanly verified.
Colivelin (AGA-(C8R)-HNG17)	Hybrid of HNG and ADNF (activity-dependent neurotrophic factor)	Designed for enhanced potency and stability. PMID 26964005.
P3S (natural longevity variant)	Pro³ → Ser³	Found enriched in centenarians, especially in APOE4 carriers (PMID 38520065).

No PubMed-indexed clinical trial of humanin in humans exists. All human evidence is observational biomarker work.

Domain	Evidence	PMIDs
Neuroprotection (Alzheimer’s)	Wild-type humanin rescues neuronal cells in vitro	11371646, 11717357, 11327724
HNG analog cognition (mouse)	S14G improves memory in Aβ-injection and APPswe/PS1dE9 models	15678515, 21993310
Anti-apoptosis / Bax	Humanin binds Bax, blocks mitochondrial translocation	12732850
IGFBP-3 partnership	Humanin / IGFBP-3 interaction regulates cell survival	14561895
Cytokine-receptor signaling	CNTFR/WSX-1/gp130 mediates humanin signaling	19386761
Central regulation of insulin action	ICV humanin improves peripheral insulin sensitivity (rodents)	19623253
Cardio-protection (cardiac IR injury)	Reduces myocardial ischemia-reperfusion injury (rodents)	27434747, 34896254 (review)
Coronary endothelial function (human observational)	Higher circulating humanin associated with preserved endothelial function (n=102)	23220334
Cognitive aging (mouse + human observational)	Humanin treatment prevents age-related cognitive decline; circulating humanin associated with cognitive age	30242290
Aging-related decline of MDPs	Endogenous humanin and SHLPs decline with age	27070352
Retinal protection (in vitro)	Humanin and other MDPs protect retinal pigment epithelial cells from oxidant injury	32768357
Mitokine biomarker in T2DM and AD	Plasma humanin levels differ between T2DM, AD, and healthy aging	33131010
Longevity variant P3S	P3S enriched in centenarians, especially APOE4 carriers	38520065

No human-trial-derived dose exists. Same caveat that applies to MOTS-c: any specific protocol (mg/kg, frequency, duration) circulating in vendor or forum copy is community practice, not clinically validated.

Common community / clinic practice:

Parameter	Common Range
Dose per injection	500–1000 µg SC
Frequency	Daily, EOD, or twice weekly (highly variable)
Cycle length	4–8 weeks on / similar off
Route	SC injection (community standard); intranasal occasionally reported

Wild-type humanin has a short circulating half-life (minutes) in rodents. Stabilized analogs (HNG, HNGF6A, colivelin) have longer half-lives — the design intent of those analogs is partly to overcome wild-type humanin’s rapid clearance.

Standard SC peptide reconstitution. For a typical 5 mg lyophilized vial:

• Add 2 mL bacteriostatic water → 2.5 mg/mL (2500 µg/mL).
• On a U-100 insulin syringe, 1 unit = 25 µg.
• So a 500 µg dose = 20 units; a 1000 µg dose = 40 units.

Storage:

• Lyophilized: stable at room temperature short-term; refrigerate for longer.
• Reconstituted: refrigerate. Use within 28 days.

For the full reconstitution protocol, see the Bacteriostatic Water guide.

No published human safety data on humanin or any analog. No FAERS, EudraVigilance, or Yellow Card entries.

Mechanism-derived theoretical concerns:

• IGFBP-3 / IGF-axis interactions. Humanin binds IGFBP-3; chronic dosing could plausibly alter IGF-1 bioavailability.
• Cancer-axis caution. Anti-apoptotic mechanisms (Bax inhibition) and pro-survival signaling (STAT3) are pharmacologically attractive for neuroprotection but mechanistically aligned with tumor survival. Active or prior cancer is a class contraindication.
• Mitochondrial-derived peptide family — humanin is endogenous; theoretical immunogenicity is low. No published immunogenicity data.

Community user reports describe injection-site mild irritation as the most common acute issue. None of this is anchored in a peer-reviewed safety paper.

• Pregnancy / breastfeeding — no safety data.
• Active or prior cancer — class concern (anti-apoptotic + STAT3 activation).
• Concurrent IGF-axis modulators (HGH, IGF-1 LR3, IGF-1 DES) — uncharacterized stacking via the IGFBP-3 partnership.
• Athletes subject to anti-doping testing — do not assume Humanin is permitted. The S2 catch-all language plausibly covers it; consult your governing body.

• MOTS-c — sister mitochondrial-derived peptide. Different sequence, different gene origin (12S rRNA vs 16S), different mechanism (AMPK activation vs Bax/IGFBP-3/STAT3). Both Cohen-lab MDP family but mechanistically distinct.
• SHLP1–6 — small humanin-like peptides; further MDP family members from the Cohen lab. Less studied; not commonly available as research chemicals.
• Cerebrolysin — porcine brain extract, multi-component; different family entirely.
• HNG vs wild-type humanin — if the goal is the published preclinical effect, HNG (S14G) is the molecule the strongest mouse studies actually used.