Humanin (HN / HNG / S14G-Humanin)
Humanin — the founding mitochondrial peptide: rich biology, biomarker status, no human trials

Class: peptide
Synonyms: Humanin
HN
HNG / S14G-Humanin / [Gly14]-Humanin (the potent synthetic analog)
HNGF6A (a further-modified metabolic analog)
rattin (the rat ortholog). INCI: none
Function tags: mitochondrial
longevity-biomarker
(preclinical:) neuroprotection (Alzheimer's / amyloid)
insulin-sensitising
cardioprotection
Overall evidence grade: C
WADA prohibited: no
Last updated: 2026-07-13

In brief: Humanin is the founding mitochondrial-derived peptide — a 24-amino-acid signal encoded in mitochondrial DNA, discovered in 2001 from an Alzheimer's-resistant neuron. Its molecular biology is unusually well-mapped: it binds a specific cell-surface receptor complex to switch on survival signalling, directly blocks the cell-death protein BAX, and modulates IGF-1 signalling — engaging two of the most conserved longevity pathways (mitochondrial health and IGF-1/insulin) at once. In humans, circulating humanin falls with age, is lower in Alzheimer's and coronary disease, and is higher in centenarians and their children — making it a compelling longevity biomarker. But that is the ceiling of the human evidence: it is correlational and observational. There is no completed interventional human trial of administering humanin for anything, no established human pharmacokinetics, and no dose-ranging data — and most of the striking preclinical work used the HNG analog (~1000× more potent), not the native peptide typically sold. It is an intriguing hypothesis, not a demonstrated therapy.

## Identity a **24-amino-acid peptide** (< 40 aa → peptide) translated from a short open reading frame in the **16S ribosomal RNA gene (MT-RNR2)** of mitochondrial DNA. This mitochondrial (not nuclear) origin places it in a **molecularly distinct class**: the **mitochondrial-derived peptides (MDPs)**, of which Humanin is the **founding, first-described, and most-characterised member** — the same family as **MOTS-c (#10)** and the SHLP1-6 peptides. ## Mechanism (as proposed) Humanin is **cytoprotective** through several mapped routes: (1) it binds a **trimeric receptor complex (CNTFR / WSX-1 / gp130)** to activate **JAK2/STAT3** survival signalling; (2) it directly **antagonises BAX**, a pro-apoptotic protein, preventing it from permeabilising the mitochondrial membrane (blocking the cell-death cascade); (3) it binds **IGFBP-3**, modulating **IGF-1** signalling and apoptosis — tying it into the conserved IGF-1/insulin longevity axis; (4) it engages **formyl-peptide receptors (FPRL1/2)** and activates **PI3K/Akt**, upregulating anti-apoptotic **BCL-2** and lowering ROS. This mechanistic richness is exactly why it's scientifically exciting — and it makes the **absence of human interventional data** all the more conspicuous.

Evidence grades by outcome:
outcome: Longevity biomarker (levels correlate with lifespan/health)
grade: C
base: Multiple human observational/epidemiological datasets (USC, Barzilai): humanin ↓ with age, ↓ in AD/CAD, ↑ in centenarians + their offspring; correlates across mammalian species
caveat: This is the strongest human evidence — but it's a biomarker correlation, not proof that giving humanin helps. Human association studies are even called "equivocal" in some reviews. Biomarker ≠ drug
outcome: Neuroprotection / Alzheimer's (the discovery context)
grade: F
base: Rich preclinical: blocks amyloid-beta toxicity, prevents tau hyperphosphorylation, anti-apoptotic in neuron/animal models (mostly HNG)
caveat: Powerful mechanism, zero completed human trials; no RCT shows exogenous humanin prevents or treats AD. Founding story ≠ clinical proof
outcome: Insulin sensitivity / metabolic
grade: F
base: Rodent clamp studies (Muzumdar 2009 — central STAT3-mediated; HNGF6A analog lowered glucose in diabetic rats)
caveat: Preclinical rodent only, small n; CNS-mediated mechanism; not shown in humans
outcome: Cardioprotection (ischemia, age-related fibrosis)
grade: F
base: Animal: ischemia-reperfusion protection; 14-month HNG dosing prevented age-related myocardial fibrosis in aged mice
caveat: Animal-only; native-vs-HNG gap applies
outcome: "Anti-aging / healthspan" (the popular use)
grade: F
base: Transgenic worms + multiple mammalian species (levels track lifespan); HNG improved healthspan markers, lowered inflammation in mice
caveat: The headline longevity-therapeutic claim is animal + biomarker, not human-interventional. This is what most buyers want — and it's unproven in people
outcome: Safety (exogenous administration in humans)
base: No completed human trials → no human safety dataset
caveat: Endogenous peptide (present in everyone), which is reassuring mechanistically, but injected exogenous safety/PK is simply not characterised in humans

Legal status:
region: EU
status: Not FDA-approved (gray-market)
note: not approved anywhere for any indication; not a cosmetic; investigational research peptide only. No EMA/FDA marketing authorisation, no compounding pathway.

Cosmetic claims:

Note: The mitochondrial trio's third face — and the register's clearest "gorgeous mechanism, zero human trials" case. Three honest points define this entry: (1) it is the founding member of the mitochondrial-derived peptide (MDP) family — the same class as MOTS-c (#10) — with an unusually rich, well-mapped molecular biology; (2) it is a genuine longevity biomarker (higher in centenarians and their children) — but a biomarker is not a drug, and there is not one completed human trial of giving it; (3) almost all the impressive preclinical data uses the HNG analog (~1000× more potent), not the native "Humanin" sold in research channels — so even the animal data doesn't map cleanly onto the product.
Status note: watch for any first-in-human interventional trial — that would change the grades materially

Sources:
Hashimoto Y, et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ. PNAS. 2001 (original discovery).
Muzumdar RH, et al. Humanin: a novel central regulator of peripheral insulin action. PLoS One. 2009 (rodent metabolic).
Cohen P / Yen K, et al. & Barzilai N, et al. — humanin, IGF-1 signalling, centenarian/offspring cohorts (USC & Albert Einstein).
The mitochondrial-derived peptide humanin is a regulator of lifespan and healthspan. Aging (Albany NY). 2020 (worms + multiple mammals + centenarian offspring; notes human associations are equivocal).
Coradduzza et al. (Biology, 2023) & Karachaliou/Livaniou (2023) — reviews explicitly flagging absence of human clinical data as the primary limitation.