Humanin
HN, HNG (humanin analogue S14G), mitochondrial-derived peptide, MT-RNR2 peptide
Humanin is a 24-amino-acid peptide encoded within the mitochondrial 16S ribosomal RNA gene, discovered in 2001 in surviving neurons from an Alzheimer's brain. It was the first identified mitochondrial-derived peptide and acts as a cytoprotective signal released from mitochondria to the rest of the body. Circulating levels fall with age. All therapeutic evidence is preclinical; humanin appears in human research only as a measured biomarker, never as an administered drug.
Mechanism
Humanin is unusual in being encoded not in the nuclear genome but within the mitochondrial MT-RNR2 gene, in an open reading frame nested inside the 16S rRNA sequence. This makes it part of a small class of mitochondrial-derived peptides, alongside MOTS-c and the SHLP family, that appear to function as signals from the mitochondrion to the cell and to distant tissues, a retrograde communication system.
It acts through at least two distinct routes. Extracellularly it binds a trimeric receptor complex made of CNTFR, WSX-1 (IL-27 receptor alpha) and gp130, activating JAK2 and STAT3 signalling, and it also interacts with formyl peptide receptor-like 1 (FPRL1/FPR2). Intracellularly, humanin binds and sequesters the pro-apoptotic BCL2-family protein BAX, preventing its translocation to the mitochondrial outer membrane, and it binds IGFBP-3, modulating insulin-like growth factor signalling. The common thread is suppression of apoptosis under stress.
Metabolically, humanin appears to act centrally as well as peripherally. Intracerebroventricular administration in rodents improved peripheral insulin action and suppressed hepatic glucose production, an effect attenuated by vagotomy, implying a hypothalamic-vagal circuit rather than a direct hepatic effect. It also influences hepatic triglyceride secretion through central mechanisms. The S14G analogue, commonly called HNG, is reported to be far more potent than native humanin in neuroprotection assays and is the form used in most animal work.
What the research shows
The original 2001 PNAS report identified humanin from a cDNA library of an occipital lobe that had survived in an Alzheimer's brain, and showed it abolished neuronal death caused by a wide spectrum of familial Alzheimer's mutations and by amyloid-beta. This remains a striking result and has been reproduced in multiple neuronal models. Subsequent preclinical work has reported protection in cardiac myoblasts against oxidative stress, preservation of mitochondrial integrity, improvement of insulin sensitivity in rodents, and benefit in models of atherosclerosis, stroke and retinal degeneration.
Human research is entirely observational. Circulating humanin declines with age, and studies of centenarians and their offspring have examined whether higher mitokine levels track with longevity. Trials registered on ClinicalTrials.gov that mention humanin measure it as a biomarker in acute kidney injury, cardiac surgery and kidney transplantation. Not one administers it. There is no registered interventional trial of humanin or HNG in humans, no published human pharmacokinetic study, and no human dose-finding or toxicology data.
This is the crux for anyone encountering humanin as a purchasable compound. The biology is real, well characterised and genuinely interesting, and humanin is a legitimate object of academic study. The step from 'this peptide is a physiological cytoprotective signal whose levels fall with age' to 'injecting it will slow ageing' has never been taken in a human being. Observational correlation between a biomarker and longevity is a weak basis for supplementation: lower humanin in older people may be a consequence of mitochondrial decline rather than a cause of it, in which case restoring the signal would achieve nothing.
Evidence assessment
Preclinical only
Extensive cell and animal work supports cytoprotective and metabolic effects, but humanin has never been administered to humans in a registered trial; all human data are observational biomarker measurements.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta Preclinical only
Identified humanin and showed it prevented neuronal death induced by familial Alzheimer's disease mutations and by amyloid-beta.
Humanin: a novel central regulator of peripheral insulin action Preclinical only
Central humanin administration improved peripheral insulin action and suppressed hepatic glucose production through a hypothalamic-vagal pathway.
Central effects of humanin on hepatic triglyceride secretion Preclinical only
Humanin acting centrally reduced hepatic triglyceride secretion, supporting a brain-liver signalling role.
A humanin analog decreases oxidative stress and preserves mitochondrial integrity in cardiac myoblasts Preclinical only
The humanin analogue reduced reactive oxygen species and preserved mitochondrial membrane integrity.
Humanin Isoforms in Cardiac Muscle and Blood Plasma and Major Complications After Cardiac Operation Limited evidence
Measured humanin isoform concentrations in cardiac muscle and plasma against postoperative complications; humanin was quantified, not administered.
Safety
No human safety data. No toxicology study, no dose-finding, no adverse event record. Rodent studies have not flagged consistent toxicity, but they were not designed as safety studies. One theoretical concern deserves stating plainly: humanin's core activity is inhibition of apoptosis through BAX sequestration, and apoptosis is a principal mechanism by which the body eliminates damaged and pre-malignant cells. A sustained systemic anti-apoptotic signal is not self-evidently benign, and this question has not been addressed in any long-term study.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No MHRA marketing authorisation. Supply for human use engages the Human Medicines Regulations 2012 irrespective of a 'research use only' label. |
| United States | Not approved by the FDA for any indication and never studied as an interventional agent in a registered US trial. Sold only through research-chemical channels. |
| WADA (sport) | Not individually named on the Prohibited List but captured by section S0 (non-approved substances), prohibited at all times. |
Questions
Not in any registered trial. Every ClinicalTrials.gov study mentioning humanin measures it as a biomarker in blood or tissue, in settings like acute kidney injury and cardiac surgery. There is no human pharmacokinetic, dose-finding or toxicology data for administered humanin.
HNG is the S14G analogue, in which serine at position 14 is replaced by glycine. It is substantially more potent than native humanin in neuroprotection assays and is the form used in most animal experiments, so results attributed to 'humanin' often derive from HNG.
Circulating humanin does fall with age in observational studies. Whether that decline causes age-related decline or merely reflects reduced mitochondrial output is unresolved, and it matters: if the fall is a consequence rather than a cause, restoring the peptide would not be expected to help.
Yes. It is encoded in an open reading frame inside the mitochondrial 16S rRNA gene (MT-RNR2), making it the first identified mitochondrial-derived peptide, a class that also includes MOTS-c and the SHLP family.