Humanin

Humanin is a 24-amino acid peptide encoded by a short open reading frame within the 16S ribosomal RNA region of mitochondrial DNA. It is endogenous: any cell with functional mitochondria can produce it, though circulating levels decline substantially with age in mice, primates and humans.

Hashimoto and colleagues discovered it in 2001, isolating it from the brain of an Alzheimer's disease patient and showing that it rescued neuronal cells from amyloid-beta toxicity. Since then it has been investigated for neuroprotection, cardioprotection, insulin sensitisation, metabolic regulation and longevity.

Humanin is the prototypical mitochondrial-derived peptide (MDP), a class that also includes MOTS-C (encoded in the 12S rRNA region) and the small humanin-like peptides (SHLPs). MDPs function as retrograde signalling molecules coordinating stress responses and metabolism between mitochondria and the nucleus and periphery.

The longevity association rests on observational data from Pinchas Cohen's lab at USC and Nir Barzilai's group at Albert Einstein College of Medicine: offspring of centenarians carry circulating humanin up to threefold higher than age-matched controls, and in the naked mole-rat, a species with negligible senescence, levels remain stable across the lifespan rather than declining.

Pharmacokinetics are a limitation. Circulating half-life is approximately 30 minutes in mice, although rat data suggest it may exceed 4 hours in larger species. Several analogs address potency and stability, most notably HNG (S14G-humanin or S14G-HN), a serine-to-glycine substitution at position 14 that confers roughly 1,000-fold greater potency than native humanin. Most research and practical protocols use HNG rather than the native peptide.

No humanin product is FDA approved, no human intervention trials with direct administration have been completed, and all dosing is extrapolated from animal work and extremely limited user experience.

Humanin signals both extracellularly through receptor complexes and intracellularly through direct protein binding.

Tripartite receptor. Humanin binds a cell-surface complex of CNTFR-alpha (ciliary neurotrophic factor receptor alpha), WSX-1 (IL-27 receptor alpha) and gp130. Engagement activates three cascades in parallel. JAK2, constitutively associated with gp130, phosphorylates STAT3, which translocates to the nucleus and drives transcription of survival, anti-inflammatory and neuroprotective genes. PI3K/AKT suppresses apoptosis and supports growth and metabolism, and is a principal mediator of cytoprotection. ERK1/2 supports proliferation, differentiation and survival. Humanin also signals through formyl peptide receptors (FPR2/FPRL1), which participate in inflammation resolution and immune regulation and may account for part of its anti-inflammatory activity.

Intracellular targets. Humanin binds BAX and prevents its oligomerisation at the outer mitochondrial membrane, blocking pore formation, cytochrome c release and the intrinsic apoptotic cascade. This is central to its neuroprotective and cardioprotective actions. It also binds IGFBP-3, which can induce apoptosis independently of IGF signalling, and neutralises that pro-apoptotic activity.

Metabolic regulation. Humanin acts as a central regulator of peripheral insulin action. Delivered to the hypothalamus, it improves whole-body insulin sensitivity in liver and skeletal muscle via hypothalamic STAT3 signalling. A highly potent analog lowered blood glucose in diabetic rats after a single treatment, and humanin enhances glucose-stimulated insulin secretion from pancreatic beta cells.

Mitochondrial protection. Humanin reduces reactive oxygen species production, preserves mitochondrial membrane potential under stress, maintains ATP during oxidative challenge and upregulates mitochondrial glutathione (GSH).

Autophagy. Humanin enhances autophagy, and in C. elegans the lifespan extension from humanin overexpression required intact autophagy pathways.

The evidence base is preclinical plus human observational data; no human intervention trials have been completed.

Neuroprotection. Humanin and HNG protect neurons from amyloid-beta toxicity. Chronic HNG in transgenic Alzheimer's mice improved spatial learning and memory, reduced plaque burden and decreased tau hyperphosphorylation. Humanin converts fibrillar amyloid-beta into less toxic amorphous forms and competes with it for receptor binding. Benefits extend to Parkinson's models (mitochondrial biogenesis via PI3K/AKT), traumatic brain injury (restoration of astrocyte metabolic pathways), stroke (reduced infarct size, suppressed inflammatory cytokines) and age-related decline in normal aged mice. Cerebrospinal fluid humanin is reduced in Alzheimer's patients, and the m.2706A>G variant (rs2854128) affecting humanin translation associates with accelerated cognitive ageing in African Americans.

Cardioprotection. In murine ischaemia-reperfusion, HNG reduced infarct size dose-dependently with maximal protection at 2 mg/kg, improved left ventricular ejection fraction and preserved post-ischaemic dimensions via AMPK-eNOS activation and BAX/BCL-2 regulation. In pigs, HNG at 2 mg/kg reduced infarct size, though the effect was abolished with extended ischaemic time. Low circulating humanin associates with endothelial dysfunction, impaired coronary endothelial function and higher major adverse cardiac event risk in angina patients. Humanin upregulates KLF2, regulates eNOS and endothelin-1, and suppresses atherosclerosis in animals.

Metabolic. Intracerebroventricular humanin improved hepatic and skeletal muscle insulin sensitivity in rats; a potent analog increased glucose-stimulated insulin secretion from islets of normal and diabetic mice.

Lifespan and healthspan. Overexpression extended C. elegans lifespan FOXO-dependently. Twice-weekly HNG in middle-aged mice did not extend lifespan but reduced body weight and visceral fat without altering intake, increased lean mass, lowered IGF-I and inflammatory markers, and improved memory.

Other. HNG partially preserved myotube area and reduced STAT3 activation in dexamethasone-treated human muscle cells (2026), with MOTS-C more effective. Efferocytic macrophages produce humanin to promote inflammation resolution (2025). HNGF6A at 0.4 mg/kg daily for 16 weeks in ApoE-deficient mice reduced proximal aortic plaque from 0.09 mm squared to 0.01 mm squared without lowering cholesterol; humanin is expressed at twice the concentration in symptomatic versus asymptomatic human plaques. HNG reduced chemotherapy side effects and metastasis in some models, contradicted by tumour-promoting data in others.

There is no human clinical data describing the subjective or objective course of exogenous humanin administration. Expectations are extrapolated from animal timelines and extremely limited user reports.

The short circulating half-life means each subcutaneous dose clears rapidly. This is the most likely explanation for why twice-weekly HNG in middle-aged mice improved healthspan markers without extending lifespan: intermittent dosing did not deliver sustained exposure. Any effects in practice are expected to be cumulative over repeated cycles rather than acute.

The user base is tiny relative to most research peptides. Users report better sleep quality and smoother energy within the first several days, and some report improved exercise recovery. Others report no subjective effects despite completing standard protocols. Most describe effects as subtle and difficult to attribute to humanin specifically, since they are typically running multiple compounds concurrently. Reports are sparse, uncontrolled for confounders, and placebo effects cannot be excluded.

The plausible model is that humanin exerts cellular-level actions, reducing ROS, preserving mitochondrial membrane potential, blocking BAX-mediated apoptosis, and supporting hypothalamic insulin signalling, without producing measurable day-to-day changes in performance or wellbeing. The value proposition is long-term cytoprotection, not acute enhancement, and no conclusions about efficacy can be drawn from current anecdotal data.

No dose-finding studies exist for subcutaneous humanin in humans. Protocols are extrapolated from animal work and extremely limited user precedent.

Animal studies span 0.16 mcg/kg/min by intracerebroventricular infusion to 2 mg/kg intraperitoneal bolus; neither converts meaningfully to human subcutaneous dosing. The short half-life (approximately 30 minutes in mice, possibly greater than 4 hours in rats) drives once- or twice-daily administration in practice.

Most research and practical protocols use HNG (S14G-humanin), which is roughly 1,000 times more potent than native humanin. Dose figures below assume HNG.

Low-dose protocol: 25 to 50 mcg daily, subcutaneous.

Standard protocol: 500 mcg to 1 mg once or twice daily, subcutaneous. Cycle length 10 to 15 days, with cycles repeated several times per year.

Reconstitution (typical): 10 mg vial in 2 mL bacteriostatic water gives 5 mg/mL (5,000 mcg/mL); a 1 mg dose is 20 units on an insulin syringe.

Timing: morning administration is common, but there is no published data on optimal timing. No fasting requirement; any time of day is acceptable. Twice-daily dosing likely provides more sustained exposure than once-daily given rapid clearance, and the same pharmacokinetic limitation probably explains healthspan improvement without lifespan extension in mice dosed twice weekly.

More stable analogs and alternative delivery systems are under investigation but not available for practical use.

Humanin has a substantial preclinical evidence base and no completed human intervention trials.

Hashimoto et al. (2001) isolated humanin from the brain of an Alzheimer's patient and showed it rescued neurons from amyloid-beta-induced death, founding the mitochondrial-derived peptide field. Hashimoto et al. (2009) later characterised the CNTFR-alpha/WSX-1/gp130 receptor complex, and Guo et al. (2003) showed humanin suppresses apoptosis by interfering with BAX activation. Kim et al. (2016) confirmed ERK1/2, AKT, and STAT3 activation with age-dependent signalling differences in the hippocampus.

Muzumdar et al. (2010) demonstrated dose-dependent infarct reduction with HNG in mice (45 minutes ischaemia, 24-hour reperfusion), maximal at 2 mg/kg intraperitoneal, with improved left ventricular ejection fraction via AMPK-eNOS activation, downregulated BAX, and maintained BCL-2. Thummasorn et al. (2017) reported reduced arrhythmia incidence and infarct size in rats. Sharp et al. (2020) reproduced infarct sparing with HNG at 2 mg/kg in a porcine model, though the effect was abolished with extended ischaemic time.

Muzumdar et al. (2009) established humanin as a central regulator of peripheral insulin action: intracerebroventricular HN at 0.16 mcg/kg/min improved hepatic and skeletal muscle insulin sensitivity via hypothalamic STAT3, and a single potent analogue dose lowered glucose in Zucker diabetic fatty rats. Kuliawat et al. (2013) showed a potent analogue increased glucose-stimulated insulin secretion in normal and diabetic mice.

Yen et al. (2020) showed FOXO-dependent lifespan extension in C. elegans; twice-weekly HNG in middle-aged mice improved healthspan (reduced visceral fat, increased lean mass, decreased IGF-I, improved memory) without lifespan extension; circulating humanin was up to threefold higher in centenarian offspring and stable across life in naked mole-rats.

Moreno Ayala et al. (2020): exogenous HN at 10 mcg/mouse every other day accelerated triple negative breast cancer growth and lung metastasis and impaired doxorubicin efficacy; TCGA data confirmed receptor expression in human breast cancer.

Elhusseiny et al. (2026): HNG partially preserved myotube area and reduced STAT3 activation under dexamethasone, but MOTS-C was more effective. Maraux et al. (2025): efferocytic human macrophages produce humanin, promoting inflammation resolution. Widmer et al. (2013) linked circulating humanin to preserved coronary endothelial function.