Humanin
The first mitochondrial-derived peptide ever described — a cytoprotective, anti-apoptotic signaling molecule encoded inside mitochondrial DNA.
Humanin is a small peptide encoded within the MT-RNR2 (mitochondrial 16S ribosomal RNA) region of mitochondrial DNA, making it the founding member of the mitochondrial-derived peptide (MDP) class. First identified in 2001 in a surviving region of an Alzheimer's brain, it protects neurons and other stressed cells from apoptosis, oxidative stress, and amyloid-beta toxicity, and shows metabolic effects such as improved insulin sensitivity in rodents. Circulating humanin is measurable in human blood and cerebrospinal fluid and declines with age. Despite an unusually well-characterized mechanism, there are no completed interventional human trials, and humanin remains a research-only compound.
Class
Mitochondrial-derived peptide (MDP), ~24-amino-acid cytoprotective signaling peptide
Half-life
Wild-type humanin is short-lived in plasma (minutes to tens of minutes); PeptideBase cites ~2–4 hours. Stabilized analogs such as HNG persist longer, and downstream signaling effects outlast the peptide itself.
Routes
Subcutaneous, Intranasal, Intraperitoneal (preclinical)
Category
Immune & Mitochondrial
Researched benefits
What it's studied for
Neuroprotection
Humanin was discovered for its ability to protect cultured neurons from amyloid-beta toxicity associated with Alzheimer's disease. In cell and rodent models it suppresses stress-induced neuronal apoptosis, with mechanisms mapped to STAT3 signaling and JNK inhibition.
Anti-apoptotic / cytoprotection
It directly binds the pro-apoptotic protein Bax and prevents its translocation to mitochondria, inhibiting the intrinsic apoptosis pathway. This protects cells from oxidative stress, hypoxia-reoxygenation, and serum starvation in preclinical assays.
Metabolic improvement
Rodent studies report improved insulin sensitivity, enhanced glucose disposal, reduced fasting hyperglycemia, and protection against diet-induced metabolic dysfunction, acting through both central (hypothalamic) and peripheral mechanisms plus IGFBP-3 modulation of IGF-1 signaling.
Cardiovascular protection
Preclinical work shows protection against atherosclerosis in mouse models, and humanin (with MOTS-c) attenuated atrial fibrillation in mice by suppressing fibrosis and mitochondrial dysfunction; circulating levels correlate inversely with disease severity.
Mitochondrial stress resistance
As a mitokine, humanin enhances cellular antioxidant defenses (e.g., via SIRT3/Nrf2/HO-1 signaling) and supports mitochondrial function and mitophagy under stress in cell and animal models.
Exercise-linked mitokine biology
Plasma humanin rises with acute exercise in humans, and trained individuals show higher baseline and exercise-induced levels, supporting a role as a mitochondrial-derived myokine mediating some systemic benefits of physical activity.
Mechanism
How it works
Humanin is encoded not in the nuclear genome but within the MT-RNR2 region of mitochondrial DNA (the gene for the mitochondrial 16S rRNA), translated from a short open reading frame. This makes it the founding example of the mitochondrial-derived peptide (MDP) class — a group that now includes MOTS-c and SHLP1 through SHLP6 — reframing mitochondria as signaling hubs rather than mere power plants.
Extracellularly, humanin signals through a heterotrimeric cell-surface receptor complex composed of CNTFR-alpha, WSX-1 (IL-27R-alpha), and glycoprotein 130 (gp130), as well as formyl peptide-like receptors (FPRL1, FPRL2). Activation of this complex drives pro-survival cascades including the JAK/STAT3 and PI3K/Akt pathways. It also binds insulin-like growth factor-binding protein 3 (IGFBP-3) with high affinity, modulating IGFBP-3's pro-apoptotic signaling and its interaction with nuclear import machinery.
Intracellularly, humanin inhibits apoptosis at an early step by binding the pro-apoptotic protein Bax and preventing its translocation to mitochondria. It additionally suppresses c-Jun N-terminal kinase (JNK) activation through SH3-binding protein 5 (SH3BP5), blocking stress-induced apoptotic signaling in neurons. Together these mechanisms underlie its broad cytoprotective effect against amyloid-beta, oxidative stress, and hypoxia.
Practically, wild-type humanin has a short circulating half-life and does not cross the blood-brain barrier efficiently. Most preclinical therapeutic work uses the synthetic analog HNG (humanin S14G), which is roughly 1000-fold more potent. Research-chemical vendors typically sell the wild-type 24-amino-acid peptide, which has substantially less in vivo activity than the HNG data would suggest — a key caveat when interpreting mechanism summaries against what is actually being purchased.
Dosing protocols
Dosing & administration
Dosing reflects protocols reported in research and community literature for educational purposes. It is not medical advice or a recommendation. Most peptides here are not approved for human use.
Reconstitution
Supplied as lyophilized powder in sealed glass vials (commonly 5, 10, or 20 mg). Keep refrigerated/frozen before reconstitution; bring to room temperature before mixing. Reconstitute with bacteriostatic water (0.9% benzyl alcohol preserved) — a typical protocol is 2 mL added slowly down the vial wall to a 10 mg vial, yielding 5 mg/mL (at this concentration, 20 insulin units = 1 mg). Swirl gently, do not shake. Store reconstituted solution refrigerated and use within 2–4 weeks; discard if cloudy or discolored.
Beginner
- Dose
- 1–2 mg
- Frequency
- Once daily
- Timing
- Morning
- Duration
- 4–8 weeks on, followed by an equal or longer washout
- Route
- Subcutaneous
Use humanin alone (no stacking) to attribute any effects. Monitor subjective energy, sleep, recovery, and basic labs (fasting glucose, lipids) before and after. Effects are expected to be subtle to undetectable at physiologic doses.
Intermediate
- Dose
- 2–5 mg
- Frequency
- Once or twice daily
- Timing
- Morning (and evening if divided)
- Duration
- 8–12 weeks on, 4–8 weeks off, repeated 2–3x/year
- Route
- Subcutaneous
Twice-daily dosing is sometimes used to offset the short half-life, at the cost of doubled injection burden. Often combined with training and mitochondrial support. More detailed lab monitoring every 3 months.
Advanced
- Dose
- 5–10 mg
- Frequency
- Once daily
- Timing
- Morning
- Duration
- 12–24 weeks or semi-continuous with built-in breaks
- Route
- Subcutaneous
No evidence supports advanced ranges over intermediate; receptor-mediated signaling likely saturates. Reserved for experienced self-experimenters with comprehensive baseline data and quarterly/annual monitoring. HNG or stabilized analogs allow lower effective doses if available.
- All dosing is extrapolated from rodent studies and self-report community patterns — there are no human pharmacokinetic, safety, or efficacy data, and no FDA-approved administration protocol exists.
- Typical overall range spans 1–10 mg subcutaneously daily, with most users at 2–5 mg/day.
- Wild-type humanin's short half-life means once-daily dosing produces brief peaks; whether transient peaks or sustained receptor occupancy matters for effect is unknown.
- Rotate injection sites (abdomen, thighs, arms) using a 29–31 gauge insulin syringe. Timing (morning) and food status make no meaningful pharmacokinetic difference for subcutaneous injection.
- Short cycles (4–12 weeks on with 4–8 weeks off) are preferred over continuous indefinite dosing to limit cumulative exposure to an unvalidated peptide.
- Cost is significant: research-peptide humanin runs roughly $100–$300 per 10 mg vial, so 5 mg/day can reach thousands of dollars per year.
Evidence
Research & clinical studies (12)
Humanin inhibits neuronal cell death by interacting with a cytokine, IGFBP-3
Humanin binds IGFBP-3 with high affinity, inhibiting IGFBP-3-induced neuronal apoptosis, while IGFBP-3 potentiates humanin's rescue of neurons from amyloid-beta toxicity — a bidirectional neuroprotective interaction relevant to Alzheimer's pathology.
PMID 14561895SH3BP5 mediates the neuroprotective effects of humanin by inhibiting c-Jun N-terminal kinase
Identified SH3BP5 as a downstream effector of humanin that directly binds and inhibits JNK, suppressing pro-apoptotic signaling in neurons exposed to Alzheimer's-related insults.
PMID 23861391Humanin and MOTS-c Attenuate Atrial Fibrillation by Suppressing Fibrosis and Mitochondrial Dysfunction
In mouse models, humanin and MOTS-c attenuated atrial fibrillation by suppressing atrial fibrosis, reducing mitochondrial dysfunction, and lowering inflammatory markers, with an inverse correlation between peptide levels and disease severity in human AF patients.
PMID 42193373Humanin-G protects septic ARDS by mediating mitochondrial function in lung vascular endothelial cells
HNG protected lung vascular endothelial cells in septic acute respiratory distress syndrome by restoring mitochondrial function and reducing inflammation via inhibition of IL-6/STAT3 signaling.
PMID 42153337Humanin improved the rotenone-induced reactive oxygen species formation in PC12 cells by modulating the SIRT3/Nrf2/HO-1 signaling pathway
Humanin protected PC12 cells from rotenone-induced damage by reducing ROS formation through activation of the SIRT3/Nrf2/HO-1 antioxidant pathway.
PMID 42041115Humanin Mitigates Aβ-Induced Retinal Pigment Epithelium Injury via AMPK-Beclin1-Dependent Mitophagy
Humanin protected retinal pigment epithelium from amyloid-beta-induced injury by promoting AMPK-Beclin1-dependent mitophagy.
PMID 42333946Humanin Restores Metabolic Hormone Homeostasis of Leptin, Ghrelin, Irisin and Asprosin in Streptozotocin-Induced Diabetic Mice
In streptozotocin-induced diabetic mice, humanin restored homeostasis of the metabolic hormones leptin, ghrelin, irisin, and asprosin.
PMID 42346352Neuroprotective Effect of Intraperitoneal Humanin-G in Retinal Degeneration of Royal College of Surgeons Rats
Intraperitoneal HNG showed neuroprotective effects in a Royal College of Surgeons rat model of retinal degeneration.
PMID 42245781Mitochondrial-derived Peptides and Cytoprotection in ARDS: Emerging Therapeutic Promise of Humanin
Reviews the cytoprotective role of mitochondrial-derived peptides in acute respiratory distress syndrome and the emerging therapeutic promise of humanin.
PMID 42262906Humanin: a novel central regulator of peripheral insulin action (Muzumdar et al.)
In rodents, humanin administration improved insulin sensitivity, reduced fasting hyperglycemia, and protected against diet-induced metabolic dysfunction via central and peripheral mechanisms.
Naturally occurring mitochondrial-derived peptides are age-dependent regulators (Cobb et al.)
Plasma humanin declines progressively with age in humans — levels in 80-year-olds are roughly one-third of those in 20-year-olds — correlating with increased oxidative stress and metabolic dysfunction markers.
Human aging and circulating humanin response to exercise (Conte et al.)
Plasma humanin rises with acute exercise in humans; trained individuals have higher baseline and exercise-induced humanin, and aerobic fitness correlates with the humanin response.
Combinations
Stacking & blends
Mitochondrial-Derived Peptide Duo
Combined mitochondrial and metabolic support
MOTS-c is a companion mitochondrial-derived peptide with a metabolic focus; the two act through distinct pathways (humanin via cell-adhesion/cytoprotective signaling, MOTS-c via metabolic processes) and are labeled synergistic by community sources.
Longevity Peptide Stack
Broad aging and cellular-maintenance support
Epithalon is used for telomere/pineal support and NAD+ for mitochondrial cofactor support; combined with humanin's cytoprotective signaling in longevity-oriented protocols. No clinical evidence supports superior outcomes from stacking.
Mitochondrial Support Adjuncts
Reinforce cellular energy metabolism
Common mechanistically coherent additions in intermediate protocols to support mitochondrial function alongside humanin's mitokine signaling.
GH + Longevity Protocol
Growth-hormone axis plus cytoprotection
Self-experimenters combine humanin with GH secretagogues in longevity protocols; no clinical evidence for benefit, but no obvious contraindication in healthy adults with normal IGF-1 baseline.
Safety
Side effects & considerations
Commonly reported effects
Contraindications & cautions
- Active or recently treated malignancy or high cancer risk (humanin inhibits Bax-mediated apoptosis and activates STAT3 — pathways cancer cells can exploit)
- Pregnancy, breastfeeding, or attempting to conceive (no reproductive safety data)
- Children and adolescents (not studied in developmental age groups)
- Autoimmune disease on immunomodulatory therapy (uncharacterized interaction via FPRL receptors)
- Transplant recipients on immunosuppression (potential rejection risk)
- Uncontrolled or unstable diabetes (insulin-sensitivity effects may interact with diabetes medications)
- Significant cardiovascular, hepatic, or renal impairment (effects and clearance uncharacterized)
No well-established contraindications exist because there is no completed interventional human trial; the safety profile in humans is unknown. Preclinical work has not flagged a consistent toxicity signal, and humanin appears well-tolerated in rodent and anecdotal use, but the contraindications above are theoretical concerns grounded in its mechanism. Anyone on prescription medication — especially insulin/secretagogues, corticosteroids, chemotherapy, immunomodulators, or anticoagulants — should consult a physician first.
FAQ
Humanin — common questions
What is humanin and where does it come from?
Humanin is a mitochondrial-derived peptide (commonly reported as 24 amino acids, sequence MAPRGFSCLLLLTSEIDLPVKRRA) encoded within the MT-RNR2 (mitochondrial 16S rRNA) gene. It was the first MDP ever described, identified in 2001 by Hashimoto and colleagues from a surviving region of an Alzheimer's patient's brain.
What does humanin do?
In cell and rodent models it is cytoprotective and anti-apoptotic — protecting cells from amyloid-beta toxicity, oxidative stress, and Bax-mediated apoptosis — with signaling through STAT3, IGFBP-3, and a CNTFR-alpha/WSX-1/gp130 receptor complex. It also improves insulin sensitivity in rodents. In humans, circulating humanin is measurable and declines with age, but that is biomarker data, not the result of administering the peptide.
Has humanin been tested in human clinical trials?
No. There are no completed Phase 1 or later interventional trials of exogenous humanin administration. The human evidence base is observational — correlating endogenous humanin levels with aging, exercise, and disease states. The therapeutic case rests on mechanism plus animal data plus an age-associated biomarker.
What is HNG and how does it differ from wild-type humanin?
HNG is humanin S14G, a synthetic analog with a glycine substitution at position 14 that increases potency roughly 1000-fold and improves stability. Most preclinical therapeutic studies actually use HNG, but research-chemical vendors typically sell the less potent wild-type peptide — so HNG dose-response data should not be assumed to apply to wild-type purchases.
Do humanin levels change with aging?
Yes. Plasma humanin declines progressively with age, with levels in 80-year-olds roughly one-third of those in 20-year-olds, and the decline correlates with increased oxidative stress and metabolic dysfunction. This is the foundation for the anti-aging hypothesis, though it has not been demonstrated in interventional trials.
Is humanin released during exercise?
Yes. Plasma humanin rises with acute exercise in humans, and trained individuals show higher baseline and exercise-induced levels, supporting its role as a mitochondrial-derived myokine (mitokine) mediating some systemic benefits of physical activity.
Is humanin FDA approved?
No. Humanin has no FDA approval, NDA, or IND. It is an investigational research peptide studied in cell and animal models and in human observational work, with no approved administration protocol. It is sold for research use only.
Should I use humanin if I have a history of cancer?
Anyone with active, recently treated, or high-risk cancer should not use humanin without explicit oncology guidance. It inhibits apoptosis via Bax binding and activates STAT3 — pathways cancer cells can exploit. There is no clinical evidence it accelerates cancer in humans, but the mechanism warrants conservative avoidance.
