Humanin

Humanin is a 24-amino acid micropeptide. It is a mitochondrial-derived peptide (MDP) encoded by the mitochondrial DNA (16S ribosomal RNA gene, MT-RNR2). Humanin is known for its cytoprotective and neuroprotective roles, supporting cell survival during stress and aging.

Key Benefits

• Supports healthy aging by helping protect cells from age-related stress and damage.
• Promotes brain health and may help protect neurons from oxidative stress and toxic proteins.
• Supports metabolic function by improving insulin sensitivity and helping regulate glucose metabolism.
• Protects cells from apoptosis (programmed cell death), helping maintain cellular health under stressful conditions.
• Reduces oxidative stress by enhancing the body’s natural defense mechanisms against free radicals.
• Supports cardiovascular health by helping protect blood vessels and heart tissue from cellular damage.

FDA-Approved Uses

Humanin has no FDA-approved use. No Investigational New Drug (IND) applications are on public record. No human clinical trials are registered on ClinicalTrials.gov as of March 2026.

Regulatory status (as of May 2026)

• NOT on the FDA 503A Bulks List — no legal compounding pathway
• No PCAC review scheduled
• No IND or NDA filed by any company
• Available only as research-use-only chemical from grey-market vendors
• WADA S0 (Non-Approved Substances): Prohibited in competition
• ‘Any pharmacological substance with no current approval by any governmental regulatory health authority for human therapeutic use is prohibited at all times’ — WADA
• Note: Humanin is not NAMED on the list but falls under S0 category by default as an unapproved substance

Discovery context

• Discovered in 2001 by Hashimoto et al. at the University of Tokyo/RIKEN
• Isolated from an Alzheimer’s disease patient’s surviving brain tissue using functional expression screening
• Named ‘Humanin’ because it was associated with a surviving, functionally preserved neuron population
• FOUNDING MEMBER of the mitochondrial-derived peptide (MDP) family — predates MOTS-c discovery by 14 years

Conditions under research investigation:

• Alzheimer’s disease and neurodegeneration — primary research focus
• General aging / longevity — centenarian offspring data link
• Type 2 diabetes and insulin resistance (beta cell protection)
• Cardiovascular disease — cardiomyocyte cytoprotection
• Stroke and ischemia — neuroprotection
• Parkinson’s disease — dopaminergic cell protection
• Male fertility — testicular cell protection from chemotherapy
• Eye aging / retinal degeneration
• Metabolic syndrome

Trade Names in the USA and Manufacturers

No FDA-approved trade name or manufacturer in USA.

Discovery of Humanin

• Discovered by Hashimoto et al. (2001), University of Tokyo / RIKEN Research Institutes, Japan
• Published in PNAS: ‘A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta’
• Primary ongoing research: USC (University of Southern California) longevity research group (Pinchas Cohen et al.) and Albert Einstein College of Medicine

Key analog — HNG (S14G-Humanin / Humanin-G):

• Serine → Glycine substitution at position 14 of the native sequence
• Makes HNG approximately 1,000 times MORE POTENT than native Humanin
• Most published research studies use HNG, not native Humanin
• Research vendors typically sell HNG labeled as ‘Humanin-G’ or ‘HNG’
• When purchasing ‘Humanin’ from vendors, clarify whether you are receiving native Humanin or the HNG analog

Additional analog of Humanin

– HNGF6A: Further modified; ~10,000 times more potent than native Humanin; used in advanced preclinical research

US availability (as of May 2026):

• Grey-market research peptide vendors: Available as lyophilized powder (native Humanin and HNG analog)
• No licensed 503A compounding pharmacy access
• No active US clinical trials

Molecular identity:

• 24-amino acid peptide: MAPRGFSCLLLLTSEIDLPVKRRA
• Encoded by: 16S rRNA gene of MITOCHONDRIAL DNA (mtDNA)
• This is extraordinary — unlike virtually all other peptides which are encoded by nuclear DNA
• MW: ~2,700 Daltons (native Humanin)
• The mitochondrial origin is shared with MOTS-c — distinguishing both from nuclear-encoded peptides

Physiological context:
– Humanin is naturally present in human circulation and tissues
– Levels DECLINE significantly with age and in neurodegenerative disease states
– Centenarian offspring data (USC, Pinchas Cohen group): Offspring of centenarians have significantly HIGHER Humanin levels than age-matched controls — suggesting Humanin levels may contribute to exceptional longevity

Dosage

⚠️ No FDA-approved dosing. No human clinical trials. No established human dose.

Native Humanin vs. HNG analogs:
Most research studies use HNG (1,000x more potent). If community protocols reference doses that seem low, they may assume HNG potency. Always clarify which form is being used.

Community/research reported protocols (SC injection):

Native Humanin:
Typical dose: 5–10 mg per week
Divided into: 2–3 SC injections (e.g., Mon/Wed/Fri)
Cycle length: 2–4 weeks on
Rest period: 2–4 weeks off
Annual cycles: 2–4 per year

HNG (S14G-Humanin — 1,000x more potent):
Typical dose: 0.5–2 mg SC per injection
Frequency: 1–3x per week
Cycle: 2–4 weeks on / 2–4 weeks off
[Much lower doses needed vs. native Humanin due to potency advantage]

Timing:
Morning injections preferred — may support mitochondrial activation
Commonly cycled with MOTS-c for complementary mitochondrial MDP stack
Also combined with DHEA in some anti-aging protocols

Reconstitution:
Lyophilized powder; reconstitute with Bacteriostatic Water
Store lyophilized at -20°C
Reconstituted solution: 2–8°C; use within 14–21 days
HNG is more stable than native Humanin due to the S14G modification

Pricing

No FDA-approved commercial pricing.

Research peptide vendors (unregulated):
Native Humanin (1 mg vial): ~$30–$60
HNG (S14G-Humanin, 1 mg vial): ~$40–$80 (slightly more expensive due to modified synthesis)
Monthly cost varies widely:
– HNG at 1 mg 2x/week: ~$32–$64/month (affordable — low doses effective due to high potency)
– Native Humanin at 5 mg 3x/week: ~$200–$400/month

Humanin combined with MOTS-c (common longevity stack):
Combined monthly cost: ~$250–$600/month depending on doses and vendors

Note: HNG is generally the preferred form for research protocols due to ~1,000x potency advantage — requiring significantly less peptide mass per dose and thus being more cost-effective despite slightly higher per-mg cost.

Tips

• WADA S0 PROHIBITED: Humanin and its analogs are prohibited in competition under the ‘Non-Approved Substances’ category. No TUE is available since there is no approved therapeutic use. Athletes must not use during competition season if subject to testing.
• Clarify what you are purchasing: Most commercial ‘Humanin’ products are actually HNG (S14G-Humanin), which is ~1,000x more potent.
• The USC centenarian offspring finding is scientifically compelling: Higher Humanin levels correlate with exceptional longevity. However, correlation ≠ causation — higher Humanin may be a MARKER of longevity mechanisms, not the cause.
• The anti-apoptotic mechanism (BAX antagonism) is Humanin’s key cytoprotective feature — but it also raises the same theoretical cancer concern as other anti-apoptotic compounds.
• Humanin has insulin-sensitizing effects — monitor blood glucose carefully if on insulin, sulfonylureas, or other hypoglycemic agents. The hypoglycemia risk is lower than IGF-1 LR3 but real.
• Humanin + MOTS-c is the most scientifically coherent MDP stack: Humanin handles neuroprotection and anti-apoptosis; MOTS-c handles AMPK-mediated metabolic reprogramming.

Side Effects

⚠️ No human clinical trial safety data exists. No completed Phase 1 human trials.

From animal studies and community reports:

Generally excellent tolerability profile in animal studies:
– No significant toxicity at research doses in multiple animal species
– Blood panels remained normal in treated animals
– No weight loss or organ toxicity consistent with toxic compounds

Commonly reported in community use:
– Injection site reactions: Redness, mild swelling, minor discomfort (most common)
– Mild transient fatigue (first 24 hours post-injection; uncommon)
– Occasional mild headache
– Rare lightheadedness: Particularly when stacked with AMPK activators (MOTS-c, metformin) on an empty stomach — insulin-sensitizing effect interaction

Theoretical / mechanism-derived concerns:
– Anti-apoptotic concern (BAX antagonism): Humanin blocks BAX-mediated apoptosis
→ In healthy neurons: PROTECTIVE (prevents unnecessary death)
→ In cancer cells: Could theoretically protect cancer cells from apoptosis
→ This is the same theoretical oncological concern raised for Pinealon (caspase-3 inhibition)
– Insulin-sensitizing effects: Glucose-lowering potential; clinical hypoglycemia risk if combined with insulin/sulfonylureas
– Immunological effects at pharmacological doses: Not fully characterized — pharmacological doses may exceed endogenous concentrations by orders of magnitude

⚠️ Long-term human safety: Entirely unknown. No chronic studies in humans.

Contraindications

No formal FDA contraindications (no approved label; no human trials).

Based on mechanism:

Absolute avoid:
– Active malignancy: BAX antagonism / anti-apoptotic mechanism — theoretical cancer cell survival promotion
Oncologist consultation required before any use in cancer patients
– Athletes in competition: WADA S0 prohibited — absolute contraindication for tested athletes
– Pregnancy and breastfeeding: No safety data; not recommended

Strong caution:
– Patients on insulin, sulfonylureas, or other hypoglycemic agents: Insulin-sensitizing effects → hypoglycemia risk; monitor blood glucose carefully
– Patients undergoing chemotherapy: Anti-apoptotic effects may theoretically protect cancer cells from chemotherapy-induced death; consult oncologist
– Hypersensitivity to Humanin, HNG, or excipients

Combination precaution:
– Combined MOTS-c + Humanin on empty stomach: Both have metabolic/glucose-modulating effects; combined effect on blood glucose requires monitoring
– Concurrent mitochondrial-targeting drugs (SS-31/elamipretide, etc.): Interactions not characterized

Pharmacology

Humanin is a 24-amino acid peptide encoded within the 16S rRNA gene of mitochondrial DNA — the founding member of the mitochondrial-derived peptide (MDP) family. Discovered in 2001 by Hashimoto et al. from functional expression screening of human brain tissue from an Alzheimer’s disease patient.

Mitochondrial encoding (extraordinary property):
– Unlike virtually all other known human peptides (encoded by nuclear DNA), Humanin is encoded by mtDNA
– Shares this mitochondrial origin with MOTS-c — the other major characterized MDP
– Mitochondrial encoding and local synthesis may allow Humanin to serve as an intra-organelle stress signal

Native sequence: MAPRGFSCLLLLTSEIDLPVKRRA
MW: ~2,700 Daltons
Physiological levels: Present in human plasma and cerebrospinal fluid; detectable in tissues
– Levels decline with aging and in neurodegenerative conditions
– Centenarian offspring: Significantly higher Humanin levels than age-matched controls (USC, Pinchas Cohen)

Key analog — HNG (S14G-Humanin):
– Single amino acid substitution: Serine (Ser) → Glycine (Gly) at position 14
– Result: ~1,000x greater potency than native Humanin in neuroprotection assays
– Mechanisms of potency increase: Improved receptor binding; reduced degradation
– Used in most published research studies

Stability: Native Humanin has moderate stability; HNG improved due to S14G substitution
Storage: Lyophilized at -20°C; stable in solution 14–21 days at 4°C

Mechanism of action

Humanin exerts cytoprotective effects through four primary mechanisms:

1. BAX Antagonism — Anti-Apoptotic (primary cytoprotective mechanism):
Humanin directly binds the pro-apoptotic protein BAX (BCL-2-Associated X protein)
→ Prevents BAX from inserting into the mitochondrial outer membrane
→ Blocks mitochondrial outer membrane permeabilization (MOMP)
→ No MOMP → no cytochrome c release → no caspase cascade activation → NO APOPTOSIS
This is the most direct and well-characterized anti-cell-death mechanism
Particularly relevant in neurons, cardiomyocytes, and beta cells where unnecessary cell loss is devastating

2. CNTFR/WSX-1/gp130 Trimeric Receptor Complex (JAK2/STAT3 pathway):
Humanin binds a trimeric receptor complex composed of CNTFR (Ciliary Neurotrophic Factor Receptor), WSX-1, and gp130
→ Activates JAK2 (Janus Kinase 2) → phosphorylates STAT3 (Signal Transducer and Activator of Transcription 3)
→ Activated STAT3 enters nucleus → promotes expression of neuroprotective and anti-apoptotic genes
→ Cell survival signaling in neurons, cardiomyocytes, immune cells

3. IGFBP-3 Binding (IGF-1 signaling modulation):
Humanin binds insulin-like growth factor binding protein-3 (IGFBP-3) — a pro-apoptotic signaling protein
→ Blocks IGFBP-3’s pro-apoptotic nuclear translocation
→ Reduces IGFBP-3-mediated cell death pathway
→ Additional anti-apoptotic effect independent of BAX pathway

4. Formyl Peptide Receptor Activation (FPRL1/FPRL2):
Humanin acts as an agonist at formyl peptide receptors FPRL1 and FPRL2
→ Anti-inflammatory signaling in macrophages and microglia
→ Reduces neuroinflammation
→ May contribute to Alzheimer’s protective effects via reduction of microglial inflammation

5. Mitochondrial Function Optimization:
Reduces ROS production by optimizing electron transport chain efficiency
→ Decreases oxidative stress at the mitochondrial level
→ Protects mitochondrial DNA from oxidative damage

6. Insulin Sensitization:
Improves insulin receptor signaling in peripheral tissues and pancreatic beta cells
→ Beta cell survival support (relevant to Type 2 diabetes)
→ Modest glucose-lowering effect

Result Claims from Different Companies

Hashimoto et al. / University of Tokyo (discovery and initial characterization, 2001):
– PNAS 2001: Humanin identified as ‘a rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta’
– Demonstrated rescue of neurons from multiple Alzheimer’s-associated insults (APP mutations, PS1/PS2 mutations, amyloid-beta toxicity)
– Established the founding concept of mitochondrial-derived neuroprotective peptides

USC Longevity Institute (Pinchas Cohen group — primary ongoing research):
– Centenarian offspring study: Offspring of centenarians have significantly HIGHER plasma Humanin levels than age-matched controls — first evidence linking Humanin to exceptional human longevity
– Multiple studies establishing Humanin decline with aging and Alzheimer’s disease progression
– Humanin analog (HNG) studies: Enhanced neuroprotection in Alzheimer’s disease mouse models

Albert Einstein College of Medicine:
– Cardiac protection studies: Humanin protects cardiomyocytes from ischemia-reperfusion injury
– Metabolic studies: Humanin improves insulin sensitivity and protects beta cells in diabetic animal models

Male fertility research:
– Zhang et al.: HNG protected male germline cells from chemotherapy (cisplatin)-induced damage in animal models

2026 research assessment (PeptideDeck):
‘Humanin is the founding member of mitochondrial-derived peptides, with broad cytoprotective effects. Research focuses on Alzheimer’s, diabetes, cardiovascular disease, and aging. No FDA approval, no completed Phase 2 or 3 human trials as of May 2026.’

⚠️ KEY LIMITATIONS:
– No human RCTs for any indication
– All efficacy data from in vitro cell studies and animal models
– No IND applications filed; no clinical trial registrations on ClinicalTrials.gov
– Translation from animal to human results not validated
– WADA S0 prohibited

Disclaimer

This content about “Humanin” is for informational and educational purposes only, is not medical advice, does not replace consultation with a licensed healthcare professional, and affiliate links may result in compensation at no additional cost to you.