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The Peptide Effect
preclinicalNeuroprotection & Longevity

Humanin

Also known as: HN, Humanin peptide, rHumanin, [Gly14]-Humanin

Humanin is a 24-amino acid peptide encoded in the mitochondrial 16S ribosomal RNA gene, making it the first mitochondrial-derived peptide (MDP) ever discovered. Originally identified in 2001 from a cDNA library of surviving neurons in an Alzheimer's disease brain, Humanin has demonstrated powerful cytoprotective effects against amyloid-beta toxicity, apoptosis, and oxidative stress. It represents a paradigm shift in understanding mitochondria as active signaling organelles rather than mere powerhouses.

Key Facts

Mechanism
Humanin exerts its cytoprotective effects through multiple mechanisms. It binds directly to BAX (a pro-apoptotic protein), preventing its translocation to mitochondria and blocking the intrinsic apoptosis pathway. It also binds the formyl peptide receptor-like 1 (FPRL1/FPR2), activating ERK1/2 and STAT3 signaling cascades that promote cell survival. In metabolic regulation, Humanin binds IGFBP-3 (insulin-like growth factor binding protein 3), modulating insulin/IGF-1 signaling. Humanin also interacts with the trimeric CNTFR/WSX-1/gp130 receptor complex, activating STAT3-mediated transcription of survival genes. Circulating Humanin levels decline significantly with age, correlating with increased susceptibility to age-related diseases.
Research Status
preclinical
Half-Life
Short (minutes in plasma); analogs like S14G-Humanin (HNG) have extended activity
Molecular Formula
C₁₁₇H₁₈₅N₃₅O₃₂S₂
Primary Use
Neuroprotection & Longevity
Table of Contents

Benefits

  • Neuroprotective against amyloid-beta toxicity — protects neurons from Alzheimer's-related cell deathmoderate
  • Powerful cytoprotective and anti-apoptotic effects across multiple tissue typesmoderate
  • Cardioprotective — reduces infarct size and improves cardiac function in ischemia-reperfusion modelspreliminary
  • Improves insulin sensitivity and glucose homeostasis via IGFBP-3 and STAT3 modulationpreliminary
  • Potential longevity biomarker — circulating levels decline with age and correlate with healthspanpreliminary
  • Protects against oxidative stress-induced cell death in retinal and endothelial cellspreliminary

Dosage Protocols

RouteDosage RangeFrequencyNotes
Subcutaneous injectionExperimental — no established human doseVaries by research protocolAnimal research typically uses 1–4 mg/kg; human equivalent dosing not established
IntranasalExperimentalVaries by research protocolIntranasal delivery explored for CNS bioavailability in neuroprotection research
Subcutaneous injection (analog S14G-Humanin / HNG)Experimental — 1000× more potent than native HumaninVaries by research protocolHNG is the most commonly used analog in research due to enhanced stability and potency

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Generally well tolerated in all animal studies conducted to datecommon
  • Injection site irritation (in animal models)common
  • No significant adverse effects reported in preclinical literaturerare
  • Extremely limited human safety data — long-term effects entirely unknownserious
  • Theoretical concern: anti-apoptotic activity could interfere with tumor surveillanceserious

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Frequently Asked Questions

What was the first mitochondrial-derived peptide discovered?
Humanin was the first mitochondrial-derived peptide (MDP) ever identified, published in 2001 by Nishimoto and colleagues. They discovered it while screening a cDNA library from the occipital lobe of an Alzheimer's patient's brain, looking for factors that could protect neurons from amyloid-beta toxicity. This discovery challenged the long-held assumption that mitochondrial DNA only encoded 13 proteins, 22 tRNAs, and 2 rRNAs. It opened an entirely new field of research into mitochondrial-derived signaling peptides.
How does Humanin protect against Alzheimer's disease?
Humanin protects neurons through multiple mechanisms relevant to Alzheimer's. It directly inhibits amyloid-beta-induced cell death by blocking BAX-mediated apoptosis. It also binds IGFBP-3, which is involved in amyloid-beta toxicity signaling. Additionally, Humanin activates the STAT3 survival pathway through the CNTFR/WSX-1/gp130 receptor complex, promoting neuronal survival. In animal models, Humanin analogs (particularly HNG) have reduced amyloid plaque burden, improved memory, and decreased neuroinflammation. However, these findings have not yet been tested in human clinical trials.
Do Humanin levels change with age?
Yes, significantly. Circulating Humanin levels decline substantially with age in both rodents and humans. Studies have shown that plasma Humanin levels in elderly individuals can be less than half of those in younger adults. This age-related decline correlates with increased vulnerability to age-related diseases including Alzheimer's, cardiovascular disease, and type 2 diabetes. Some researchers have proposed Humanin as a biomarker of biological aging, though this concept requires further validation.
What are Humanin analogs and why are they used?
Native Humanin has a very short plasma half-life, limiting its therapeutic utility. Researchers have developed several analogs with improved stability and potency. S14G-Humanin (also called HNG or Humanin G) is the most widely used — it replaces serine at position 14 with glycine, resulting in approximately 1,000-fold greater potency. Other analogs include HNGF6A, which retains cytoprotective properties while being resistant to IGFBP-3 binding. These analogs are critical tools in preclinical research.
Is Humanin available for human use?
No. Humanin and its analogs are strictly research compounds. There are no FDA-approved Humanin therapies, no completed human clinical trials, and no established human dosing protocols. The peptide is available through research chemical suppliers, but the quality and purity of these products is highly variable. Anyone interested in Humanin should understand that it remains firmly in the preclinical research stage.

References

  1. 1
    Humanin, a newly identified neuroprotective factor: cloning and characterization of cDNAs from the brain of Alzheimer's disease patients(2001)PubMed ↗
  2. 2
    The mitochondrial-derived peptide humanin activates the ERK1/2, AKT, and STAT3 signaling pathways and has age-dependent signaling differences in the hippocampus(2016)PubMed ↗
  3. 3
    Humanin: a mitochondrial-derived peptide hormone that protects against disease and aging(2017)PubMed ↗
  4. 4
    Circulating levels of the mitochondrial-derived peptide humanin decline with age and are associated with metabolic health(2020)PubMed ↗

Last updated: 2026-02-14