# Humanin — Research Peptide Profile

> Humanin is a mitochondrial-DNA-encoded peptide that blocks cell death. Children of centenarians carry more of it, yet no human has received it in a trial.

Source: https://peptpedia.org/peptide/humanin | Published: 2026-09-18 | Last updated: 2026-09-18

Humanin is a small peptide made by your own mitochondria that helps cells resist programmed death. Discovered in 2001 during Alzheimer's research, it circulates at higher levels in children of centenarians and declines with age. Every interventional result so far is preclinical - no human has received humanin in a published trial.

## Overview

Humanin is a 24-amino-acid peptide encoded by a short open reading frame inside the 16S ribosomal RNA gene (MT-RNR2) of the mitochondrial genome, making it a founding member of the mitochondrial-derived peptide family alongside [MOTS-c](/peptide/mots-c). It was discovered in 2001 by Hashimoto and colleagues through an expression-cloning screen for factors that protect neurons from familial Alzheimer's disease genes and amyloid-beta, and a 2003 Nature paper showed it suppresses apoptosis by binding the pro-death protein Bax. Circulating humanin declines with age in humans, is reduced in Alzheimer's disease and the mitochondrial disorder MELAS, and is markedly higher in the children of centenarians, the observational result that tied humanin to human longevity. Interventional evidence is entirely preclinical: humanin or its potent S14G analog HNG protects neurons in culture, reduces infarct size in mouse cardiac ischemia-reperfusion, and improves metabolic healthspan markers in aged mice. The only pharmacokinetic study, in rodents, found a minutes-scale plasma half-life with no detectable brain penetration, and no human administration has been published.

## Molecular Profile

- **Category:** anti-aging
- **Molecular formula:** C119H204N34O32S2
- **Molecular weight:** 2687.2 g/mol
- **CAS number:** 330936-69-1
- **Amino acid sequence:** MAPRGFSCLLLLTSEIDLPVKRRA
- **Also known as:** HN, MT-RNR2 Peptide, HNG, S14G-Humanin, Mitochondrial-Derived Peptide Humanin
- **Half-life:** Minutes-scale in rodents after IP injection; longer in rats than in mice; no human data
- **Storage:** Store lyophilized at -20°C. Refrigerate reconstituted solution and use promptly.

## Mechanism of Action

Humanin acts through at least three receptor systems. Extracellularly it signals through formyl peptide receptor-like 1 (FPRL1/FPR2) and through a tripartite receptor complex of CNTFR, WSX-1, and gp130 that activates JAK2-STAT3 and PI3K-Akt survival pathways. Intracellularly, humanin binds Bax directly and prevents Bax translocation to the mitochondrial outer membrane, blocking cytochrome c release and the intrinsic apoptosis cascade (Guo 2003). It also associates with circulating IGFBP-3, and rodent work showed HNG treatment lowers IGF-1 and IGFBP-3 over time, indicating endocrine cross-talk that is uncharacterized in humans (Chin 2013). The S14G substitution analog HNG is markedly more potent than the native peptide in neuroprotection assays, and structure-activity mapping identified Cys8, Ser14, and the Pro3-to-Pro19 core as essential for rescue activity (Hashimoto 2001).

## Key Research Findings

- Humanin is encoded in the mitochondrial genome (16S rRNA gene MT-RNR2), making it one of the first discovered mitochondrial-derived peptides.
- Its core mechanism is direct binding to Bax, preventing Bax-driven mitochondrial apoptosis (Nature 2003).
- Children of centenarians have markedly higher circulating humanin than age-matched controls; levels decline with age and are reduced in Alzheimer's disease and MELAS.
- The only pharmacokinetic study (rodents) found a minutes-scale half-life and undetectable brain levels; no human has received humanin in a published trial.

## Safety & Tolerability

Humanin has never been administered to humans in a published study, so every safety statement rests on rodent work and human observational data. Its core mechanism, suppressing apoptosis, is exactly why caution applies: systemic anti-apoptotic activity could theoretically protect damaged or malignant cells, and this has never been tested.

**Human data status:** No human interventional data exist. Human evidence is observational only: circulating humanin correlates with familial longevity and is reduced in Alzheimer's disease and MELAS.

**Regulatory status:** Not approved by any regulatory agency; a preclinical research compound.

- The only pharmacokinetic study (rodents, intraperitoneal injection) found a minutes-scale plasma half-life, interspecies differences between mice and rats, and undetectable brain levels; no human PK, dose-finding, or safety-pharmacology data exist. (evidence tier: animal; [PMID 23836030](https://pubmed.ncbi.nlm.nih.gov/23836030/))
- Humanin suppresses apoptosis by binding Bax. A theoretical oncology concern follows: systemic anti-apoptotic signaling could impair clearance of damaged or malignant cells or blunt cytotoxic chemotherapy, and this risk has never been tested in any human setting. (evidence tier: theoretical; [PMID 12732850](https://pubmed.ncbi.nlm.nih.gov/12732850/))
- HNG treatment altered circulating IGF-1 and IGFBP-3 over time in mice, indicating endocrine cross-talk whose significance for human hormone physiology is unknown. (evidence tier: animal; [PMID 23836030](https://pubmed.ncbi.nlm.nih.gov/23836030/))
- Higher circulating humanin tracks with familial longevity and lower levels with disease states in observational human data; the correlation does not establish that raising humanin is safe or beneficial. (evidence tier: human-observational; [PMID 32575074](https://pubmed.ncbi.nlm.nih.gov/32575074/))

## Dosing Information (Research Context)

No human dosing protocol exists: humanin has never been administered to humans in a published trial. In the most cited animal regimen, the potent analog HNG was given intraperitoneally at 4 mg/kg twice weekly to 18-month-old female mice (Yen 2020), and pharmacokinetic studies used single intraperitoneal injections in mice and rats (Chin 2013). Community dosing protocols circulating online have no peer-reviewed human basis.

| Route | Dose | Frequency | Notes |
| --- | --- | --- | --- |
| Intraperitoneal (mouse) | 4 mg/kg (HNG analog) | Twice weekly | Yen 2020 regimen in 18-month-old female C57BL/6N mice; improved metabolic healthspan and inflammatory markers |
| Intraperitoneal (rodent PK) | Single injection | Acute | Chin 2013; minutes-scale plasma half-life, longer in rats than mice; brain levels undetectable |

## Researched Effects

- **Neuroprotection in Alzheimer-Relevant Models** (evidence: moderate): Humanin was discovered as a factor that abolishes neuronal death driven by familial Alzheimer's disease genes (mutant APP, PS1, and PS2) and amyloid-beta peptides (PMID: 11371646). Detailed characterization showed action specificity: humanin rescued neurons from a broad panel of Alzheimer-relevant insults but not from glutamate excitotoxicity, prion-fragment toxicity, or SOD1/polyglutamine toxicity, and mapping identified Cys8, Ser14, and the Pro3-to-Pro19 domain as essential, with the S14G analog HNG far more potent than the native sequence (PMID: 11717357). All of this work is in cell culture and animal models; no human neuroprotection trial exists.
- **Anti-Apoptotic Cytoprotection** (evidence: moderate): The core humanin mechanism is suppression of the intrinsic apoptosis pathway. Guo and colleagues demonstrated in Nature (2003) that humanin binds Bax directly and prevents Bax activation and translocation to mitochondria, blocking cytochrome c release (PMID: 12732850). Receptor-level work adds FPRL1/FPR2 and the CNTFR/WSX-1/gp130 tripartite complex driving JAK2-STAT3 and Akt survival signaling. This cytoprotective profile extends beyond neurons to cardiac and testicular cells in preclinical models, which is why humanin is studied as a general stress-resistance factor rather than a single-disease agent.
- **Cardiac Ischemia-Reperfusion Protection** (evidence: preliminary): In a mouse model of myocardial ischemia-reperfusion, acute intraperitoneal humanin given 1 hour before or at the time of reperfusion significantly reduced infarct size and cardiomyocyte apoptosis, with anti-apoptotic Akt signaling implicated as the mechanism (PMID: 20651283). This single-study finding positions humanin as a candidate cardioprotective agent for reperfusion injury, but it has not been independently replicated at scale and no large-animal or human work has followed.
- **Metabolic Healthspan in Aging Animals** (evidence: preliminary): Middle-aged (18-month-old) female mice treated with the potent analog HNG at 4 mg/kg intraperitoneally twice weekly showed improved metabolic healthspan parameters and reduced inflammatory markers, and humanin overexpression extended lifespan in C. elegans in a daf-16/FOXO-dependent manner (PMID: 32575074). Related work links humanin to insulin sensitization in rodent models. These are animal findings from a small number of laboratories, and the effect sizes and durability in higher species are unknown.
- **Human Longevity Association** (evidence: preliminary): Circulating humanin is substantially higher in the children of centenarians than in age-matched controls, is stable across life in the negligibly senescent naked mole-rat while declining with age in other species, and is reduced in patients with Alzheimer's disease and MELAS (PMID: 32575074). These correlations made humanin a longevity biomarker candidate. They are observational: no study has shown that raising humanin in humans changes any outcome, and the same research groups account for much of the published evidence base.

## Research Applications

- Alzheimer's Disease Research
- Mitochondrial-Derived Peptide Biology
- Aging and Longevity Research
- Ischemia-Reperfusion Injury Models
- Apoptosis Pathway Research

## Key Studies

### A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta

Hashimoto Y, Niikura T, Tajima H, et al. — *Proceedings of the National Academy of Sciences USA* (2001) — [PMID 11371646](https://pubmed.ncbi.nlm.nih.gov/11371646/)

The discovery paper. Using an expression-cloning screen of cDNA from the occipital lobe of an Alzheimer's disease patient, the authors isolated humanin as a secreted factor that abolished neuronal cell death induced by multiple familial Alzheimer's disease genes (mutant APP, PS1, PS2) and by amyloid-beta. The work introduced humanin as an endogenous neuroprotective peptide and founded the field of mitochondrial-derived peptide research.

### Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults

Hashimoto Y, Niikura T, Ito Y, et al. — *Journal of Neuroscience* (2001) — [PMID 11717357](https://pubmed.ncbi.nlm.nih.gov/11717357/) | [doi:10.1523/JNEUROSCI.21-23-09235.2001](https://doi.org/10.1523/JNEUROSCI.21-23-09235.2001)

The mechanistic companion study mapped humanin's structure-activity relationship. Humanin protected against an extended panel of Alzheimer-relevant insults but not against glutamate or prion-fragment toxicity, demonstrating action specificity. Cys8 and Ser14 proved essential, the Pro3-to-Pro19 domain carried the rescue activity, and the S14G-substituted analog HNG showed markedly stronger neuroprotective potency than the native peptide - the reason HNG, not native humanin, is used in most subsequent animal work.

### Humanin peptide suppresses apoptosis by interfering with Bax activation

Guo B, Zhai D, Cabezas E, et al. — *Nature* (2003) — [PMID 12732850](https://pubmed.ncbi.nlm.nih.gov/12732850/)

This Nature paper defined humanin's core intracellular mechanism: humanin binds the pro-apoptotic protein Bax directly, preventing Bax conformational activation and translocation from cytosol to the mitochondrial outer membrane, thereby blocking cytochrome c release and the intrinsic apoptosis cascade. It established humanin as a direct apoptosis modulator rather than a generic trophic factor and remains the mechanistic citation for the peptide's cytoprotective profile.

### Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice

Muzumdar RH, Huffman DM, Calvert JW, et al. — *Arteriosclerosis, Thrombosis, and Vascular Biology* (2010) — [PMID 20651283](https://pubmed.ncbi.nlm.nih.gov/20651283/) | [doi:10.1161/ATVBAHA.110.205997](https://doi.org/10.1161/ATVBAHA.110.205997)

In a mouse cardiac ischemia-reperfusion model, acute intraperitoneal humanin administered 1 hour before or at the time of reperfusion significantly reduced myocardial infarct size and cardiomyocyte apoptosis. The protection was linked to anti-apoptotic Akt signaling. The study extended humanin's cytoprotection from neurons to heart and suggested a peri-reperfusion therapeutic concept that has not yet been pursued in large animals or humans.

### Pharmacokinetics and tissue distribution of humanin and its analogues in male rodents

Chin YP, Keni J, Wan J, et al. — *Endocrinology* (2013) — [PMID 23836030](https://pubmed.ncbi.nlm.nih.gov/23836030/) | [doi:10.1210/en.2012-2004](https://doi.org/10.1210/en.2012-2004)

The only published pharmacokinetic study of humanin. Following intraperitoneal injection of HNG or the non-IGFBP-3-binding analog HNGF6A in mice and rats, plasma half-life was minutes-scale and varied by species (longer in rats than mice) and by analog. Humanin associates with IGFBP-3 in circulation, and HNG treatment lowered IGF-1 and IGFBP-3 over time. Tissue measurement in rats found the highest levels in plasma, detectable levels in liver, and undetectable levels in brain and heart, indicating negligible blood-brain barrier penetration after peripheral dosing.

### The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan

Yen K, Mehta HH, Kim SJ, et al. — *Aging (Albany NY)* (2020) — [PMID 32575074](https://pubmed.ncbi.nlm.nih.gov/32575074/) | [doi:10.18632/aging.103534](https://doi.org/10.18632/aging.103534)

A cross-species study linking humanin to longevity. Humanin overexpression extended C. elegans lifespan dependent on daf-16/FOXO; middle-aged mice treated twice weekly with HNG (4 mg/kg IP) improved metabolic healthspan markers and reduced inflammatory markers; circulating humanin declined with age across species but stayed stable in the negligibly senescent naked mole-rat; and children of centenarians had markedly higher circulating humanin than age-matched controls, while levels were reduced in Alzheimer's disease and MELAS. The paper supplies the principal human observational evidence tying humanin to longevity phenotypes.

## Frequently Asked Questions

### Is humanin the same peptide as MOTS-c?

No. Both are mitochondrial-derived peptides encoded by short open reading frames in mitochondrial DNA, which is why they are discussed together, but they come from different genes and act differently. Humanin is encoded in the 16S ribosomal RNA gene (MT-RNR2) and works mainly by suppressing apoptosis through Bax binding and STAT3/Akt survival signaling. MOTS-c is encoded in the 12S ribosomal RNA gene and acts through AMPK on metabolic homeostasis. They are complementary research subjects, not interchangeable compounds.

### Has humanin been tested in humans?

No human has received humanin in a published trial as of 2026. The human evidence is observational: circulating humanin is higher in children of centenarians and lower in Alzheimer's disease and MELAS (PMID: 32575074). Everything interventional - neuroprotection, cardioprotection, metabolic benefit - comes from cell culture and rodent studies, and no pharmacokinetic or dose-finding work exists in humans.

### What is HNG, and how does it differ from native humanin?

HNG is humanin with a single amino-acid substitution: glycine replacing serine at position 14 (S14G). Structure-activity mapping in the original characterization study showed this change makes the analog markedly more potent than native humanin in neuroprotection assays, which is why most animal studies use HNG rather than the native sequence (PMID: 11717357). When reading humanin research, checking whether the study used native humanin or HNG matters, because potency and dosing are not directly comparable.

### Does injected humanin reach the brain?

In the only pharmacokinetic study published, peripheral intraperitoneal injection of humanin analogs in rats produced measurable levels in plasma and liver but undetectable levels in brain (PMID: 23836030). Neuroprotection in animal models therefore likely reflects central administration in some paradigms, peripheral signaling, or concentrations below detection limits. Any claim that peripherally injected humanin acts directly on the human brain goes well beyond the evidence.

### Why is humanin linked to longevity?

Three findings converged: humanin overexpression extended lifespan in C. elegans through the daf-16/FOXO longevity pathway; circulating humanin declines with age in humans and several species but stays stable in the negligibly senescent naked mole-rat; and children of centenarians, who are themselves more likely to reach 100, carry markedly higher circulating humanin than age-matched controls (PMID: 32575074). These associations make humanin a longevity biomarker candidate. They do not show that supplementing humanin extends human life or healthspan.

## Related Peptides

- [MOTS-c](https://peptpedia.org/peptide/mots-c)
- [SS-31](https://peptpedia.org/peptide/ss-31)
- [Klotho](https://peptpedia.org/peptide/klotho)
- [Epithalon](https://peptpedia.org/peptide/epithalon)

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This content is for educational and research purposes only. It is not medical advice, and the compounds covered are research chemicals not approved for human use unless explicitly stated otherwise.

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