Humanin: Mitochondrial Peptide Research
In 2001, a Japanese research team led by Ikuo Nishimoto was studying the brains of Alzheimer's patients -- not the damaged regions, but the parts that had survived. They were looking for genes that could protect neurons from amyloid-beta toxicity.
In 2001, a Japanese research team led by Ikuo Nishimoto was studying the brains of Alzheimer's patients -- not the damaged regions, but the parts that had survived. They were looking for genes that could protect neurons from amyloid-beta toxicity. What they found was unexpected: a tiny peptide, just 24 amino acids long, encoded not in the cell's nuclear DNA but in its mitochondrial genome. They named it humanin, chosen to reflect the molecule's potential to restore the humanity of patients losing themselves to dementia. (Hashimoto et al., 2001)
Humanin was the first mitochondrial-derived peptide (MDP) ever identified -- the first evidence that mitochondria were producing their own signaling molecules (Lee et al., 2016). In the two decades since, researchers have found that humanin levels decline with age, that centenarians carry higher levels than the general population, and that the peptide protects against cell death across multiple organ systems. The research spans Alzheimer's disease, cardiovascular aging, metabolic dysfunction, and longevity itself.
None of this has reached the clinic. Humanin remains a research peptide with no FDA-approved applications and no completed human clinical trials. But the preclinical evidence is substantial, and the biology is worth understanding.
Table of Contents
- Quick Facts
- What Is Humanin?
- Discovery: A Peptide from Mitochondrial DNA
- How Humanin Works: Mechanisms of Action
- Research Evidence
- Humanin Analogs
- Administration and Dosing
- Safety Profile and Side Effects
- Legal and Regulatory Status
- Limitations of Current Research
- Frequently Asked Questions
- The Bottom Line
Quick Facts
| Property | Detail |
|---|---|
| Full Name | Humanin (HN) |
| Type | Mitochondrial-derived peptide (MDP) |
| Length | 24 amino acids (cytosolic form); 21 amino acids (mitochondrial form) |
| Amino Acid Sequence | MAPRGFSCLLLLTSEIDLPVKRRA |
| Molecular Weight | ~2,687 Da |
| Gene | MT-RNR2 (within 16S ribosomal RNA gene, mitochondrial DNA) |
| Year Discovered | 2001 |
| Discovered By | Hashimoto et al. (Nishimoto laboratory, Japan) |
| Primary Actions | Anti-apoptotic, cytoprotective, insulin-sensitizing, neuroprotective |
| Notable Analog | HNG (S14G-humanin) -- approximately 1,000x more potent |
| FDA Status | Not approved; research use only |
| Related Peptides | MOTS-c, SS-31 (Elamipretide), SHLPs 1-6 |
What Is Humanin?
Humanin is a 24-amino-acid peptide encoded by the MT-RNR2 gene within the 16S ribosomal RNA region of mitochondrial DNA. It belongs to a recently identified class of molecules called mitochondrial-derived peptides (MDPs) -- small proteins produced from short open reading frames (sORFs) hidden within the mitochondrial genome.
The peptide's sequence -- MAPRGFSCLLLLTSEIDLPVKRRA -- breaks into three functional regions: a positively charged N-terminal segment (MAPR), a central hydrophobic core (GFSCLLLLTSEIDL), and a polar C-terminal tail (PVKRRA). This structure allows humanin to interact with both intracellular proteins and cell-surface receptors, giving it a dual mechanism that operates inside and outside cells simultaneously.
Humanin exists in two forms. When translated inside mitochondria, the peptide is 21 amino acids long. When translated in the cytosol, it reaches its full 24-amino-acid length. Both forms are biologically active.
What makes humanin notable is its conservation across species. It has been found in organisms from nematodes to naked mole rats to primates -- the most highly conserved of all known MDPs. Your body produces humanin right now, in tissues throughout the body. Circulating levels have been measured in plasma and cerebrospinal fluid. Those levels decline with age -- a pattern that has become central to research on this peptide and its connection to age-related disease.
Discovery: A Peptide from Mitochondrial DNA
Humanin's discovery involved three independent laboratories approaching the same molecule from different angles.
The Nishimoto laboratory published first. In 2001, Hashimoto and colleagues built a cDNA library from the surviving brain tissue of an Alzheimer's patient and screened for genes that could resist amyloid-mediated cell death. Multiple protective clones mapped to a single location: a 75-base-pair open reading frame within the 16S ribosomal RNA gene of mitochondrial DNA. The mitochondrial genome had been sequenced in 1981 -- for twenty years, no one had found a functional peptide encoded there. Humanin was the first.
Around the same time, the Reed laboratory found humanin while screening for proteins that interact with BAX (Guo et al., 2003), and the Cohen laboratory at UCLA identified it through a screen for proteins that bind IGFBP-3 (Ikonen et al., 2003). Three labs, three different experiments, one peptide.
This convergence also forced a rethinking of mitochondrial biology. The mitochondrial genome had been understood as encoding only energy-production machinery. The idea that mitochondria produce signaling peptides was new. Since humanin, additional MDPs have been found, including MOTS-c (Lee et al., 2015) and six small humanin-like peptides (SHLPs 1-6) (Miller et al., 2022).
How Humanin Works: Mechanisms of Action
Humanin operates through both intracellular and extracellular pathways -- an unusual feature for a peptide of its size. Research has identified several distinct mechanisms.
Intracellular: Blocking Programmed Cell Death
Inside cells, humanin's best-characterized function is preventing apoptosis (programmed cell death) through direct protein-protein interactions.
BAX binding. Humanin binds BAX, a pro-apoptotic protein in the Bcl-2 family. Normally, BAX moves from the cytoplasm to the outer mitochondrial membrane during apoptosis, forming pores that release cytochrome c and trigger cell death. Humanin retains the BAX complex in the cytoplasm, preventing this (Guo et al., 2003). It also binds related pro-apoptotic proteins Bid and BimEL (Luciano et al., 2005).
IGFBP-3 interaction. IGFBP-3 can independently trigger apoptosis by moving to the nucleus via importin-beta. Humanin binds to IGFBP-3's C-terminal domain, blocking nuclear translocation and suppressing IGFBP-3-mediated cell death (Ikonen et al., 2003; Bhajan et al., 2015).
Extracellular: Receptor-Mediated Signaling
When secreted outside the cell, humanin activates at least two receptor systems.
FPRL1/FPRL2 receptors. Humanin binds formyl peptide receptor-like 1 (FPRL1), a G-protein-coupled receptor, activating MAP kinase pathways (ERK1/2, ASK1, JNK). Through FPRL1, humanin can competitively block amyloid-beta from accessing the receptor -- directly relevant to Alzheimer's research (Harada et al., 2004).
Trimeric receptor complex (CNTFR/WSX-1/gp130). Humanin also binds a three-part receptor that activates the JAK2/STAT3 signaling cascade, one of the body's primary cell survival pathways. STAT3 activation has been linked to both neuroprotection and metabolic regulation (Hashimoto et al., 2009).
Metabolic Signaling
Humanin activates AMPK (AMP-activated protein kinase), a master metabolic regulator, and stimulates chaperone-mediated autophagy (CMA) -- the selective degradation of damaged proteins through lysosomal pathways. Gong et al. showed that humanin's protective effects are lost in CMA-deficient cells (Gong et al., 2018).
These overlapping mechanisms help explain why humanin research spans so many different disease areas.
Research Evidence
Alzheimer's Disease and Neuroprotection
Neuroprotection was humanin's first identified function, and it remains the most extensively studied.
In cell culture, humanin protects neurons from death induced by amyloid-beta, mutant presenilin-1, and mutant presenilin-2 -- three major proteins implicated in familial Alzheimer's disease (Hashimoto et al., 2001). In APP/PS1 transgenic mice (a standard Alzheimer's model), three months of HNG treatment significantly improved spatial learning and memory, reduced amyloid-beta plaque deposition, and dampened neuroinflammation -- even in animals with pre-existing amyloid pathology (Zhang et al., 2012).
In stroke models, HNG pretreatment reduced cerebral infarct volume by 54% when administered directly to the central nervous system and by 36% when given peripherally (Xu et al., 2006). The peptide suppressed inflammatory cytokines TNF-alpha, IL-1-beta, IL-6, and MCP-1 in cortical tissue.
Human observational data adds another dimension. A mitochondrial-wide association study (MiWAS) identified a SNP (rs2854128) in the humanin-coding region associated with reduced circulating levels and accelerated cognitive aging. When mice carrying the equivalent variant received humanin supplementation, their cognition improved -- linking the genetic finding directly to a functional outcome (Yen et al., 2018).
For more on peptides studied for brain health, see: Best Peptides for Cognitive Enhancement. Related neuroprotective peptides include Cerebrolysin, Selank, and Semax.
Cardiovascular Protection
Humanin has shown protective effects across several cardiovascular models, including atherosclerosis, ischemia-reperfusion injury, and age-related cardiac fibrosis.
A 2018 study in the American Journal of Physiology provided some of the most striking data (Qin et al., 2018). Mice began receiving twice-weekly HNG injections at 18 months of age and continued for 14 months. At 32 months -- extreme old age for a mouse -- treated animals showed significantly less myocardial fibrosis. Interstitial collagen deposition was 0.24% in untreated aged mice versus 0.07% in HNG-treated animals (compared to 0.02% in young controls). HNG also shifted the cardiomyocyte-to-fibroblast ratio back toward a younger profile.
In atherosclerosis, Oh and colleagues showed that humanin preserves endothelial function and slows plaque progression in ApoE-deficient mice. Population studies have found that patients with coronary heart disease have lower circulating humanin levels than healthy controls, and that levels correlate with preserved coronary endothelial function in humans (Widmer et al., 2013).
For related research, see: Best Peptides for Cardiovascular Health.
Metabolic Health and Insulin Sensitivity
The metabolic effects have been studied most thoroughly by Nir Barzilai's group at Albert Einstein College of Medicine.
Using hyperinsulinemic-euglycemic clamp technology (the gold standard for measuring insulin sensitivity), Muzumdar and colleagues (2009) showed that humanin infusion significantly improved insulin sensitivity in rats -- both hepatic and peripheral. The effect depended on hypothalamic STAT3 activation; blocking STAT3 in the hypothalamus eliminated the response.
A more potent analog, HNGF6A, dramatically improved insulin action in Zucker diabetic fatty rats -- a model of severe type 2 diabetes -- with a single dose. HNGF6A also increased glucose-stimulated insulin secretion from isolated pancreatic islets in a dose-dependent manner, through mechanisms independent of K-ATP channel activity (Kuliawat et al., 2013).
Humanin levels in the hypothalamus, skeletal muscle, and cortex decrease with age in rodents, and circulating levels fall with age in humans. Researchers have proposed that this decline contributes to age-related insulin resistance and type 2 diabetes.
Aging and Longevity
The most compelling data connecting humanin to human aging comes from centenarian studies. Barzilai's group found that offspring of centenarians have significantly higher circulating humanin levels than age-matched controls (Muzumdar et al., 2009). This propensity appears heritable, following a pattern similar to HDL cholesterol in long-lived families.
In C. elegans (roundworms), overexpression of the humanin homolog extends lifespan through the daf-16/FOXO pathway -- a conserved longevity mechanism (Yen et al., 2020). In mice, chronic HNG treatment starting in middle age improved metabolic healthspan and reduced inflammatory markers. The naked mole rat, famous for exceptional longevity and cancer resistance, maintains stable humanin levels throughout life -- unlike other rodent species where levels decline steadily (Yen et al., 2020).
For a broader look at longevity peptides, see: Best Peptides for Anti-Aging and Longevity. Related peptides in this space include Epitalon and SS-31.
Humanin Analogs
Because native humanin has a short half-life (approximately 30 minutes in mice) and relatively modest potency, researchers have developed several modified versions.
HNG (S14G-Humanin)
The most widely studied analog. Replacing serine with glycine at position 14 produces a peptide approximately 1,000 times more potent than native humanin (Hashimoto et al., 2001). HNG retains all of humanin's known mechanisms while dramatically improving efficacy. Most animal studies cited in this article used HNG rather than native humanin. Its plasma half-life is roughly 30 minutes in mice but over 4 hours in rats.
HNGF6A
A double-mutant combining the S14G change with a phenylalanine-to-alanine substitution at position 6, designed to optimize metabolic effects. HNGF6A showed dramatically improved insulin-sensitizing activity in both whole-animal and cell-culture experiments.
Colivelin
A fusion peptide combining a potent humanin analog with activity-dependent neurotrophic factor (ADNF). Neuroprotective at femtomolar concentrations -- roughly one million times more potent than native humanin (Chiba et al., 2005). Developed for Alzheimer's disease research but remains purely experimental.
Other Modifications
Researchers have created variants with D-amino acid substitutions (for protease resistance), PEGylated forms (for extended circulation time), and truncated versions to map functional domains. Structure-activity studies confirm that leucines at positions 9, 10, and 11 are critical for biological activity.
Administration and Dosing
There is no established human dosing protocol for humanin. All dosing data comes from animal research.
In animal studies, humanin and its analogs have been administered through multiple routes:
- Intracerebroventricular (ICV): 0.1 micrograms of HNG reduced stroke infarct volume by 54% in mice
- Intraperitoneal (IP): 4 mg/kg of HNG twice weekly for 14 months reduced cardiac fibrosis in aged mice
- Intravenous (IV): Continuous infusion improved insulin sensitivity in rat clamp studies
Some peptide therapy providers cite ranges of 2-10 mg per day via subcutaneous injection, cycled 2-4 weeks on and off. These figures are not backed by clinical trial data and should be viewed with appropriate skepticism. Blood-brain barrier penetration of exogenous humanin remains an active area of investigation.
Safety Profile and Side Effects
What the Research Shows
As an endogenously produced peptide -- something your body already makes -- humanin is expected to have reasonable biocompatibility. Animal studies using chronic dosing over many months have not reported significant adverse effects.
However, several important caveats apply:
No human clinical trials exist. The safety profile is entirely extrapolated from animal research.
Cancer concerns are theoretical but real. Humanin prevents cell death, which is beneficial for healthy tissues but could theoretically protect cancer cells too. A 2020 study in Scientific Reports found that exogenous humanin protected triple-negative breast cancer cells from apoptotic stimuli (Moreno Ayala et al., 2020). Humanin has also been found at elevated levels in gastric cancer (Shen et al., 2014). The long-term implications are unknown.
Injection-related risks apply to any injectable peptide: infection, dosing errors, and contamination from research-grade products.
No pregnancy or pediatric data exists.
Legal and Regulatory Status
United States: Humanin is not approved by the FDA for any therapeutic indication. It may be sold for research purposes (labeled "for research use only") but cannot be legally marketed or sold for human injection or consumption.
WADA/Sports: Humanin is not specifically named on the World Anti-Doping Agency prohibited list but falls under the S0 category (Non-Approved Substances), making it prohibited in competition. No therapeutic use exemptions (TUEs) are currently granted.
International: In Canada, the UK, EU, and Australia, humanin is legal for research but not approved for clinical use. Import restrictions may apply if the peptide is intended for human administration.
Regulation of peptides has been tightening. The FDA's 2023 actions on compounded peptides reflect a broader trend toward stricter oversight of unapproved peptide products. Humanin, as a molecule still in preclinical development, would need to complete the standard drug approval pathway -- including phase I, II, and III clinical trials -- before becoming available as a therapy.
Limitations of Current Research
The humanin literature, while extensive for a peptide discovered in 2001, has significant gaps that deserve honest acknowledgment.
No human clinical trials. All therapeutic evidence comes from cell culture, animal models, or human observational studies. Whether exogenous humanin supplementation produces meaningful benefits in humans remains unproven.
Animal-to-human translation uncertainty. The peptide's half-life varies threefold between mice and rats alone. Doses effective in rodents may not translate to humans predictably.
Short study durations. Most animal studies run weeks to months. Long-term consequences of chronic supplementation -- particularly effects on cancer surveillance -- have not been studied.
Biomarker reliance. Many studies report improvements in surrogate markers rather than hard outcomes like disease incidence or mortality.
The cancer question remains open. Until long-term cancer surveillance data exists from treated populations, the risk-benefit calculation stays incomplete.
Publication bias. Positive results are more likely to be published. The full scope of negative findings in humanin research is difficult to assess.
Frequently Asked Questions
What does humanin do in the body?
Humanin is a naturally occurring mitochondrial peptide that protects cells from programmed death, improves insulin sensitivity, and reduces inflammation. It works both inside cells (binding pro-apoptotic proteins like BAX and IGFBP-3) and outside cells (activating surface receptors that trigger survival signaling). Circulating levels decline with age.
Is humanin approved for medical use?
No. Humanin is not approved by the FDA or any other regulatory body for therapeutic use. No human clinical trials have been completed. All evidence of benefit comes from laboratory and animal studies.
What is the difference between humanin and HNG?
HNG (S14G-humanin) is a synthetic analog with a single amino acid change at position 14. This makes it approximately 1,000 times more potent than native humanin. Most published animal studies use HNG rather than the natural peptide.
How is humanin related to MOTS-c?
Both are mitochondrial-derived peptides from different genes. Humanin (from MT-RNR2) is primarily associated with cell protection. MOTS-c (from MT-RNR1) is better known for metabolic regulation and has been called an "exercise mimetic." Both decline with age and have shown life-extending properties in animal models.
Do centenarians have higher humanin levels?
Research from Nir Barzilai's group at Albert Einstein College of Medicine found that offspring of centenarians have significantly higher circulating humanin levels than age-matched controls (Muzumdar et al., 2009). This suggests a heritable component to humanin production. However, correlation does not prove causation -- higher levels may be a marker of better mitochondrial health rather than the direct cause of longer life.
Can humanin cause cancer?
This remains an open question. Humanin prevents apoptosis, and apoptosis is a natural defense against cancer. A 2020 study found that exogenous humanin promoted tumor progression in experimental triple-negative breast cancer (Moreno Ayala et al., 2020), and elevated humanin has been found in gastric cancer tissue (Shen et al., 2014). Whether chronic supplementation would increase cancer risk is unknown.
What are the side effects of humanin?
Animal studies using chronic dosing over many months have not reported significant adverse effects. However, no human safety data exists. Theoretical concerns include effects on cancer surveillance, immune modulation, and unknown long-term consequences. Injection-site reactions are possible with any injectable peptide.
The Bottom Line
Humanin was the first peptide discovered from the mitochondrial genome, and its connections to aging, neurodegeneration, cardiovascular disease, and metabolism are backed by a substantial body of preclinical work.
The centenarian data is provocative -- long-lived families produce more of this specific mitochondrial peptide. The animal data on Alzheimer's disease, cardiac fibrosis, and insulin sensitivity is consistent across multiple research groups. But the gap between preclinical promise and clinical reality remains wide. Humanin has not been tested in any well-controlled human trial. Its cancer implications are unresolved. Its pharmacokinetics in humans are unstudied.
For now, humanin is best understood as a window into how mitochondria communicate with the rest of the body -- and a reminder that the mitochondrial genome still has surprises to offer. Whether those surprises translate into therapies depends on clinical trials that have yet to begin.
This article is for educational purposes only and does not constitute medical advice. Humanin is not approved for human therapeutic use. Consult a qualified healthcare provider before considering any peptide-related interventions.
Last updated: February 2026