Humanin
Humanin (HN / [Gly14]-Humanin / HNG)
Also known as: HN, HNG, [Gly14]-Humanin, Humanin G, Humanin peptide
Prompted by Jack Butcher (Visualize Value) · AI-authored by Claude · Research-sourced
The first identified mitochondrial-derived peptide — a 24-amino acid cytoprotective factor that declines with age. Children of centenarians maintain higher levels, linking it to longevity.
Quick Facts
Research compound only. Not approved for human therapeutic use in any country. All data is preclinical or observational. Endogenous Humanin levels are studied as biomarkers of aging.
Overview
Humanin is a 24-amino acid peptide encoded within the mitochondrial genome (16S ribosomal RNA gene, MT-RNR2). Discovered in 2001 by Nishimoto and colleagues during a screen for factors protecting neurons against Alzheimer's disease-related toxicity, it was the first identified mitochondrial-derived peptide (MDP) — a class of signaling molecules encoded in the mitochondrial DNA that exert cytoprotective effects throughout the body.
Humanin has demonstrated broad cytoprotective, anti-apoptotic, and anti-inflammatory properties across multiple organ systems and disease models. Circulating Humanin levels decline with age, and this decline correlates with age-related diseases including Alzheimer's disease, cardiovascular disease, and type 2 diabetes.
The most studied analog is [Gly14]-Humanin (HNG), in which the serine at position 14 is replaced with glycine, producing a variant approximately 1,000 times more potent than native Humanin. HNG is the primary form used in research studies due to its enhanced activity and improved stability.
Mechanism of Action
Humanin exerts its effects through multiple receptor systems and intracellular signaling pathways. The primary receptor is a heterotrimeric complex composed of CNTFR (ciliary neurotrophic factor receptor), WSX-1, and gp130. Activation of this receptor complex triggers the JAK/STAT3 signaling pathway, which promotes cell survival gene expression and suppresses apoptotic signaling.
Humanin also binds to FPRL1 (formyl peptide receptor like-1) and FPRL2, members of the formyl peptide receptor family involved in innate immunity and inflammation. Activation of these receptors mediates Humanin's anti-inflammatory effects.
Intracellularly, Humanin directly interacts with Bax (Bcl-2-associated X protein), a pro-apoptotic protein, preventing its translocation to the mitochondrial outer membrane. This interaction blocks the intrinsic apoptotic cascade at an early stage, preventing cytochrome c release and downstream caspase activation.
Humanin also interacts with IGFBP-3 (insulin-like growth factor binding protein 3), which normally promotes apoptosis by sequestering IGF-1. By binding IGFBP-3, Humanin blocks its pro-apoptotic effects and may modulate IGF-1 signaling.
Additionally, Humanin activates AMPK (AMP-activated protein kinase) signaling, improving cellular energy metabolism and promoting autophagy. It reduces endoplasmic reticulum stress and oxidative stress through upregulation of antioxidant enzyme expression.
Research Summary
Humanin was discovered through functional screening for factors that protect against amyloid-beta (Abeta) toxicity. Nishimoto et al. (2001) identified it as a gene product that rescued neurons from Abeta-induced cell death, immediately connecting it to Alzheimer's disease research.
Neuroprotection studies have been extensive. Humanin and HNG protect against toxicity from amyloid-beta peptides, mutant presenilin-1, and mutant APP (amyloid precursor protein) — the three major genetic causes of familial Alzheimer's disease. Protection occurs at nanomolar concentrations (HNG at picomolar concentrations).
Cardiovascular research shows that Humanin protects cardiomyocytes against oxidative stress and ischemia-reperfusion injury. In mouse models of myocardial infarction, HNG administration reduced infarct size, preserved cardiac function, and reduced cardiomyocyte apoptosis.
Metabolic research reveals that Humanin improves insulin sensitivity and glucose homeostasis. HNG treatment in diet-induced obese mice improved glucose tolerance and reduced hepatic steatosis. Circulating Humanin levels are inversely correlated with insulin resistance in human observational studies.
Aging biomarker studies from the Leiden Longevity Study and other cohorts demonstrate that higher circulating Humanin levels associate with longevity. Children of centenarians have higher Humanin levels than age-matched controls, suggesting a protective role in healthy aging.
Limitations: All therapeutic data is preclinical. The endogenous peptide has a very short half-life. Exogenous administration protocols are not established for humans. Large-scale human studies are epidemiological, not interventional.
Key References
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 (2001) · 10.1073/pnas.101032998
The discovery paper of Humanin. Identified the peptide as a factor encoded in the mitochondrial genome that rescues neurons from cell death induced by amyloid-beta and familial Alzheimer's disease gene mutations.
The mitochondrial-derived peptide humanin protects RPE cells from oxidative stress, senescence, and outer retinal degeneration
Sreekumar PG, et al. · Redox Biology (2016) · 10.1016/j.redox.2016.01.004
Demonstrated that Humanin protects retinal pigment epithelium cells from oxidative stress-induced senescence and degeneration, with implications for age-related macular degeneration.
Humanin: a mitochondrial-derived peptide is a novel biomarker of aging and longevity
Muzumdar RH, et al. · Aging Cell (2009) · 10.1111/j.1474-9726.2009.00505.x
Established that circulating Humanin levels decline with age in mice and humans, and that higher levels correlate with improved metabolic health and longevity markers.
Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid beta in rats
Tajima H, et al. · Journal of Neuroscience Research (2005) · 10.1002/jnr.20340
In vivo study demonstrating that Humanin administration attenuated amyloid-beta-induced cognitive deficits and neuronal damage in rats, supporting its therapeutic potential for Alzheimer's disease.
Protocols
Neuroprotection / longevity (research reference)
No established human dosing. [Gly14]-Humanin (HNG) is preferred over native Humanin due to approximately 1,000-fold greater potency and improved stability. Community doses are extrapolated from animal studies using allometric scaling. Most animal studies used intraperitoneal injection.
Animal research reference
Dosing used across published rodent studies. HNG (Gly14 analog) is used in most research. Native Humanin requires approximately 1,000x higher doses for equivalent effects. These are animal research parameters, not human dosing guidelines.
Side Effects & Safety
| Frequency | Effect |
|---|---|
| common | Injection site irritation Mild local reaction at injection site including redness and transient discomfort. |
| uncommon | Hypotension Humanin has vasodilatory and cardioprotective effects that could theoretically lower blood pressure in susceptible individuals. |
| rare | Gastrointestinal effects Nausea or digestive changes. Limited reporting in research settings. |
| rare | Hypoglycemia Humanin enhances insulin sensitivity — individuals on glucose-lowering medications should exercise caution. |
Contraindications
- —Active cancer (anti-apoptotic peptides may theoretically protect tumor cells from cell death)
- —Pregnancy or breastfeeding (no safety data)
- —Concurrent use of insulin or sulfonylureas (potential additive hypoglycemia)
- —Known hypersensitivity to mitochondrial-derived peptides
Interactions
- —Insulin and glucose-lowering medications (Humanin improves insulin sensitivity — monitor for hypoglycemia)
- —Chemotherapy agents (anti-apoptotic effects may interfere with treatment-induced tumor cell death)
- —Other cytoprotective peptides (potential additive effects — limited data on combinations)
Reconstitution & Storage
Related Peptides
Humanin and MOTS-c are both mitochondrial-derived peptides but act through distinct mechanisms — Humanin is primarily cytoprotective and anti-apoptotic while MOTS-c activates AMPK for metabolic regulation. SS-31 stabilizes mitochondrial structure at the cardiolipin level. Together, these three peptides represent complementary approaches to mitochondrial aging: structural support (SS-31), survival signaling (Humanin), and metabolic regulation (MOTS-c).