Humanin
RecoveryPreclinicalAlso known as: HNG
Humanin is a 24-amino-acid peptide (MAPRGFSCLLLLTSEIDLPVKRRA) encoded within the mitochondrial 16S ribosomal RNA gene and translated from a short open reading frame that was not recognized as biologically active until 2001, when Hashimoto and colleagues identified it in a screen for factors that protect neurons from Alzheimer's disease-associated toxicity (Hashimoto et al., 2001). The discovery was methodologically elegant: using a cDNA library from the occipital lobe of a patient who had died of Alzheimer's disease but whose specific brain region had remained clinically unaffected, they identified a peptide that protected cultured neurons from beta-amyloid toxicity, and traced its origin back to an unexpected locus in the mitochondrial genome.
Overview
At A Glance
Humanin signals through a heterotrimeric cell-surface receptor complex consisting of ciliary neurotrophic factor receptor alpha (CNTFR-alpha), WSX-1 (also known as IL-27R-alpha), and glycoprotein 130 (gp130) (Ying et al., 2004; Hashimoto et al., 2009). This receptor complex is ex…
Mechanism of Action
Humanin signals through a heterotrimeric cell-surface receptor complex consisting of ciliary neurotrophic factor receptor alpha (CNTFR-alpha), WSX-1 (also known as IL-27R-alpha), and glycoprotein 130 (gp130) (Ying et al., 2004; Hashimoto et al., 2009). This receptor complex is expressed broadly across tissues, which explains why humanin has effects on neurons, cardiomyocytes, beta cells, hepatocytes, endothelial cells, and immune cells. Activation of the CNTFR-alpha/WSX-1/gp130 complex by humanin triggers JAK/STAT signaling, particularly STAT3 phosphorylation, which drives transcription of anti-apoptotic and cytoprotective genes including Bcl-2 family members, XIAP, and heat shock proteins. Humanin also binds formyl peptide receptor-like 1 (FPRL1, also called FPR2) and formyl peptide receptor-like 2 (FPRL2), which mediate some of its neuroprotective and anti-inflammatory effects through distinct G-protein coupled pathways (Ying et al., 2004). The peptide's most mechanistically well-characterized activity is direct binding to and inhibition of the pro-apoptotic protein Bax. Bax is a key mediator of the intrinsic apoptotic pathway; upon cellular stress, Bax translocates from the cytoplasm to the outer mitochondrial membrane, oligomerizes, and forms channels that release cytochrome c into the cytoplasm, triggering caspase activation and programmed cell death. Humanin binds Bax and prevents its mitochondrial translocation and oligomerization, effectively inhibiting the intrinsic apoptosis pathway at an early stage (Guo et al., 2003; Tajima et al., 2002; Zhai et al., 2005). This anti-apoptotic activity is why humanin protects neurons from beta-amyloid, why it protects cardiomyocytes from ischemia-reperfusion injury, and why it protects beta cells from cytokine-induced death. Humanin also binds insulin-like growth factor binding protein 3 (IGFBP-3), which modulates IGF-1 signaling and contributes to humanin's metabolic effects (Ikonen et al., 2003). The interaction with IGFBP-3 is relevant because IGFBP-3 has its own pro-apoptotic activities in some contexts, and humanin binding appears to neutralize some of these while preserving IGF-1 bioavailability. Downstream of receptor engagement, humanin activates multiple pro-survival pathways: PI3K/Akt signaling promoting cellular metabolism and inhibiting apoptosis; MAPK/ERK signaling supporting proliferation and differentiation; STAT3-mediated transcription of cytoprotective genes; and AMPK activation under metabolic stress conditions. The metabolic effects of humanin, which include enhanced insulin sensitivity, improved glucose disposal, and protection against diet-induced obesity, appear to involve central nervous system signaling via the hypothalamus as well as direct peripheral effects on skeletal muscle, liver, and adipose tissue (Muzumdar et al., 2009). Central humanin administration in rodents reduces food intake and improves glucose homeostasis, while peripheral administration improves insulin signaling in liver and muscle. The exercise-related effects of humanin are mediated through its interaction with the skeletal muscle and cardiac response to exertion. Plasma humanin rises with exercise in humans, correlates with cardiorespiratory fitness, and is elevated in endurance-trained individuals, suggesting it functions as an exercise-induced myokine or mitokine that contributes to the systemic benefits of physical activity (Conte et al., 2019). In models of stroke and traumatic brain injury, humanin and its analogs reduce infarct volume, preserve neuronal survival in the penumbra, and improve functional recovery through combined anti-apoptotic and anti-inflammatory mechanisms (Oh et al., 2011). The combination of receptor-mediated signaling and direct protein-protein interaction with Bax makes humanin mechanistically unusual among peptide therapeutics; most peptides work exclusively through receptor engagement, but humanin has both an extracellular mode (through its receptor complex and FPRL receptors) and an intracellular mode (through Bax binding and possibly other interactions with apoptotic machinery). This dual mechanism may explain why humanin has cytoprotective effects that are broader and more strong than would be expected from receptor signaling alone, but it also means that different analogs and different administration routes may access different modes of action to different degrees. HNG and other stabilized analogs may be more potent at the receptor complex than at Bax binding, or vice versa, which is one reason the preclinical data do not always translate cleanly across experimental systems.
Overview
Humanin is a 24-amino-acid peptide (MAPRGFSCLLLLTSEIDLPVKRRA) encoded within the mitochondrial 16S ribosomal RNA gene and translated from a short open reading frame that was not recognized as biologically active until 2001, when Hashimoto and colleagues identified it in a screen for factors that protect neurons from Alzheimer's disease-associated toxicity (Hashimoto et al., 2001). The discovery was methodologically elegant: using a cDNA library from the occipital lobe of a patient who had died of Alzheimer's disease but whose specific brain region had remained clinically unaffected, they identified a peptide that protected cultured neurons from beta-amyloid toxicity, and traced its origin back to an unexpected locus in the mitochondrial genome. The finding launched an entire field — mitochondrial-derived peptides or MDPs — that now includes humanin, MOTS-c, SHLP1 through SHLP6, and related small peptides encoded within mitochondrial DNA that have systemic endocrine and autocrine signaling functions. Humanin itself has since been shown to protect cells from a range of stressors including beta-amyloid toxicity, Bax-induced apoptosis, oxidative stress, hypoxia-reoxygenation, and serum starvation (Guo et al., 2003; Tajima et al., 2002; Zhai et al., 2005). It also has metabolic effects including improved insulin sensitivity, enhanced glucose disposal, and protection against atherosclerosis in mouse models (Muzumdar et al., 2009). Plasma humanin concentrations are relatively high in young humans and decline with age, which has prompted speculation that restoring humanin to youthful levels could be a longevity intervention (Cobb et al., 2016). The practical reality of humanin as a research peptide is more complicated than the mechanism summary suggests. The endogenous peptide has a short circulating half-life (minutes), is rapidly cleared, and does not cross the blood-brain barrier efficiently in its native form. Synthetic analogs with substitutions to improve stability and potency have been developed — the most studied is HNG (humanin S14G), which is roughly 1000-fold more potent than wild-type humanin in several assays and has been used in most of the preclinical therapeutic work (Hashimoto et al., 2001; Yen et al., 2013). Other analogs with different substitution patterns (HNA, [Gly14]-HN, colivelin which fuses humanin with the activity-dependent neurotrophic factor peptide) have been generated for various experimental purposes. What is being sold as "humanin" by research-chemical peptide vendors is typically the wild-type 24-amino-acid sequence, not HNG, and the wild-type peptide has substantially less in vivo activity than the published HNG data would suggest. Consumers reading mechanism summaries that cite HNG mouse studies and then buying wild-type humanin are effectively purchasing a different compound than the one described in the research. Humanin has not been developed as an FDA-approved drug and has no human trial data establishing a therapeutic dose or efficacy profile. It remains an investigational peptide with strong mechanistic rationale, extensive preclinical evidence, and no clinical validation. This entry covers what the peptide actually does, how it signals through its receptor complex, what the animal data show in models of aging, neurodegeneration, diabetes, and cardiovascular disease, where the evidence is strongest and where it is thin, and what realistic use looks like for someone interested in mitochondrial-derived peptide biology. If the goal is neuroprotection or metabolic improvement, FDA-approved interventions (lifestyle, approved medications) should be fully explored first. If the goal is participating in the cutting edge of mitochondrial peptide research as a self-experimenter, this page is the most honest summary available of what the evidence does and does not support.
Chemical Information
IUPAC Name
Met-Ala-Pro-Arg-Gly-Phe-Phe-Ser-Cys-Leu-Leu-Leu-Thr-His-Ser-Glu-Ile-Asp-Leu-Pro-Val-Lys-Arg-Arg-Ala
CAS Number
312781-62-3
Molecular Formula
C127H204N34O35S
Molecular Mass
2816.29 g/mol
Dosing & Protocols
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Interactions
Interaction Matrix
Contraindications
Humanin is a mitochondrial-derived peptide with cytoprotective and anti-apoptotic activity, and the contraindications reflect conditions where inhibiting apoptosis or modulating metabolic signaling could be problematic. The most significant theoretical contraindication is active malignancy or recent cancer treatment. Humanin inhibits Bax-mediated apoptosis and activates STAT3 signaling, both of which are pathways that cancer cells can exploit to evade normal cell death mechanisms. There is no clinical evidence that humanin accelerates cancer progression in humans, but the mechanism is a reasonable concern, and anyone with active cancer, recently treated cancer, or high cancer risk should discuss humanin with an oncologist before use. This applies particularly to cancers with known dependence on Bax-related pathways (some leukemias, breast cancer, glioma) and to those on surveillance after treatment where any intervention that might favor tumor survival warrants caution. Pregnancy and breastfeeding are contraindications because no reproductive safety data exist in humans, and the effects of exogenous humanin on placental function, fetal development, and neonatal physiology are entirely uncharacterized. Anyone trying to conceive should also avoid humanin because effects on gametogenesis, implantation, and early embryonic development are unknown. Children and adolescents should not use humanin because the peptide has not been studied in developmental age groups, and metabolic and growth-related signaling during development could be altered in unpredictable ways. Autoimmune disease on immunomodulatory therapy is a relative contraindication — humanin modulates inflammatory signaling through FPRL1/FPRL2 receptors and affects immune cell apoptosis, and the interaction with immunomodulatory drugs (biologics targeting TNF, IL-6, IL-17, IL-23; conventional DMARDs; corticosteroids) is not characterized. Patients with rheumatoid arthritis, lupus, inflammatory bowel disease, psoriasis, multiple sclerosis, or other autoimmune conditions on active treatment should discuss humanin with their treating specialist before use. Transplant recipients on immunosuppression should avoid humanin because any immune modulation is a potential rejection risk. Active infection is a relative contraindication — cytoprotective signaling that protects host cells may theoretically also protect pathogens in infected cells, though this is speculative. Acute severe infection is not a time to experiment with immunomodulatory peptides. Significant cardiovascular disease — unstable angina, recent myocardial infarction, decompensated heart failure, significant arrhythmia — warrants caution because peptide effects on cardiac tissue in disease states have not been characterized, and any peptide can theoretically alter hemodynamics or tissue responses. Patients with stable cardiovascular disease, appropriately medicated, are more likely to tolerate humanin, but the decision should involve a cardiologist. Hepatic impairment (active hepatitis, cirrhosis, significant elevations in liver enzymes) warrants caution because peptide metabolism and clearance may be altered, and liver stress responses involving apoptosis are disease-relevant. Renal impairment similarly warrants caution for clearance reasons. Bleeding disorders and anticoagulant therapy are not clear contraindications for subcutaneous peptide injection (the volumes are small and the injection sites are not highly vascular), but prolonged oozing or bruising at injection sites warrants evaluation. Uncontrolled diabetes is a relative contraindication because humanin has effects on insulin sensitivity that may interact unpredictably with exogenous insulin or other diabetes medications; patients with well-controlled diabetes on stable regimens may use humanin with monitoring, but unstable glycemia is not the right context for adding uncharacterized peptides. Medications that warrant discussion with a physician before humanin use include: insulin and insulin secretagogues (hypoglycemia risk); sulfonylureas; meglitinides; GLP-1 agonists (appetite and glucose effects may overlap); corticosteroids (apoptosis-related effects); chemotherapy agents; immunomodulators; anticoagulants (bleeding at injection sites); psychiatric medications with narrow therapeutic windows; and any drug with known apoptosis-modulating activity. The general principle is that humanin is an endogenous peptide with a benign-looking safety profile in rodent studies and anecdotal human use, but the absence of controlled clinical trials means that any patient on any prescription medication should have their physician's input before starting, and the burden of demonstrating safety in specific clinical contexts falls on the patient and their clinician rather than on the published evidence base. Anyone considering humanin should also verify the legal and regulatory status of research peptides in their jurisdiction. Research peptides are sold for research use only, not for human consumption, and importation or use for personal consumption exists in a gray legal zone that varies by country and region. The contraindications section cannot address every individual situation, and the overall recommendation for anyone uncertain about their eligibility is to err toward not using humanin rather than using it without adequate information.
Research Disclaimer
This interaction data is compiled from published research and community reports. It may not be exhaustive. Always consult a healthcare professional before combining compounds.
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Protocols, calculator & safety for Humanin
Research Score
257 PubMed studies
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Quick Facts
Molecular Weight
2816.29 g/mol
CAS Number
312781-62-3
Trial Phase
Preclinical
Research Disclaimer
This information is for educational and research purposes only. Not intended as medical advice. Consult a healthcare professional before use.
Frequently Asked Questions
What is humanin and where does it come from?
Humanin is a 24-amino-acid peptide encoded within the mitochondrial 16S rRNA gene and translated from a short open reading frame in the mitochondrial genome. It was discovered in 2001 through a screen for factors that protect neurons from Alzheimer's disease toxicity (Hashimoto et al., 2001). It is one of several mitochondrial-derived peptides (MDPs) that include MOTS-c, SHLP1-6, and related small peptides with endocrine and autocrine signaling functions.
How does humanin protect cells from damage?
Humanin has two main mechanisms. First, it signals through a cell-surface receptor complex (CNTFR-alpha/WSX-1/gp130) and formyl peptide-like receptors (FPRL1, FPRL2) to activate pro-survival pathways including JAK/STAT3 and PI3K/Akt (Ying et al., 2004). Second, it directly binds the pro-apoptotic protein Bax and prevents its translocation to mitochondria, inhibiting the intrinsic apoptosis pathway at an early stage (Guo et al., 2003; Zhai et al., 2005).
Do humanin levels change with aging?
Yes. Plasma humanin concentrations in humans decline progressively with age, with levels in 80-year-olds approximately one-third of levels in 20-year-olds, and the decline correlates with increased markers of oxidative stress and metabolic dysfunction (Cobb et al., 2016). This observation is the foundation for the hypothesis that restoring humanin to youthful levels might have anti-aging effects, though this has not been demonstrated in interventional trials.
Has humanin been tested in human clinical trials?
No published Phase 1 or later interventional trials of exogenous humanin administration in humans have been completed as of April 2026. The human evidence base consists of observational studies correlating endogenous humanin levels with aging, exercise, and disease states. Several biotech companies have pursued humanin-related peptides for therapeutic indications, but none have publicly reported Phase 1 data or advanced to late-stage development.
What is HNG and how does it differ from wild-type humanin?
HNG is humanin S14G, a synthetic analog with a glycine substitution at position 14 that increases potency roughly 1000-fold in several assays and improves stability (Hashimoto et al., 2001). Most preclinical therapeutic studies of humanin actually use HNG rather than wild-type peptide. Research-chemical vendors typically sell wild-type humanin, which has lower potency than HNG, and users should not assume HNG dose-response data apply to wild-type peptide purchases.
Does humanin improve insulin sensitivity?
In rodent studies, humanin administration improves insulin sensitivity, reduces fasting hyperglycemia, and protects against diet-induced metabolic dysfunction (Muzumdar et al., 2009). The mechanism involves both central (hypothalamic) and peripheral (liver, muscle) effects on glucose homeostasis, and the peptide also binds IGFBP-3 to modulate IGF-1 signaling (Ikonen et al., 2003). Translation to human metabolic benefit has not been validated in clinical trials.
Is humanin released during exercise?
Yes. Conte et al. 2019 demonstrated that plasma humanin rises with acute exercise in humans, that trained individuals have higher baseline and exercise-induced humanin than untrained individuals, and that aerobic fitness correlates with humanin response (Conte et al., 2019). This supports the concept of humanin as a mitochondrial-derived myokine or mitokine that mediates some systemic benefits of physical activity.
What are the main concerns about long-term humanin use?
Principal theoretical concerns include effects on cancer risk (humanin inhibits apoptosis, which cancer cells exploit to evade cell death), unknown effects of chronic supraphysiologic dosing on endogenous humanin regulation, potential immune modulation through FPRL receptor signaling, and the general uncertainty that accompanies any unvalidated research peptide over extended use. Short cycles (4-12 weeks) are preferred over continuous indefinite dosing until more data are available.
Can I stack humanin with other longevity peptides like Epithalon or MOTS-c?
Self-experimenters commonly stack humanin with Epithalon (telomere support), Thymosin Alpha-1 (immune function), GH secretagogues (CJC-1295 + Ipamorelin), and tissue-repair peptides (BPC-157, TB-500) without apparent adverse effects. There is no clinical evidence that multi-peptide stacks produce superior outcomes, and the principle of single-agent experimentation for attribution is lost when stacking multiple unvalidated compounds simultaneously. Cost and complexity escalate quickly with stacking.
Should I use humanin if I have a history of cancer?
Anyone with active cancer, recently treated cancer, or significant cancer risk factors should not use humanin without explicit oncology guidance. Humanin inhibits apoptosis through Bax binding and activates STAT3 signaling, both of which are pathways that cancer cells can exploit. While there is no clinical evidence humanin accelerates cancer progression in humans, the mechanism warrants conservative avoidance in people where cancer surveillance or risk modification is a priority. The potential benefit of humanin for aging-related targets does not outweigh the theoretical oncologic risk in high-risk individuals.
Research Tools
Related Compounds
View AllARA-290
RecoveryPreclinicalARA-290, also known as Cibinetide or pHBSP (Helix B Surface Peptide), is an 11-amino-acid peptide — QEQLERALNSS — designed to mimic a specific region of the tissue-protective surface of erythropoietin (EPO) without activating the classical hematopoietic EPO receptor that drives red blood cell production.
BPC-157/TB-500 Blend
RecoveryPreclinicalCombined healing peptide blend.
Bronchogen
RecoveryPreclinicalBronchogen is a short synthetic peptide developed in Russia by Vladimir Khavinson and his collaborators at the St.
CAG
RecoveryPreclinicalCAG (often referring to a collagen-derived or cartilage-targeting peptide sequence) is a short research peptide studied for connective tissue and joint applications.
Cardiogen
RecoveryPreclinicalCardiogen is a short synthetic peptide developed in Russia by Vladimir Khavinson and his collaborators at the St.
Cartalax
RecoveryPreclinicalCartalax is a short synthetic peptide developed in Russia by Vladimir Khavinson and colleagues at the St.
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