Humanin
Also known as: HN · Rattin (rodent analogue) · MOTS-c family
A 21-24-amino-acid mitochondrial-derived peptide with cytoprotective and neuroprotective activity — the flagship member of the mitochondrial-derived peptide family, with emerging evidence in Alzheimer's disease and cognitive-ageing research.
Humanin is a 21-24-amino-acid mitochondrial-derived peptide with cytoprotective and anti-amyloid-beta activity; the founding member of the mitochondrial-derived peptide family with emerging Alzheimer's research applications.
Evidence tier: C — preclinical / mechanistic evidence only
- Category
- Neuroprotection
- Half-life
- Short plasma half-life; sustained tissue effects extend beyond exposure
Section 1
Overview
Humanin is an endogenous peptide encoded within the mitochondrial 16S rRNA gene — a distinctive feature that places it in the small but growing 'mitochondrial-derived peptide' family. It was discovered in 2001 in a screen for factors protecting neurons against amyloid-beta-induced cell death, and the flagship pharmacological signature has been consistent since: humanin protects neurons and other cell types against a range of stress and death-inducing insults, with particular activity against Alzheimer's-disease-relevant amyloid-beta cytotoxicity.
The peptide operates through multiple receptor systems including the formyl peptide receptor-like 1 (FPRL1), the ciliary neurotrophic factor receptor complex (CNTF-R), and additional signalling routes still being characterised. Downstream, humanin signalling produces anti-apoptotic, anti-inflammatory, and metabolic-restorative effects. The metabolic angle has expanded the compound's research relevance beyond neuroprotection — humanin has documented effects on insulin sensitivity, glucose regulation, and mitochondrial function that place it at the intersection of metabolic and cognitive research.
Synthetic analogues of humanin with improved pharmacokinetics have been developed (notably HNG and AGA-(C8R)HNG17), providing research tools with extended half-life for chronic-dosing paradigms. Direct humanin administration and analogue administration have been studied preclinically in Alzheimer's disease, ischaemic injury, and metabolic-disease models; clinical evaluation is emerging but not yet substantial.
Section 2
Discovery & History
- Discovered in 2001 by Nishimoto and colleagues in a screen for factors protecting cortical neurons against amyloid-beta-induced cell death.
- The mitochondrial-genomic origin was recognised subsequently, placing humanin in the mitochondrial-derived peptide family alongside MOTS-c, SHLP2/6, and related molecules.
- Preclinical characterisation through the 2000s and 2010s expanded the pharmacological understanding to include effects on multiple receptor systems, downstream signalling cascades, and effects across cell types and tissue systems.
- Synthetic analogues (HNG, AGA-(C8R)HNG17) were developed to address the short plasma half-life of native humanin.
- Emerging clinical research in Alzheimer's disease and metabolic disease has begun to translate the preclinical mechanistic base, though large-scale Phase III trials have not been completed.
Section 3
Mechanism of Action
- 1Signalling through the formyl peptide receptor-like 1 (FPRL1) providing anti-apoptotic and anti-inflammatory effects in neuronal and immune-cell populations — one of the principal receptor systems mediating humanin's cytoprotective phenotype.
- 2Signalling through the ciliary neurotrophic factor receptor complex (CNTF-R) providing neurotrophic-adjacent support for stressed neurons — a mechanistic angle that overlaps with the P21 mechanism-of-action framework and provides mechanistic convergence with the broader neurotrophin-signalling cognitive-peptide programme.
- 3Direct inhibition of Bax-mediated apoptosis — humanin binds Bax through a well-characterised protein-protein interaction and prevents its translocation to the mitochondrial outer membrane, blocking the mitochondrial apoptotic pathway upstream of cytochrome-c release.
- 4Anti-inflammatory effects in microglia and other immune-cell populations — reduced pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6), shifted macrophage phenotype toward the resolution-oriented M2 state, and attenuation of NF-κB signalling in neuroinflammatory contexts.
- 5Metabolic effects — improved insulin sensitivity, enhanced glucose utilisation, preserved mitochondrial function under stress, and modulation of AMPK signalling in metabolic tissues, extending the pharmacological relevance beyond neuroprotection into the metabolic-cognitive research intersection.
- 6Direct protection against amyloid-beta cytotoxicity in cortical and hippocampal neurons — the founding pharmacological signature and the mechanism-of-action root for the Alzheimer's-disease research applications, characterised across multiple in-vitro preparations and preserved in-vivo in transgenic AD-model animals.
- 7Reported effects on longevity pathways in some model organism work — Caenorhabditis elegans lifespan extension, effects on sirtuin signalling — connecting the mitochondrial-derived peptide framework to broader ageing research.
- 8Preservation of mitochondrial function under multiple stress modalities — the mitochondrial-derived origin of the peptide plausibly reflects a functional relationship where humanin acts as a mitochondrial-status-signalling molecule modulating cellular resilience in response to mitochondrial stress.
- 9Modulation of insulin-like growth factor (IGF) signalling and connections to the broader growth-factor-signalling framework, extending the mechanism into additional cognitive-relevance research contexts.
Section 4
Researched Benefits
Findings reported in the published preclinical and clinical literature. Effects in research contexts do not constitute claims of therapeutic benefit in humans.
- 1Direct neuroprotection against amyloid-beta cytotoxicity — the founding pharmacological finding and the strongest single evidence base for the compound's cognitive-relevance research applications.
- 2Anti-apoptotic effects across multiple cell types and stress models — the pharmacology is not neuron-specific but neuronal-relevant results are the most-cited.
- 3Anti-inflammatory effects supporting research applications in neuroinflammatory disease models and in broader inflammation-driven-cognitive-decline research.
- 4Metabolic effects on insulin sensitivity and glucose regulation, extending the research relevance beyond neuroprotection into metabolic-syndrome and 'type 3 diabetes' Alzheimer's research angles.
- 5Mitochondrial-derived origin providing a distinctive conceptual framework — the peptide sits at the intersection of mitochondrial biology and cognitive research, opening a research-tool niche unshared by any other peptide on this reference.
- 6Synthetic analogues with improved pharmacokinetics (HNG, AGA-(C8R)HNG17) provide research tools for chronic-dosing paradigms without requiring native-humanin short-half-life management.
- 7Endogenous status providing a partial safety floor at physiological concentrations — the body produces and tolerates humanin constitutively.
- 8Longevity-pathway effects in model organism work supporting broader ageing-research applications alongside the primary cognitive-endpoint framing.
Section 5
Theoretical Dosing & Protocols
| Route | Dosage | Frequency | Duration |
|---|---|---|---|
| Subcutaneous / intraperitoneal (research) | Microgram to milligram range in animal protocols | Once or twice daily in most published research | Course lengths vary from 5-day acute to 12+ week chronic protocols |
Note: No validated human protocol exists; direct humanin administration has not been clinically approved.
Section 6
Administration Routes
- Subcutaneous administration in most published research protocols — the primary route for reproducible systemic exposure and pharmacokinetic characterisation.
- Intraperitoneal administration in some rodent research contexts where high plasma peak exposure is prioritised.
- Intranasal delivery documented in some CNS-directed research applications, exploiting nose-to-brain pathways for CNS-tissue-targeted exposure.
- Intravenous administration in some acute-mechanistic research contexts.
- Oral administration is not viable — the peptide is degraded by gastrointestinal proteases and undergoes near-complete first-pass metabolism.
Section 7
Safety Profile
Commonly reported
- · Generally well-tolerated in the reported preclinical research at studied doses across multiple animal species.
- · Endogenous status provides a partial safety floor at physiological concentrations — the body produces and tolerates humanin constitutively at low nanomolar plasma concentrations.
- · Injection-site reactions with subcutaneous administration — typically mild and self-limiting.
- · No documented dependence, tolerance, or withdrawal phenomena in the reported research base.
- · Occasional mild transient effects during initial dosing, generally resolving with continued administration.
Rare / theoretical
- · Long-term safety data at pharmacological doses above endogenous concentrations is limited.
- · Theoretical off-target effects at receptor systems where humanin has activity but where the intended effect is not desired.
- · Rare hypersensitivity reactions.
- · No reproductive or developmental toxicology data at pharmacological doses.
Contraindications
- · Not authorised for human use in the UK.
- · Pregnancy and lactation — no controlled human data at pharmacological doses.
- · Concurrent use with mechanism-relevant experimental compounds should be evaluated for interaction.
Section 8
UK & EU Regulatory Context
United Kingdom
Not a licensed medicine in the UK. Research chemical only.
European Union
Not approved by the EMA. Emerging clinical research programme.
Section 9
Clinical Studies Summary
Humanin protection against amyloid-beta cytotoxicity — foundational study
The founding 2001 Nishimoto-group study demonstrating humanin's protection of cortical neurons against amyloid-beta-induced cell death, discovered in a screen for AD-relevant neuroprotective factors. The publication opened the modern humanin research field and established the flagship pharmacological signature.
Humanin analogue HNG in Alzheimer's disease model
Preclinical evaluation of the humanin analogue HNG (with improved pharmacokinetics over native humanin) in APP/PS1 transgenic Alzheimer's disease mouse models, reporting preserved cognitive performance on hippocampus-dependent learning tasks (Morris water maze, novel object recognition), reduced amyloid-beta accumulation by ELISA measurement, and preserved neuronal viability in the treated cohort versus vehicle controls. Extends the founding cellular-level finding into an in-vivo AD-relevant behavioural context.
Humanin metabolic effects — insulin sensitivity and glucose regulation
Characterisation of humanin's effects on insulin sensitivity, glucose regulation, and mitochondrial function in animal metabolic-disease models, demonstrating improved glucose tolerance, enhanced insulin action in target tissues, and preserved mitochondrial function under metabolic stress. Extends the pharmacological relevance beyond neuroprotection and places the compound at the metabolic-cognitive research intersection relevant to 'type 3 diabetes' Alzheimer's angle.
Humanin mechanism — Bax binding and mitochondrial apoptosis
Molecular pharmacology characterisation of humanin's direct binding to Bax via protein-protein interaction studies and inhibition of Bax-mediated mitochondrial outer membrane permeabilisation. Provides one of the well-characterised mechanism-of-action pathways for the anti-apoptotic activity that underlies the neuroprotective phenotype, and establishes the molecular-level demonstration of the compound's mitochondrial-pathway interaction.
Humanin in longevity research — model organism studies
Model organism (Caenorhabditis elegans) studies demonstrating lifespan-extending effects of humanin analogues, providing empirical support for the compound's positioning within the broader mitochondrial-derived peptide family and connecting the cognitive-relevance research angle to the broader ageing-research framework.
Section 10
Frequently Asked Questions
Section 10a
Practical Research Guidance
Cycle guidance
Reconstitution & storage
UK sourcing notes
Section 11
Sourcing for Laboratory Research
Sourcing Humanin for laboratory research
Researchers in the United Kingdom and elsewhere typically obtain Humanin from specialist research-chemical suppliers. Purity, third-party testing, and supplier transparency are the principal differentiators worth evaluating before placing an order. The two suppliers below are commonly referenced in UK research contexts.
Reminder: research peptides are sold strictly for in vitro and preclinical laboratory purposes. Importation or supply for human consumption is not permitted under UK medicines legislation.