---
title: "Humanin"
slug: "humanin"
type: "compound"
category: "Longevity"
url: "https://peptidesciencethailand.com/compounds/humanin"
description: "A small mitochondrial-derived peptide with anti-apoptotic and neuroprotective properties studied in Alzheimer's models. Mechanism and preclinical evidence."
---
# Humanin

*Mitochondrial-Derived Cytoprotective Peptide, Defending Cellular Integrity Against Age-Related Decline*

**Category:** Longevity  
**Format:** Lyophilized Vial  
**Amount:** 5mg  
**Purity:** >98% (HPLC)

## Overview

Humanin is a 24-amino acid peptide encoded by the 16S ribosomal RNA region of the mitochondrial genome, making it one of the first identified mitochondrial-derived peptides (MDPs). Discovered in 2001 by Nishimoto and colleagues through a functional expression screening of a cDNA library from the occipital cortex, Humanin was initially identified for its ability to protect neuronal cells from apoptosis induced by multiple neurotoxic insults. The peptide's sequence (Met-Ala-Pro-Arg-Gly-Phe-Ser-Cys-Leu-Leu-Leu-Leu-Thr-Ser-Glu-Ile-Asp-Leu-Pro-Val-Lys-Arg-Arg-Ala) is highly conserved across species, suggesting fundamental biological importance, and has since become a cornerstone of mitochondrial-derived peptide research in aging biology.

Humanin's discovery revealed an entirely new paradigm in cell biology: the mitochondrial genome, long considered to encode only components of the oxidative phosphorylation machinery and mitochondrial translation apparatus, also encodes bioactive peptides with potent cytoprotective functions. This discovery led to the identification of additional MDPs including MOTS-c and small humanin-like peptides (SHLPs), collectively forming a family of mitochondrial signaling molecules that regulate cellular stress responses, metabolism, and aging processes.

At the molecular level, Humanin exerts its cytoprotective effects through interaction with multiple receptor systems and intracellular targets. The primary extracellular receptor for Humanin is a trimeric complex consisting of ciliary neurotrophic factor receptor alpha (CNTFRalpha), interleukin-27 receptor beta (WSX-1/IL-27Rbeta), and glycoprotein 130 (gp130). This receptor complex is structurally related to the IL-6 family cytokine receptor system and activates the JAK-STAT3 (Janus kinase-signal transducer and activator of transcription 3) signaling pathway upon Humanin binding. STAT3 activation drives transcription of anti-apoptotic genes including Bcl-2, Bcl-xL, and Mcl-1, establishing a cellular survival program that protects against diverse apoptotic triggers.

Intracellularly, Humanin directly interacts with several pro-apoptotic proteins, providing an additional layer of cytoprotection independent of receptor-mediated signaling. Humanin binds to Bax (Bcl-2-associated X protein), preventing its oligomerization and translocation to the mitochondrial outer membrane, a critical step in the intrinsic apoptotic cascade. By sequestering Bax, Humanin prevents mitochondrial outer membrane permeabilization (MOMP), the release of cytochrome c into the cytoplasm, and subsequent activation of the caspase-9/caspase-3 effector pathway. Additionally, Humanin interacts with tBid (truncated BH3 interacting-domain death agonist), a key mediator that connects extrinsic (death receptor) and intrinsic (mitochondrial) apoptotic pathways, further reinforcing its multi-level anti-apoptotic activity.

Humanin also binds to insulin-like growth factor binding protein 3 (IGFBP-3), a major carrier protein for IGF-1 in the circulation. IGFBP-3 has IGF-independent pro-apoptotic activity, and Humanin's interaction with IGFBP-3 neutralizes this death-promoting function. This interaction also influences IGF-1 bioavailability, connecting Humanin to the somatotropic axis, a central regulatory pathway in aging biology. The GH/IGF-1 axis is one of the most well-characterized determinants of lifespan across species, and Humanin's modulation of this pathway positions it within the broader network of longevity-regulating signals.

Research into Humanin's neuroprotective properties has demonstrated its efficacy against a range of neurotoxic challenges. The peptide protects hippocampal neurons from amyloid-beta peptide toxicity, glutamate excitotoxicity, and serum starvation-induced apoptosis. In animal models, Humanin administration has been shown to improve cognitive performance on spatial memory tasks and reduce neuroinflammatory markers. The neuroprotective mechanism involves both STAT3-mediated anti-apoptotic gene expression and direct interaction with Bax/tBid pro-apoptotic proteins at the mitochondrial level.

Humanin's metabolic regulatory functions represent a major area of current research. The peptide has been shown to improve insulin sensitivity in animal models of diet-induced obesity and type 2 diabetes through STAT3-dependent upregulation of insulin receptor substrate (IRS) proteins and enhanced Akt phosphorylation in insulin-responsive tissues. Humanin also reduces hepatic glucose output and improves peripheral glucose disposal, effects that may be mediated through its interaction with the IGFBP-3/IGF-1 axis and direct effects on mitochondrial bioenergetics.

Circulating Humanin levels decline with age in both human populations and animal models, paralleling the age-related decline in mitochondrial function and the accumulation of mitochondrial DNA damage. Studies of human centenarians and their offspring have found higher circulating Humanin levels compared to age-matched controls, suggesting an association between endogenous Humanin production and extended longevity. This epidemiological correlation, combined with the peptide's preclinical cytoprotective and metabolic benefits, has positioned Humanin as a key molecule in geroscience research.

Structure-activity relationship studies have led to the development of potent Humanin analogs. The S14G substitution (replacing serine at position 14 with glycine) creates the analog known as HNG (Humanin G), which demonstrates approximately 1000-fold greater cytoprotective potency than the native peptide. The C8A substitution (replacing cysteine at position 8 with alanine) prevents disulfide bond-mediated dimerization, improving stability and pharmacological consistency. These analogs have been instrumental in advancing Humanin research across neuroprotection, metabolism, and aging biology.

Research on Humanin has been published in journals including the Proceedings of the National Academy of Sciences, Cell Metabolism, the Journal of Neuroscience, and Aging Cell. The peptide continues to be a central focus of mitochondrial-derived peptide research, with ongoing studies exploring its therapeutic potential in neurodegenerative disease, metabolic syndrome, cardiovascular protection, and fundamental aging processes.

## Mechanism of Action

### Step 1: Trimeric Receptor Complex Binding

Humanin binds the extracellular receptor complex consisting of CNTFRalpha, WSX-1 (IL-27Rbeta), and gp130. This trimeric receptor system is structurally related to IL-6 family cytokine receptors and initiates intracellular signaling upon Humanin engagement.

### Step 2: JAK-STAT3 Pathway Activation

Receptor engagement activates the JAK-STAT3 signaling cascade. Phosphorylated STAT3 translocates to the nucleus and drives transcription of anti-apoptotic genes including Bcl-2, Bcl-xL, and Mcl-1, establishing a cellular survival program.

### Step 3: Bax Sequestration & MOMP Prevention

Humanin directly binds the pro-apoptotic protein Bax, preventing its oligomerization and translocation to the mitochondrial outer membrane. This blocks mitochondrial outer membrane permeabilization (MOMP), cytochrome c release, and downstream caspase activation.

### Step 4: IGFBP-3 Interaction

Humanin binds insulin-like growth factor binding protein 3 (IGFBP-3), neutralizing its IGF-independent pro-apoptotic activity. This interaction also modulates IGF-1 bioavailability, connecting Humanin to the somatotropic (GH/IGF-1) axis that regulates aging processes.

### Step 5: Metabolic & Insulin Signaling Enhancement

Through STAT3-dependent mechanisms, Humanin upregulates insulin receptor substrate (IRS) proteins and enhances Akt phosphorylation in insulin-responsive tissues, improving insulin sensitivity, reducing hepatic glucose output, and supporting mitochondrial bioenergetics.

## Researched Benefits

### Potent Cytoprotection

Humanin provides multi-level cellular protection through both receptor-mediated STAT3 activation and direct intracellular interaction with pro-apoptotic proteins. This dual mechanism guards against diverse apoptotic triggers including oxidative stress, endoplasmic reticulum stress, and mitochondrial dysfunction, making it one of the most broadly cytoprotective peptides identified.

### Neuroprotection

Research demonstrates Humanin's ability to protect neurons from amyloid-beta toxicity, glutamate excitotoxicity, and serum deprivation-induced cell death. Animal studies show improved cognitive performance and reduced neuroinflammatory markers following Humanin administration, supporting its relevance to neurodegenerative disease research.

### Metabolic Regulation

Humanin improves insulin sensitivity, reduces hepatic glucose output, and enhances peripheral glucose disposal in preclinical models. These metabolic benefits, mediated through STAT3/IRS signaling and IGFBP-3 interactions, connect Humanin to the broader metabolic dysregulation observed in aging.

### Longevity Association

Circulating Humanin levels decline with age, while centenarians and their offspring maintain higher levels compared to age-matched controls. This epidemiological association, combined with Humanin's role in the GH/IGF-1 axis and mitochondrial function, positions it as a key molecule linking mitochondrial biology to aging and lifespan regulation.

## Dosage & Administration

| Parameter | Detail |
| --- | --- |
| Protocol | Research protocols typically use weight-based dosing; preclinical studies commonly employ 1-4mg/kg in animal models. Human-equivalent dosing is determined by specialist assessment |
| Route | Subcutaneous or intraperitoneal injection (research context dependent) |
| Duration | Protocol dependent, typically 4-12 weeks in preclinical studies |
| Cycle Notes | Preclinical longevity research often employs extended treatment protocols of 8-12 weeks or longer. Neuroprotection studies may use shorter, more intensive courses. The optimal cycling strategy for Humanin in humans has not been established and requires specialist determination based on individual assessment. |
| Reconstitution | Reconstitute lyophilized Humanin with bacteriostatic water or sterile water for injection. The native peptide contains a cysteine residue (C8) susceptible to oxidation; handle under inert conditions when possible. Store reconstituted solution at 2-8°C protected from light and use within 14 days. |

> **Specialist note:** A your specialist must evaluate the individual's metabolic profile, insulin sensitivity, IGF-1 levels, and mitochondrial health markers before initiating Humanin protocols. The peptide's interactions with the GH/IGF-1 axis and insulin signaling require monitoring of glucose homeostasis and growth factor levels throughout treatment.

## Compound Reference Data

| Property | Value |
| --- | --- |
| Format | Lyophilized Powder |
| Amount | 5mg per vial |
| Purity | >98% |
| Purity Method | HPLC (High-Performance Liquid Chromatography) |
| Sequence | Met-Ala-Pro-Arg-Gly-Phe-Ser-Cys-Leu-Leu-Leu-Leu-Thr-Ser-Glu-Ile-Asp-Leu-Pro-Val-Lys-Arg-Arg-Ala |
| Molecular Weight | 2687.3 g/mol |
| Storage | Store lyophilized powder at -20°C under inert atmosphere if possible. Reconstituted solution at 2-8°C. Protect from light and oxidation. |
| Appearance | White to off-white lyophilized powder |

## Medical Guidance

Humanin interacts with the GH/IGF-1 somatotropic axis and modulates insulin signaling pathways. Individuals with diabetes, insulin resistance, growth hormone disorders, or those taking insulin-sensitizing medications require comprehensive specialist evaluation. The peptide's effects on IGFBP-3 and IGF-1 bioavailability necessitate monitoring of growth factor levels and metabolic parameters throughout any treatment protocol.

## Frequently Asked Questions

### What is Humanin and where does it come from?

Humanin is a 24-amino acid peptide encoded by the mitochondrial genome, specifically within the 16S ribosomal RNA gene. Discovered in 2001, it was among the first identified mitochondrial-derived peptides (MDPs), revealing that mitochondrial DNA encodes bioactive signaling molecules beyond its known role in oxidative phosphorylation machinery. Humanin is produced by cells throughout the body and circulates in the bloodstream.

### Why is Humanin relevant to aging research?

Circulating Humanin levels decline with age, paralleling the well-documented decline in mitochondrial function. Studies of centenarians have found higher Humanin levels compared to age-matched controls, suggesting an association with extended longevity. The peptide's cytoprotective, neuroprotective, and metabolic regulatory properties address multiple hallmarks of aging, and its connection to the GH/IGF-1 axis links it to one of the most conserved longevity pathways across species.

### How does Humanin protect cells from death?

Humanin provides multi-level cytoprotection. Extracellularly, it activates JAK-STAT3 signaling through a trimeric receptor complex, driving expression of anti-apoptotic genes. Intracellularly, it directly binds and sequesters pro-apoptotic proteins Bax and tBid, preventing mitochondrial membrane permeabilization and caspase activation. It also neutralizes the pro-apoptotic activity of IGFBP-3. This multi-mechanism approach protects against diverse cellular stressors.

### What is the HNG analog and how does it differ from native Humanin?

HNG (Humanin G) is a synthetic analog created by substituting glycine for serine at position 14 (S14G). This single amino acid change increases cytoprotective potency approximately 1000-fold compared to native Humanin. The enhanced potency allows lower dosing while maintaining or exceeding the biological effects of the native peptide, making HNG a preferred variant in many research applications.

### Does Humanin require specialist supervision?

Yes. Humanin interacts with the GH/IGF-1 axis (through IGFBP-3 binding) and modulates insulin signaling pathways. These interactions require professional assessment of metabolic status, growth factor levels, and glucose homeostasis. A specialist consultation is essential for determining appropriate dosing, monitoring parameters, and managing potential interactions with concurrent medications, particularly insulin-sensitizing agents and growth hormone therapies.

## Related Compounds

- /compounds/mots-c
- /compounds/epithalon
- /compounds/ghk-cu