Humanin Research, Specifications & Scientific Information

Humanin is a 24-residue peptide encoded within the 16S ribosomal RNA region of mitochondrial DNA, identified in 2001 as a factor that prevented death of neuronal cells in Alzheimer's disease models. It was the first described member of the mitochondrial-derived peptide class. No interventional clinical trial of it has been identified, and it is not approved by the FDA for any indication.

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Category: Mitochondrial peptides

Introduction

Humanin was found the way interesting things sometimes are: by screening for a gene that stopped something from happening, and then discovering that the gene was in the wrong genome.

In 2001, a functional expression screen looking for factors that prevented death of neuronal cells identified a complementary DNA that abolished cell death caused by a range of familial Alzheimer's disease genes and by amyloid beta. It was not a general rescue — death caused by Q79 polyglutamine expansion or by superoxide dismutase-1 mutants was unaffected. The transfected sequence was transcribed, translated, and secreted into the culture medium, and the rescue depended on the peptide's primary structure [1].

The open reading frame turned out to lie within the 16S ribosomal RNA region of mitochondrial DNA. That placement is what made humanin more than one peptide: it implied that the mitochondrial genome encodes signals directed outward, at the cell and at other tissues, rather than only the components of oxidative phosphorylation. An in silico search of the same region later turned up six more peptides, and MOTS-c was found elsewhere in the mitochondrial genome [5, 4]. Humanin is the founding member of that class.

No interventional clinical trial of humanin has been identified. This page is a reference record of what has been published. It describes research, and it contains no guidance of any kind on handling the material.

What Is Humanin?

A 24-residue peptide, MAPRGFSCLLLLTSEIDLPVKRRA, carried in the FDA/NCATS Global Substance Registration System under UNII H975EUX36G with CAS registry number 330936-69-1.

Three features distinguish it from most entries in this library.

Its gene is in the mitochondrion. Not in a nuclear gene encoding a mitochondrial protein — in mitochondrial DNA itself, within the 16S ribosomal RNA sequence [5].

There are two translations of the same frame. Mitochondria use a genetic code that differs from the cytoplasmic one at several codons. Translated by cytoplasmic ribosomes the frame yields the 24-residue peptide above; translated by mitochondrial ribosomes it yields a 21-residue form. Both are described in the literature, and they are different substances.

It is a family, not a molecule. The small humanin-like peptides share the region of mitochondrial DNA that encodes humanin and differ from it and from each other in activity [5]. Analogues with substitutions — most often the serine-to-glycine change at position 14, written S14G or HNG — are common in the preclinical literature and are also separate substances.

It is not an approved medicine anywhere.

Humanin Specifications

Compound name
Humanin
Full chemical name
L-Methionyl-L-alanyl-L-prolyl-L-arginylglycyl-L-phenylalanyl-L-seryl-L-cysteinyl-L-leucyl-L-leucyl-L-leucyl-L-leucyl-L-threonyl-L-seryl-L-alpha-glutamyl-L-isoleucyl-L-alpha-aspartyl-L-leucyl-L-prolyl-L-valyl-L-lysyl-L-arginyl-L-arginyl-L-alanine
Aliases
HN, protein humanin (human), humanin 1-24, mitochondrial-derived peptide humanin
Development code
Not publicly characterised
CAS number
330936-69-1
PubChem CID
16131438
UNII
H975EUX36G
Compound type
Mitochondrial-derived peptide (endogenous 24-residue sequence)
Peptide family
Mitochondrial-derived peptides
Amino acid sequence
MAPRGFSCLLLLTSEIDLPVKRRA
Sequence length
24 residues
Molecular formula
C119H204N34O32S2
Molecular weight
2687.2 g/mol
Primary target
Not definitively established. A trimeric receptor complex comprising the ciliary neurotrophic factor receptor, WSX-1 and gp130 has been proposed for the extracellular actions, and formyl peptide receptor-like 1 has been reported as a further binding site; neither assignment is settled.
Secondary targets
Intracellular interaction with the pro-apoptotic protein BAX has been reported
Receptor family
Class I cytokine receptor family, for the proposed trimeric complex
Agonist / antagonist status
Reported as a cytoprotective agonist at the proposed receptor complex; assignment not settled

Humanin is recorded in the FDA/NCATS Global Substance Registration System under UNII H975EUX36G with CAS registry number 330936-69-1, PubChem compound identifier 16131438, molecular formula C119H204N34O32S2 and a molecular weight of 2687.2 g/mol. The 24-residue sequence above is the human form, and its origin is what makes the compound unusual: it is encoded within the 16S ribosomal RNA region of mitochondrial DNA rather than in the nuclear genome. Because mitochondria use a genetic code that differs from the nuclear one, the same open reading frame translated by the mitochondrial machinery and by the cytoplasmic machinery does not give the same peptide, and the 24-residue form above is the cytoplasmically translated species. A 21-residue form corresponding to mitochondrial translation is also described in the literature. The single cysteine at position 8 is a reactive site and is one reason preparations may differ between lots. Analogues with substitutions at position 14, most commonly the serine-to-glycine substitution written S14G or HNG, appear throughout the preclinical literature and are separate substances from the one described here.

Values that a public register does not carry are shown as not publicly characterised rather than estimated. Identifiers are reference values; the certificate of analysis supplied with a laboratory order is the record for a given lot.

How Does Humanin Work?

Not definitively established, and the uncertainty is about location as much as about identity.

An extracellular route. A trimeric receptor complex comprising the ciliary neurotrophic factor receptor, WSX-1 and gp130 has been proposed for humanin's extracellular actions, with formyl peptide receptor-like 1 reported as an additional binding site [9]. That the peptide is secreted into culture medium and acts on neighbouring cells was part of the original description, so an extracellular receptor is a reasonable expectation [1].

An intracellular route. Interaction with the pro-apoptotic protein BAX has been reported, which would place at least part of the activity inside the cell and upstream of mitochondrial outer-membrane permeabilisation.

A systemic route. Central administration in rodents altered peripheral insulin action under clamp conditions, which implicates signalling from the brain to liver and periphery rather than a purely local cytoprotective effect [3].

These are not mutually exclusive, and the literature has not settled which predominates in any given tissue. The specification table records the primary target as not definitively established, and that is the accurate entry rather than an incomplete one.

What the original work did establish is a selectivity constraint that any mechanism has to satisfy: humanin rescued cells from Alzheimer's-disease-related insults and not from unrelated ones, and the rescue depended on primary structure [1, 2]. A general antioxidant or a non-specific survival factor would not behave that way.

Humanin Mechanism of Action

In vitro research

The identification, and the controls inside it

Functional expression screening produced a complementary DNA that abolished death of neuronal cells caused by multiple different familial Alzheimer's disease genes and by amyloid beta. The same construct had no effect on death caused by Q79 or by superoxide dismutase-1 mutants. Transfected cells transcribed and translated the sequence and secreted the polypeptide into the medium, and the rescue action depended on the primary structure of the peptide rather than merely on its presence [1].

Three controls are embedded in that one paragraph: a negative control on the insult, a demonstration that the active species is secreted, and a structure-dependence test. A follow-up study characterised the neuroprotective profile against a wider set of Alzheimer's-disease-relevant insults [2].

What the family comparison showed

The small humanin-like peptides were identified in silico in the same region of mitochondrial DNA and then tested. They differed in their ability to regulate cell viability, which is the first point: a shared genomic neighbourhood does not confer shared activity. Two of them, SHLP2 and SHLP3, shared protective effects with humanin — significantly reducing apoptosis and reactive oxygen species generation and improving mitochondrial metabolism in culture — and enhanced 3T3-L1 pre-adipocyte differentiation [5].

Humanin administration also had neuroprotective effects in human cell culture models in later work [6].

What Is Humanin Being Researched For?

Three lines, with markedly different evidence behind each.

  • Neuroprotection in Alzheimer's disease models. The founding line, entirely in cell culture and animals [1, 2, 6].
  • Metabolic regulation. Central and peripheral insulin action in rodents, and apoptosis, insulin sensitivity and inflammatory markers in the family comparison [3, 5].
  • Ageing biology. Circulating concentrations against age in humans, lifespan and healthspan in model organisms, and a genotype-to-cognition association in a human cohort [5, 6, 7].

No interventional clinical trial appears in public registers. The human literature is observational, and it is set out separately below so that it is not mistaken for trial evidence.

Human Observational Data on Humanin

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

Everything in this section measures an endogenous peptide. None of it administers one.

Concentrations fall with age

Circulating humanin concentrations decline with age, and the same was found for circulating SHLP2 [5]. An age-dependent decline in a cytoprotective factor is a correlation, and on its own it cannot distinguish a cause of ageing from a consequence of it.

A genetic association

Using mitochondrial genome-wide association analysis in a human cohort, a specific variant in the humanin-coding region, rs2854128, was identified as associated with lower circulating humanin concentrations. In a large independent cohort — a nationally representative sample of older adults — the same variant was associated with accelerated cognitive ageing [6].

Why this design is stronger than a plain correlation. A germline variant is fixed before the outcome and is not influenced by it, which removes the most common reverse-causation objection to a biomarker association. It remains an association, in observational cohorts, with the usual limits: population stratification, linkage with other variants in the mitochondrial genome, and no demonstration that raising the peptide would change the outcome.

Response to exercise

Circulating concentrations of mitochondrial-derived peptides rise acutely after a bout of endurance exercise in humans [8]. That establishes the peptides are regulated rather than merely present, which is a prerequisite for calling them signals.

Disease states

Circulating humanin has been examined prospectively in chronic haemodialysis patients in relation to cardiovascular risk, in a study its authors describe as a pilot [10].

The boundary

None of the above tests what administered humanin does in a person. They describe how much of it is present, in whom, and when.

Preclinical Research on Humanin

Animal research

Cognition in aged mice. Humanin administration was sufficient to improve cognition in aged mice, in the same paper that reported the human cohort association [6]. Pairing an interventional animal result with an observational human one is the standard design for a candidate of this kind, and the two halves carry different weight: the mouse half establishes that the peptide can change an outcome, and the human half establishes only that the peptide tracks one.

Insulin action. Humanin was reported as a central regulator of peripheral insulin action, on the basis of rodent clamp studies [3]. The related work on the small humanin-like peptides used systemic hyperinsulinaemic-euglycaemic clamps and found that intracerebrally infused SHLP2 increased glucose uptake and suppressed hepatic glucose production, which its authors read as insulin sensitisation acting both centrally and peripherally [5].

Lifespan and healthspan. Humanin has been studied as a regulator of lifespan and healthspan in model organisms [7].

Findings described in this section were observed in animals, and nothing in them establishes anything about humans. The route of administration in the central studies — intracerebral infusion — is worth noting in particular, since it bypasses every barrier that would apply to a peripherally administered compound.

Current Research Status

Regulatory status (United States)
Not approved. Humanin has not been approved by the U.S. Food and Drug Administration for any indication.
Investigational status
No interventional clinical trial of administered humanin has been identified in public trial registers or in the peer-reviewed literature. Human research consists of observational measurement: circulating concentrations in cohorts of different ages and disease states, an association between a mitochondrial genome variant in the humanin-coding region and cognitive ageing, and the response of circulating concentrations to a bout of exercise. The interventional literature is entirely in cell culture and in animals.
Highest research phase reached
No interventional clinical study identified; human observational research plus animal and in vitro research
Approved uses
None
Approval is compound-specific
No

Status as of . This block is rendered from maintained fields, not from prose, so it cannot go stale in one place and stay current in another.

Chemical & Molecular Characteristics

The register record is consistent. UNII H975EUX36G, CAS registry number 330936-69-1, PubChem compound identifier 16131438, molecular formula C119H204N34O32S2, molecular weight 2687.2 g/mol. The register and PubChem agree.

Two sulfurs, and one of them is reactive. The formula's two sulfur atoms are the methionine at position 1 and the cysteine at position 8. A single free cysteine in a synthetic peptide is an oxidation-sensitive site and a route to dimer formation, which is a practical reason why preparations of this sequence may differ between lots and why the analytical documentation matters.

The chain length depends on which ribosome read the frame. Because the mitochondrial genetic code differs from the cytoplasmic one, the same open reading frame gives a 24-residue peptide when translated in the cytoplasm and a 21-residue peptide when translated inside the mitochondrion. The identifiers above are for the 24-residue form. Material described simply as "humanin" may be either, and the mass distinguishes them.

The name is not a family name. Humanin, the small humanin-like peptides and the position-14 analogues are distinct substances with distinct register identities where they have them at all. The sequence and identifiers on this page apply to the native 24-residue human peptide only.

Frequently Asked Questions

What is humanin?
A 24-residue peptide with the sequence MAPRGFSCLLLLTSEIDLPVKRRA, identified in 2001 by functional expression screening as a factor that abolished death of neuronal cells caused by several familial Alzheimer's disease genes and by amyloid beta [1]. The FDA/NCATS register carries it under UNII H975EUX36G with CAS registry number 330936-69-1.
Where does humanin come from?
From mitochondrial DNA, not from the nuclear genome. Its open reading frame lies within the 16S ribosomal RNA region of the mitochondrial genome [5]. That origin is the reason it was described as the first of a class — the mitochondrial-derived peptides — rather than as an isolated curiosity [4]. An in silico search of the same region later identified six further peptides, named the small humanin-like peptides [5].
How does humanin work?
Not definitively established. Two routes are described in the literature. Extracellularly, a trimeric receptor complex of the ciliary neurotrophic factor receptor, WSX-1 and gp130 has been proposed, with formyl peptide receptor-like 1 reported as a further binding site [9]. Intracellularly, interaction with the pro-apoptotic protein BAX has been reported. The original identification showed that the rescue effect depended on the peptide's primary structure and did not extend to unrelated death stimuli, which is a selectivity finding rather than a mechanism [1].
Is humanin FDA approved?
No. Humanin has not been approved by the U.S. Food and Drug Administration for any indication, and no interventional clinical trial of it has been identified.
Has humanin been studied in humans?
Observationally, yes; as an administered compound, no. Circulating concentrations have been measured across age groups and found to decline with age [5], a mitochondrial genome variant in the humanin-coding region has been associated with lower circulating concentrations and with accelerated cognitive ageing in a nationally representative cohort of older adults [6], concentrations have been measured after a bout of endurance exercise [8], and they have been examined in chronic haemodialysis patients [10]. Measuring an endogenous peptide in blood is a different kind of evidence from administering it.
What is a mitochondrial-derived peptide?
A short peptide whose coding sequence lies within mitochondrial DNA rather than in the nuclear genome. Humanin was the first described; MOTS-c and the small humanin-like peptides followed [4, 5]. The concept matters because it implies a signalling route from the mitochondrion outward to the rest of the cell and to other tissues, which is the opposite of the usual nuclear-to-mitochondrial direction.
What is the difference between humanin and HNG?
One residue. HNG, also written S14G-humanin, carries glycine in place of the serine at position 14 and is a separate substance from the sequence described on this page. It appears widely in the preclinical literature, often because it was reported as more potent than the native sequence in particular assays. Results obtained with an analogue are evidence about that analogue.
What identifiers are published for humanin?
UNII H975EUX36G, CAS registry number 330936-69-1 and PubChem compound identifier 16131438, with molecular formula C119H204N34O32S2 and a molecular weight of 2687.2 g/mol. Those figures correspond to the 24-residue cytoplasmically translated form; a 21-residue form corresponding to translation by the mitochondrial machinery is also described in the literature and is a different substance.

Scientific References

  1. Hashimoto Y, Niikura T, Tajima H, et al.. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta Proceedings of the National Academy of Sciences of the United States of America; 2001. PMID 11371646 doi:10.1073/pnas.101133498
  2. Hashimoto Y, Niikura T, Ito Y, et al.. Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults The Journal of neuroscience : the official journal of the Society for Neuroscience; 2001. PMID 11717357 doi:10.1523/JNEUROSCI.21-23-09235.2001
  3. Muzumdar RH, Huffman DM, Atzmon G, et al.. Humanin: a novel central regulator of peripheral insulin action PloS one; 2009. PMID 19623253 doi:10.1371/journal.pone.0006334
  4. Lee C, Yen K, Cohen P. Humanin: a harbinger of mitochondrial-derived peptides? Trends in endocrinology and metabolism: TEM; 2013. PMID 23402768 doi:10.1016/j.tem.2013.01.005
  5. Cobb LJ, Lee C, Xiao J, et al.. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers Aging; 2016. PMID 27070352 doi:10.18632/aging.100943
  6. Yen K, Wan J, Mehta HH, et al.. Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans Scientific reports; 2018. PMID 30242290 doi:10.1038/s41598-018-32616-7
  7. Yen K, Mehta HH, Kim SJ, et al.. The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan Aging; 2020. PMID 32575074 doi:10.18632/aging.103534
  8. von Walden F, Fernandez-Gonzalo R, Norrbom J, et al.. Acute endurance exercise stimulates circulating levels of mitochondrial-derived peptides in humans Journal of applied physiology (Bethesda, Md. : 1985); 2021. PMID 34351816 doi:10.1152/japplphysiol.00706.2019
  9. Zhu S, Hu X, Bennett S, et al.. The Molecular Structure and Role of Humanin in Neural and Skeletal Diseases, and in Tissue Regeneration Frontiers in cell and developmental biology; 2022. PMID 35372353 doi:10.3389/fcell.2022.823354
  10. Bolignano D, Greco M, Presta P, et al.. Unbalanced circulating Humanin levels and cardiovascular risk in chronic hemodialysis patients: a pilot, prospective study Journal of nephrology; 2024. PMID 39102184 doi:10.1007/s40620-024-02032-4

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Research-Use Information

For in vitro research use only. This material is a laboratory reagent. It is not a drug, food, dietary supplement, or cosmetic and is not for human or veterinary use, including ingestion, injection, or any other administration. No information on this page describes or implies any effect in humans or animals. Sold only to researchers under our Terms of Sale.