Article

Humanin: the mitochondrial-derived peptide and its research record

Published 30 October 2026 · CognitivePepti Research Desk

Abstract illustration of a mitochondrion with folded inner membranes, cover image for Humanin: the mitochondrial-derived peptide and its research record

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Published 30 October 2026

At a glance

What it is: humanin is a 24-amino-acid peptide encoded by a short open reading frame in the mitochondrial 16S ribosomal RNA gene, and the first of the mitochondrial-derived peptides to be described
How it was found: in 2001, in a screen for genes that stopped neuronal cell death caused by familial Alzheimer's disease genes and amyloid-β
Proposed mechanisms: binding to the pro-death protein Bax and to IGFBP-3 inside cells, and signalling through a cell-surface receptor complex and the FPRL1 receptor
Evidence base: cell studies, rodent studies and human genetic association studies
Human trials: none found on PubMed or ClinicalTrials.gov

Discovery

Humanin was reported in 2001 by Ikuo Nishimoto's group at Keio University. Using functional expression screening, they found a cDNA that, when expressed, stopped the death of neuronal cells caused by several familial Alzheimer's disease genes and by amyloid-β, but not cell death from other causes they tested (Hashimoto et al., 2001, PNAS). The encoded peptide was secreted into the culture medium, and its activity depended on its exact sequence. A follow-up paper the same year mapped which residues mattered for that activity (Hashimoto et al., 2001, J Neurosci).

Where humanin acts

Several partners have been proposed, and they are not mutually exclusive.

Bax: a 2003 Nature paper reported that humanin binds Bax and stops it moving to mitochondria, where it would trigger cell death. The authors noted that the mitochondrial genome contains an identical reading frame (Guo et al., 2003).
IGFBP-3: the same year, another group reported that humanin binds insulin-like growth factor binding protein 3 and blocks the cell death it induces (Ikonen et al., 2003).
FPRL1: a 2004 study reported that humanin activates formyl peptide receptor-like 1 on immune cells and competes with amyloid-β there (Ying et al., 2004).
A receptor complex: later work from the discovering group proposed a three-part receptor made of CNTFRα, WSX-1 and gp130 (Matsuoka and Hashimoto, 2010, review).

Studies relevant to cognition

A 2018 study from Pinchas Cohen's group at the University of Southern California reported that humanin given to aged mice was followed by better performance on cognitive tests. In human data, the authors linked a mitochondrial variant (rs2854128) to lower circulating humanin and, in a separate cohort of older adults, to faster cognitive ageing (Yen et al., 2018). The authors disclosed consulting roles with, and stock in, CohBar, a company developing mitochondrial-derived peptides.

In 2024 the same group reported a rare humanin variant, P3S, that was more common among centenarians carrying the APOE4 allele. In an APP/PS1/APOE4 mouse model, the P3S variant was associated with less brain amyloid-β than ordinary humanin, and cell work pointed to increased amyloid-β uptake by phagocytic cells (Miller et al., 2024). A commentary in the same journal discussed the finding (Logan, 2024).

Much of the animal literature uses a synthetic analogue, HNG, in which serine 14 is replaced with glycine (S14G). It was reported to be far more potent than humanin in cell assays and appears in many of the rodent studies summarised in reviews (Niikura, 2022).

What reviews conclude

Recent reviews describe humanin as a mitochondrial signalling peptide with cell-survival, metabolic and anti-inflammatory activity in experimental systems (Karachaliou et al., 2023; Alqahtani et al., 2025). They also point out open questions: whether the circulating peptide comes from the mitochondrial or nuclear copies of the reading frame, how reliable the immunoassays used to measure it are, and how results in mice relate to people.

Limitations

No human trials: we found no interventional human studies of humanin or HNG on PubMed or ClinicalTrials.gov as of 30 October 2026.
Model systems: the cognition findings come from cell lines and mice; the human data are genetic associations, which do not show cause and effect.
Analogues: many studies use HNG rather than native humanin, so results are not interchangeable.
Measurement: blood humanin levels depend on the assay used, and different kits have given different values.
Conflicts of interest: several key papers come from groups with commercial ties to mitochondrial-peptide development.

Key terms

Mitochondrial-derived peptide (MDP): a short peptide encoded within mitochondrial DNA; humanin and MOTS-c are examples
Open reading frame: a stretch of DNA that can be read as a protein-coding sequence
Bax: a protein that promotes programmed cell death by acting on mitochondria
APOE4: a variant of the apolipoprotein E gene associated with higher Alzheimer's disease risk
HNG (S14G): a synthetic humanin analogue with glycine at position 14

Supplier

Purita is a store that sells peptides for laboratory research use only. The link below goes to its neurological research category; check the product page and certificate of analysis for what is actually listed.

Purita neurological category

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