Humanin vs MOTS-c
Humanin and MOTS-c are mitochondrial-derived peptides encoded within mitochondrial ribosomal RNA genes. This page compares their discovery, sequences, proposed mechanisms, research areas, evidence level, regulatory status and analytical concerns.
Humanin and MOTS-c belong to a small group of peptides whose coding sequences lie within the mitochondrial genome, a discovery that challenged the idea that mitochondrial DNA encodes only a handful of proteins plus RNAs. Humanin was identified in 2001 in a screen for factors that protected cultured neurons from insults associated with Alzheimer's disease. MOTS-c was described in 2015 by a group that had also worked on humanin and related peptides.
Humanin is encoded within the 16S ribosomal RNA gene and MOTS-c within the 12S ribosomal RNA gene. Both have been studied for roles in cell survival and metabolism, mostly in cell and rodent models, and both are now widely discussed in aging research. Human evidence for either peptide given as a compound is very limited.
Side-by-side
| Attribute | Humanin | MOTS-c |
|---|---|---|
| Origin | Open reading frame within mitochondrial 16S rRNA gene (MT-RNR2); described 2001 | Open reading frame within mitochondrial 12S rRNA gene (MT-RNR1); described 2015 |
| Length | 24 residues (MAPRGFSCLLLLTSEIDLPVKRRA) | 16 residues (MRWQEMGYIFYPRKLR) |
| Oxidation-prone residues | One methionine and one cysteine | Two methionines and one tryptophan |
| Common analogues | HNG (Ser14 to Gly), reported as more potent in cell assays | MOTS-c-based analogues in early development |
| Proposed targets | FPRL1-type receptor and a CNTFR/WSX-1/gp130 receptor complex; intracellular binding to BAX and IGFBP-3 (proposed) | AMPK activation via folate cycle and AICAR accumulation; nuclear gene regulation under stress (proposed) |
| Research areas | Neuronal survival, Alzheimer's-related models, cardiovascular and metabolic models | Insulin sensitivity, obesity, exercise capacity and aging in mice |
| Evidence level | Preclinical; human data observational | Early-clinical; human interventional data very limited |
| FDA / compounding | Not FDA-approved; check current FDA lists | Not FDA-approved; PCAC voted 7-5 (2 abstentions) in July 2026 to recommend 503A bulk listing, no final FDA action |
| Analytical pitfalls | Cysteine can form disulfide dimers; HNG vs native sequence; hydrophobic leucine stretch | Methionine and tryptophan oxidation; strongly cationic |
| Storage | Lyophilized at -20 °C, protected from light and oxygen; avoid freeze-thaw | Lyophilized at -20 °C, protected from light and oxygen; avoid freeze-thaw |
Different genes, a shared concept
Both peptides are encoded by short open reading frames that overlap mitochondrial ribosomal RNA genes, which is why they are grouped as mitochondrial-derived peptides. Where each is actually translated is not fully settled: for humanin, translation in the cytoplasm and in mitochondria would give peptides of slightly different lengths because of differences in the genetic code, and nuclear sequences resembling the humanin reading frame complicate interpretation. MOTS-c has been reported to move to the nucleus under metabolic stress. These localization questions remain active research topics.
Proposed mechanisms and research focus
Humanin was first studied as a survival factor for neurons, with proposed actions at cell-surface receptors and through intracellular binding partners involved in apoptosis. Later work extended to cardiovascular and metabolic models. MOTS-c research has centered on metabolism, beginning with a 2015 mouse study linking it to the folate cycle, AMPK activation and protection from diet-induced insulin resistance. For both peptides, mechanisms come largely from cell and rodent studies and are not established in humans; circulating-level studies in people are correlational.
Analytical considerations
Humanin contains a single cysteine, so it can form disulfide-linked dimers on storage, and its leucine-rich core makes it relatively hydrophobic. Certificates should also make clear whether material is native humanin or the HNG analogue, which differ in mass. MOTS-c has two methionines and a tryptophan, making oxidized species the main impurities to monitor by mass spectrometry. Both are commonly supplied as acetate or TFA salts. See MOTS-c vs SS-31 for a comparison with another mitochondria-focused peptide.
Frequently asked questions
What is the difference between humanin and MOTS-c?
Both are peptides encoded within mitochondrial DNA, but they come from different ribosomal RNA genes and have unrelated sequences. Humanin is 24 residues and was discovered as a neuronal survival factor in 2001. MOTS-c is 16 residues and was described in 2015 in work on metabolism and insulin sensitivity in mice. Their proposed mechanisms also differ.
Are humanin or MOTS-c FDA approved?
Neither is approved by the FDA for any use. In July 2026 the FDA's Pharmacy Compounding Advisory Committee voted 7-5, with two abstentions, to recommend adding MOTS-c to the 503A bulk drug substances list; the vote is advisory and no final FDA action has been announced. Humanin was not part of that vote. For sport, check the current WADA Prohibited List.
What is HNG?
HNG is an analogue of humanin in which serine at position 14 is replaced by glycine. In cell-based studies it was reported to be considerably more potent than native humanin, and it has been used widely in animal research. Because the substitution changes the mass, a certificate of analysis should state whether the native peptide or HNG was confirmed.
Full entries
- Humanin
Humanin is a 24-amino-acid mitochondrial-derived peptide first described in 2001 as a factor protecting neurons from death linked to Alzheimer's disease genes. It is studied in cell and animal models of neurodegeneration, metabolism and aging and is not approved for any use.
- MOTS-c
MOTS-c is a 16-amino-acid peptide encoded within the mitochondrial 12S rRNA gene, described in 2015 as a regulator of metabolic homeostasis. Research is mainly in cell and rodent models, with limited human data.
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