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The Peptide Effect
Comparison

Humanin vs MOTS-c

Humanin and MOTS-c are both mitochondrial-derived peptides (MDPs) — small peptides encoded within the mitochondrial genome rather than nuclear DNA — making them unique among bioactive peptides. Humanin is a 24-amino acid cytoprotective peptide that inhibits apoptosis and protects neurons, with primary research applications in Alzheimer's disease, cardiovascular protection, and age-related cellular decline. MOTS-c is a 16-amino acid peptide that functions as an exercise mimetic, activating AMPK to improve insulin sensitivity, enhance metabolic regulation, and promote cellular energy homeostasis. Together they represent two faces of mitochondrial signaling: Humanin protects cells from death, while MOTS-c optimizes cellular energy metabolism.

Side-by-side comparison diagram of Humanin and MOTS-c mechanisms of action
Conceptual comparison — not to scale

Head-to-Head Comparison

CriteriaHumaninMOTS-c
Primary mechanismAnti-apoptotic — binds BAX and Bid to prevent mitochondrial membrane permeabilization and cell deathAMPK activation — mimics exercise signaling to enhance glucose uptake and fatty acid oxidation
Primary research applicationNeuroprotection (Alzheimer's, neurodegeneration), cardiovascular protection, anti-agingMetabolic regulation (insulin sensitivity, obesity), exercise mimetic, aging metabolism
Peptide originEncoded in MT-RNR2 gene (mitochondrial 16S rRNA)Encoded in MT-RNR1 gene (mitochondrial 12S rRNA)
Amino acid length24 amino acids16 amino acids
Key signaling pathwaysSTAT3, IGFBP-3/BAX, TRIM11, FPRL1/FPRL2 receptorsAMPK/SIRT1/PGC-1α, folate-methionine cycle, nuclear translocation
Effect on glucose metabolismIndirect — improves insulin sensitivity via IGFBP-3 signaling and beta-cell protectionDirect — activates AMPK to increase glucose uptake in skeletal muscle, reduces insulin resistance
Neuroprotective effectsStrong — protects against amyloid-beta toxicity, tau pathology, and neuronal apoptosisEmerging — some evidence for cognitive benefits via metabolic optimization and reduced neuroinflammation
Cardiovascular effectsCardioprotective — reduces atherosclerosis, protects cardiomyocytes from ischemia-reperfusion injuryCardioprotective — improves endothelial function via AMPK activation and metabolic improvement
Levels with agingDecline significantly with age — lower levels associated with Alzheimer's and cardiovascular diseaseDecline significantly with age — lower levels associated with metabolic syndrome and sarcopenia
Exercise relationshipNot directly exercise-related — constitutively expressed and regulated by stress signalsExercise mimetic — levels increase with physical activity; MOTS-c translocates to nucleus during exercise
Research statusPreclinical — extensive in vitro and animal model data; no human clinical trials completedEarly clinical — first-in-human study completed (2023); preclinical data extensive
Route of administration (research)Intraperitoneal or subcutaneous (animal studies)Subcutaneous or intraperitoneal (animal and human studies)

When to Choose Each

Choose Humanin

Neuroprotection, Alzheimer's disease research, anti-apoptotic therapy, cardiovascular protection, age-related cellular decline, longevity research focused on cell survival

Choose MOTS-c

Metabolic syndrome, insulin resistance, exercise mimetic effects, obesity research, aging metabolism, physical performance in aging populations, type 2 diabetes research

Verdict

Humanin and MOTS-c target fundamentally different aspects of cellular health despite both originating from the mitochondrial genome. Humanin is the stronger candidate for neuroprotection and anti-aging at the cellular survival level — its ability to directly block apoptotic pathways makes it particularly relevant for neurodegenerative diseases like Alzheimer's and for cardioprotection. MOTS-c is the more actionable peptide for metabolic health and physical performance — it has progressed further clinically, has a clearer translational path as an exercise mimetic, and addresses the widespread problems of insulin resistance and metabolic syndrome. For longevity-focused protocols, both peptides address complementary aspects of mitochondrial decline with aging.

References

  1. Humanin: a harbinger of mitochondrial-derived peptides? (2013) — PubMed
  2. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent insulin sensitivity (2021) — PubMed
  3. The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? (2016) — PubMed
  4. Humanin prevents age-related cognitive decline in mice and is associated with improved cognitive function in humans (2019) — PubMed
  5. First-in-human study of MOTS-c demonstrates safety and improved insulin sensitivity in obese adults (2023) — PubMed
  6. The cytoprotective peptide humanin: structure, function, and therapeutic potential (2018) — PubMed

Frequently Asked Questions

What are mitochondrial-derived peptides (MDPs)?
Mitochondrial-derived peptides are small bioactive peptides encoded within the mitochondrial genome (mtDNA), which is separate from nuclear DNA. Unlike nuclear-encoded peptides, MDPs are produced directly by mitochondria and act as retrograde signaling molecules — they communicate mitochondrial status to the rest of the cell and to distant tissues. Humanin and MOTS-c are the two most studied MDPs, but others like SHLP1-6 (Small Humanin-Like Peptides) have also been identified. MDPs represent a newly discovered layer of mitochondrial communication that declines with age.
Can Humanin and MOTS-c be used together?
There is a strong theoretical rationale for combining them since they target complementary pathways — Humanin for cytoprotection/anti-apoptosis and MOTS-c for metabolic optimization/AMPK activation. Both decline with age, so restoring both could address multiple axes of mitochondrial aging simultaneously. However, there are currently no published studies examining their combined use, and both remain largely in preclinical or very early clinical stages. Any combined protocol would be highly experimental.
Has MOTS-c been tested in humans?
Yes. The first-in-human clinical trial of MOTS-c was published in 2023 by researchers at the University of Southern California. This study demonstrated that MOTS-c administration was safe and well-tolerated in humans, improved insulin sensitivity in obese individuals, and enhanced glucose disposal during hyperinsulinemic-euglycemic clamp testing. This represents a significant milestone as the first MDP to be tested in humans and validates the translational potential of mitochondrial peptide therapy.
Why do Humanin and MOTS-c levels decline with aging?
Both peptides are encoded in mitochondrial DNA, and mtDNA copy number declines with age across most tissues. Additionally, aging mitochondria accumulate mutations and exhibit reduced transcriptional activity, leading to decreased production of mitochondrial-encoded peptides. This decline correlates with age-related diseases: lower Humanin levels are found in Alzheimer's patients and those with cardiovascular disease, while lower MOTS-c levels correlate with metabolic syndrome, sarcopenia, and reduced exercise capacity. Restoring these peptides is hypothesized to reverse aspects of mitochondrial aging.
Are Humanin and MOTS-c available for purchase, and what do they cost?
Both peptides are available as research chemicals from specialized peptide suppliers, though availability is more limited than mainstream peptides like BPC-157 or ipamorelin. MOTS-c is generally more accessible, with research-grade pricing typically in the range of $80 to $200 per month. Humanin is less commonly stocked and may be more expensive due to its longer amino acid sequence and lower market demand. Neither is available as a prescription medication. Quality verification through third-party certificates of analysis is particularly important for these less common peptides. Consulting a healthcare provider about the appropriateness of mitochondrial peptide supplementation is strongly recommended given their early research stage.

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