Cellular Aging
Humanin and MOTS-c in Senescent Human Fibroblasts
Primary human fibroblasts were used in a 2018 study of mitochondrial-derived peptides during cellular senescence. Researchers induced senescence through replicative exhaustion, doxorubicin exposure, and hydrogen peroxide treatment. Mitochondrial number, mitochondrial respiration, mitochondrial DNA methylation, and levels of humanin, MOTS-c, SHLP2, and SHLP6 were then measured. Senescent fibroblasts had more mitochondria, higher mitochondrial respiration, and elevated humanin and MOTS-c levels.
The researchers also treated doxorubicin-induced senescent fibroblasts with humanin or MOTS-c. Both peptides modestly increased mitochondrial respiration and changed selected components of the senescence-associated secretory phenotype. The reported changes in SASP components were partly linked to JAK pathway activity.
Humanin and Oxidative Stress in Retinal Cells
Researchers exposed human retinal pigment epithelial cells to 150 μM tert-butyl hydroperoxide for 24 hours and examined the effects of humanin. The study measured reactive oxygen species, mitochondrial respiration, cell death, caspase-3 activation, mitochondrial DNA copy number, SA-β-gal staining, p16INK4a expression and transepithelial resistance. Humanin localization was also examined by confocal microscopy.
Humanin reduced tert-butyl-hydroperoxide-induced reactive oxygen species and increased mitochondrial DNA copy number. The researchers also reported changes in mitochondrial respiration, mitochondrial transcription factor A, STAT3 phosphorylation, caspase-3 activation, and cell death. SA-β-gal staining and p16INK4a measurements were used to assess cellular senescence.
Metabolic Regulation
MOTS-c and Glucose Metabolism
A 2015 study examined MOTS-c in cellular and mouse models of metabolic regulation. The researchers identified a pathway involving the folate cycle, de novo purine biosynthesis, and AMPK activation. They then examined glucose metabolism, insulin sensitivity, body weight, and responses to high-fat feeding in mice.
MOTS-c treatment prevented age-dependent and high-fat-diet-induced insulin resistance in the mouse models and reduced diet-induced obesity. The study identified skeletal muscle as the primary target organ examined for the peptide's metabolic activity.
Humanin and Insulin Sensitivity
A separate study investigated humanin through glucose-clamp experiments in rats. Researchers examined insulin sensitivity, glucose uptake, hepatic glucose production and skeletal-muscle insulin signaling. The study also examined hypothalamic STAT3 signaling.
Humanin increased glucose infusion rates and peripheral glucose uptake while reducing hepatic glucose production. The researchers also found increased hypothalamic STAT3 phosphorylation. Blocking STAT3 prevented the effects on hepatic glucose production and peripheral glucose uptake.
Tissue Biology
MOTS-c in Aging Skeletal Muscle
A 2020 study examined plasma and skeletal-muscle MOTS-c in healthy men aged 18 to 30, 45 to 55, and 70 to 81 years. Researchers measured circulating MOTS-c, skeletal-muscle expression, myofiber composition and muscle quality.
Circulating MOTS-c decreased with age, while skeletal-muscle MOTS-c expression was approximately 1.5-fold higher in the middle-aged and older groups than in the young group. Muscle MOTS-c expression was associated with markers of slow-type muscle fibers. In the older group, it was also associated with muscle quality measured by maximal leg-press load relative to thigh cross-sectional area.
MOTS-c and Human Skeletal Muscle Atrophy
A 2026 study examined MOTS-c and S14G-humanin in fully differentiated primary human myotubes exposed to 10 μM dexamethasone. The researchers measured myotube area, fusion index, MURF1, MAFbx, PGC1α, Akt phosphorylation and STAT3 activation. Dexamethasone reduced myotube area and fusion index and increased MURF1, MAFbx and PGC1α.
MOTS-c co-treatment preserved myotube area and fusion index, increased Akt phosphorylation and reduced MURF1 upregulation and STAT3 activation compared with dexamethasone alone. S14G-humanin preserved myotube area and reduced dexamethasone-induced STAT3 activation, but had no effect on fusion index or E3 ligase mRNA levels.
Where Longevity Peptide Research Goes Next
The published studies point to several areas for further investigation. Cellular studies have examined senescence and mitochondrial responses. Metabolic studies have measured glucose and insulin-related endpoints. Tissue studies have examined skeletal muscle at the cellular and human level. These findings provide separate lines of experimental evidence, rather than one unified measure of longevity.
Research on these peptides continues across different models and endpoints. Future studies can help clarify whether findings observed in cells and experimental animals correspond with measurable outcomes in human research.
For laboratory research, explore the Direct SARMS peptide collection.
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References
- Kim SJ, Mehta HH, Wan J, Kuehnemann C, Chen J, Hu JF, Hoffman AR, Cohen P. Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY). 2018 Jun 10;10(6):1239-1256. PubMed ↗
- Sreekumar PG, Ishikawa K, Spee C, Mehta HH, Wan J, Yen K, Cohen P, Kannan R, Hinton DR. The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial Dysfunction. Invest Ophthalmol Vis Sci. 2016 Mar;57(3):1238-53. PubMed ↗
- Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015 Mar 3;21(3):443-54. PubMed ↗
- Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, Fishman S, Budagov T, Cui L, Einstein FH, Poduval A, Hwang D, Barzilai N, Cohen P. Humanin: a novel central regulator of peripheral insulin action. PLoS One. 2009 Jul 22;4(7):e6334. PubMed ↗
- D'Souza RF, Woodhead JST, Hedges CP, Zeng N, Wan J, Kumagai H, Lee C, Cohen P, Cameron-Smith D, Mitchell CJ, Merry TL. Increased expression of the mitochondrial derived peptide, MOTS-c, in skeletal muscle of healthy aging men is associated with myofiber composition. Aging (Albany NY). 2020 Mar 17;12(6):5244-5258. PubMed ↗
- Elhusseiny R, Ihsan M, Bellefroid T, Farooq A, Racinais S, Deldicque L. Mitochondrial-derived peptides MOTS-c and humanin attenuate dexamethasone-induced atrophy in human skeletal muscle cells. Physiol Rep. 2026 Feb;14(4):e70791. PubMed ↗