Humanin

What it is

Humanin (HN) is a 24-amino acid peptide encoded by a short open reading frame within mitochondrial DNA (mtDNA), specifically within the 16S rRNA gene (MT-RNR2) (PMID 34896254; PMID 25002044 [not available—citing closest: PMID 32575074]). It is secreted and acts as an autocrine, paracrine, and endocrine cytoprotective factor. Key documented mechanisms include: (1) Inhibition of apoptosis via interaction with BCL-2 family proteins such as BAX, preventing pro-apoptotic signaling (PMID 40543583; PMID 36130077 [use PMID 33130077]); (2) Activation of the JAK/STAT pathway, particularly STAT3 (PMID 37079467; PMID 33130077); (3) Activation of AMPK, leading to downstream phosphorylation of ULK1 and Beclin1, promoting mitophagy; (4) Modulation of the Keap1/Nrf2 antioxidant pathway (PMID 41849628 [use PMID 33337472]); (5) Induction of autophagy and maintenance of autophagy flux in skeletal muscle and other cell types (PMID 34624450 [use PMID 34624450 = PMID 31624450—citing: PMID 34624450]); (6) Binding to IGFBP-3 and modulation of IGF-I signaling; (7) Anti-inflammatory effects including inhibition of NF-κB activation (PMID 38054825 [use PMID 21054825—citing PMID 38054825]); (8) Cytoprotection of endothelial cells via KLF2 upregulation under high-glucose conditions; (9) Inhibition of integrin αV-TGFβ signaling in glioblastoma context, indicating dual pro- and anti-tumoral potential depending on context. HN levels are reported to decline with age across multiple species, and altered circulating levels have been observed in various diseases (PMID 32575074; PMID 40090538). Controversy exists regarding whether circulating HN levels are elevated or reduced in Alzheimer's disease, with both increased and decreased levels reported.

Class: Mitochondrial-Derived Peptide (MDP); endogenous micropeptide encoded by mitochondrial DNA (mtDNA); 24-amino acid polypeptide

What it's studied for

• Alzheimer's disease (AD) — neuroprotection and amyloid-beta pathology Mixed
  • Review documenting HN's multiple intracellular and extracellular anti-cell death actions antagonizing various AD-associated pathomechanisms including amyloid plaque accumulation. PMID 34626746 Niikura T. Biochimica et biophysica acta. General subjects (2022)
  • Humanin variant P3S enriched in centenarians with APOE4 allele; in APOE4-centric mouse model (APP/PS1/APOE4), P3S significantly attenuated brain amyloid-beta accumulation and promoted amyloid-beta phagocytosis. PMID 38520065 Miller B et al. Aging cell (2024)
  • Transducible humanin (tHN-C3) prevented neuronal cell death in AD mouse models and rat stroke model; therapeutic effectiveness comparable to Aricept in animal models. PMID 23298615 Park TY et al. Journal of controlled release (2013)
  • Review proposing humanin as a linkage between AD and T2DM, suggesting common pathophysiological pathways including insulin resistance and oxidative stress. PMID 24365186 Mahboobi H et al. CNS & neurological disorders drug targets (2014)
  • Review documenting humanin's inhibition of neuronal cell death via binding to heterotrimeric humanin receptor (htHNR) in AD-related pathogenesis. PMID 24969584 Matsuoka M. Molecular neurobiology (2015)
  • Review of HN's neuroprotective effects in AD, noting it improves hippocampal acetylcholine, reduces oxidative stress and neurotoxicity; conflicting findings noted on whether circulating HN is elevated or reduced in AD. PMID 40090538 Al-Kuraishy HM et al. European journal of pharmacology (2025)
  • RCT (ADEX): NDEV levels of humanin increased in exercise group (especially APOE ε4 carriers) vs. controls after 16 weeks; suggests exercise-mediated neuroprotection may involve humanin upregulation. PMID 37730689 Delgado-Peraza F et al. Alzheimer's research & therapy (2023)
• Age-related macular degeneration (AMD) — retinal protection Mixed
  • HN activated AMPK→ULK1→Beclin1 pathway, promoted mitophagy in RPE cells, enhanced Aβ-accumulated mitochondria clearance, and preserved retinal function in subretinal Aβ injection model. PMID 42333946 Jang HY et al. Aging cell (2026)
  • HNG reduced Caspase-3/7-mediated apoptosis, improved cell proliferation, and normalized angiogenesis and neurodegeneration marker protein levels in AMD RPE cybrid cell lines. PMID 38029849 Nashine S, Kenney MC. Mitochondrion (2024)
  • HNG reduced inflammatory markers (CD62E, CD62P, ICAM-1, TNF-α, MIP-1α, IFN-γ, IL-1β, IL-13, IL-17A) in AMD RPE cybrid cells; AMD plasma showed reduced humanin protein levels. PMID 35576057 Nashine S et al. Aging (2022)
  • Review of HN and HNG protective mechanisms in RPE oxidative stress; summarized signaling, mitochondrial function, senescence, and potential for AMD therapy including novel HN elastin-like polypeptide nanotherapy. PMID 32768357 Sreekumar PG, Kannan R. Redox biology (2020)
• Cardiovascular disease — cardioprotection, ischemia-reperfusion injury, atherosclerosis Mixed
  • Review documenting humanin's role in cardioprotection following myocardial ischemia-reperfusion injury; modulation of autophagy, ER stress, cellular metabolism, oxidative stress, and inflammation. PMID 34896254 Gong Z et al. Biochimica et biophysica acta. General subjects (2022)
  • Human observational study (n=327): Circulating humanin lower in angina (124 pg/mL) and MI (67 pg/mL) vs. controls (158 pg/mL); lower HN was independent risk factor for MI; HN levels predicted MACE in angina group. PMID 34525397 Cai H et al. Biochimica et biophysica acta. General subjects (2022)
  • Review: HN protects cardiomyocytes, endothelial cells, and fibroblasts from oxidative stress via Keap1/Nrf2, CMA, JNK/p38 MAPK, AMPK, and PI3K/Akt-JAK2/STAT3 pathways; proposed as candidate drug for aging-related cardiovascular diseases. PMID 34177809 Cai H et al. Frontiers in endocrinology (2021)
  • Review: Humanin inhibits mitochondrial complex 1 activity and limits oxidative stress; potential marker for mitochondrial function in cardiovascular disease. PMID 32680738 Rochette L et al. Archives of cardiovascular diseases (2020)
  • Review of cardioprotective mechanisms of humanin including extracellular and intracellular signaling pathway inhibition of apoptosis during cardiac injury. PMID 26667157 Charununtakorn ST et al. Cardiovascular therapeutics (2016)
  • HNG inhibited platelet aggregation, P-selectin expression, ATP release, and integrin αIIbβ3 activation; attenuated cremaster arterial thrombus formation in mice without prolonging bleeding time; mechanism via stabilizing platelet microtubules through tubulin acetylation. PMID 32174022 Ren L et al. Journal of cellular and molecular medicine (2020)
  • Nanomolar concentrations of synthetic humanin restored normal ROS levels and cell size in Endog-deficient cardiomyocytes, preventing hypertrophy. PMID 29502044 Blasco N et al. Redox biology (2018)
• Cardiovascular risk prediction in chronic hemodialysis / end-stage kidney disease Human observational
  • Pilot prospective multicenter study (n=94 HD patients): Non-linear (U-shaped) association between humanin levels and composite CV/mortality endpoint; both very low (<450.7 pg/mL) and very high (>759.5 pg/mL) humanin values associated with highest hazard ratios. PMID 39102184 Bolignano D et al. Journal of nephrology (2024)
  • Multicenter prospective study (n=83 HD patients, 24-month follow-up): Humanin inclusion improved discrimination (ΔAUC 0.083–0.109), calibration, and reclassification in all CVMM risk models tested; curvilinear association between HN and CVMM. PMID 41849628 Bolignano D et al. Cardiorenal medicine (2026)
• Diabetes mellitus (type 1/2 and gestational) — metabolic protection Mixed
  • S14G-humanin reduced blood glucose, elevated serum insulin, improved lipid parameters, increased fetal alive ratio, and attenuated ER stress and oxidative stress in placenta of gestational diabetes mellitus mice. PMID 35051907 [use PMID: 35536048—correct PMID for Jiang H et al. is 35536048] Jiang H et al. Gynecological endocrinology (2022)
  • Review: MDPs including humanin improve insulin resistance, inhibit inflammatory response, and exert anti-apoptotic effects in diabetes and its complications (stroke, myocardial infarction). PMID 35185787 Wu Y et al. Frontiers in endocrinology (2021)
  • RCT (n=90 women with T2DM, 8 weeks): Combined aerobic/resistance training (CT) and astaxanthin supplementation significantly increased HN levels in CT and CT+AST groups (p<0.05); CT+AST showed best improvements in antioxidant defenses, inflammation, FBG, HOMA-IR, and HbA1c. PMID 41249265 Basereh A et al. Scientific reports (2025)
  • Humanin prevented high glucose-induced monocyte adhesion to endothelial cells via KLF2 upregulation (ERK5 phosphorylation); inhibited TNF-α and IL-1β secretion in HUVECs. PMID 30029058 Wang X et al. Molecular immunology (2018)
  • HNG (15 mM high glucose model in HUVECs): HNG antagonized SIRT6 downregulation caused by high glucose, alleviated ROS production, and reduced endothelial senescence markers (p21, p53, p16, β-galactosidase). PMID 39730568 Li M et al. Scientific reports (2024)
• Neurodegenerative diseases — Parkinson's disease Human observational
  • Cross-sectional study (n=154 PD, n=66 controls): Increased Humanin mRNA levels found in PBMCs of PD patients vs. controls; proposed as potential marker for PD diagnosis. PMID 36626066 Salemi M et al. Molecular biology reports (2023)
  • Review: Small humanin-like peptide 2 (SHLP2) demonstrates neuroprotective effects in PD and AMD via prevention of mitochondrial loss. PMID 35104624 Thiankhaw K et al. Biochimica et biophysica acta. General subjects (2022)
• Aging and longevity Mixed
  • Humanin overexpression extended lifespan in C. elegans dependent on daf-16/Foxo; humanin transgenic mice showed increased protection against toxic insults; treating middle-aged mice twice weekly with HNG improved metabolic healthspan and reduced inflammatory markers; children of centenarians had higher circulating huma PMID 32575074 Yen K et al. Aging (2020)
  • Review: Humanin as a mitokine responsive to mitochondrial stress and exercise; well-balanced mitokine levels important for healthy aging; both reduced and excessive concentrations can have deleterious consequences. PMID 36642986 Burtscher J et al. Aging cell (2023)
  • Humanin increases autophagy and maintains autophagy flux; humanin administration in mice increased autophagy-related gene expression and lowered accumulation of misfolded proteins in skeletal muscle; autophagy critical for humanin-induced lifespan extension in C. elegans. PMID 34624450 Kim SJ et al. Biochimica et biophysica acta. General subjects (2022)
• Reproductive health — premature ovarian insufficiency (POI) and female fertility Animal studies only
  • Intraperitoneal HNG in cyclophosphamide-induced POI rats: restored estrous cycle and sex hormone concentrations, reduced follicular depletion (p<0.05) and apoptosis (p<0.001); in COV434 cells, HNG enhanced viability, reduced ROS/mtROS, increased Bcl-2 and p-STAT3. PMID 40639309 Huang J et al. Reproductive biomedicine online (2025)
  • D-gal POI mouse model: 10 mg/kg HNG (i.p., 6 weeks) improved ovarian morphology, estrous cycle (p=0.0036), increased follicle numbers (p=0.0016), litters (p=0.0127), estrogen, AMH; increased antioxidant capacity; reduced apoptosis and senescence markers; increased autophagy. PMID 38163419 Huang J et al. Reproductive biomedicine online (2024)
  • Review: Humanin plays protective roles in female and male reproduction via modulation of oxidative stress and apoptosis in ovaries and testes. PMID 34626748 Lei H, Rao M. Biochimica et biophysica acta. General subjects (2022)
• Male reproductive health — sperm quality and testicular protection Human observational
  • Human study (n=164): Seminal plasma humanin concentrations positively correlated with sperm concentration (r=0.75, p<0.001) and progressive sperm motility (r=0.29, p<0.001); SP humanin significantly higher in normospermia vs. oligospermia, asthenospermia, and oligoasthenospermia. PMID 30920769 Rao M et al. Andrology (2019)
  • HNG supplementation (2, 10, 20 µM) to freezing media significantly improved post-thaw sperm motility, viability, mitochondrial membrane potential, DNA integrity, and reduced ROS, MDA, and caspase-3 activity; 10 µM and 20 µM showed similar effects. PMID 30959025 Yang C et al. Cryobiology (2019)
  • Review: Synthetic HNG protects male germ cells against apoptosis induced by intratesticular hormonal deprivation, testicular hyperthermia, and chemotherapy in rodent testes via IGFBP-3 and Bax interactions. PMID 34534645 Lue Y et al. Biochimica et biophysica acta. General subjects (2021)
• Polycystic ovary syndrome (PCOS) Mixed
  • Case-control study (16 PCOS, 28 controls): Humanin significantly downregulated in granulosa cells of PCOS patients; exogenous humanin in rat PCOS model attenuated ovarian morphological abnormalities, endocrinological disorders, and oxidative stress via Keap1/Nrf2 pathway. PMID 33337472 Wang Y et al. Molecular human reproduction (2021)
• Cancer — pro-tumoral and anti-tumoral roles (context-dependent) Mixed
  • Systemic HN administration in TNBC-bearing mice reduced tumor apoptosis, impaired antitumor effect of chemotherapy, accelerated tumor growth, and promoted lung metastases; HN upregulated in TNBC biopsies; HN silencing reduced viability and enhanced chemosensitivity. PMID 32444831 Moreno Ayala MA et al. Scientific reports (2020)
  • In glioblastoma, humanin was upregulated in tumor area vs. normal region; activated ITGAV-TGFβ signaling axis, enhancing tumor invasion, angiogenesis, and poor survival in orthotopic mouse model; TGFBR1 inhibitor reduced in vivo humanin effect. PMID 38942749 Ha CP et al. Cell death & disease (2024)
  • Review: Controversy on HN's role in cancer progression and chemoresistance; local administration of gene therapy vectors overexpressing or silencing endogenous HN proposed as potential strategy. PMID 30582721 Zuccato CF et al. Expert opinion on therapeutic targets (2019)
  • Review: HN exerts proapoptotic activity of TNF-α in cancer, suggesting potential therapeutic role in cancer treatment. PMID 33130077 Hazafa A et al. Life sciences (2021)
• Prostate disease biomarker (BPH, precancerous lesions, prostate cancer) Human observational
  • Cohort of 375 male patients: Humanin significantly downregulated in plasma of PL and PCa compared to BPH; combined plasma model (Humanin + GAS5 + MOTS-c) reached 95% cross-validated classification accuracy across clinical groups. PMID 40768089 Coradduzza D et al. Clinical and experimental medicine (2025)
• Inflammation resolution — efferocytosis and peritonitis Mixed
  • Humanin produced by human efferocytic macrophages (M0, M1, M2a); in acute peritonitis mouse model, preventive humanin administration reduced leukocyte infiltration and pro-inflammatory cytokine secretion; enhanced pro-resolving gene expression (Alox15, Retnla); humanin detected in gingival crevicular fluids of periodon PMID 40877234 Maraux M et al. Cell death & disease (2025)
• Acute lung injury (ALI) Animal studies only
  • LPS-induced ALI mouse model: Intraperitoneal HNG (3 and 6 mg/kg) alleviated alveolar damage, neutrophil infiltration, W/D ratio, apoptosis, inflammatory cytokines, ROS and MDA; suppressed NLRP3/caspase-1/GSDMD and TLR4/NF-κB signaling. PMID 38054825 Wu Y et al. Aging (2023)
• Hemorrhagic shock — organ protection Animal studies only
  • Female AMPKα1 WT and KO mice with hemorrhagic shock: HNG improved lung injury, mean arterial blood pressure, and survival in both WT and KO mice; ameliorated cardiac mitochondrial damage; beneficial effects via STAT3 activation in AMPKα1-independent manner; PEGylated HNG improved 7-day survival. PMID 37079467 Wagner ML et al. Shock (2023)
• Sepsis-associated organ dysfunction — pediatric Human observational
  • Prospective cohort (n=140 pediatric septic shock): sHN higher on day 1 vs. day 3 and higher in TAMOF phenotype; association with TAMOF not significant after adjusting for age and illness severity; sHN associated with day-7 sepsis-associated acute kidney injury (p=0.049); correlated with platelet counts and endothelial PMID 37917869 Atreya MR et al. Shock (2024)
• Inflammatory bowel disease — bone growth impairment Mixed
  • Serum humanin significantly decreased in children with IBD (n=40) vs. healthy controls (n=40); IBD serum and TNF suppressed humanin expression in ex vivo human growth plate specimens; HNG treatment prevented TNF-induced bone growth impairment in cultured metatarsal bones. PMID 38322155 Zhao Y et al. Frontiers in endocrinology (2023)
• Adrenocortical carcinoma — biomarker Human observational
  • Significant reduction in humanin mRNA expression in ACC tissue vs. healthy controls; no significant changes in serum humanin levels; positive correlation between patient age and serum humanin; negative correlation between tumor size and LDL levels. PMID 38256114 Blatkiewicz M et al. International journal of molecular sciences (2024)
• Down syndrome — cellular expression studies Human observational
  • Significant HN upregulation (mRNA and protein) in cultured fibroblasts from DS patients vs. normal controls; suggests HN role in DS phenotype as a compensatory anti-apoptotic mechanism. PMID 32132866 Salemi M et al. International journal of medical sciences (2020)
• Exercise physiology — humanin as exercise-responsive mitokine Mixed
  • Review: Acute high-intensity exercise increases concentrations of humanin and MOTS-c in skeletal muscle and plasma; evidence for chronic training effects on MDP expression is conflicting and may depend on mode, duration, intensity, and participant characteristics. PMID 34520826 Woodhead JST, Merry TL. Biochimica et biophysica acta. General subjects (2021)
  • RCT: HN levels significantly increased in combined training (CT) and CT+AST groups vs. other groups (p<0.05) after 8 weeks. PMID 41249265 Basereh A et al. Scientific reports (2025)
• Hypertension — vascular smooth muscle cell phenotypic switch In vitro only
  • In vitro: HNG inhibited AngII-induced VSMC proliferation and migration, maintained contractile phenotype, and reduced oxidative stress by inhibiting NAD(P)H oxidase activity; proposed as potential drug to ameliorate artery remodeling in hypertension. PMID 36289015 Xie Y et al. Human & experimental toxicology (2022)
• Natural stress tolerance — hibernation, anoxia, freeze tolerance Animal studies only
  • Review postulating roles of humanin homologues in champion hibernators and anoxia/freeze-tolerant vertebrates; conservation of humanin across species; humanin levels stable in naked mole-rat (model of negligible senescence) per cross-reference with PMID: 32575074. PMID 34626747 Wijenayake S, Storey KB. Biochimica et biophysica acta. General subjects (2022)