Humanin
Humanin (HN); Mitochondrial-derived peptide encoded by MT-RNR2 (16S rRNA)
A 24-amino acid mitochondrial-derived peptide (MDP) first discovered in 2001 from surviving neurons of Alzheimer's disease brain tissue, with cytoprotective, anti-apoptotic, and neuroprotective properties demonstrated in preclinical models but no human interventional data (PMID 11606574, PMID 23416677, PMID 35432758).
Last updated: 2026-03-10
Safety Summary
No systematic human safety data exists. No controlled human adverse-event dataset or phase 1 tolerability study was identified. The ADDF states: 'Clinical human testing has not been conducted, and therapeutic dosing has not been established.' The most significant safety concern is humanin's anti-apoptotic effect potentially promoting tumor cell survival in certain cancer contexts. Humanin was shown to promote tumor progression in experimental TNBC by protecting tumor cells from apoptosis (PMID 32427890). A separate 2023 preprint found humanin enhanced glioblastoma progression via integrin alphaV-TGFbeta signaling (DOI 10.21203/rs.3.rs-2702693/v1). Humanin was upregulated in gastric cancer, bladder tumor cells, and pituitary tumor cells (PMID 32427890). However, HNG showed anti-tumor effects in neuroblastoma/medulloblastoma models, indicating context-dependent effects across tumor types. In preclinical animal studies, humanin was generally well-tolerated with no major adverse effects reported. Humanin transgenic mice showed decreased fertility with reduced brood size (PMID 32575077). The ADDF notes humanin effects may be sex-dependent, influenced by ovarian hormones.
Known Side Effects
common
rare
unknown
unknown
Who Should NOT Use This
Humanin's anti-apoptotic properties may protect tumor cells from programmed cell death. Humanin promotes tumor progression in experimental TNBC models and is upregulated in gastric cancer, bladder tumors, and pituitary tumors (PMID 32427890). A preprint also links humanin to glioblastoma progression via integrin alphaV-TGFbeta axis (DOI 10.21203/rs.3.rs-2702693/v1). Multiple cancer types show humanin upregulation.
No reproductive safety data in humans. Humanin transgenic animals showed decreased fertility and reduced brood size (PMID 32575077). Effects on human pregnancy unknown. One preprint tracked humanin levels across gestation (DOI 10.21203/rs.3.rs-588198/v1) but did not administer it.
While humanin protects normal cells (germ cells, leukocytes) from chemotherapy-induced damage, its effects on chemosensitivity of tumor cells remain controversial. HNG protected bone cells from bortezomib toxicity while improving apoptotic response of neuroblastoma and medulloblastoma in xenograft models (PMID 32427890 references Jia Y et al.). Requires careful clinical assessment.
Talk to Your Doctor
Before considering Humanin, discuss it with your healthcare provider. Ask about potential interactions with your current medications, whether it is appropriate for your health conditions, and what monitoring may be needed.
Sources: [1-20]
Evidence Assessment
Tier 5: No human interventional clinical trials have been conducted administering exogenous humanin or its analogs. All therapeutic efficacy evidence comes from animal models (C. elegans lifespan, mouse AD models, mouse neuropathic pain, mouse metabolic models, rat hippocampal models, mouse TBI model) and in vitro studies. Human data is limited to observational/correlational studies measuring endogenous humanin levels (centenarian children, diabetics, AD patients, IVF cohort PMID 30503199 n=179, CABG patients NCT03431844 n=106, pediatric septic shock DOI 10.21203/rs.3.rs-3078685/v1 n=140, pregnancy GDM DOI 10.21203/rs.3.rs-588198/v1 n=73). Multiple ClinicalTrials.gov entries (NCT05506228, NCT07438002, NCT03431844, NCT06125249, NCT06105229, NCT04104958) use humanin as a biomarker endpoint but none administer it as an intervention. The ADDF notes that 'clinical human testing has not been conducted, and therapeutic dosing has not been established' as of December 2020.
1A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and AbetaPMID 11606574
Hashimoto Y et al. - Proceedings of the National Academy of Sciences USA (2001) - in vitro - Cell culture
Discovery paper. Identified humanin from cDNA library of AD patient occipital lobe. Humanin abolished neuronal cell death induced by all tested FAD mutants and amyloid-beta. First identification of a mitochondrial-derived peptide with cytoprotective function.
Limitations: In vitro only. Cell culture models.
2The emerging role of the mitochondrial-derived peptide humanin in stress resistancePMID 23416677
Yen K, Lee C, Mehta H, Cohen P - Journal of Molecular Endocrinology (2013) - review - N/A
Comprehensive review establishing humanin as a stress resistance factor. Detailed extracellular (FPRL1, WSX1/CNTFR/gp130 receptors) and intracellular (BAX, tBID, BimEL interaction) mechanisms. Humanin protects against oxidative stress, serum starvation, hypoxia. Expressed in heart, kidney, liver, testes, skeletal muscle, and brain.
Limitations: Review article. Predominantly preclinical data.
3The mitochondrial derived peptide humanin is a regulator of lifespan and healthspanPMID 32575077
Yen K, Mehta HH, Kim SJ et al. - Aging (Albany NY) (2020) - animal study + human observational - C. elegans transgenic worms; mice (N=5/group); human centenarian children cohort; AD patients; MELAS patients
Humanin overexpression increased lifespan in C. elegans (19.0 vs 17.7 days, dependent on daf-16/FOXO). Children of centenarians had higher circulating humanin than age-matched controls. Humanin levels decreased in AD patients (CSF) and MELAS patients. Humanin transgenic mice protected from cyclophosphamide toxicity. Middle-aged mice treated with HNG showed decreased IGF-I, improved metabolic parameters, but no significant lifespan extension at doses used. HN-tg worms showed decreased body size, body fat, and reproductive output.
Limitations: Mouse lifespan study at low dose showed no significant lifespan extension. C. elegans lifespan increase modest. Human data observational only. Small mouse group sizes (N=5).
4Humanin and Its Pathophysiological Roles in Aging: A Systematic ReviewPMID 37103373
Coradduzza D, Congiargiu A, Chen Z et al. - Biology (2023) - systematic review - Multiple studies reviewed
Comprehensive systematic review of humanin in aging. Humanin activates chaperone-mediated autophagy via HSP90. HNG increases autophagy proteins Beclin-1, ATG7/5/3 via AMPK/mTOR/ULK1. Humanin induces autophagy in skeletal muscle of aged mice. Six humanin-like peptides encoded by 16S RNA gene act on autophagy chaperones. Quality assessment using ROBIS tool.
Limitations: Systematic review of predominantly preclinical literature. No human interventional data to review.
5Follicular fluid humanin concentration is related to ovarian reserve markers and clinical pregnancy after IVF-ICSI: a pilot studyPMID 30503199
Rao M, Zhou F, Tang L et al. - Reproductive Biomedicine Online (2019) - observational human study - 179 IVF/ICSI patients; ovarian tissue from 2 surgical patients
Humanin expressed in granulosa cells, oocytes, and stromal cells of human ovary. Follicular fluid humanin (86.40-417.60 pg/mL) correlated with FSH (r=-0.21, P<0.01), LH (r=-0.18, P=0.02), antral follicle count (r=0.27, P<0.01), AMH (r=0.24, P=0.03), and inhibin B (r=0.46, P<0.01). Highest humanin quartile had 3.6x odds of clinical pregnancy vs lowest (OR=3.60, 95% CI 1.09-11.84).
Limitations: Pilot study. Observational only -- did not administer humanin. Single-center. Correlation does not imply causation.
6Humanin attenuates metabolic, toxic, and traumatic neuropathic pain in mice by protecting against oxidative stress and increasing inflammatory cytokinePMID 39510375
Bilgin B, Hekim MG, Bulut F et al. - Neuropharmacology (2025) - animal study - BALB/c male mice, multiple groups
Humanin (4 mg/kg i.p.) significantly increased pain thresholds in STZ-induced, oxaliplatin-induced, and sciatic nerve cuff neuropathic pain models over 15 days (P<0.05). Humanin elevated antioxidant enzymes and anti-inflammatory cytokines while reducing oxidative stress markers and pro-inflammatory cytokines (P<0.01).
Limitations: Animal study only. Single dose tested. BALB/c mice may not reflect human pharmacology. No human translation data.
7Humanin and diabetes mellitus: A review of in vitro and in vivo studiesPMID 35432758
Boutari C, Pappas PD, Theodoridis TD, Vavilis D - World Journal of Diabetes (2022) - review - N/A
Humanin increases insulin sensitivity, improves pancreatic beta cell survival, and may delay diabetes onset. Reviewed in vitro and in vivo evidence for humanin in insulin resistance and diabetes. Explicitly noted no clinical trials of humanin or its analogues had been published.
Limitations: Review of preclinical data. No human interventional trials reviewed.
8Humanin Promotes Tumor Progression in Experimental Triple Negative Breast CancerPMID 32427890
Gottardo MF et al. - Scientific Reports (Nature) (2020) - animal study + in vitro - TNBC cell lines and xenograft models
Humanin and its receptors expressed in breast cancer specimens. Humanin upregulated in TNBC biopsies vs healthy tissue. Exogenous humanin protected TNBC cells from apoptotic stimuli. shRNA-mediated knockdown of humanin reduced tumor progression. Also references Jia Y et al. showing HNG protected bone cells from bortezomib while improving apoptotic response of neuroblastoma/medulloblastoma.
Limitations: Specific to TNBC model. Context-dependent effects -- HNG showed anti-tumor effects in neuroblastoma/medulloblastoma. Complex interplay between tumor types.
9The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial DysfunctionPMID 27004903
Sreekumar PG et al. - Investigative Ophthalmology and Visual Science (2016) - in vitro - Human RPE cell cultures
Humanin protected RPE cells from oxidative stress (tBH) in a dose-dependent manner (P<0.01). Enhanced mitochondrial biogenesis via upregulation of mtTFA. Increased mitochondrial DNA copy number. Reduced mitochondrial superoxide production. Inhibited BAX translocation from cytosol to mitochondria.
Limitations: In vitro study using non-polarized RPE cells. May not fully replicate in vivo retinal conditions.
10Neuroprotective Action of Humanin and Humanin AnaloguesPMID 38168955
Reviewed in PMC10740898 - PMC (2023) - review - N/A
Comprehensive review of humanin neuroprotection. HNG (S14G) has 1000-fold higher neuroprotective activity than native humanin and 500-fold higher rescue activity against prion peptide toxicity. Colivelin (ADNF-humanin fusion) acts at femtomolar concentrations. NMR studies show HNG has flexible structure with alpha-helix in less polar environments.
Limitations: Review of preclinical literature.
11Humanin: A Multifactorial Anti-death Agent
Cohen A, Lerner-Yardeni J, Meridor D, Kasher R, Nathan I, Parola AH - Biochemistry and Molecular Biology Journal (2018) - commentary (with original in vitro and animal data) - PC-12 and NSC-34 cell lines; TBI mouse model
Humanin derivative AGA(C8R)-HNG17 protects against necrotic cell death (not just apoptosis). Demonstrated protection in neuronal cell lines under chemohypoxia. Humanin directly enhances ATP synthase activity isolated from rat-liver mitochondria. Anti-necrotic activity demonstrated in traumatic brain injury mouse model with decreased neurological severity score and reduced brain edema on MRI.
Limitations: Commentary/brief report. Limited experimental detail. Small-scale studies.
12Systems spatiotemporal dynamics of traumatic brain injury at single cell resolution reveals humanin as a therapeutic target [PREPRINT]
Arneson D et al. - Research Square (2022) - animal study / single-cell multi-tissue preprint - 78,895 single cells profiled; intervention arm n=6 HNG-treated TBI mice and n=6 vehicle-treated TBI mice
mt-Rnr2, which encodes humanin, emerged as a broad TBI-responsive target. Gly14-Humanin given i.p. twice at 1 and 6 hours after fluid percussion injury at 40 ug/kg prevented learning and memory impairment at 1 week and reversed multiple mTBI-related metabolic and oxidative-phosphorylation pathway changes in astrocytes.
Limitations: Preprint, not peer-reviewed. Mouse model. Small intervention sample size (n=6 per group).
13Humanin activates integrin alphaV-TGFbeta axis and leads to glioblastoma progression [PREPRINT]
Jeong Y, Hua T, Vo V, Om J, Han S, Cha SK, Park KS, Ha C - Research Square (2023) - in vitro and animal preprint - In vitro experiments plus orthotopic glioblastoma model
Humanin was upregulated in glioblastoma tumor areas and activated the integrin alphaV-TGFbeta axis, increasing attachment, filopodia formation, migration, angiogenesis, invasiveness, and poor-survival signaling in the orthotopic model.
Limitations: Preprint, not peer-reviewed. Oncology-specific disease model. Not a general safety trial.
14Serum Humanin in Pediatric Septic Shock Associated Multiple Organ Dysfunction Syndrome [PREPRINT]
Atreya M et al. - Research Square (2023) - observational human preprint - 140 pediatric septic shock patients, including 39 with TAMOF phenotype
Serum humanin was higher on day 1 than day 3, higher in children with TAMOF phenotype, independently associated with day-7 sepsis-associated AKI (p=0.032), and higher in the high PERSEVERE mortality-risk stratum.
Limitations: Preprint biomarker study with no humanin intervention.
15Evolution of Mitochondrial-Derived Peptides, Humanin and MOTSc and Changes in Insulin Sensitivity During Early Gestation [PREPRINT]
Ruiz D et al. - Research Square (2021) - observational human preprint - 28 pregnant women with GDM and 45 matched controls
Humanin and MOTSc levels both fell from the first to the second trimester. After BMI adjustment, low humanin was not independently associated with high HOMA-IR.
Limitations: Preprint. Small cohort. Biomarker study, not supplementation trial.
16Humanin Isoforms in Cardiac Muscle and Blood Plasma and Major Complications After Cardiac OperationNCT03431844
Kroon H (PI), University of Tartu - ClinicalTrials.gov (2018) - observational (completed) - 106 (actual enrollment)
Completed prospective observational study measuring humanin-like peptide concentration in myocard tissue and blood plasma of CABG patients, studying correlation with early complication occurrence (mortality, MI, AKI, stroke at 30 days). Humanin NOT administered as intervention. Results not yet posted.
Limitations: Biomarker measurement study only. Does not test humanin as a therapeutic. Results not publicly available.
17How Are the Muscles Affected in Cerebral Palsy? A Study of Muscle Biopsies Taken During Orthopaedic SurgeryNCT05506228
Ponten EM (PI), Region Stockholm - ClinicalTrials.gov (2022) - observational - 150 (estimated)
Observational study measuring humanin as a biomarker in plasma and muscle of children with cerebral palsy vs typically developed controls. Examining whether humanin levels in plasma correlate with muscle levels. Recruiting at Karolinska University Hospital.
Limitations: Biomarker measurement study only. Does not test humanin as a therapeutic. Results not yet posted.
18Effect of Exercise in Patients With Chronic Kidney Disease: TONE TrialNCT07438002
Battaglia Y (PI), Casa di Cura Dott. Pederzoli - ClinicalTrials.gov (2026) - RCT (humanin is exploratory outcome, not intervention) - 50 (estimated)
Randomized trial of combined exercise vs control in CKD patients. Humanin measured as exploratory outcome to investigate effect of physical activity on mitochondrial biomarker expression. Exercise is the intervention, not humanin. Recruiting in Italy.
Limitations: Humanin is measured as a secondary/exploratory biomarker, not administered. Results not yet available.
19[Gly14]-humanin protects against A-beta-31-35-induced impairment of spatial learning and memory in rats [Chinese language]PMID 23258324
Not specified (Chinese study) - Chinese journal (PMID 23258324) (2012) - animal study - Rat groups
Bilateral intrahippocampal injection of A-beta-31-35 impaired spatial learning in Morris water maze. HNG (0.2 and 2.0 nmol) pretreatment dose-dependently prevented A-beta-induced learning/memory deficits. Genistein (tyrosine kinase inhibitor, 40 nmol) blocked HNG's protective effects, suggesting tyrosine kinase pathway involvement.
Limitations: Animal study. Chinese language (English abstract used). Intrahippocampal administration route not translatable to human use.
20Mitochondrial derived peptide humanin improved semen quality of crossbred bull
Not fully specified - Scientific Reports (Nature) (2025) - animal study (veterinary) - Vrindavani crossbred bull semen ejaculates
Humanin improved post-thaw semen quality, freezability, antioxidant status, and in-vitro fertility of crossbred bull sperm. Humanin acts as antioxidant protecting sperm from cryo-induced damage.
Limitations: Veterinary application in bovine. Not directly translatable to human therapeutic use. Full text not available in papers/ directory.