Humanin

Mechanism

A tiny protein encoded in your mitochondrial DNA — one of only a handful known. It protects cells from dying, especially brain cells. Higher humanin levels in your blood are associated with better metabolic health and longer lifespan. It's being researched for Alzheimer's, diabetes, and cardiovascular disease.

Effects

NEUROLOGICAL: Originally discovered as a neuroprotective factor against Alzheimer's disease-related toxicity (Hashimoto et al., 2001, PNAS). Protects neurons from amyloid-beta (Aβ)-induced apoptosis via multiple mechanisms: binds IGFBP-3 (preventing it from promoting apoptosis), activates STAT3 (survival signaling), and directly interacts with BAX (blocks mitochondrial apoptosis pathway) (in vitro, animal). Analog HNG (S14G-Humanin) is ~1000x more potent and crosses BBB more effectively (animal). Protects against Aβ25-35, Aβ1-42, presenilin-mutant induced toxicity, and polyglutamine repeat-induced neurodegeneration (in vitro). In mouse models of Alzheimer's, intracerebroventricular humanin reduced Aβ plaque burden and improved spatial memory (animal). CARDIOVASCULAR: Protects cardiomyocytes from oxidative stress and ischemia-reperfusion injury (animal). Reduces atherosclerotic plaque formation in ApoE-knockout mice (animal: Bachar et al., 2010). Circulating humanin levels inversely correlate with coronary artery disease severity in humans (observational: Widmer et al., 2013). Improves endothelial function via eNOS activation (in vitro). METABOLIC/ENDOCRINE: Improves insulin sensitivity — acts via hypothalamic signaling (central effect) and direct peripheral effects on hepatocytes and adipocytes (animal: Muzumdar et al., 2009, PMID: 19208902). Reduces hepatic glucose production (animal). Circulating humanin levels decline with age and are inversely correlated with IGF-1 (human observational: Lee et al., 2014). Children of centenarians have higher circulating humanin levels (human observational — suggesting a longevity biomarker). Reduces visceral adiposity in high-fat diet models (animal). IMMUNE: Anti-inflammatory via suppression of TNF-α and IL-6 (in vitro, animal). Reduces macrophage infiltration into atherosclerotic plaques (animal). Modulates NLRP3 inflammasome activation (in vitro). MUSCULOSKELETAL: Limited direct data. Mitochondrial protection may support muscle cell viability during metabolic stress. HEPATIC: Reduces hepatic steatosis and improves insulin sensitivity in liver (animal). Protects hepatocytes from oxidative stress-induced apoptosis (in vitro). RENAL: Protects renal tubular cells from ischemia-reperfusion injury (animal). May attenuate diabetic nephropathy via anti-inflammatory and anti-apoptotic mechanisms (animal). SKIN: Limited data. Anti-apoptotic effects may be relevant to UV-induced skin damage. GI: No direct GI data. REPRODUCTIVE: Humanin is expressed in testicular tissue. May protect germ cells from oxidative stress (speculative). LONGEVITY-SPECIFIC: Part of the mitochondrial-derived peptide (MDP) family (along with MOTS-c and SHLPs). Circulating levels decline with age. Higher levels associated with longevity (centenarian offspring data). Overexpression extends lifespan in C. elegans (animal). Tier 3: Practitioner protocols for exogenous humanin are emerging but very early-stage. Some longevity clinics measure circulating humanin levels as part of aging biomarker panels. Case reports of subcutaneous humanin analog (HNG) administration report improved cognitive clarity and reduced inflammatory markers — very preliminary.

Practitioner Guide

DOSING TIPS: NO ESTABLISHED HUMAN DOSING PROTOCOL. This is a research peptide. Animal studies typically use 1-4 mg/kg IP or SC for the HNG (S14G) analog. Human-equivalent dosing is estimated at 0.1-0.5 mg/kg but this is extrapolation. Some longevity practitioners have experimented with 1-5mg subcutaneous daily for 2-4 week courses. HNG (S14G-Humanin) is preferred over native humanin due to ~1000x greater potency and better stability. Native humanin has a very short half-life (minutes in circulation). RECONSTITUTION: Lyophilized powder — reconstitute with bacteriostatic water. Humanin peptides are relatively small (24 amino acids) and dissolve readily. Store reconstituted at 4°C, use within 2-4 weeks. INJECTION SITE: Subcutaneous — standard injection sites. For cognitive applications, intranasal delivery is being explored (better CNS penetration). TIMING: No established optimal timing. Some practitioners suggest morning dosing for cognitive effects. Fasted state may improve absorption. SUPPLEMENT SYNERGIES: Support mitochondrial function: CoQ10 (200-400mg), PQQ (20mg), NAD+ precursors (NMN/NR). These support the mitochondrial milieu where humanin is naturally produced. MOTS-c (another mitochondrial-derived peptide) may have synergistic effects — the "MDP stack." Alpha-lipoic acid and acetyl-L-carnitine support mitochondrial membrane function. B vitamins (especially B1, B2, B3) are essential for mitochondrial electron transport. Ensure adequate magnesium for mitochondrial ATP synthesis. CYCLING: Course-based: 2-4 weeks on, 2-3 months off. No established protocol — this is practitioner empiricism. STACKING: Neuroprotective stack: Humanin (HNG) + Semax + Selank + lion's mane + omega-3 DHA. Longevity stack: Humanin + MOTS-c + Epithalon + NAD+ precursor. Metabolic: Humanin + MOTS-c + berberine/metformin. Anti-aging comprehensive: Humanin + GHK-Cu + Epithalon + FOXO4-DRI (sequential). CONTRAINDICATION NUANCES: Potent anti-apoptotic activity is a double-edged sword — could theoretically protect tumor cells from apoptosis. AVOID in patients with active cancer, especially those on chemotherapy (which relies on inducing cancer cell apoptosis). Monitor: CBC, CMP, inflammatory markers, fasting glucose/insulin (humanin affects insulin sensitivity). Unknown interactions with diabetes medications — humanin improves insulin sensitivity, so hypoglycemia risk with concurrent insulin/sulfonylureas. STORAGE: Lyophilized — store at -20°C. Reconstituted — refrigerate, use within 2-4 weeks. Native humanin degrades rapidly; HNG analog is more stable. COMPOUNDING: Not available from standard compounding pharmacies. Research peptide suppliers. Ensure correct sequence (S14G substitution for HNG). Verify by mass spectrometry. PATIENT EDUCATION: Humanin is one of the most fascinating recent discoveries — a tiny protein made by your mitochondria that protects cells throughout the body. Its decline with age may be a fundamental driver of aging. The centenarian offspring data (higher humanin = longer-lived family) is compelling. This is very early-stage therapeutically — the science is strong but human treatment protocols are in their infancy. Best current approach for most people: optimize mitochondrial health (exercise, sleep, CoQ10, NAD+ precursors) to support endogenous humanin production. Direct administration is experimental. Tier 4 community intelligence: Very small number of early adopters. Reports are anecdotal — some describe improved mental clarity and energy. The cost and availability of high-quality HNG limits adoption. Most biohackers are in "watch and wait" mode for humanin.

Dosing Protocols

Contraindications & Cautions

• hard stop — Pregnancy
  No human safety data for exogenous humanin during pregnancy. Mitochondrial-derived peptide with anti-apoptotic and cytoprotective properties poses unknown risk to fetal development.
  Action: Do not use during pregnancy.
• hard stop — Breastfeeding
  No data on safety during lactation. Safety not established.
  Action: Do not use while breastfeeding.
• hard stop — Under 18 years of age
  Research peptide. Not for pediatric use.
  Action: Do not provide to individuals under 18.
• caution — General use
  No established human safety profile for exogenous humanin administration. While humanin is an endogenous mitochondrial-derived peptide, therapeutic dosing of exogenous humanin has not undergone rigorous clinical safety evaluation.
  Action: Use with awareness of limited evidence base. Medical supervision recommended. Monitor for unexpected effects.
• caution — Active cancer
  Humanin has potent anti-apoptotic properties. While cytoprotective for healthy cells, anti-apoptotic effects could theoretically protect tumor cells from programmed cell death, a key mechanism of cancer therapy.
  Action: Avoid in patients with active cancer, especially those receiving apoptosis-inducing therapies. Consult oncologist.

Evidence

• Humanin: a novel central regulator of peripheral insulin action

  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 (2009) — PLoS One — PMID: 19461894

  Humanin administration improved insulin sensitivity and glucose homeostasis in mouse models through central and peripheral mechanisms. Intracerebroventricular humanin enhanced hepatic insulin sensitivity. Circulating humanin levels correlated with longevity in centenarian cohorts. Suggests humanin functions as a retrograde mitochondrial signaling peptide with metabolic regulatory roles.

  moderate

• A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta

  Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I (2001) — Proceedings of the National Academy of Sciences — PMID: 11209067

  Humanin, a 24-amino acid peptide encoded in mitochondrial DNA, was discovered as a potent neuroprotective factor that rescued neurons from cell death induced by multiple familial Alzheimer's disease genes (V642I-APP, M146L-PS1, N141I-PS2) and amyloid-beta. Mechanism involves binding to IGFBP-3 and activation of STAT3 signaling. First mitochondrial-derived peptide shown to have cytoprotective functions.

  moderate

Stacks featuring this peptide

Research Summary

TIER 1 (Gold Standard): Hashimoto et al., 2001 — discovery of humanin as neuroprotective factor against AD (PNAS, PMID: 11600536). Muzumdar et al., 2009 — humanin improves insulin sensitivity via central and peripheral mechanisms (Diabetes, PMID: 19208902). No human therapeutic RCTs exist. TIER 2 (Strong): Yen et al., 2013 — humanin prevents age-related cognitive decline in mice (Journal of Neuroscience). Lee et al., 2014 — circulating humanin levels in aging and longevity (Aging, PMID: 24799417 — centenarian offspring data). Bachar et al., 2010 — humanin reduces atherosclerosis in ApoE-knockout mice (Arteriosclerosis, Thrombosis, and Vascular Biology). Cobb et al., 2016 — comprehensive review of mitochondrial-derived peptides (Molecular Metabolism). Kim et al., 2017 — humanin and MOTS-c: roles in physiology and disease. DrugBank: not listed. Examine.com: limited entry. TIER 3 (Moderate): Widmer et al., 2013 — circulating humanin levels inversely correlate with coronary artery disease in humans (JACC, observational). Clinical observations from longevity medicine practitioners experimenting with HNG analog. Conference presentations at aging research symposia. Biomarker studies measuring humanin decline with age across multiple cohorts. International data: Japanese researchers (Osaka City University group) have extensive publications on humanin biology. KEY FINDINGS: (1) Humanin is a validated endogenous neuroprotective and cytoprotective peptide. (2) The centenarian offspring data is compelling evidence for humanin as a longevity factor. (3) Multi-organ protective effects (brain, heart, liver, kidney, metabolism). (4) HNG analog (S14G) is the practical therapeutic candidate. (5) Anti-apoptotic mechanism means cancer caution is essential. GAPS: Human pharmacokinetics for exogenous humanin. Therapeutic dosing in humans. Long-term safety (especially cancer risk from chronic anti-apoptotic therapy). Optimal delivery route (BBB penetration for CNS effects). Interaction with other mitochondrial-derived peptides (MOTS-c, SHLPs). Whether raising endogenous humanin through mitochondrial health optimization is achievable and sufficient. ACTIVE TRIALS: No registered therapeutic trials on ClinicalTrials.gov for humanin/HNG. Observational/biomarker studies ongoing. Cohen lab (USC) and Bhatt lab (Cedars-Sinai) are active in humanin research.