HNG

HNG (S14G-humanin) is a synthetic 24-amino-acid analogue of the endogenous mitochondrial peptide humanin. A single amino acid swap (serine to glycine at position 14) boosts its neuroprotective potency approximately 1,000-fold in cell studies A humanin derivative, S14G-HN, prevents amyloid-β-induced memory impairment in mice. First identified in 2001 from an Alzheimer's patient brain library, humanin was later engineered into HNG for greater stability and activity A humanin derivative, S14G-HN, prevents amyloid-β-induced memory impairment in mice. Since then, HNG has been tested in over 100 preclinical studies, revealing profound cell-survival and anti-inflammatory effects across multiple organ systems.

Research in animal models demonstrates that HNG can reduce brain damage after stroke Humanin Is a Novel Neuroprotective Agent Against Stroke, lower amyloid plaques and improve memory in Alzheimer's models S14G-humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice, and protect heart muscle during a heart attack Efficacy of a Novel Mitochondrial-Derived Peptide in a Porcine Model of Myocardial Ischemia/Reperfusion Injury. It also shows promise for metabolic health, reproductive protection, and slowing age-related tissue decline Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice+1. Its wide-ranging benefits stem from a combination of direct mitochondrial defense and activation of key protective signaling pathways.

HNG is available only as a research compound; no human trials have yet confirmed these effects in people. Nonetheless, the breadth and consistency of preclinical data make it one of the most studied mitochondrial peptides for cell protection.

HNG works through three main layers of cellular defense. First, it binds to surface receptors that trigger internal survival signals. The primary receptor complex includes gp130, which activates the STAT3 pathway, a master switch that turns on anti-death genes and dials down inflammation Mechanisms of protection of retinal pigment epithelial cells from oxidant injury by humanin and other mitochondrial-derived peptides: Implications for age-related macular degeneration+1. HNG also engages the FPRL1 receptor to fine-tune autophagy and metabolic responses Effects of Humanin G (HNG) on angiogenesis and neurodegeneration markers in Age-related Macular Degeneration (AMD).

Second, at the mitochondria, HNG steps directly into the cell's death machinery. It latches onto the pro-death proteins Bax and Bid, preventing them from punching holes in the mitochondrial membrane Mechanisms of protection of retinal pigment epithelial cells from oxidant injury by humanin and other mitochondrial-derived peptides: Implications for age-related macular degeneration. This stops the release of cytochrome c and the cascade that leads to cell suicide. HNG also boosts the cell's own antioxidant defenses by activating Nrf2 and SIRT6, which help clear reactive oxygen species [Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6+1.

Third, HNG dampens harmful inflammation by blocking NF-κB, a key inflammatory switch, and reducing the assembly of the NLRP3 inflammasome The protective effects of S14G-humanin (HNG) against streptozotocin (STZ)-induced cardiac dysfunction. Together, these actions make HNG a versatile protector: it can rescue neurons after a stroke, heart cells during a heart attack, and even ovarian follicles from chemotherapy damage Humanin Is a Novel Neuroprotective Agent Against Stroke+2.

Neuroprotection

In rodent models of Alzheimer's disease, HNG treatment reduced amyloid plaque buildup, tau tangles, and brain inflammation, while improving spatial memory S14G-humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice+1. After ischemic stroke, HNG decreased infarct size by 30-50% and sped up neurological recovery Humanin Is a Novel Neuroprotective Agent Against Stroke. It also lessened brain swelling and cell death in models of traumatic brain injury and intracerebral hemorrhage [Gly14]-Humanin reduces histopathology and improves functional outcome after traumatic brain injury in mice+1.

Cardioprotection

In a porcine model of heart attack, a single dose of HNG at the time of reperfusion reduced the size of damaged heart tissue Efficacy of a Novel Mitochondrial-Derived Peptide in a Porcine Model of Myocardial Ischemia/Reperfusion Injury. In rats, HNG given during ischemia cut down dangerous arrhythmias and preserved mitochondrial function High-dose Humanin analogue applied during ischemia exerts cardioprotection against ischemia/reperfusion injury by reducing mitochondrial dysfunction. Long-term treatment in aged mice prevented age-related heart muscle stiffening (fibrosis) Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice.

Metabolic Health

Humanin analogues, including HNG, enhance insulin secretion from pancreatic beta cells and improve insulin sensitivity in diabetic mice Potent humanin analog increases glucose-stimulated insulin secretion through enhanced metabolism in the β cell+1. HNG also helps restore metabolic hormone balance, lowering elevated asprosin and raising protective ghrelin levels in diabetic animals Humanin Restores Metabolic Hormone Homeostasis of Leptin, Ghrelin, Irisin and Asprosin in Streptozotocin-Induced Diabetic Mice.

Reproductive Protection

HNG shields germ cells from chemotherapy-induced damage in both male and female animals. It preserved sperm production and fertility in cyclophosphamide-treated mice Effect of Humanin and MOTS-c on ameliorating reproductive damage induced by prepubertal cyclophosphamide chemotherapy in male mice, and improved human sperm viability after freezing Potent humanin analogue (HNG) protects human sperm from freeze-thaw-induced damage. In female rodents, HNG maintained ovarian reserve and egg quality following chemotherapy-induced premature ovarian failure S14G-Humanin ameliorates ovarian dysfunction in a cyclophosphamide-induced premature ovarian insufficiency mouse model+1.

Ocular and Pulmonary Protection

In cellular models of age-related macular degeneration, HNG protected retinal cells from oxidative stress and reduced markers of abnormal blood vessel growth Mechanisms of protection of retinal pigment epithelial cells from oxidant injury by humanin and other mitochondrial-derived peptides: Implications for age-related macular degeneration+1. In acute lung injury, HNG dampened inflammation and protected lung tissue Humanin-G Ameliorates Hemorrhage-Induced Acute Lung Injury in Mice Through AMPKα1-Dependent and -Independent Mechanisms+1.

Representative research protocols for HNG are drawn primarily from animal studies, as no human clinical protocols exist. Doses in rodents typically range from 0.4 mg/kg to 10 mg/kg via intraperitoneal or intravenous routes, with treatment durations from a single acute dose to 14 months of chronic therapy The protective effects of S14G-humanin (HNG) against streptozotocin (STZ)-induced cardiac dysfunction+2.

For neuroprotection in stroke or head trauma, single intracerebroventricular injections of 0.1-1 nmol (roughly 0.26-2.6 μg) have been effective in mice Humanin Is a Novel Neuroprotective Agent Against Stroke+1. Systemic delivery for cardioprotection often uses intravenous doses of 84-252 μg/kg in rats High-dose Humanin analogue applied during ischemia exerts cardioprotection against ischemia/reperfusion injury by reducing mitochondrial dysfunction+1. Chronic protocols for metabolic or anti-aging effects involve daily intraperitoneal injections for several weeks, such as 10 mg/kg daily for 6 weeks to preserve ovarian function S14G-Humanin ameliorates ovarian dysfunction in a cyclophosphamide-induced premature ovarian insufficiency mouse model.

Extrapolating these findings to human research with allometric scaling suggests potential subcutaneous doses in the range of 0.5-5 mg, administered daily or a few times per week. Community protocols often cycle HNG for 8-12 weeks followed by a 4-week washout to maintain receptor sensitivity. The interactive timeline above summarizes a typical phased approach grounded in animal data and practitioner consensus.

HNG is typically supplied as a lyophilized powder in 5 mg or 10 mg vials. For research purposes, it is reconstituted with bacteriostatic water (0.9% benzyl alcohol) rather than plain sterile water, to inhibit bacterial growth and improve stability.

After adding the diluent, the vial should be gently swirled, not shaken, to dissolve the peptide. Vigorous agitation can cause aggregation and loss of activity. The reconstituted solution should be kept in the refrigerator at 2-8°C and used within 28 days for optimal integrity Stability Determination of Intact Humanin-G with Characterizations of Oxidation and Dimerization Patterns. HNG in aqueous solution is susceptible to oxidation at its methionine residues, which can form dimers and reduce potency, so minimizing time at room temperature is important Stability Determination of Intact Humanin-G with Characterizations of Oxidation and Dimerization Patterns.

Researchers often prepare single-use aliquots and freeze them at -20°C for longer storage, avoiding repeated freeze-thaw cycles. The interactive calculator below determines the amount of solution to draw for a desired research dose.

Research into HNG's interactions with drugs and other compounds is limited to preclinical models. HNG modulates multiple protective pathways, so co-administration with certain drug classes has been examined.

Chemotherapy agents: HNG can reduce damage to healthy tissues without blunting anti-tumor effects. In mice, it protected the heart from doxorubicin when combined with dexrazoxane Humanin analog enhances the protective effect of dexrazoxane against doxorubicin-induced cardiotoxicity, and shielded germ cells and blood cells from cyclophosphamide while enhancing suppression of melanoma metastases The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice. However, caution is warranted: humanin released by tumor cells in glioblastoma has been linked to chemoresistance TMIC-76. HUMANIN RELEASE FROM TUMOR ASSOCIATED MYELOID CELLS PROMOTES GLIOMA CHEMORESISTANCE+1.

Antiplatelet and anticoagulant drugs: HNG inhibits platelet activation and clot formation in mice, though it did not prolong bleeding time Humanin analogue, HNG, inhibits platelet activation and thrombus formation by stabilizing platelet microtubules. An additive effect with blood thinners is theoretically possible, so caution is advised.

Glucose-lowering medications: Because HNG enhances insulin secretion and insulin sensitivity Potent humanin analog increases glucose-stimulated insulin secretion through enhanced metabolism in the β cell+1, it may amplify the effects of insulin or sulfonylureas, raising the risk of low blood sugar. Monitoring glucose is recommended.

Pathway inhibitors: Drugs that block JAK2/STAT3 or PI3K/Akt signaling would likely counteract HNG's protective effects, as these are core mediators of its action Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway+1. Similarly, tyrosine kinase inhibitors like genistein can block HNG's neuroprotective benefits The protective effects of S14G-humanin (HNG) against streptozotocin (STZ)-induced cardiac dysfunction.

HNG is often combined with other mitochondrial or repair peptides in research to amplify cytoprotective outcomes.

MOTS-c: Another mitochondrial-derived peptide, MOTS-c activates AMPK to improve metabolic health. In muscle atrophy models, MOTS-c and HNG together preserved myotube size better than either alone, with MOTS-c adding Akt activation and suppression of muscle-wasting signals Mitochondrial‐derived peptides <scp>MOTS</scp> ‐c and humanin attenuate dexamethasone‐induced atrophy in human skeletal muscle cells.

SS-31 (elamipretide): This mitochondrial-targeted antioxidant peptide has been fused with HNG into a hybrid molecule (HNSS) that showed amplified mitochondrial rescue and doubled brain penetration in Alzheimer's models compared to HNG alone Rational fusion design inspired by cell-penetrating peptide: SS31/S-14 G Humanin hybrid peptide with amplified multimodal efficacy and bio-permeability for the treatment of Alzheimer's disease. Co-administration may similarly enhance effects, though no combination toxicity was observed.

BPC-157: Though no formal studies exist, community protocols sometimes combine BPC-157, a gut-derived healing peptide, with HNG for synergistic tissue repair. BPC-157 promotes blood vessel growth, while HNG reduces oxidative stress and inflammation, making them complementary for recovery.

Stacking HNG with other anti-apoptotic peptides like MOTS-c or SS-31 may cross-amplify mitochondrial protection, but researchers should be mindful of excessive survival signaling in tissues with high cell turnover.

HNG (S14G-humanin) is not approved by the FDA or any regulatory agency for human use. It is available solely as a research peptide, with all efficacy data coming from preclinical animal and cell studies. No human clinical trials have been conducted.

Despite its unapproved status, HNG is not a controlled substance and is not scheduled by the DEA. It falls into a gray market category often sold for 'research purposes only'. Internationally, it is similarly unapproved and subject to import restrictions in many countries.

For athletes, HNG is not listed on the WADA Prohibited List as of 2026. However, WADA's catch-all provision for non-approved substances could apply if HNG were deemed performance-enhancing, though no such determination has been made.

HNG has been well-tolerated across a wide range of doses and treatment durations in animal studies, with no organ toxicity or serious adverse events reported even after 14 months of chronic use in mice Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice+2. In community use, HNG is generally well-received, with only occasional mild injection site reactions.

A known effect is a slight reduction in blood glucose, which aligns with its insulin-sensitizing properties. This rarely causes problems in healthy animals but could lead to hypoglycemia in those with impaired glucose regulation or on diabetes medications Potent humanin analog increases glucose-stimulated insulin secretion through enhanced metabolism in the β cell+1. HNG also mildly inhibits platelet aggregation in lab tests, but this has not translated into prolonged bleeding in mice Humanin analogue, HNG, inhibits platelet activation and thrombus formation by stabilizing platelet microtubules.

Theoretical risks require more study. Because humanin can promote survival in certain cancer cells, especially glioblastoma, exogenous HNG could potentially accelerate tumor growth or confer chemoresistance in specific cancers TMIC-76. HUMANIN RELEASE FROM TUMOR ASSOCIATED MYELOID CELLS PROMOTES GLIOMA CHEMORESISTANCE+1. Conversely, in some models it actually helped chemotherapy suppress metastases The Potent Humanin Analogue (HNG) Protects Germ Cells and Leucocytes While Enhancing Chemotherapy-Induced Suppression of Cancer Metastases in Male Mice. Until more is known, HNG is best avoided in individuals with active malignancies.

Long-term human safety data are absent. Monitoring blood glucose and watching for unusual bleeding is prudent during research use High-intensity interval exercise increases humanin, a mitochondrial encoded peptide, in the plasma and muscle of men.