Humanin

Also known as: HN, MT-RNR2 peptide, HNG (S14G-humanin analog)

Evidence: Preclinical

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Overview

24-amino-acid peptide encoded within mitochondrial DNA that protected neurons and other cells from oxidative and apoptotic stress in animal and cell studies.

Humanin is a 24-amino acid peptide encoded in mitochondrial DNA. It was originally discovered as a neuroprotective factor against Alzheimer's disease. Research shows broad cytoprotective effects including protection against oxidative stress, apoptosis, and age-related cellular decline. Studies indicate roles in metabolic regulation, cardiovascular protection, and longevity pathways.

Benefits

Neuroprotection against amyloid-beta toxicity (cell culture), insulin sensitisation and cardioprotection (rodent, mostly via the HNG analog), lifespan extension (C. elegans); human data are observational only

Dosing reference

Research dose: 1 to 5 mg daily (community range, no published human dose; animal work used the HNG analog at milligram-per-kilogram doses by intraperitoneal or intracerebroventricular routes)
Range: 1000 to 5000 mcg, 1x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 5 mg, 10 mg

Subcutaneous injection is community practice. No human dosing study exists in any indication. Published animal dosing is weight-based and by other routes: HNG at 2 mg/kg intraperitoneally in the mouse ischaemia-reperfusion model (Muzumdar et al., 2010), continuous intracerebroventricular infusion and intravenous analog in rats (Muzumdar et al., 2009), and twice-weekly HNG in middle-aged mice (Yen et al., 2020). Most in vivo results belong to HNG, which is more potent than the native peptide.

Mechanism

Humanin is a 24-residue peptide encoded in the 16S rRNA region of mitochondrial DNA, found by expression screening for factors that block neuronal death caused by familial Alzheimer genes and amyloid-beta (Hashimoto et al., 2001). It binds Bax and keeps it from translocating to mitochondria, which is how it suppresses apoptosis (Guo et al., 2003), and it also binds and blocks Bid and BimEL. Central infusion improved insulin sensitivity in rats through hypothalamic STAT-3; blocking hypothalamic STAT-3 removed the liver effect, and the peptide had no direct effect on isolated hepatocytes (Muzumdar et al., 2009). Cardioprotection in mice ran through AMPK and endothelial nitric oxide synthase phosphorylation (Muzumdar et al., 2010). Note that most in vivo work used the more potent analog HNG (S14G-humanin), not the native peptide.

Evidence

Preclinical: animal or in vitro data only

Identified by expression screening as a factor that abolishes neuronal death caused by multiple familial Alzheimer's disease genes and by amyloid-beta in cell culture (Hashimoto et al., 2001)
Suppresses apoptosis by interfering with Bax activation (Guo et al., 2003)
Intracerebroventricular infusion improved whole-body insulin sensitivity in rats via hypothalamic STAT-3, and an intravenous analog lowered blood glucose in Zucker diabetic fatty rats (Muzumdar et al., 2009)
The analog HNG given intraperitoneally before or at reperfusion reduced infarct size and improved ejection fraction in a mouse coronary occlusion model, best at 2 mg/kg (Muzumdar et al., 2010)
Overexpression extended lifespan in C. elegans, and twice-weekly HNG in middle-aged mice improved metabolic healthspan markers; circulating levels were higher in children of centenarians than age-matched controls (Yen et al., 2020)
Human-trial status: no interventional trial of humanin exists. Human data are observational: lower circulating humanin in coronary artery disease, prognostic for cardiac events (Cai et al., 2022), and higher skeletal muscle humanin after resistance training in men with impaired glucose metabolism (Gidlund et al., 2016). Registry entries listing humanin are biomarker studies, not dosing studies

References

Side effects

No human safety data; effects unknown beyond animal studies, which used intracerebroventricular or intraperitoneal routes that do not translate to subcutaneous dosing. Injection-site irritation is the only commonly reported complaint. Native humanin and the potent analog HNG differ substantially in potency.

Storage

Storage: Refrigerated (2-8°C)
Lyophilized: 24+ months at room temperature
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Not established. No pharmacokinetic study of humanin exists in humans or animals.
Bioavailability: Not measured by any route. Animal studies used intraperitoneal, intravenous or intracerebroventricular administration.
Molecular weight: 2687.14 Da
Sequence: MAPRGFSCLLLLTSEIDLPVKRRA