Humanin

What Is Humanin?

Humanin is a 24-amino-acid mitochondrial-derived peptide (MDP) encoded within the mitochondrial 16S rRNA gene, the same family as MOTS-c, which is encoded in the 12S rRNA. It was the founding member of the MDP family, discovered in 2001 by Hashimoto and characterised over the following two decades chiefly by Pinchas Cohen's laboratory at the USC Leonard Davis School of Gerontology. Mitochondria themselves encode and secrete Humanin as a stress-response signal, and production declines with age.

Humanin acts through four overlapping protective mechanisms. It binds and antagonises the pro-apoptotic proteins BAX and tBID, preventing mitochondrial outer-membrane permeabilisation. It activates a trimeric receptor complex (CNTFR, WSX-1, gp130) that drives JAK2/STAT3 survival signalling along with ERK1/2 and AKT, the same axes that confer neuronal resistance to amyloid-beta toxicity. It binds IGFBP-3 and lowers circulating IGF-1, a pattern associated with extended lifespan in model organisms. It also activates autophagy and the formyl peptide receptors FPRL1 and FPRL2.

The strongest preclinical evidence is in neuroprotection (Alzheimer models, amyloid-beta toxicity) and metabolic regulation (beta-cell preservation, insulin sensitisation). The synthetic analogue S14G-Humanin (HNG) is roughly 1,000-fold more potent than the native sequence and is what most preclinical work uses. Humanin has not completed Phase 2 or Phase 3 human trials.