Humanin

Humanin is a micropeptide encoded by the mitochondrial 16S ribosomal RNA gene (MT-RNR2), discovered in 2001 during research on Alzheimer's disease survival factors. When translated in the cytoplasm, it produces a 24-amino-acid peptide; mitochondrial translation yields a 21-amino-acid variant. Both forms are biologically active. The synthetic analog HNG (S14G-Humanin) features a serine-to-glycine substitution at position 14 that increases potency approximately 1000-fold.

Humanin exerts its cytoprotective effects through multiple receptors and pathways. It binds to the FPRL1 (formyl peptide receptor-like 1) receptor and activates the STAT3 signaling pathway, promoting cell survival. It also interacts with IGFBP-3 and Bax, inhibiting apoptotic cascades. Humanin reduces oxidative stress by improving mitochondrial function and reducing reactive oxygen species (ROS) production. It also modulates inflammatory responses through suppression of NF-kB activation.

Research has demonstrated humanin's protective effects against amyloid-beta toxicity (relevant to Alzheimer's disease), oxidative stress-induced cell death, and ischemia-reperfusion injury in cardiac tissue. Studies show that humanin levels decline with age and are inversely correlated with age-related diseases. Animal studies have demonstrated improved cognitive function, enhanced insulin sensitivity, and extended healthspan. The GH-IGF-1 axis appears to regulate humanin levels, with growth hormone reducing circulating humanin, providing a potential mechanistic link between the GH axis and longevity.