Humanin

Humanin is a 24-amino-acid mitochondrial-derived peptide encoded by mitochondrial DNA that plays a cytoprotective role, helping preserve mitochondrial function and cell viability under stressful and senescence conditions. ^[1] It was the first newly discovered peptide encoded in the mitochondrial genome in over three decades and the first member of a novel class of mitochondrial-derived peptides. ^[2] It was first identified in 2001 in the surviving neurons of a patient with Alzheimer's disease, and has since been characterized for its neuroprotective effect through inhibition of apoptosis. ^[3]

Humanin inhibits neuronal cell death and dysfunction by binding to an IL-6-receptor-related receptor on the cell surface involving CNTFRalpha, WSX-1, and gp130. ^[4] It modulates multiple biological processes including autophagy, endoplasmic reticulum stress, cellular metabolism, oxidative stress, and inflammation. ^[3] Humanin functionally interfaces with insulin-like growth factor 1 (IGF-I) signaling, binding IGFBP-3 and decreasing circulating IGF-I levels, and its plasma levels are inversely correlated with growth hormone and IGF-1 expression. ^{[2] [5]}

Humanin acts as a mitokine, a signaling molecule that communicates local mitochondrial stress to distant cells and tissues, alongside FGF21 and GDF15. ^[6] In rodent models, humanin protects cells from beta-amyloid toxicity, preserves endothelial cell function in atherosclerosis, and improves insulin sensitivity in type 2 diabetes. ^[5] Levels of mitochondrial-derived peptides diminish with aging and in the presence of cardiovascular disease, making them potential new indicators for diagnosis. ^[7] Contrary to a simple pro-longevity picture, humanin and MOTS-c have been reported to exacerbate the senescence-associated secretory phenotype in senescent cells by stimulating secretion of IL-6, IL-1beta, IL-8, IL-10 and tumor necrosis factor alpha. ^[5]

A decline in the levels of mitochondrial-derived peptides such as humanin is proposed to contribute to aging and age-related diseases, including cellular senescence, chronic inflammation, and cognitive decline. ^[8] Because humanin is cytoprotective under stress, it is being explored in strategies aiming to counteract cardiovascular disease, neurodegeneration, and cancer. ^[1] The evidence remains largely preclinical and mechanistic, and further research is needed to understand the roles of these processes in aging and disease and to identify potential interventions. ^{[1] [9]}