Humanin

Humanin is a 24-amino acid mitochondrial-derived peptide (MDP) encoded within the 16S ribosomal RNA gene of the mitochondrial genome. First identified in 2001 from brain tissue of an Alzheimer's patient, humanin is an endogenous cytoprotective factor that declines with age. It protects neurons from amyloid-beta toxicity, improves insulin sensitivity, reduces systemic inflammation, and extends healthspan in multiple animal models. Humanin represents a novel class of mitochondria-encoded signaling peptides with broad implications for aging and neurodegeneration.

Humanin acts through two main receptor systems. Extracellularly, it signals via a heterotrimeric receptor complex comprising ciliary neurotrophic factor receptor alpha (CNTFRα), WSX-1, and gp130, activating JAK2/STAT3 and PI3K/Akt pro-survival pathways. Intracellularly, humanin directly binds and inhibits pro-apoptotic Bax protein, preventing mitochondrial outer membrane permeabilization and cytochrome c release. In neuronal contexts, humanin blocks amyloid-beta (Aβ) oligomer-induced apoptosis by inhibiting Aβ binding to cell surface receptors and downstream caspase activation. It also suppresses inflammatory NF-κB signaling, improves mitochondrial membrane potential, and enhances autophagy to clear damaged organelles. Humanin levels in plasma and CSF correlate inversely with Alzheimer's disease severity.

Animal studies demonstrate that humanin and its potent synthetic analogue HNG (S14G-Humanin) extend lifespan in C. elegans, improve cognitive function in aged mice, protect against diet-induced obesity and insulin resistance, and reduce amyloid plaque burden in AD models. Human studies show CSF humanin levels are significantly reduced in Alzheimer's disease patients versus controls. Epidemiological data links higher plasma humanin to better cognitive aging outcomes. A Nature Scientific Reports study found twice-weekly HNG administration improved metabolic healthspan markers and reduced inflammatory markers in middle-aged mice. No human clinical trials of exogenous humanin have been completed as of 2026.

Peptides commonly paired with Humanin for synergistic effects.