Humanin is a tiny protein made by mitochondria that appears to protect brain cells from the damage that causes Alzheimer’s, mainly by fighting oxidative stress and the toxic effects of amyloid‑beta. As we age, the brain makes less of it, which may contribute to memory loss, while blood levels sometimes rise as a possible emergency response, though studies disagree. The review highlights these mixed findings but suggests Humanin could be a useful target for future anti‑aging or brain‑health strategies.

Humanin (HN) is an endogenous micropeptide also known as a mitochondria-derived peptide. It has a neuroprotective effect against Alzheimer's disease (AD) and other neurodegenerative diseases by improving hippocampal acetylcholine and attenuating the development of oxidative stress and associated neurotoxicity. HN protects the neuron from the toxic effects of amyloid beta (Aβ). HN is regarded as a biomarker of mitochondrial stress. Interestingly, aging reduces brain expression of HN, leading to cognitive impairment and elevating the risk of neurodegeneration, including AD. However, in old subjects and AD patients, circulating HN levels increase as a compensatory mechanism to reduce neurodegeneration and mitochondrial dysfunction in AD. Conversely, other studies demonstrated a reduction in circulating HN levels in AD. These findings indicated controversial points regarding the precise mechanistic role of HN in AD. Therefore, the aim of this review was to discuss the exact role of HN in AD neuropathology and also to discuss the molecular mechanisms of HN in AD.