In human cohort data and two mouse models of aging, ghrelin emerged as the metabolic factor most strongly associated with cognitive impairment, and its administration reduced hippocampal microglial senescence and inflammation while improving cognition. The mechanism traced to restored autophagic flux in microglia through suppression of sex hormone-binding globulin, JNK1 activation, and Beclin1 upregulation. Notably, high-dose ghrelin desensitized its receptor, indicating a dose-dependent therapeutic window.
Key Points
- Ghrelin ranked as metabolic factor most associated with cognitive impairment
- Ghrelin restored microglial autophagy via SHBG/JNK1/Beclin1, reducing senescence
- High-dose ghrelin desensitized GHSR, narrowing the effective dose range
Longevity Analysis
Cognitive decline here is framed as a failure of cellular housekeeping in the brain's resident immune cells — when microglia lose autophagic capacity, they accumulate senescent phenotypes and sustain low-grade inflammation in hippocampal tissue. Ghrelin is a gut-derived signal that rises with fasting and falls with continuous feeding, which places eating frequency and meal timing within the same regulatory circuit that governs microglial clearance. The receptor desensitization at high doses is the more instructive detail: amplifying a hormonal signal beyond its physiological range degrades the response, and restoring the conditions under which the signal naturally cycles is likely more durable than saturating the pathway.
Original published by Wiley Aging Cell, by Lixing Zhou, Ying Cheng, Wanyu Zhao, Xuelian Sun, Fengjuan Hu, Meiling Ge, Yan Zhang, Gongchang Zhang, Birong Dong, Xiaolei Liu .