The embedding of stress: mitophagy as a mechanism for the central nervous system (CNS) programming and lifelong disease vulnerability.

Growing epidemiological evidence shows that psychological stress is strongly associated with pathogenesis in modern society a correlational finding). Its effects on CNS are highly age- and cell-type specific. This review outlines how stress regulates mitophagy and dynamically disrupt CNS homeostasis across different life stages, including fetal development, adolescence, and aging, as well as across distinct cell types such as neurons, astrocytes, and microglia. These alterations ultimately increase susceptibility to neurodevelopmental and neurodegenerative disorders.): We propose an integrated "cell-age-stress" framework (Hypothesis 1) that highlights the bidirectional crosstalk between stress-induced mitochondrial damage and nuclear epigenetic reprogramming. We also present a "lifespan intervention hypothesis" (Hypothesis 2) and discuss precision fine-tuning strategies targeted to specific life stages and cell types, offering new directions for neuroprotective therapies.