Corticotropin-releasing factor (CRF) in brain aging: from mitochondrial dysfunction to inflammaging

Aging is a complex biological process. The corticotropin-releasing factor (CRF) signaling pathway has gained increasing attention for its potential role in regulating aging, acting as a key bridge connecting neuroendocrine stress mechanisms with both central and peripheral aging processes. As a core neuropeptide of the stress response, CRF primarily mediates downstream effects through its type 1 receptor (CRFR1), while its type 2 receptor (CRFR2) may play a modulatory, often opposing, role. Evidence from preclinical models indicates that excessive CRF signaling is associated with mitochondrial dynamics imbalance and biogenesis defects, leading to overproduction of reactive oxygen species (ROS) and mitochondrial DNA damage. These damaged mitochondria can subsequently release damage-associated molecular patterns (DAMPs), which activate innate immune pathways and may trigger a chronic low-grade inflammatory state, ultimately contributing to cellular senescence. Elucidating the cascading mechanisms by which CRF signaling could drive aging-from mitochondrial dysfunction to chronic inflammation-is essential for understanding the molecular basis of stress-accelerated aging. This review aims to systematically integrate research advances at the intersection of the CRF signaling pathway and aging hallmarks, focusing on a proposed "CRF-mitochondrial dysfunction-inflammation-aging" axis. We explore this regulatory network and its clinical translational potential to provide a theoretical foundation for unraveling the molecular mechanisms of stress-driven aging and identifying novel intervention targets.