FGF13 Alleviates the Aging Process in Mice by Regulating Astrocyte Function in the Medial Prefrontal Cortex via Phafin2 Signaling Pathway

Aging is an intrinsic biological process; specifically, brain aging leads to cognitive decline, memory loss, and numerous neurodegenerative diseases. Fibroblast growth factor 13 (FGF13) is expressed in the central nervous system (CNS) and plays a critical role in several neuropathological conditions; however, the specific role of FGF13 in brain aging remains unclear. In this study, screening of public gene expression databases revealed that FGF13 is significantly downregulated in the brain tissues of aging mice and macaques, particularly within the medial prefrontal cortex (mPFC) and astrocytes. Specific knockout of FGF13 in cortical astrocytes accelerates the aging phenotype and impairs neurological function in mice. Conversely, overexpression of FGF13 effectively delays the aging process and ameliorates aging‐induced cognitive impairment. RNA‐seq analysis indicated that FGF13 primarily influences astrocyte‐mediated inflammatory responses and cellular autophagy. Mechanistically, FGF13 targets and binds to Phafin2, promoting autophagy in astrocytes. Homeostatic astrocytes not only ameliorate neuronal damage but also reduce the release of inflammatory factors by microglia, playing a crucial role in mitigating the aging process in mice. In summary, FGF13 improves the cerebral microenvironment by regulating astrocyte function, ultimately exerting an anti‐aging effect. These findings provide a theoretical basis for neuroscience and aging research, offering new insights into age‐related genetic phenotypes in the brain and body, as well as the interplay between aging and various diseases.