Reprogramming the GRHL2-CDK19 axis by gene therapy alleviates prostate aging

The prostate is a multifunctional organ of the male reproductive system whose aging process impairs sexual and urinary function and fertility and increases disease susceptibility, thereby compromising quality of life. However, the mechanisms underlying human prostate aging remain poorly understood. Here we integrated single-nucleus transcriptomics and histological analyses to elucidate the aging mechanisms of the primate prostate. We identified epithelial cell senescence, chronic inflammation and fibrosis as key hallmarks of prostate aging. In young epithelial cells, GRHL2 promotes CDK19 transcription, which sequesters p53, leading to the suppression of p21^Waf1/Cip1. Aging-related downregulation of GRHL2 releases p53 from the CDK19-p53 complex, activating p21^Waf1/Cip1 transcription and inducing cell senescence. Accordingly, a single injection of a GRHL2-based gene therapy strategy delayed prostate aging and alleviated age-related urinary dysfunction in vivo. Our findings elucidate key mechanisms of primate prostate aging and provide a foundation for developing therapies targeting prostate aging and associated pathologies.