Nuclear receptors in age-related diseases: From mechanisms to drug discovery

Nuclear receptors (NRs), a superfamily of ligand-activated transcription factors, serve as master regulators linking signaling molecules to the genome, coordinating a variety of essential physiological processes in development, homeostasis, metabolism, and reproduction. As the central biological sensors, NRs respond to a wide range of endogenous substances and xenobiotics, thereby orchestrating critical processes such as metabolic homeostasis, inflammatory and immune responses, cellular differentiation and apoptosis. Emerging evidence has suggested that activation of specific NRs (such as PXR, FXR and CAR) can modulate cellular senescence, genomic instability, telomere attrition, epigenetic alterations, inflammation, proteostasis, dysbiosis, autophagy, and other hallmarks of aging. Conversely, dysregulation of NR-related signaling is implicated in accelerating aging and contributing to the pathogenesis of age-related disorders, including metabolic and neurodegenerative diseases. The crucial roles of NRs in both metabolic homeostasis and aging make them as promising therapeutic targets for mitigating aging and age-related disorders. Herein, a comprehensive review of the research progress on NRs in aging and age-related diseases was provided. We systematically summarize the involvement of key NRs in regulating fundamental aging hallmarks, delve into their mechanistic roles in specific age-related diseases, and evaluate emerging therapeutic strategies targeting NR pathways. This work aims not only to intergrate existing knowledge to offer deeper insights into the molecular mechanisms of aging but also to critically assess the translational potential of NRs as targets for promoting longevity and developing novel interventions against age-associated decline.