CD47 signaling in aging and age-related diseases: mechanisms, challenges, and therapeutic opportunities.

Abstract

Aging is marked by progressive dysfunction in cellular maintenance pathways, including mitochondrial impairment, reduced autophagic capacity, and accumulation of senescent cells, which contribute to chronic low-grade inflammation. The transmembrane protein CD47 best known for delivering a "don't eat me" signal through SIRPα is increasingly recognized as an important modulator of several aging-related processes. Its upregulation in aged or inflamed tissues can inhibit the clearance of damaged or senescent cells, reinforce inflammatory signaling through pathways such as NF-κB, and influence metabolic and autophagy-related regulation in a context-dependent manner. This review synthesizes current evidence identifying CD47 as an integrative node that intersects with multiple hallmarks of aging. We examine its roles across cardiovascular, neurodegenerative, and metabolic pathologies, and evaluate the emerging therapeutic landscape targeting the CD47-SIRPα axis. Although CD47 blockade has shown promise in enhancing immune clearance and improving tissue homeostasis, clinical translation remains challenged by on-target toxicities such as anemia and by age-dependent variability in immune responsiveness. Targeting CD47 therefore represents a mechanistically grounded but inherently complex strategy for mitigating age-related functional decline.