The systemic costs of hematopoietic stem cell aging

Stem cell behavior is tightly regulated by signals from the surrounding immune environment. Immune cells play an indispensable role in the maintenance, activation and differentiation of tissue-resident stem cells (TSCs). These interactions are dynamic and adapt across the lifespan, profoundly influencing regenerative capacity under both physiological and pathological conditions. Notably, immune dysfunction originating from aging hematopoietic stem cells (HSCs) disrupts tissue regeneration across distant organs, including the brain, muscle and skin. In this Review, we synthesize current knowledge on the interplay between HSC aging and TSC function, emphasizing how age-related changes in HSC-derived immune outputs impair local tissue homeostasis. We explore potential mechanisms underlying HSC-TSC communication, including inflammaging, cytokine signaling and the secretion of bioactive factors. Finally, we discuss emerging strategies aimed at rejuvenating aged HSCs, restoring immune equilibrium and enhancing systemic tissue regeneration. By linking systemic immune remodeling to local niche dysfunction, this Review proposes a hierarchical model in which HSC aging acts as a central regulator of tissue regenerative decline.