Hematopoietic stem cell senescence and opportunities for intervention.

How the cellular state of senescence manifests in hematopoietic stem cells (HSCs) is currently poorly understood and likely orchestrated by a complex interplay of intrinsic and extrinsic factors, such as genetic instability, epigenetic reprograming, alterations in the stem cell niche, and metabolic dysregulation. Accumulating senescence may contribute to the age-related functional decline of HSCs, which manifests as reduced self-renewal, impaired differentiation, altered hematopoietic regenerative potential, expansion of dysfunctional HSC clones, and increased susceptibility to hematologic disorders. Recent work has advanced our understanding of the molecular hallmarks and signaling pathways that contribute to HSC senescence, nominating promising therapeutic targets to ameliorate age-associated hematopoietic dysfunction and malignancy. Here, we review the intrinsic and extrinsic factors that likely contribute to HSC senescence during homeostasis and pathological conditions. We further summarize senescence targeting strategies that may be leveraged to mitigate HSC senescence and restore hematopoietic function during aging or hematologic disease.