Abstract
Hematopoietic stem cells (HSCs) are essential for lifelong blood production and immune homeostasis. However, aging induces functional declines in HSCs, leading to hematological disorders, immune dysfunction, and increased susceptibility to malignancies. This review explores the biological underpinnings of HSC aging, highlighting the intrinsic and extrinsic factors that drive this process. We discuss the molecular and cellular mechanisms contributing to HSC aging, including genetic instability, epigenetic alterations, metabolic shifts, and inflammation signaling. Additionally, we examine the role of the bone marrow microenvironment in modulating HSC aging, emphasizing the impact of niche interactions, stromal cell dysfunction, and extracellular matrix remodeling. To advance our understanding of HSC aging, pluripotent stem cell differentiation platforms provide a valuable tool for modeling aged HSC phenotypes and identifying potential therapeutic targets. We review current strategies for HSC rejuvenation, including metabolic reprogramming, epigenetic modifications, pharmacological interventions, and niche-targeted approaches, aiming to restore HSC function and improve regenerative potential. Finally, we present emerging perspectives on the clinical implications of HSC aging, discussing potential translational strategies for combating age-associated hematopoietic decline. By integrating insights from stem cell biology, aging research, and regenerative medicine, this review provides a comprehensive overview of HSC aging and its therapeutic potential. Addressing these challenges will be critical for developing interventions that promote hematopoietic health and improve outcomes in aging populations.