Reconsidering the usual suspects in age-related hematologic disorders: is stem cell dysfunction a root cause of aging?

Aging exerts a profound impact on the hematopoietic system, leading to increased susceptibility to infections, autoimmune diseases, chronic inflammation, anemia, thrombotic events, and hematologic malignancies. Within the field of experimental hematology, the functional decline of hematopoietic stem cells (HSCs) is often regarded as a primary driver of age-related hematologic conditions. However, aging is clearly a complex multifaceted process involving not only HSCs but also mature blood cells and their interactions with other tissues. This review reappraises an HSC-centric view of hematopoietic aging by exploring how the entire hematopoietic hierarchy, from stem cells to mature cells, contributes to age-related disorders. It highlights the decline of both innate and adaptive immunity, leading to increased susceptibility to infections and cancer, and the rise of autoimmunity as peripheral immune cells undergo aging-induced changes. It explores the concept of “inflammaging,” where persistent, low-grade inflammation driven by old immune cells creates a cycle of tissue damage and disease. Additionally, this review delves into the roles of inflammation and homeostatic regulation in age-related conditions such as thrombotic events and anemia, arguing that these issues arise from broader dysfunctions rather than stemming from HSC functional attrition alone. In summary, this review highlights the importance of taking a holistic approach to studying hematopoietic aging and its related pathologies. By looking beyond just stem cells and considering the full spectrum of age-associated changes, one can better capture the complexity of aging and attempt to develop preventative or rejuvenation strategies that target multiple facets of this process.