Reassessment of hematopoietic stem cell aging through metabolic uncoupling and mitochondrial resilience

Hematopoietic stem cell (HSC) aging is often described as a gradual loss of stem cell fitness that culminates in impaired blood production, immune dysfunction, and increased susceptibility to hematologic disease. However, recent work suggests that this view is too simple. Rather than a uniform decline, aging appears to remodel the HSC compartment into metabolically and functionally distinct states, including maladaptive trajectories as well as surprisingly resilient subsets. In this review, we argue that HSC aging is best understood through the interplay of mitochondrial regulation, metabolic uncoupling, and niche-derived stress, with particular emphasis on how recent findings revise several longstanding assumptions in the field (Box 1).