Metabolic regulation of aged hematopoietic stem cells: key players and mechanisms

Aging is accompanied by a gradual decline in the function and regenerative capacity of hematopoietic stem cells (HSCs), which leads to increased susceptibility to blood disorders. Recent studies have highlighted the critical role of metabolic regulation in governing the fate and function of HSCs, and alterations in metabolism play a critical role in the age-related changes observed in HSCs. Metabolic processes including glycolysis, mitochondrial function, nutrient sensing and inflammation, profoundly influence the maintenance, self-renewal and differentiation potential of the HSC pool. This review focuses on the metabolic alterations that occur in HSCs during aging and the systemic factors which contribute to HSC metabolic dysregulation, leading to impaired cellular function and reduced regenerative capacity. We highlight the impact of age-associated changes in oxidative stress, mitochondrial dysfunction, nutrient availability and inflammation on HSC metabolism and function. Targeting metabolic pathways and modulating key regulators of metabolism hold promise for reducing age-related HSC dysregulation, thus maintaining functional potential as a path towards healthy aging. Exploiting these metabolic interventions has the potential to improve hemopoietic recovery, enhance immune function and pave the way for novel therapeutic interventions to combat age-related blood disorders.