A Discussion of Hematopoietic Stem Cell Aging
The aging of hematopoietic stem cells is an important contributing factor in the decline of the immune system in later life, resulting in reduced clearance of senescent cells and pathogens, alongside increasing chronic inflammation. One of the problems deriving from impaired hematopoiesis is that the production of immune cells becomes skewed towards myeloid lineages, biasing the immune system towards the above mentioned declines. There are a range of potential approaches that might help with these issues, from introducing new hematopoietic stem cells to suppressing chronic inflammation to small molecules that may favorably adjust the behavior of native cells. Age-related dysfunction of hematopoiesis isn't a simple challenge, however, as stem cell function depends on the supporting cells of the stem cell niche and the systemic signaling environment, rather than only on the integrity of the stem cell population itself.
There is a hot topic in stem cell research to investigate the process of hematopoietic stem cell (HSC) aging characterized by decreased self-renewal ability, myeloid-biased differentiation, impaired homing, and other abnormalities related to hematopoietic repair function. It is of crucial importance that HSCs preserve self-renewal and differentiation ability to maintain hematopoiesis under homeostatic states over time. Although HSC numbers increase with age in both mice and humans, this cannot compensate for functional defects of aged HSCs.
The underlying mechanisms regarding HSC aging have been studied from various perspectives, but the exact molecular events remain unclear. Several cell-intrinsic and cell-extrinsic factors contribute to HSC aging including DNA damage responses, reactive oxygen species (ROS), altered epigenetic profiling, polarity, metabolic alterations, impaired autophagy, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, nuclear factor- (NF-) κB pathway, mTOR pathway, transforming growth factor-beta (TGF-β) pathway, and wingless-related integration site (Wnt) pathway.
To determine how deficient HSCs develop during aging, we provide an overview of different hallmarks, age-related signaling pathways, and epigenetic modifications in young and aged HSCs. Knowing how such changes occur and progress will help researchers to develop medications and promote the quality of life for the elderly and possibly alleviate age-associated hematopoietic disorders. The present review is aimed at discussing the latest advancements of HSC aging and the role of HSC-intrinsic factors and related events of a bone marrow niche during HSC aging.