A Review of Approaches to Rejuvenate Aging Hematopoietic Stem Cells
Technically, even very small effects can be classed as rejuvenation if they move the right markers, if they in some way reduce the burden of damage and dysfunction of aging. Exercise probably rejuvenates to some degree, by any reasonable definition. Yet we know the bounds of the possible when it comes to exercise and other widely used interventions, and the outcomes are nowhere near as large as we would like. Fit people are still aging to death, and end up frail in the later stages of life.
In the matter of restoring lost function to the hematopoietic stem cell populations of the bone marrow that are responsible for generating the cells that make up the immune system, there are a number of interventions that have been shown to outperform the effects of exercise in mice. One of the more interesting examples is the results of a single treatment of CASIN, which improves stem cell function globally, improves immune function, and extends life. Restored immune function is an important goal in the treatment of aging, given the sizable influence the immune system has over the course of aging.
Aged hematopoietic stem cells (HSCs) are characterized by increased phenotypic number, decreased self-renewal and long-term reconstitution capacity, myeloid-biased differentiation, and clonal hematopoiesis. In this review, we summarize the life cycle of HSCs, integrate recent advances in understanding the cell-intrinsic and extrinsic mechanisms that drive HSC aging, and highlight innovative rejuvenation strategies that could be harnessed to delay HSC and systemic aging.
Exercise enhances systemic health through improved circulation and metabolism. However, it was found that exercise has little effect on rejuvenating HSCs. It is plausible that exercise preferentially accelerates lymphopoiesis via niche remodeling rather than directly rejuvenates aged HSCs. Dietary restriction (DR) modulates HSC function through multiple nutrient-sensing pathways. Pharmacological approaches targeting the same metabolic pathways also show rejuvenation effects on HSCs. Nicotinamide riboside (NR) enhances mitochondrial function and restores the metabolic competence and regenerative capacity of aged HSCs. Similarly, mTOR inhibition with rapamycin reverses age-related functional decline of HSCs, improving self-renewal, reconstitution potential, and antiviral immunity in aged mice.
Sirt3 is a mammalian deacetylase that exhibits age-dependent expression decline in HSCs. Sirt3 knockout in aged mice impairs HSC self-renewal capacity, while its overexpression enhances regenerative potential. Sirt7 deletion induces premature activation, lymphoid differentiation bias, and functional exhaustion of HSCs. In contrast, Sirt7 overexpression reverses these aging hallmarks, and restores balanced lineage output and reconstitution capacity in geriatric murine models. Transient expression of Yamanaka factors (e.g., Oct4, Sox2, Klf4, and c-Myc) showed systemic rejuvenation effects and extended life span in mice, whether it can reverse HSC aging remains to be tested.
A marked increase in non-polarized cells is observed among aged HSCs, attributed to elevated Rho-GTPase activity of Cdc42 during aging. Casin, a small-molecule Cdc42 inhibitor, restored the proportion of polarized HSCs in aged mice and moderately enhanced their long-term reconstitution potential. In vivo Casin treatment significantly extended the lifespan of aged mice and reduced systemic inflammatory cytokines. Aged HSCs exhibit MMP reduction and pronounced mitochondrial heterogeneity, with low-activity subpopulations displaying characteristic aging phenotypes. Mito-Q treatment in aged mice partially restored MMP and augmented transcriptional activity in HSCs.
Oral administration of the senolytic drug ABT263, an inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL, effectively cleared senescent HSCs, ameliorated irradiation-induced premature hematopoietic aging, and partially restored the regenerative ability of HSCs.