Intrinsic Factors of Aging and Hematopoiesis
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P203-205
2025-11-26
62
DNA Damage
Genomic instability and DNA damage are hallmarks of aging in different tissues. Acquired mutations at specific loci primarily caused by DNA damage in HSCs can lead to clonal hematopoiesis in elderly individuals, as discussed previously. This suggests that aged HSCs are more susceptible to DNA damage compared to young HSCs. Indeed, aged HSCs display an increased number of γH2A foci—a widely used marker of DNA damage—and have difficulty in removing these foci, indicating impaired DNA repair. However, to what extent the functional decline of aged HSCs is caused by DNA damage is not yet clear. It has been demonstrated that both young and aged murine HSCs can repair DNA equally effectively following induced DNA damage. Although HSCs from mice lacking distinct genomic maintenance pathways exhibit decreased reconstitution and self-renewal capacity, HSCs in these mice are reduced in numbers, in contrast to normal aging where HSCs expand. Telomere shortening, another hallmark of aging, is a specific kind of DNA damage. Early studies demonstrated that telomere length inversely correlated with lifespan of a cell, where older cells display shorter telomeres and progressively shorten at each cell division. Interestingly, murine serial transplantation studies revealed no change in telomere length, and HSC repopulation capacity was not improved by overexpressing telomerase. Collectively, more studies are needed to clarify to what extent normal HSC aging in fact is caused by DNA damage.
Autophagy and Reactive Oxygen Species
Autophagy is a self-catabolic process by which cellular components are sequestered into double-membrane vacuoles, generally associated with the recycling of organelles, and required for cellular hemostasis. Impaired autophagy can lead to the accumulation of toxic proteins and damaged mitochondria, which in turn induces metabolic stress. Around one-third of aged murine HSCs exhibit high autophagy levels. This subpopulation shows a low metabolic state and a high regeneration potential, resembling young HSCs. The remaining population—with decreased autophagy levels—exhibits an activated metabolic state and impaired HSC self-renewal capacity. Thus, loss of autophagy causes metabolic activation and similar myeloid bias as observed in aged HSCs.
ROS—natural products of oxygen-based metabolic processes— are produced mainly by mitochondria. It has been shown that high levels of ROS generate oxidative cellular stress. In general, HSCs are quiescent with low levels of metabolism and low ROS production. However, upon aging, HSCs start accumulating ROS, which then attenuates their fitness. It has been shown that HSCs exposed to high ROS levels have age-associated phenotypes, for example, impaired long-term engraftment. The fact that the reduced colony-forming potential of ROShigh HSCs can be rescued by ROS inhibition further implies a role of ROS in HSC aging and presents potential pharmacological targets to counter age-associated HSC dysfunction.
Epigenetic Modifications
Epigenetic modifications, including DNA methylation and histone modifications, are responsible for the regulation of gene expression without affecting the underlying DNA sequence—a change in phenotype without a change in genotype. Epigenetic modifiers, generally characterized as writers, readers, or erasers, play essential roles in HSC self-renewal and differentiation. As discussed, individuals displaying clonal hematopoiesis, specially CHIP, but also patients with MDS or full-blown AML, very frequently have acquired loss-of-function mutations in epigenetic genes, denoting the importance of this regulatory layer. Moreover, in murine models, some epigenetic genes have been reported to be differentially expressed following HSC aging, suggesting that the epigenome is remodeled during aging.
DNA methylation is often linked to transcriptional gene repression. Age-associated changes in the methylome occur, but their functional significance still remains controversial. However, regardless of whether overall hypo- or hypermethylation occurs in aged HSCs, similar patterns at specific loci have been found. For instance, the Polycomb Repressive Complex-2 (PRC2), which deposits the repressive histone modification H3 lysine 27 tri-methylation (H3K27me3), targets genes that are DNA hypermethylated in aged HSCs, suggesting a crosstalk between these two epigenetic marks.
Histone modifications, including active and repressive marks, impact gene expression by altering chromatin structure to render it more or less accessible to transcription factors and the transcriptional machinery or by recruiting “readers” of the histone code. There are multiple histone modifications, but profiles of certain typical modifications occurring in young or aged HSCs have already provided insight into HSC aging. For example, global levels of H4 lysine 16 acetylation (H4K16ac), an activating histone modification, have been shown to be elevated in aged HSCs. Interestingly, H4K16ac also affects HSC polarity changes that have been reported to be controlled by a small Rho GTPase, cell division control protein 42 (Cdc42). The molecular function of Cdc42 is discussed in the following section.
Epigenetic regulation also provides a potential mechanism under lying myeloid skewing. It has been observed that some myeloid genes gain active histone modifications such as H3 lysine 4 tri-methylation (H3K4me3) and lose DNA methylation in aged HSCs, leading to transcriptional up-regulation of these genes. This raises the possibility that targeting the epigenetic state can potentially restore the function of aged HSCs. Indeed, induced pluripotent stem (iPS) cells generated from reprogrammed young and aged hematopoietic progenitors showed similar repopulating capacity and appear to be rejuvenated.
Chromatin Architecture and Polarity
Recently, overall chromatin architecture has been implicated as a pivotal player of gene expression, cell division, fate determination, growth and development, disease, and even genome evolution. In HSC biology, disease-associated mutations of proteins involving 3D chromatin organization have occasionally been observed and linked to hematopoietic disorders in the elderly. Studies of chromatin archi tecture during HSC cell division revealed that young HSCs display a more “asymmetrical” division pattern—where one of the daughter cells retains the stem cell properties—whereas aged HSCs have preferentially “symmetrical” division patterns due to loss of cell polarity, resulting in reduced regenerative capacity and lymphoid potential. Cdc42 activity is elevated in aged HSCs and correlates with the loss of polarity of aged HSCs. Pharmacological reduction of Cdc42 activity restored the level and spatial distribution of H4K16ac to a similar status to that seen in young HSCs and eventually rejuvenated aged HSCs.
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