Reviewing What is Known of the Aging of Neural Stem Cells

Neural stem cells produce the new neurons necessary for memory function and maintenance of brain tissue throughout adult life. This process of neurogenesis declines with age, however. Neural stem cell activity is reduced with age, in much the same way as all stem cell populations (and their niche structures) appear to become damaged and impaired as a result of the mechanisms of aging. Do we know enough about the way in which neural stem cells age in order to attempt prevention? As researchers point out here, some strategies may make the situation worse by exhausting rather than renewing stem cell pools. A few inroads are being made, however.

Extensive research in recent years has significantly advanced our knowledge of the mechanisms underlying neural stem cell (NSC) aging and age-related decline in neurogenesis, although much remains obscure. Central to this decline is an escalating impairment of the NSC pool, characterized by increased quiescence, altered lineage specification, and progressive depletion of NSCs. The mechanisms underlying NSC aging in the dentate gyrus (DG) are complex and multifactorial. Over the course of their life, NSCs accumulate several defects, including a failure to maintain a healthy proteome, metabolic alterations, DNA damage, and epigenetic drift. It is now recognized that, in addition to intrinsic mechanisms, extrinsic changes in the NSC niche and systemic environment are the primary contributors to NSC aging, and that these mechanisms are not mutually exclusive, but rather interrelated and interacting with each other.

To safeguard the NSC pool from depletion, it is vital to gain a comprehensive understanding of the cellular and molecular mechanisms regulating NSCs and their aging. The advent of innovative new techniques such as single-cell RNA sequencing and spatial transcriptomics holds immense potential for unravelling the full complexity of the mechanisms involved in the declining capacities of NSCs during aging. Other technologies, such as CRISPR-Cas or adenovirus-mediated gene transfer, enable diverse types of gene function screens, facilitating the exploration of molecular interdependencies and their impact on NSC aging. Understanding the mechanisms that control NSC functions and their aging holds potential for the identification of novel therapeutic targets to either slow the aging process or rejuvenate aged NSCs, thereby enhancing the regenerative and cognitive capacities of the aging hippocampus.

Preventively, simple interventions with few side effects, such as diet or exercise, are particularly promising. Curatively, it becomes more difficult, as the interventional activation of NSCs usually leads to premature exhaustion and accelerated depletion of the pool. However, recent findings that have been able to identify targets whose manipulation increases the self-renewal of NSCs in the aged DG without accelerating their depletion (VEGF, combination of Plagl2 with anti-Dyrk1a) give cause for optimism.


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