Aging and Rejuvenation of Neural Stem Cells and Their Niches

Abstract

Aging has a profound and devastating effect on the brain. Old age is accompanied by declining cognitive function and enhanced risk of brain diseases, including cancer and neurodegenerative disorders. A key question is whether cells with regenerative potential contribute to brain health and even brain "rejuvenation." This review discusses mechanisms that regulate neural stem cells (NSCs) during aging, focusing on the effect of metabolism, genetic regulation, and the surrounding niche. We also explore emerging rejuvenating strategies for old NSCs. Finally, we consider how new technologies may help harness NSCs' potential to restore healthy brain function during physiological and pathological aging.

Figure 1.. Neurogenesis during aging.

The ability of NSCs to proliferate and produce new neurons declines sharply after development and continues to decline during aging while the incidence of neurodegeneration and age-related diseases increases (the diagram shows conceptual trajectories for neurogenesis and neurodegeneration). The adult mammalian brain contains two reservoirs of regenerative neural stem cells (NSCs): the dentate gyrus of the hippocampus and the subventricular zone of the lateral ventricles (teal green). These niches contain quiescent NSCs that can be activated to produce actively proliferating (activated) NSCs. Activated NSCs have the potential to differentiate into neurons, oligodendrocytes or astrocytes.

Figure 2.. Cellular pathways involved in NSC aging.

Cellular and metabolic pathways involved in maintaining NSC and differentiated progeny homeostasis that change during aging.

Figure 3.. The role of the niche and inflammation in NSC aging.

Changes that occur in the NSC niche (SVZ is depicted) during aging (left: young, right: old). Inflammation increases in the niche, highlighted by the increase in inflammatory cytokines, activated microglia, and T cell infiltration.

Figure 4.. Interventions to rejuvenate old neurogenic niches.

Comparison of three promising interventions to rejuvenate old neurogenic niches – the subventricular zone (SVZ) and hippocampus dentate gyrus (DG). Dietary interventions are divided into three sub-categories (caloric restriction (CR), intermittent fasting (IF), and fasting-mimicking diets (FMD)). Exercise is divided into moderate and strenuous groupings. Systemic factors are divided between those in blood or plasma. The neuroprotective effects of these interventions were assessed in various diseases and injuries: Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Multiple Sclerosis (MS), Traumatic Brain Injury (TBI), Stroke, and Epilepsy. A question mark (“?”) signifies conflicting or insufficient evidence to support the claim.

Figure 5.. Frontiers in the aging neural stem cell field.

The advent and refinement of new technologies (right) should further improve our understanding of how aging influences NSCs and their niche, and how NSCs interact with brain circuity and systemic and organismal signals.