Stem Cells of the Aging Brain

Abstract

The adult central nervous system (CNS) contains resident stem cells within specific niches that maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. Physiological aging is associated with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS stem cells. Also, the biggest risk factor for neurodegenerative diseases is age, and current in vivo and in vitro models of neurodegenerative diseases rarely consider this. Therefore, combining both aging research and appropriate interrogation of animal disease models towards the understanding of the disease and age-related stem cell failure is imperative to the discovery of new therapies. This review article will highlight the main intrinsic and extrinsic regulators of neural stem cell (NSC) aging and discuss how these factors impact normal homeostatic functions within the adult brain. We will consider established in vivo animal and in vitro human disease model systems, and then discuss the current and future trajectories of novel senotherapeutics that target aging NSCs to ameliorate brain disease.

3D Image Analysis of the Complete Ventricular-Subventricular Zone Stem Cell Niche Reveals Significant Vasculature Changes and Progenitor Deficits in Males Versus Females with Aging

“…Therefore, age-dependent changes in these local sources deserve further investigation, as do changes in the various receptors to progesterone, androgens, and estrogens that exhibit differential expression on brain cell subtypes (Contreras-Zárate and Cittelly, 2020). It will also be worthwhile exploring whether similar sexual dimorphism of the periventricular region or other zones that harbor NPCs in humans (Nicaise et al, 2020;Seki, 2020), occurs with aging, such as altered vascular structure and abnormal progenitor proliferation (Matarredona and Pastor, 2019), as these could contribute to different courses in age-related brain diseases in men and women.…”

Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration

“…Various environmental and behavioral activities have been shown to activate quiescent NSCs (e.g., exercise, sleep, learning) through diverse cell signaling pathways (e.g., neurotransmitters, Notch, neurotrophins, Wnt) [ 87 ]. Once activated, NSCs proliferate, migrate, and differentiate toward NPCs and OPCs and terminally differentiate into neurons, astrocytes, and oligodendrocytes [ 88 , 89 ]. Given that aberrant NSC activation may contribute to cancer, the ability for them to utilize the senescence stress response may benefit short-term health and survival.…”

Modeling Neuroregeneration and Neurorepair in an Aging Context: The Power of a Teleost Model

“…The multiple levels of damage caused by the hallmarks described above eventually also influence the intrinsic capacity of stem cells to proliferate and generate new neurons, glia, or neural stem cells ( Nicaise et al, 2020 ). As in the adult mammalian brain, neurogenesis in the teleost brain declines with age ( Terzibasi Tozzini et al, 2012 ; Edelmann et al, 2013 ; Nicaise et al, 2020 ). In the zebrafish olfactory bulb, the number of newborn neurons decreases steeply between 3 and 6 months of age, holds constant levels until 10 months of age, and then diminishes further.…”