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Review
. 2020 Aug 6:12:247.
doi: 10.3389/fnagi.2020.00247. eCollection 2020.

Stem Cells of the Aging Brain

Alexandra M Nicaise  1 , Cory M Willis  1 , Stephen J Crocker  2 , Stefano Pluchino  1
Affiliations
Review

Stem Cells of the Aging Brain

Alexandra M Nicaise et al. Front Aging Neurosci. .

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.

Keywords: aging; cell metabolism; disease modeling; mitochondria; neural stem cells; senescence; senotherapeutics.

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Figures

Figure 1
Figure 1
Intrinsic and extrinsic regulators of NSC aging. Intrinsic regulators include transcriptional changes, such as upregulation of p16Ink4a and p53; mitochondrial damage, resulting from mtDNA mutations and excessive ROS; toxic protein aggregates, due to a dysregulation in proteostasis; SA-β-gal expression, induced by senescence; telomere shortening and DNA damage caused by replication-associated stress and dysfunctional repair amongst other factors; and changes in epigenetic patterns. Extrinsic regulators include SASP, secreted by nearby senescent cells, and secreted by senescent NSCs themselves; modifications in ECM, such as increases in HA composition; and inflammatory molecules secreted by activated astrocytes, microglia, and T-cells. Abbreviations: ECM, extracellular matrix; HA, hyaluronic acid; mtDNA, mitochondrial DNA; NSC, neural stem cells; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype.
Figure 2
Figure 2
Hallmarks and phenotype of NSC aging. The main phenotypes, hallmarks, and models that can be used to investigate aspects of NSC aging. Genomic instability, metabolic dysfunction, inflammaging, and senescence are all aspects that affect the normal proliferation and differentiation function of NSCs. These causes of aging have specific hallmarks that can be identified using in vivo and in vitro methods. Abbreviations: CSF, cerebrospinal fluid; iPSC, induced pluripotent stem cell; mtDNA, mitochondrial DNA; NSC, neural stem cell; OPC, oligodendrocyte progenitor cell; OXPHOS, oxidative phosphorylation; PPMS, primary progressive multiple sclerosis; ROS, reactive oxygen species; SA-β-gal, senescence-associated β-galactosidase; SASP, senescence-associated secretory phenotype.
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