Molecular Mechanisms of Neurogenic Aging in the Adult Mouse Subventricular Zone

Abstract

In the adult rodent brain, the continuous production of new neurons by neural stem/progenitor cells (NSPCs) residing in specialized neurogenic niches and their subsequent integration into pre-existing cerebral circuitries supports odour discrimination, spatial learning, and contextual memory capabilities. Aging is recognized as the most potent negative regulator of adult neurogenesis. The neurogenic process markedly declines in the aged brain, due to the reduction of the NSPC pool and the functional impairment of the remaining NSPCs. This decline has been linked to the progressive cognitive deficits of elderly individuals and it may also be involved in the onset/progression of neurological disorders. Since the human lifespan has been dramatically extended, the incidence of age-associated neuropsychiatric conditions in the human population has increased. This has prompted efforts to shed light on the mechanisms underpinning the age-related decline of adult neurogenesis, whose knowledge may foster therapeutic approaches to prevent or delay cognitive alterations in elderly patients. In this review, we summarize recent progress in elucidating the molecular causes of neurogenic aging in the most abundant NSPC niche of the adult mouse brain: the subventricular zone (SVZ). We discuss the age-associated changes occurring both in the intrinsic NSPC molecular networks and in the extrinsic signalling pathways acting in the complex environment of the SVZ niche, and how all these changes may steer young NSPCs towards an aged phenotype.

Granulins Regulate Aging Kinetics in the Adult Zebrafish Telencephalon

“…Typical aging hallmarks such as genomic instability, telomere shortening, metabolic dysregulation, cellular senescence, stem cell exhaustion, and decreased neurogenesis are observed in the brain and affect a broad range of cellular functions [2], thereby leading to impaired tissue homeostasis and regeneration. a primary reason for this impaired tissue homeostasis and regeneration is age-related exhaustion of tissue-specific stem cells, a process observed in various organs [3][4][5], including the mammalian brain [6][7][8][9][10]. Although prominent age-associated changes, including decreased neurogenesis and changes in the lateral ventricle choroid plexus [11][12][13], have Cells 2020, 9, 2 of 25 been detected in the aging mammalian brain, comparisons of neural stem cell transcriptomes have revealed a remarkably small set of differentially regulated transcripts, which are largely associated with cell cycle regulation, neuronal differentiation, and inflammation [10,[14][15][16].…”

X-ray irradiated cultures of mouse cortical neural stem/progenitor cells recover cell viability and proliferation with dose-dependent kinetics

“…In particular, NSPCs of the developing brain, such as those located in the ventricular and subventricular zones (VZ/SVZ) of the foetal cerebral cortex and in the VZ/SVZ lining the lateral ventricle in the neonatal brain, are generally highly proliferative and broadly sensitive to IR-induced apoptosis, but those NSPCs that survive irradiation resume proliferation and repopulate the NSPC niche [22][23][24][25] . In contrast, NSPCs of the adult VZ/SVZ niche can exist in an actively proliferating or in a quiescent status 34 . The former subpopulation is radiosensitive and responds to IR by undergoing apoptosis or terminal differentiation, in either case depleting the proliferating NSPC pool; the latter subpopulation is radioresistant and responds to IR by entering the cell cycle and replenishing the proliferating NSPC pool, although the response was shown to depend on the total dose and the dose fractionation scheme that were applied 22,[35][36][37][38][39] .…”

“…In the case of NSPCs, several studies have investigated their response to IR both in vivo and in vitro, reporting heterogeneous and even contradictory findings. Notably, in vivo analyses in rodents have suggested that the specific response of NSPCs to IR-dependent DNA damage may depend, at least in part, on the age of the animal, possibly due to the known age-associated changes in the NSPC population occurring between foetal and adult stages 33,34 . In particular, NSPCs of the developing brain, such as those located in the ventricular and subventricular zones (VZ/SVZ) of the foetal cerebral cortex and in the VZ/SVZ lining the lateral ventricle in the neonatal brain, are generally highly proliferative and broadly sensitive to IR-induced apoptosis, but those NSPCs that survive irradiation resume proliferation and repopulate the NSPC niche [22][23][24][25] .…”

Molecular Signatures of the Aging Brain: Finding the Links Between Genes and Phenotypes

“…In the following sections, we will focus on the key age-related molecular changes revealed in specific cell types and regions of the human brain. Recent studies using mouse models to analyze the genome-wide transcriptomic and epigenomic modifications occurring in NSPCs of the aging neurogenic niches have been reviewed elsewhere [12]. [15], DNA methylation [19], and histone H3 lysine 9 acetylation (H3K9ac) [18] datasets from dorsolateral prefrontal cortex (DLPFC) postmortem samples of longitudinal cohorts of human subjects of different ages.…”

“…Finally, aging has a major impact on the generation of new neurons in the adult brain. At least in rodents, in which adult neurogenesis has been best characterized, a sharp age-dependent drop in the production of new neurons is detectable at the level of both of the main adult neurogenic niches, the subventricular zone (SVZ), flanking the lateral ventricles, and the hippocampal subgranular zone (SGZ) [11,12]. Thus, aging can hinder the remodelling of neural circuits by affecting synaptic connectivity and the integration of new neuronal elements, leading to a progressive decline in the functional plasticity of the brain and in cognitive abilities.…”