Neurogenesis in aging and age-related neurodegenerative diseases

Abstract

Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aβ, α-synuclein, …). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.

Keywords: Aging; Dentate gyrus; Hippocampus; Memory; Neurodegeneration; Neurogenesis.

Figure 1.. Key aggregation-prone proteins involved in neurodegenerative diseases and adult hippocampal neurogenesis during aging

Adult hippocampal neurogenesis decreases with aging. Aggregation-prone proteins, like Aβ, tau and APOE in AD, α-syn in PD and HTTs in HD accumulate during the aging process and induce neurodegeneration as well as impair hippocampal neurogenesis, resulting in the imbalance between these two processes. Various factors that are tightly connected with neurogenesis are involved in the pathologies of aging and neurodegenerative diseases and are discussed in this review. In the hippocampus, the process of neurogenesis starts with radial glia-like (RGL) cells (type 1 cells). The RGL cells keep self-renewing and give rise to astrocytes (1) and intermediate progenitor cells (IPCs or type 2 cells) (2). IPCs proliferate and differentiate into bipolar neuroblasts (3). Those neuroblasts differentiate into immature neurons (4). Then these immature neurons undergo a dynamic maturation process, with some of them dying, and some surviving to become mature neurons and form functional connections to existing neural networks (5). Several studies have demonstrated that markers of senescence, like p16, p19, p53 and HMGB1, are increased in some neurons and neural stem cells (6 &7) (Molofsky et al., 2006; Negredo et al., 2020; Nicaise et al., 2019). This age-associated NSC senescence could result in the depletion of NSCs, ultimately decreasing adult hippocampal neurogenesis and impairing brain function. At the bottom is the schematic of specific markers expressed during hippocampal neurogenesis and senescence.

Figure 2.. The effects of certain life/healthspan interventions on adult neurogenesis in rodents.

This illustration encapsulates the effects of several common life/healthspan manipulations on adult neurogenesis in rodents, which are described in this review. Environmental enrichment, physical exercise, calorie restriction, NAD-boosting molecules (NMN/NR), resveratrol and metformin all increase neurogenesis in animal models, while the effects of rapamycin have not yet been comprehensively established in that regard.