Vascular Senescence: A Potential Bridge Between Physiological Aging and Neurogenic Decline

Abstract

The adult mammalian brain contains distinct neurogenic niches harboring populations of neural stem cells (NSCs) with the capacity to sustain the generation of specific subtypes of neurons during the lifetime. However, their ability to produce new progeny declines with age. The microenvironment of these specialized niches provides multiple cellular and molecular signals that condition NSC behavior and potential. Among the different niche components, vasculature has gained increasing interest over the years due to its undeniable role in NSC regulation and its therapeutic potential for neurogenesis enhancement. NSCs are uniquely positioned to receive both locally secreted factors and adhesion-mediated signals derived from vascular elements. Furthermore, studies of parabiosis indicate that NSCs are also exposed to blood-borne factors, sensing and responding to the systemic circulation. Both structural and functional alterations occur in vasculature with age at the cellular level that can affect the proper extrinsic regulation of NSCs. Additionally, blood exchange experiments in heterochronic parabionts have revealed that age-associated changes in blood composition also contribute to adult neurogenesis impairment in the elderly. Although the mechanisms of vascular- or blood-derived signaling in aging are still not fully understood, a general feature of organismal aging is the accumulation of senescent cells, which act as sources of inflammatory and other detrimental signals that can negatively impact on neighboring cells. This review focuses on the interactions between vascular senescence, circulating pro-senescence factors and the decrease in NSC potential during aging. Understanding the mechanisms of NSC dynamics in the aging brain could lead to new therapeutic approaches, potentially include senolysis, to target age-dependent brain decline.

Keywords: adult neural stem cell; endothelial cell senescence; neurogenic niche; parabiosis; senescence-associated secretory phenotype.

FIGURE 1

Schematic representation of the cellular senescence process and its impact on tissues.

FIGURE 2

NSCs in adult brain neurogenic niches. (A) Representation of the location and organization of the SEZ neurogenic niche. NSCs contact the ependymal cell layer apically and the blood vessels through a basal process. Due to their specific position, NSCs receive signals from the choroid plexus (CP) through their access to the CSF (domain I), from other cell components of the niche (domain II) and from the vasculature (domain III). The box below identifies the components of the niche and provides an overview of the NSC lineage within the SEZ, from quiescent (q) to activated (a) NSCs to neural progenitor cells (NPCs) to neuroblasts. (B) Illustration of the location and organization of the hippocampal neurogenic niche. In the SGZ, NSCs or RGLs contact blood vessels and give rise to intermediate progenitor cells (IPCs) that progress into type 3 neuroblasts or intermediate granule cells (IGCs), to finally differentiate into granule cells (GC) that are located in the granule cell layer (GLC) and the inner molecular layer (IML). Mature granule cells constitute the neuronal circuitry of the DG. The box below includes an overview of the RGL lineage.

FIGURE 3

Schematic representation depicting the impact of aging on the vascular niche.