The accumulation of senescent cells with age occurs throughout the body. The pace at which cells become senescent increases, thanks to growing levels of damage, and the pace at which senescent cells are destroyed slows down, largely due to immune system decline. Senescent cell secrete a mix of signals that provokes chronic inflammation, disruption of tissue structure and maintenance, and, further, detrimentally alters cellular behavior in a variety of other ways. This signaling environment actively creates and maintains dysfunction in the immune system and organs. Targeted removal of senescent cells in mice, using senolytic therapies, produces rapid and sizable rejuvenation of numerous aspects of aging.
Researchers are steadily exploring the enormous number of proven and potential connections between senescent cells in specific locations in the body and specific age-related conditions or aspects of degenerative aging. In today's example, researchers propose a direct link between the senescent cells that arise in the vascular system and the age-related decline of neurogenesis in the brain. Neurogenesis is the creation of new neurons that occurs in at least some parts of the mammalian brain, followed by the integration of those cells into established neural networks. It is vital to maintenance of brain tissue, memory, and other cognitive functions, and reversing its decline with age is an important goal for the regenerative medicine community.
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 including senolysis, to target age-dependent brain decline.