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.
There is a growing need for non-invasive, cheap, and versatile diagnostic methods and the development of low-cost point-of-care assays constitutes a potential solution. Here, we describe the design of a renal clearable fluorogenic probe (Cy7Gal) which produces a fluorogenic signal readable in the urine. The Cy7Gal probe is applied to the detection of the burden of senescence in several in vivo models. The probe is composed of a dye (Cy7) conjugated with a galactose derivative. Upon administration of the probe in vivo, the up-regulated β-galactosidase enzyme in senescent cells cleaves the O-glycosidic bond in Cy7Gal, releasing the highly emissive Cy7 dye that is renally cleared and measured in unmodified urine by an IVIS imaging system or by a fluorimeter. A good correlation between the burden of senescence and emission in urine is observed. Cy7Gal probe is the first example for the fluorogenic in vivo detection of senescence in urine and may serve as a basis for the development of generalized fluorogenic diagnostic platforms for the easy diagnosis in the urine of different diseases as well as for monitoring therapeutic treatments without the use of expensive equipment or trained personnel.
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