NEURONAL STEM CELLS AND AGING (8 OF 11)Aging is associated with increased susceptibility to a variety of diseases and diminished capacity fortissue repair. Although many factors are likely to be involved, one proposed explanation for the lesscomplete recovery from injury or disease that is often observed in aged individuals is impairment in thenumber or function of adult (tissue) stem cells. These cells persist throughout life in many tissues, wherethey may proliferate and differentiate in response to physiological cues and pathogenic insults. Wehypothesize that although basal levels of neurogenesis decline with aging, the neurogenesis response toinjury can be restored toward youthful levels for therapeutic purposes. Further, we anticipate that this isthe case for both endogenous neurogenesis and neurogenesis from transplanted neuronal precursorcells (NPCs). Finally, we propose that the mechanisms responsible for the age-related decline in adultneurogenesis can be localized to one of two compartments: the NPCs themselves or the vascular nichein which they arise. We will test these hypotheses with the following specific aims: (1) Determine howaging alters injury-induced neurogenesis in the adult mouse brain; 2) Examine whether age-relateddefects in injury-induced endogenous neurogenesis are imposed by neuronal precursor cells (NPCs)themselves or by their tissue environment; (3) Evaluate the extent to which the age of a recipient mousedetermines the transplantation efficacy of human embryonic stem cell (hESC)-derived NPCs after injury;and (4) Identify candidate mediators of the age-induced decline in injury-induced endogenousneurogenesis by screening for changes in the proteome of endogenous NPCs and DG or SVZendothelial cells.
