Aging in mammals is associated with a decline in the function and regenerative capacity of tissue specific stem cells. In the adult central nervous the age-related decline of these functional stem/progenitor cells (NSC), and subsequently neurogenesis, is correlated with impairments in olfaction and cognitive functions such as learning and memory. Interestingly, changes to the systemic milieu of an organism, such as those induced through increased exercise and dietary restriction, have been shown to partially mitigate this cellular decline, as well as enhance learning and memory. Recent pioneering work has examined intrinsic molecular mechanisms that underlie NSC aging at the cellular level, however a gap still exists in elucidating how age-dependent NSC function is impaired by changes in the systemic molecular environment during aging. The purpose of this proposal is therefore to begin to elucidate how systemic changes in an aging organism alters the functionality of NSC in the adult brain. Specifically, my hypothesis is that age-dependent changes in the systemic molecular environment regulate the maintenance and potential rejuvenation of adult NSC in the aging brain. I will address this hypothesis in three aims: 1. To identify a systemic molecular profile of soluble signaling proteins that correlate with age-dependent decline in NSC maintenance and neural regeneration, 2. To determine how molecular changes in the young and old systemic environments affect age-dependent NSC function in vivo, and 3. To determine how individual changes in the aging molecular profile alter NSC function in vitro. These studies will ultimately provide insight into mechanisms by which the aging process impairs NSC function and may identify novel therapeutic targets for combating impaired neural repair. Stem cells have been the focus of numerous scientific endeavors due to their potential for mediating enhanced tissue repair, regeneration from degenerative diseases, and the amelioration of organ dysfunction due to normal aging. The possibility of harnessing stem cells for therapeutics to combat age-related regenerative limitations raises the question as to how the aging process modulates tissue specific stem cell activity, as well as their inability to maintain both the structure and function of organs within an aging organism. In this context these experiments will provide insight into the effect of aging on NSC function in the brain which is of particular interest due to the associated onset of cognitive impairments and lack of neural repair in response to neurodegenerative diseases such as Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F05-K (20))
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Wise, Bradley C
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Stanford University
Schools of Medicine
United States
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Middeldorp, Jinte; Lehallier, Benoit; Villeda, Saul A et al. (2016) Preclinical Assessment of Young Blood Plasma for Alzheimer Disease. JAMA Neurol 73:1325-1333
Villeda, Saul A; Plambeck, Kristopher E; Middeldorp, Jinte et al. (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20:659-63
Villeda, Saul A; Luo, Jian; Mosher, Kira I et al. (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90-4