Although neural stem cells give rise to new neurons in several regions of the adult mammalian brain, rates of neurogenesis do not remain constant. Aging leads to decreased neuron production, while voluntary exercise and high-fat diet have been shown to increase rates of adult neurogenesis. We propose changes in availability of metabolic fuels as a common mechanism underlying these phenomena. Using a flow culture chamber fitted to measure multiple real-time respiratory endpoints, we have shown that both young and aged neural stem cells have extraordinarily high rates of oxidative metabolism and do not require glucose to sustain oxygen consumption. These results suggest that neural stem cells are dependent upon some novel endogenous fuel to maintain high levels of aerobic respiration necessary for cellular division. We hypothesize that adult neural stem cells are dependent upon metabolism of fatty acids or ketone bodies for metabolic and mitotic activity. During development, the brain is dependent upon polyunsaturated fatty acids and ketone bodies derived from mothers'milk;metabolic dependence upon these fuels may be a conserved energetic profile in neural stem cells across the lifespan, by which B-oxidation provides large quantities of ATP necessary for cellular division. We also hypothesize that high metabolic demand met by fewer mitochondria in aged neural stem cells leads to increased levels of reactive oxygen species and a higher occurrence of mitochondrial mutations. We propose identifying the fuel resources of neural stem cells, determining the metabolic costs of cellular division, and investigating whether fuel availability affects rates of neurogenesis in vivo. Manipulating the fuels available to neural stem cells in vitro and in vivo may uncover a novel mechanism by which organismal behavior, energy consumption, and cellular activity are coupled in the adult mammalian brain. We hope to impact public health by identifying mechanisms underlying behavior-induced changes in cellular activity, especially in cells capable of regeneration within the adult and aging brain.

Public Health Relevance

A characterization of normal aging on a molecular, cellular and organismal level will be necessary before we can fully understand the pathological aspects of age-related diseases, such as cancer or neurodegeneration. We hope to impact public health by identifying mechanisms underlying behavior-induced changes in cellular activity, especially in cells capable of regeneration within the adult and aging brain. Studying the links between metabolism and neural stem cell activity will be useful both in characterizing the cellular mechanisms of aging and in potentially treating age-related cell loss in the central nervous system in a safe manner.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MDCN-N (02))
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Wise, Bradley C
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University of Washington
Schools of Medicine
United States
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Stoll, Elizabeth A; Makin, Rebecca; Sweet, Ian R et al. (2015) Neural Stem Cells in the Adult Subventricular Zone Oxidize Fatty Acids to Produce Energy and Support Neurogenic Activity. Stem Cells 33:2306-19
Mikheev, Andrei M; Ramakrishna, Rohan; Stoll, Elizabeth A et al. (2012) Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy. Aging Cell 11:1027-35
Stoll, Elizabeth A; Habibi, Behnum A; Mikheev, Andrei M et al. (2011) Increased re-entry into cell cycle mitigates age-related neurogenic decline in the murine subventricular zone. Stem Cells 29:2005-17
Stoll, Elizabeth A; Cheung, Willy; Mikheev, Andrei M et al. (2011) Aging neural progenitor cells have decreased mitochondrial content and lower oxidative metabolism. J Biol Chem 286:38592-601