Effects of Physiologic, Metabolic and Molecular Adaptations to Calorie Restriction on Biomarkers of Longevity (original) (raw)

Calorie restriction (CR), reducing caloric intake without malnutrition, increases lifespan and delays the onset of age-related diseases. Characterizing the underlying mechanisms that mediate the effects of calorie restriction on aging and lifespan will provide insight into the fundamental biology of aging, as well as guide research into the development of therapeutics for age-related diseases. It seems likely that some combination of physiologic, metabolic and molecular adaptations to CR lead to cellular responses that in-turn increase the longevity of the organism. Thus the goal of this thesis work was to combine a kinetic biomarker strategy with classic physiologic and molecular techniques to determine the role of physiologic adaptations, fat metabolism and molecular signaling on biomarkers of CR-induced longevity in mice. The data presented here demonstrate that CR leads to significant reductions in cell proliferation rates in keratinocytes, liver cells, mammary epithelial cells and splenic T-cells. These reductions in cell proliferation rates cannot be accounted for by reductions in food intake, energy expenditure, fat mass or body weight. In addition, the CR-induced reduction in cell proliferation is not dependent on Sirt1 expression, nor can it be mimicked by resveratrol treatment. However, reductions in cell proliferation rates were associated with a CRinduced increase in whole body fatty acid oxidation and have a strong negative correlation with circulating IGF-1 levels. Taken together these results suggest that increased reliance on fatty acid oxidation and reductions in IGF-1 signaling may be metabolic pathways that mediate the effects of CR on aging and longevity. These results also point to molecular mediators that can translate changes in substrate utilization to regulation of growth factor signaling as potential regulatory nodes necessary for the CR-induced effects on cell proliferation and longevity. I would like to acknowledge the help of mentors, colleagues, family and friends, for without their support this work would not be possible. My mentor throughout my PhD work, Marc Hellerstein, has been instrumental in guiding this research and making me a better scientist. His approach to conducting research will influence the rest of my career. My committee members, George Brooks and Andreas Stahl have challenged, guided and helped me excel. In addition, Sharon Fleming, Wally Wang and Hei Suk Sul have provided outstanding guidance. Nearly all of the ideas and studies presented here were a direct result of discussions and experiments conducted with Cyrus Khambatta and Airlia Thompson. These two colleagues are excellent researchers and I am truly grateful for their contributions. In addition, Max Ruby and DJ Rhook have been critical in helping me develop as a scientist. The work presented here would not have been possible without the amazing technical support