? Calorie Restriction (CR) is the most potent, robust, and reproducible known means of extending longevity and decreasing morbidity in lab rodents. Despite 70 years of research, the relevance of this observation for humans remains unknown. Relevance is supported by the established link between obesity and morbidity in humans. Potential linkages are being directly addressed by the NIH-sponsored CALERIE (comprehensive assessment of long-term effects of reducing intake of energy) study. This study will enroll approximately 250 individuals and collect blood samples at 6 time points over 24 months. Our proposed ancillary study has two goals: (A) to support CALERIE by characterizing the plasma metabolome and proteome in these samples; the initial foci being to determine if pre-existing metabolomic profiles, and proteomic profiles being developed in NIH funded studies, enable us to follow CR in people from three geographically distinct sites (thus linking human studies to the rodent literature) and to identify metabolites and pathways of interest, and; (B) to provide data grounding and linking the PI's ongoing studies of the use of metabolomic and proteomic profiles from CR rats to predict future disease risk for type II diabetes and breast cancer with direct data on human caloric intake. Multivariate pattern recognition analysis based on a 93 metabolite profile can distinguish ad libitum fed (AL) and CR rats (100% accuracy in training sets, mean >90% in test sets), and has enabled construction of accurate models of intermediate intakes (r2=0.88) for individual rats. Analytical work has adapted this profile for human plasma. Initial sera proteome profiles also distinguish diet with 100% accuracy.
The AIMs are: (1) To determine temporal shifts that occur in the proteome and metabolome at the levels of compounds, pathways, and profiles. Then to use these data to (a) determine quantitative fit to a CR profile pre-, during, and, if possible, post- intervention, and; (b) quantitatively assess movement along a mathematical continuum related to progressive CR in rats. (2) To provide an electronic archive of the metabolomic and proteomic constituents of the blood of participants that could be repeatedly mined for future testing of new hypotheses; (3) To develop mathematical models sensitive to short and long-term low calorie diets in humans to be used in complement with models of disease prediction now being generated in the PIs lab, and; (4) To examine profile changes across the three CALERIE sites to compare and contrast observed changes. ? ? ?
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