Project 1 - Selective amino-acid supplementation to reverse age-induced bone loss

This is a competitive renewal of our currently funded project that focused on the impact of dietary amino acids on bone marrow mesenchymal stem cell (BMSC) function. Our data demonstrates that amino acids have varying anabolic or catabolic effects. There are 20 common dietary amino acids and our data demonstrates that the aromatic amino acids have the most potent anabolic effects, particularly in the aging mouse model. Aging (24-month-old) C57BL/6 mice fed a low protein diet lose bone but this loss is prevented by dietary supplementation of aromatic amino acids. Our central hypothesis is that AAs are not just fuel, broken down to provide ATP for cell function, but rather that AAs normally function as ?nutritional hormones? binding to extracellular receptors and activating cell signaling pathways. Our data are consistent with the aging process resulting in the loss of the ability of BMSCs to ?sense? these normal anabolic signals from nutrients through epigenetic mechanisms. Further aging is associated with the accumulation of toxic breakdown products of these metabolites that interfere with their normal anabolic actions. We propose to characterize these nutrient related changes so as to develop effective countermeasures. Therefore, the specific aims of the proposal are: (1) Test the hypothesis that age-induced epigenetic changes in stem cells resulting in impaired function can be reversed by dietary interventions; and (2) Test the hypothesis that age-induced epigenetic changes in stem cells resulting in impaired function can be reproduced by dietary interventions. This project also will explore synergize with the other projects included in this application looking at effects of these amino acids and metabolites in aging muscle (Project 2), inflammatory cytokines (Project 3) and histone deacetylation (Project 4).