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

这是我们目前资助的项目的竞争性更新，该项目专注于饮食氨基酸的影响 对骨髓间充质干细胞功能的影响。我们的数据表明，氨基酸具有 不同的合成代谢或分解代谢作用。有20种常见的饮食氨基酸，我们的数据表明 芳香氨基酸具有最强的合成代谢作用，特别是在衰老的小鼠模型中。 老年(24个月龄)C57BL/6小鼠喂食低蛋白饲料后骨质丢失，但这种丢失可以通过饮食来防止 补充芳香氨基酸。我们的中心假设是，氨基酸不仅仅是燃料，分解成 为细胞功能提供ATP，而不是AAs通常作为结合到 胞外受体和激活的细胞信号通路。我们的数据与老化过程一致 导致骨髓间充质干细胞失去通过营养物质“感知”这些正常合成代谢信号的能力 表观遗传机制。进一步的衰老与有毒分解产物的积累有关 这些代谢物会干扰它们正常的合成代谢作用。我们建议将这些营养物质描述为 以期制定有效的应对措施。因此，这项建议的具体目标是： (1)测试年龄诱导的干细胞表观遗传学变化可能导致功能受损的假设 通过饮食干预逆转；以及(2)检验年龄诱导茎表观遗传变化的假设 导致功能受损的细胞可以通过饮食干预进行繁殖。该项目还将探索 与本申请中包含的其他项目协同研究这些氨基酸和 衰老肌肉中的代谢物(项目2)、炎性细胞因子(项目3)和组蛋白去乙酰化(项目3) 4)。

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).