Fatty acid and ketone metabolism in the healthy elderly

该提案专门针对人体健康衰老过程中脂肪酸和酮体(酮)代谢的基本方面。作为生理过程背后的引擎，能量代谢对生活质量的两个重要方面--大脑功能和身体疲劳--有重大影响，而这两个方面在衰老过程中显得更加重要。大脑提供了成年人身体休息时所需能量的近1/4，当葡萄糖长期缺乏时，大脑是酮类的主要消耗者。酮的生产依赖于脂肪酸的氧化。因此，如果随着人类年龄的增长，能量代谢发生“强制性”(生理)变化，我们预计脂肪酸新陈代谢和酮的合成将受到影响。我们的目标是对健康老年人的脂肪酸和酮类代谢的生理学有更清晰的了解，以便为制定更有效的策略提供更好的基础，以期在整个成年期间保持最佳的健康和生活质量。我们仔细筛选健康的老年受试者。我们使用稳定同位素标记的脂肪酸和β-羟基丁酸酯的代谢测试，以及膳食补充剂或特定药物来安全地探测脂肪酸氧化和酮的产生。虽然不是详尽的，但我们的代谢测试方案足够详细，并在我们的实验室建立得很好，使我们有信心识别脂肪酸或酮类代谢的变化，这些变化真正与衰老的生理相关，即它们发生在健康的人身上，而不是由于伴随的疾病。基于我们初步研究的力量分析表明，10-12个受试者/年龄组足以进行这些研究。这些研究最终可能会为如何保护中青年的最佳能量代谢提供建议，从而可能保护老年人的大脑功能。

This proposal deals exclusively with fundamental aspects of fatty acid and ketone body (ketone) metabolism during HEALTHY human aging. As the engine behind physiological processes, energy metabolism has a major impact on two important aspects of quality of life - brain function and physical fatigue - both of which assume greater importance during aging. The brain accounts for nearly ¼ of the energy requirements of the adult human body at rest and is a major consumer of ketones whenever glucose is less available for prolonged periods. Ketone production is dependent on fatty acid oxidation. Therefore, if there are 'obligatory' (physiological) changes in energy metabolism as humans age, we expect that fatty acid metabolism and ketone synthesis would be affected. Our goal is to develop a clearer understanding the physiology of fatty acid and ketone metabolism in the healthy elderly so as to provide a better foundation for developing more effective strategies aimed at maintaining optimal health and quality of life throughout adulthood. We carefully screen for HEALTHY elderly subjects. We use metabolic tests with stable isotope-labeled fatty acids and beta-hydroxybutyrate, and dietary supplements or specific pharmaceuticals to safely probe fatty acid oxidation and ketone production. Though not exhaustive, our metabolic test protocols are sufficiently detailed and well established in our lab to give us confidence that we can identify changes in fatty acid or ketone metabolism that are truly related specifically to the physiology of aging, i.e. they occur in healthy individuals and are not due to accompanying disease. Power analysis based on our preliminary studies suggests that 10-12 subjects/age group are sufficient for these studies. These studies may eventually lead to recommendations for how to protect optimal energy metabolism in younger and middle-aged adults, thereby possibly protecting brain function in the elderly.