Fatty acid and ketone metabolism in the healthy elderly

本提案专门涉及健康人类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-有着重大影响，这两个方面在衰老过程中都变得更加重要。大脑占成年人体休息时能量需求的近1/4，并且当葡萄糖长时间不可用时，大脑是酮的主要消耗者。酮的产生取决于脂肪酸氧化。因此，如果随着人类年龄的增长，能量代谢发生“强制性”（生理性）变化，我们预计脂肪酸代谢和酮合成将受到影响。我们的目标是更清楚地了解健康老年人脂肪酸和酮代谢的生理学，以便为制定更有效的策略提供更好的基础，这些策略旨在保持整个成年期的最佳健康和生活质量。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-羟基丁酸酯以及膳食补充剂或特定药物进行代谢测试，以安全地探测脂肪酸氧化和酮的产生。尽管并非详尽无遗，但我们的代谢测试方案在我们的实验室中已经足够详细和完善，使我们相信我们可以识别真正与衰老生理学相关的脂肪酸或酮代谢变化，即它们发生在健康个体中，而不是由于伴随疾病。基于我们初步研究的功效分析表明，10-12例受试者/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年轻人和中年人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.