Optimizing ketogenic diet strategies to increase health span and longevity

项目摘要-项目4 我们第一次证明了寿命的延长和几个功能参数，包括 等卡路里生酮饮食(KD)可显著改善小鼠的记忆和运动功能 相当于CTL饮食。这些寿命和健康寿命的增加发生在小鼠身上 KD饮食在中年，体重与对照组无差异。拟议的研究将建立 并采取关键步骤，以确定所需的酮病的持续时间和周期 增加健康寿命。这些研究还将确定限制较少的饮食策略是否比连续 饲喂KD为改善晚年的生理功能提供了一条途径。我们建议测试一下这种影响 关于间歇性KDS(IKD)和膳食酮补充剂的老化。这些饮食方法旨在 模仿卡路里限制和间歇性禁食时出现的周期性酮症。我们假设饮食 导致间歇性、短暂性酮症的策略(IKD或KS)将增加健康寿命和寿命 不需要在野生型小鼠和阿尔茨海默病小鼠模型中减肥。我们提出三个建议 特定的目的是检验这一假设：1)确定如果IKD的喂养策略导致短暂的 酮病(KD在一周内连续三天喂食或连续三天喂食)增加 小鼠的健康寿命和寿命；2)确定膳食补充剂是否会增加血酮水平 (辛酸和辛酸或酮酯)将延长小鼠的健康寿命和寿命；以及3) 确定间歇饲喂KD是否改变阿尔茨海默病PSAPP小鼠模型的疾病进展 疾病。这些研究将采取必要的步骤，以确定间歇性摄入KD或 增加血酮水平的膳食补充剂为延长功能寿命提供了一种可行的方法。

Project Summary – Project 4 We demonstrated for the first time that life span is increased and several functional parameters, including memory and motor function, are significantly improved in late life in mice fed a ketogenic diet (KD) in isocaloric amounts to a CTL diet. These increases in longevity and healthspan occurred in mice that were started on the KD diet in middle age and did not differ in weight compared to the control mice. The proposed studies will build on this work and take a critical step toward determining the duration and periodicity of ketosis required to increase healthspan. The studies will also determine if less restrictive dietary strategies than continuous feeding of a KD provide a route to improve physiological function in late life. We propose to test the influence on aging of intermittent KDs (iKD) and dietary ketone supplements.These dietary approaches are intended to mimic the periodic ketosis that occurs with calorie restriction and intermittent fasting. We hypothesize that diet strategies (iKD or KS) which induce intermittent, brief periods of ketosis will increase health span and longevity without requiring weight loss in wild-type mice and a mouse model of Alzheimer's disease. We propose three specific aims to test the hypothesis: 1) To determine if iKD feeding strategies that induce brief periods of ketosis (KD fed three days spread throughout the week or three consecutive days during the week) increase health span and longevity in mice; 2) To determine if dietary supplements that increase blood ketone levels (caprylic and capric acids or a ketone ester) will increase health span and longevity in mice; and 3) To determine if intermittent feeding of a KD alters disease progression in the PSAPP mouse model of Alzheimer's disease. These studies will take a necessary step toward determining if intermittent consumption of a KD or dietary supplements that increase blood ketone levels offer a viable approach to increase functional life span.