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增加和几个功能参数，包括 记忆和运动功能，在晚年的生活中显着改善，在等热量的生酮饮食（KD）喂养的小鼠， 相当于CTL饮食。这些寿命和健康寿命的增加发生在开始服用 KD饮食在中年和没有不同的重量相比，对照组小鼠。拟议的研究将建立 在这项工作中，并采取关键步骤，确定所需的酮症的持续时间和周期， 增加健康寿命。这些研究还将确定， 喂养KD提供了改善晚年生理功能的途径。我们建议测试 关于间歇性KD（iKD）和膳食酮补充剂的老化。这些饮食方法旨在 模仿在热量限制和间歇性禁食时发生的周期性酮症。我们假设饮食 诱导间歇性、短暂酮症的策略（iKD或KS）将延长健康寿命和寿命 而不需要在野生型小鼠和阿尔茨海默病小鼠模型中减轻体重。我们提出了三 具体目的是检验这一假设：1）确定iKD喂养策略是否诱导短暂的 酮症（KD喂养三天，分布在整个星期或一周内连续三天）增加 2）为了确定增加血酮水平膳食补充剂是否 （辛酸和癸酸或酮酯）将增加小鼠的健康寿命和寿命;以及 确定间歇性喂食KD是否改变阿尔茨海默病PSAPP小鼠模型中的疾病进展 疾病这些研究将采取必要的步骤，以确定是否间歇性消费的KD或 增加血酮水平的膳食补充剂提供了增加功能寿命的可行方法。

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.