Mechanisms by which time-restricted feeding (TRF) delays the onset of age-related declines in health, cognition, and circadian rhythms

项目摘要 随着世界人口的老龄化，改善老年人的健康和福祉已成为一个社会和 经济的必要性。生物钟功能下降是在衰老的十字路口，代谢障碍 和慢性疾病。限时喂养（TRF）是一种新的饮食干预措施， 热量摄入应在时间上受到限制，而不受热量含量的影响。TRF可以保持时钟振荡 代谢器官，并可以预防和逆转高脂肪饮食喂养的年轻小鼠的代谢疾病。这 建议结合了广泛的健康和认知评估整个生命周期与复杂的组织- 对TRF和热量限制（CR）下的小鼠进行特异性全基因组转录组分析，以了解 饮食干预可以支持生物钟功能，促进健康老龄化。目标1侧重于 TRF与自由采食（ALF）和CR相比对健康的影响。以西方饮食饲养的中年小鼠 将被置于ALF或TRF或CR。定期评估广泛的健康参数，行为和 认知功能和最长寿命将检验TRF可以延迟饮食开始的假设， 与年龄相关的衰退和寿命延长。目标2着重于不同饮食干预对 生物钟的功能在同一动物队列中，定期评估 昼夜节律钟与昼夜转录组的组织特异性全基因组特征相结合， 测试TRF可以在整个生命周期内维持生物钟功能的假设。这些研究将提供一个 深入描述TRF和CR等饮食干预措施对年龄相关健康的影响， 认知和生理节奏下降。总之，这里提出的综合研究将导致一个更 基本了解食物消费的时间如何影响基因的昼夜节律性 转录和功能，以及这如何影响健康和长寿。这些发现对于检验 并开发新的基于昼夜节律的疗法来延长健康和寿命。

Project Summary As the world's population ages, improving the health and well being of elderly adults has become a social and economic imperative. Decreased function of the circadian clock is at the crossroad of aging, dysmetabolism and chronic diseases. Time-restricted feeding (TRF) is a new dietary intervention that recommends daily caloric intake to be limited in time independently of caloric content. TRF can preserve clock oscillations in metabolic organs and can prevent and reverse metabolic disease in young mice fed a high fat diet. This proposal combines extensive health and cognitive assessments throughout lifespan with sophisticated tissue- specific genome-wide transcriptome analysis of mice under TRF and caloric restriction (CR) to understand how dietary interventions can support circadian clock function and promote healthy aging. Aim 1 focuses on the health effects of TRF compared to ad libitum feeding (ALF) and CR. Middle-aged mice raised on a western-diet will be placed on ALF or TRF or CR. Periodic assessments of wide-ranging health parameters, behavioral and cognitive functions and maximum lifespan will test the hypothesis that TRF can delay the onset of diet- and age-related decline and increase longevity. Aim 2 focuses on the effect of the different dietary interventions on the function of the circadian clock. In the same animal cohort, periodic assessments of physiological outputs of the circadian clock coupled to tissue-specific genome-wide characterization of the diurnal transcriptome will test the hypothesis that TRF can sustain circadian clock function across lifespan. These studies will provide an in depth characterization of the effects of dietary interventions such as TRF and CR on age-related health, cognitive and circadian rhythms decline. Together, the integrative study proposed here will lead to a more fundamental understanding of how the timing of food consumption impacts circadian rhythmicity in gene transcription and function and how this affects healthspan and longevity. Such findings are important to test and develop new circadian-based therapies to extend health and lifespan.