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

项目摘要 随着世界人口老龄化，改善老年人的健康和福祉已成为一种社会和 经济上势在必行。生物钟功能减退处于衰老、代谢障碍的十字路口 和慢性病。限时喂养(TRF)是一种新的饮食干预措施，建议每天 卡路里摄入量在时间上受到限制，与卡路里含量无关。TRF可以保持时钟振荡 并能预防和逆转喂食高脂饮食的幼鼠的代谢性疾病。这 该提案将广泛的健康和认知评估与复杂的组织相结合- 对TRF和热量限制(CR)下的小鼠进行特定的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，促进健康衰老。目标1侧重于 TRF与自由喂养(ALF)和CR对健康的影响比较。用西式饮食饲养的中年小鼠 将被放置在ALF或TRF或CR上。定期评估范围广泛的健康参数、行为和 认知功能和最长寿命将检验TRF可以推迟饮食开始的假设--以及 与年龄相关的衰退和延长寿命。目的2重点研究不同饮食干预对健康的影响。 生物钟的功能。在同一动物队列中，定期评估动物的生理输出 昼夜转录组的昼夜生物钟与组织特定基因组范围的特征相关联 测试TRF可以在整个生命周期中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， 认知和昼夜节律下降。总之，这里提出的综合研究将导致更多的 食物摄入时间对基因昼夜节律性影响的基本认识 转录和功能，以及这如何影响健康和长寿。这样的发现很重要，需要检验 并开发基于昼夜节律的新疗法，以延长健康和寿命。

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.