Role of Clock-Modulating Small Molecules Against Aging

描述（申请人提供）：随着美国人均寿命的不断延长和人口老龄化，如何实现健康老龄化和延长健康寿命是一个紧迫的具有深远社会影响的生物医学问题。控制我们健康的关键生物机制是生物钟，这是一种内在的计时装置，它对环境变化做出反应，并在24小时周期内协调身体功能。越来越多的证据表明，衰老与昼夜节律障碍之间存在很强的相关性，特别是昼夜节律的衰减，如睡眠碎片化、体温和循环激素周期的幅度降低。我们最近通过高通量筛选确定了一组独特的时钟增强小分子，现在被称为CEMs。为了研究时钟衰减在衰老中的潜在因果作用，我们将解决这一假设

DESCRIPTION (provided by applicant): With the rising life expectancy and elderly population in the US, how to achieve healthy aging and extend health span is a pressing biomedical question with profound social ramifications. A pivotal biological mechanism governing our well-being is the circadian clock, the intrinsic timekeeping device that responds to environmental changes and coordinates bodily functions throughout the 24-h cycles. Accumulating evidence has demonstrated a strong correlation between aging and circadian dysfunctions, particularly attenuation of circadian rhythms such as sleep fragmentation and reduced amplitude of body temperature and circulating hormone cycles. We recently identified a unique group of Clock-Enhancing small Molecules, now dubbed as CEMs, via high-throughput screening. To investigate the potential causal role of clock attenuation in aging, we will address the hypothesis that CEMs can improve aged clocks and age-related metabolic decline. We focus on energy metabolism because it is closely regulated by the clock and aging is associated with significant decline in energy utilization. Three Specific Aims are proposed. Specific Aim 1: Determine the clock mechanism of CEMs in aged mice. Using aged PER2::luc reporter mice, we will determine whether CEMs can enhance the bioluminescence rhythm at tissue and single-cell levels. To understand the molecular mechanism, we will systematically characterize the core clock loops in aged tissues, and dissect transcriptional and posttranscriptional mechanisms underlying CEM-mediated enhancement of aged clocks. Specific Aim 2: Delineate the role of CEMs in age-related metabolic decline. We will determine whether CEMs can enhance energy metabolism in naturally aged mice by molecular and physiological approaches. To define the molecular mechanism of CEMs in energy homeostasis of aged mice, we will screen candidate metabolic regulators for altered expression or activity in response to CEM treatment, and investigate the metabolic regulatory mechanisms by CEMs in aged mice. Specific Aim 3: Identify the cellular networks and direct targets of CEMs. To identify both chronic and acute cellular responses to CEMs in aged mice, we will conduct RNA-seq transcriptome profiling using samples from aged mice treated with CEMs for varying periods. To identify direct targets, we will carry out chemoproteomic studies involving affinity pull-down with biotinylated CEM derivatives. Anti-aging roles of specific cellular pathways and proteins from these studies will be further investigated by pharmacological and genetic approaches. Successful completion of these Aims will address the critical question regarding a causal role of clock attenuation during aging and reveal an exciting efficacy of CEMs in prolonging health span.