Impact of Time-Restricted Feeding in Reducing Cancer Risk Through Optimizing Mitochondria Function

项目摘要 本申请是对RFA-CA-004《国家癌症研究所(NCI)研究解答》的响应 挑衅性问题(R01临床试验可选)，将解决PQ2：如何间歇性禁食 会影响癌症的发病率、治疗反应或结果吗？ 肥胖和年龄是癌症发展的两个主要风险因素。因此，治疗干预措施 预防或延缓体重过度增加和/或年龄相关的生理功能障碍的发展 在日益肥胖和老龄化的全球人口中降低癌症风险的巨大希望。这样的一个 干预是限时进食(Tre)，这是一种实用的间歇性禁食形式，每天摄入卡路里 限制在8-12小时的一致窗口内，而不明确减少总卡路里摄入量。在年轻男性中 在小鼠中，限时喂养(TRF)通过预防肥胖和代谢性疾病来降低癌症风险。扶轮基金会有 也被证明可以减少肥胖小鼠的乳腺癌异种移植进展。在人类中，短期临床试验 对TRE的研究表明，代谢的改善可以预测癌症风险的降低，以及流行病学 有证据表明，与身体变化无关，延长夜间禁食时间可以降低患癌症的风险 重量。这一有希望的初步证据表明，tre可能是一种有效的干预措施。 癌症风险。然而，在老年动物和西方肥胖饮食的背景下，TRF的影响 尚未建立，TRF降低癌症风险的机制仍不清楚。这 应用程序建立在有希望的初步数据基础上，并利用研究团队的互补技能 以解决这些知识方面的严重差距。肥胖和衰老都与线粒体有关 功能障碍和促肿瘤线粒体代谢物的产生。拟议的实验测试了 假设TRF通过细胞自主和系统机制优化线粒体功能， 从而降低患癌症的风险。在目标1中，TRF对线粒体功能和相关生理的影响将 在老龄小鼠体内建立。营养新陈代谢、能量消耗和线粒体功能 在这些小鼠身上进行了评估。在目标2中，代谢组学和线粒体呼吸的创新组合 试验将用于测试TRF对正常细胞和癌细胞线粒体功能的影响(评估 细胞自主和非细胞自主机制)。TRF对肿瘤发病率的影响将是 通过使易患肿瘤的小鼠接受TRF进行评估。在目标3中，从一个最近结束的人类身上收集的血浆 TRE干预研究将用于测试TrE对人类线粒体功能和癌症风险的影响。 对人类和小鼠的TRE的拟议比较分析将提供关键的机械学洞察，了解如何 一种形式的间歇性禁食可以帮助预防癌症发作和改善治疗结果。

Project Summary This application, in response to RFA-CA-004 “Research Answers to National Cancer Institute's (NCI) Provocative Questions (R01 Clinical Trial Optional),” will address “PQ2: How does intermittent fasting affect cancer incidence, treatment response, or outcome?” Obesity and age are two major risk factors for cancer development. Thus, therapeutic interventions that prevent or delay the development of excessive weight gain and/or age-associated physiological dysfunction hold great promise for reducing cancer risk in the increasingly obese and elderly global population. One such intervention is time-restricted eating (TRE), a pragmatic form of intermittent fasting in which daily caloric intake is constrained to a consistent window of 8–12 hours without explicitly reducing total caloric intake. In young male mice, time-restricted feeding (TRF) reduces cancer risk by preventing obesity and metabolic diseases. TRF has also been shown to reduce breast cancer xenograft progression in obese mice. In humans, short-term clinical studies of TRE have revealed metabolic improvements that predict reduced cancer risk, and epidemiological evidence suggests that prolonged nightly fasting can reduce the risk of cancer, independent of changes in body weight. This promising preliminary evidence suggests that TRE may be an effective intervention for reducing cancer risk. However, the effects of TRF in aged animals and in the context of an obesogenic Western diet have not yet been established, and the mechanisms by which TRF reduces cancer risk remain unknown. This application builds upon promising preliminary data and leverages the complementary skills of the research team to address these critical gaps in knowledge. Both obesity and aging are associated with mitochondrial dysfunction and the production of pro-tumorigenic mitochondrial metabolites. Proposed experiments test the hypothesis that TRF optimizes mitochondria function through both cell-autonomous and systemic mechanisms, thereby reducing cancer risk. In Aim 1, the impact of TRF on mitochondria function and related physiologies will be established in aged mice. Nutrient metabolism, energy consumption, and mitochondria function will be assessed in these mice. In Aim 2, an innovative combination of metabolomics and mitochondria respiration assays will be used to test the impact of TRF on mitochondria function in normal and cancer cells (assessing both cell-autonomous and non-cell-autonomous mechanisms). The effects of TRF on tumor incidence will be assessed by subjecting tumor-prone mice to TRF. In Aim 3, plasma collected from a recently concluded human TRE intervention study will be used to test the effect of TRE on mitochondria function and cancer risk in humans. The proposed comparative analysis of TRE in humans and mice will provide critical mechanistic insight into how one form of intermittent fasting can help prevent cancer onset and improve treatment outcomes.