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

限时喂养通过优化线粒体功能来降低癌症风险

基本信息

批准号：
10304821
负责人：
Satchidananda Panda
金额：
$ 76.21万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10304821
关键词：
1 year old Address Adopted Affect Age Age of Onset Aging Animal Feed Animal Model Animals Biological Assay Body Weight Cancer Biology Cancer Model Cardiovascular Diseases Cell physiology Cells Circadian Dysregulation Circadian Rhythms Clinical Clinical Research Clinical Trials Consumption Data Development Diagnosis Distal Eating Effectiveness Elderly Energy Intake Energy Metabolism Epidemiology Fasting Foundations Functional disorder Health Health Benefit Hour Human In Vitro Incidence Individual Intermittent fasting Intervention Intervention Studies Knowledge Lead Length Liver Malignant Neoplasms Measures Metabolic Metabolic Diseases Metabolism Mission Mitochondria Mus National Cancer Institute Neurodegenerative Disorders Normal Cell Nutrient Obese Mice Obesity Outcome Physiological Physiology Plasma Population Prevention strategy Production Protein Secretion Publishing Randomized Regulation Research Research Project Grants Respiration Risk Risk Factors Rodent Sampling Shotguns Solid Structure Testing Therapeutic Therapeutic Intervention Time-restricted feeding Tissues Treatment outcome Wild Type Mouse Woman Xenograft procedure aged aging population anti-cancer base cancer cell cancer prevention cancer risk cancer therapy circadian pacemaker combinatorial comparative control trial effective intervention effectiveness evaluation excessive weight gain experimental study feeding food consumption improved in vivo innovation insight juvenile animal lifestyle intervention male malignant breast neoplasm men metabolomics mitochondrial dysfunction neoplastic cell nutrient metabolism obesity prevention obesogenic pre-clinical prevent protein metabolite response sex skills treatment response tumor tumor growth tumor progression tumorigenic western diet

项目摘要

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.

项目摘要本申请是对RFA-CA-004 "美国国家癌症研究所（NCI）的研究解答"的回应。激发性问题（R01临床试验可选），"将解决" PQ2：间歇性禁食如何影响癌症发病率、治疗反应或结果？" 肥胖和年龄是癌症发展的两个主要危险因素。因此，预防或延迟过度体重增加和/或与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。一个这样干预措施是时间限制饮食（TRE），这是一种实用的间歇性禁食形式，限制在8 - 12小时的一致窗口内，而不明显减少总热量摄入。在年轻男性在小鼠中，限时喂养（TRF）通过预防肥胖和代谢疾病来降低癌症风险。扶轮基金会已也显示出减少肥胖小鼠中乳腺癌异种移植物的进展。在人类中，短期临床 TRE的研究已经揭示了预测癌症风险降低的代谢改善，有证据表明，延长夜间禁食可以降低患癌症的风险，而与身体的变化无关。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，TRF在老年动物中的作用以及在致肥胖的西方饮食的背景下，目前尚未建立，而扶轮基金会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来填补这些知识上的关键空白。肥胖和衰老都与线粒体功能障碍和促肿瘤线粒体代谢产物的产生。建议的实验测试假设TRF通过细胞自主和系统机制优化线粒体功能，从而降低癌症风险。在目标1中，TRF对线粒体功能和相关生理学的影响将在老年小鼠中建立。营养代谢，能量消耗和线粒体功能将在这些小鼠中进行评估。在目标2中，代谢组学和线粒体呼吸的创新组合将使用测定来测试TRF对正常和癌细胞中线粒体功能的影响（评估TRF对正常细胞和癌细胞中线粒体功能的影响）。小区自主和非小区自主机制）。TRF对肿瘤发生率的影响将是通过使肿瘤易感小鼠经受TRF来评估。在目标3中，从最近得出结论的人类中收集的血浆 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。拟议的TRE在人类和小鼠中的比较分析将提供关键的机制洞察如何间歇性禁食的一种形式可以帮助预防癌症发作并改善治疗效果。