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

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

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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.

项目摘要该应用于对RFA-CA-004的响应，“国家癌症研究所（NCI）的研究答案挑衅性问题（R01临床试验可选），”将解决“ PQ2：间歇性禁食如何影响癌症事件，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。那是治疗干预措施防止或延迟体重增加和/或与年龄相关的身体功能障碍的发展减少日益肥胖和全球人口越来越多的癌症风险的巨大希望。一个这样的干预是时间限制的饮食（TRE），这是一种务实的间歇性禁食形式被限制在8-12小时的一致窗口中，而不会明确减少总热量摄入量。在年轻男性小鼠，时间限制的喂养（TRF）通过预防肥胖和代谢疾病来降低癌症风险。 TRF有还显示可降低肥胖小鼠的乳腺癌异种移植进展。在人类中，短期临床 TRE的研究揭示了代谢改善，可预测癌症风险降低，流行病学有证据表明，长时间的夜间禁食可以降低癌症的风险，与身体的变化无关重量。这有望初步证据表明，TRE可能是减少的有效干预措施癌症风险。但是，TRF在老年动物和肥胖的西方饮食中的影响具有尚未建立，TRF降低癌症风险的机制尚不清楚。申请基于承诺初步数据并利用研究团队的完成技能解决知识中的这些关键差距。肥胖和衰老都与线粒体有关功能障碍和促肿瘤的线粒体代谢产物的产生。提出的实验测试 TRF通过细胞自主和全身机制优化线粒体功能的假设，从而降低癌症风险。在AIM 1中，TRF对线粒体功能和相关生理的影响将在老年小鼠中建立。营养代谢，能耗和线粒体功能将是在这些小鼠中进行评估。在AIM 2中，代谢组学和线粒体呼吸的创新组合测定将用于测试TRF对正常和癌细胞中线粒体功能的影响（评估细胞自主和非细胞自治机制）。 TRF对肿瘤发生率的影响将是通过将容易肿瘤的小鼠对TRF进行评估。在AIM 3中，从最近结束的人类收集的等离子体 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。人类和小鼠对TRE的拟议比较分析将提供有关如何如何了解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结果。