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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.

项目总结