Calorie restriction and aging

热量限制和衰老

• 批准号: 8552387
• 负责人: Rafael de Cabo
• 金额: $ 25.08万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552387
• 关键词: Adherence; Affect; Age; Aging; Aging-Related Process; Animals; Antioxidants; Attenuated; Binding; Biochemical; Bioenergetics; Biogenesis; Caloric Restriction; Carbohydrates; Carcinogens; Cell Nucleus; Cell Proliferation; Cell Respiration; Cell membrane; Cells; Chemicals; Chronic Disease; Citric Acid Cycle; Cognition; Complex; Conflict (Psychology); Coupled; Curcumin; Cytoplasm; DNA Damage; Data; Development; Diet; Dietary Intervention; Disease; Drug Formulations; Drug Metabolic Detoxication; Electron Transport; Electrons; Energy Intake; Enzymes; Equilibrium; Evaluation; Exposure to; Faculty; Family; Fasting; Fatty Acids; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glutathione S-Transferase; Goals; Growth; Health; Human; Hypothalamic structure; In Vitro; Incidence; Insulin; Insulin-Like Growth Factor I; Intervention; Invertebrates; Investigation; Investments; Laboratories; Laboratory Rat; Laboratory Study; Life; Liver; Longevity; Malignant Neoplasms; Malnutrition; Mammals; Measurable; Membrane Potentials; Mitochondria; Modeling; Molecular; Mus; NAD(P)H dehydrogenase (quinone) 1, human; NF-E2-related factor 2; NQO1 gene; Neurosecretory Systems; Nuclear; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Pathway interactions; Performance; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiological; Phytochemical; Play; Process; Production; Protons; Publishing; Quercetin; Reactive Oxygen Species; Regulation; Reporting; Repression; Research; Respiration; Response Elements; Resveratrol; Role; Scientist; Serum; Severities; Signal Pathway; Signal Transduction; Stress; Structure of nucleus infundibularis hypothalami; System; Tissues; Transplantation; Work; age effect; age related; anti aging; attenuation; biological adaptation to stress; carcinogenesis; cell growth; detection of nutrient; environmental agent; factor A; fatty acid metabolism; functional decline; growth hormone regulating factor; heme oxygenase-1; human Huntingtin protein; in vivo; insulin sensitivity; mimetics; mitochondrial dysfunction; mitochondrial genome; mutant; nuclear receptor coactivator 1; nuclear respiratory factor; nutrition; oxidation; oxidative damage; receptor; research and development; response; theories; transcription factor; tumor

The aims of this project are to assess the effects of aging and caloric restriction (CR) at a cellular and biochemical level of analysis, to identify physiological mechanisms associated with these effects, and to evaluate interventions/molecular pathways that might alter age-related declines in function. Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10-40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and severity of chronic diseases associated with aging such as cancer, and to extend the functional health span of important faculties like cognition. Less understood are the underlying mechanisms through which CR might act to induce such alterations. One theory postulates that CR's beneficial effects are intimately tied to the neuroendocrine response to low energy availability, of which the arcuate nucleus in the hypothalamus plays a pivotal role. CR induces measurable changes on circulating levels of several hormones and growth factors that regulate cell growth and proliferation. Serum obtained from CR animals alters growth, proliferation and stress responses of cells in culture. We have demonstrated that it is possible to investigate certain aspects of CR using this in vitro approach. This approach lends itself to a more rapid investigation of possible mechanisms and, perhaps more importantly to the research, development and rapid evaluation of interventions that would be able to induce or promote a phenotype similar to that seen with CR, essentially a CR mimetic. Below is the description of two of the most prominent lines of work in my laboratory associated with this project. Mitochondrial Biogenesis and Caloric Restriction. CR is hypothesized to decrease mitochondrial electron flow and proton leaks to attenuate damage due to reactive oxygen species (ROS). We have focused our research on a related, but different anti-aging mechanism of CR. Specifically, using both in vivo and in vitro analyses, we reported that CR reduces oxidative stress by stimulating the proliferation of mitochondria through a PGC1a signaling pathway. These mitochondria under CR conditions show less oxygen consumption, reduced membrane potential and generate less ROS than controls but remarkably are able to maintain their critical ATP production. Thus, CR can induce a PGC1a-dependent increase in mitochondria capable of efficient and balanced bioenergetics to reduce oxidative stress and attenuate age-dependent endogenous oxidative damage. In mammals, the regulation of mitochondrial biogenesis is complex, and it is not known whether the effects of CR on mitochondrial biogenesis are tissue-specific. Mitochondrial biogenesis is a highly regulated process that coordinates the activity of the approximately 1000 genes involved in mitochondrial function. This process requires coordination of the nuclear and mitochondrial genomes. Under CR, PGC-1α is expressed and activated, leading to an increase of mitochondrial mass. PGC-1α gene expression has been shown to be maintained with aging in CR models. In addition to PGC-1α there are other master regulators that are expressed under CR conditions like Peroxisome Proliferator Activated Receptor (PPAR) family and liver X receptor, which control fatty acid metabolism. PGC-1α seems to be a crucial factor in activation of cellular respiration. Its physiological importance has been demonstrated since repression of PGC-1α by a mutant form of the huntingtin protein leads to mitochondrial dysfunction whereas its over-expression rescues cells from the deleterious effect of huntingtin. PGC-1α specifically modulates the activity of several transcription factors and co-activators involved in mitochondrial respiration and biogenesis such as Nuclear Respiratory Factor 1 (NRF-1), NRF -2, PPARα, steroid receptor coactivator-1 and mitochondrial transcriptor factor A. NRF1 and NRF2 coordinate the expression of nuclear and mitochondrial genes that encode most of the subunits of mitochondrial complexes. Furthermore, PGC1-α activates the shift of substrate utilization from carbohydrates to fatty acids through co-regulation of PPARα. Although it has been reported that CR enhances mitochondrial performance, the mechanism remains controversial as reports conflict about the extent to which CR changes expression of genes involved in nutrient sensing, mitochondrial biogenesis, and other key mitochondrial enzymes involved in the Krebs cycle, β-oxidation, and electron transport chain activities in humans. Carcinogenesis and Caloric Restriction. Almost a century ago Moreschi and Rous published their separate observations on the impact of caloric restriction (CR) on transplanted and induced tumors. Years later, McCay and colleagues first observed lifespan extension in laboratory rats maintained on a CR diet. Since then, CR has been studied intensively with consistent results showing its beneficial effects on longevity, age-associated diseases, attenuation of functional declines, and carcinogenesis across a variety of species and diet formulations. However, the mechanism(s) underlying the effects of CR protection still remain unknown. Nevertheless, it is safe to say that the three most extensively studied hallmarks of CR are enhanced protection against induced and spontaneous carcinogenesis, reduced insulin/IGF-1 signaling, and increased median and maximum lifespan. Even if CR was shown to benefit human health, confer cancer protection, and increase longevity, it would be extremely difficult to achieve adherence to such a stringent diet that might require a reduction of 20-40% in caloric intake. To this end, considerable investment has been focused on dissecting the pathways that regulate CR benefits that could spur development of pharmacological agents potentially acting as CR mimetics. Several of the currently proposed CR mimetics are phytochemicals (resveratrol, quercetin, and curcumin) that act, at least in part, through the activation of the NF-E2-related factor 2 (Nrf2) pathway. Nrf2 is a transcription factor that binds to the antioxidant response element (ARE) of target genes as an adaptive response to oxidative stress and increases the transcription of a variety of anti-oxidative and carcinogen detoxification enzymes. Stress can result from a variety of causes including fasting, overfeeding, endogenous compounds, exposure to chemicals or environmental agents but generally leads to the production of ROS. As a result of ROS exposure, Nrf2, which is typically bound to Keap1 in the cytoplasm, where it undergoes proteolytic degradation and rapid turnover, is phosphorylated and translocates to the nucleus where it binds to ARE sequences to induce expression of multiple cytoprotective enzymes including NAD(P)H-quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GSTs), and heme oxygenase-1. We have now shown that Nrf2 is responsible for the protection of CR against carcinogenesis. However, the lack of Nrf2 did not attenuate lifespan extension or alter the CR improvement on insulin sensitivity in the Nrf2 KO mice. Similar to our findings with induced carcinogenesis, Van Remmen et al. were the first to show that reduction of an antioxidant enzyme could markedly increase DNA damage and spontaneous cancer incidence without affecting survival and lifespan. However, this study is the first to demonstrate that distinct pathways exert beneficial effects of CR and suggests that many mechanisms are involved in its protection. Recent data from invertebrates suggested that Nrf2 or at least some of its downstream effectors could hold the key to caloric restriction and longevity

该项目的目的是在细胞和生化分析水平上评估衰老和热量限制（CR）的影响，确定与这些影响相关的生理机制，并评估可能改变与年龄相关的功能下降的干预措施/分子途径。实验室研究一致表明，限制热量摄入（CR）的动物寿命延长，总热量摄入减少10-40%，但保持充足的营养。研究进一步表明，CR可以延缓癌症等与衰老相关的慢性疾病的发病和严重程度，并延长认知等重要能力的功能健康期。人们对CR诱导这种改变的潜在机制了解较少。一种理论认为，CR的有益作用与对低能量可用性的神经内分泌反应密切相关，其中下丘脑的弓状核起着关键作用。CR可诱导调节细胞生长和增殖的几种激素和生长因子的循环水平发生可测量的变化。从CR动物身上获得的血清改变了培养细胞的生长、增殖和应激反应。我们已经证明，使用这种体外方法研究CR的某些方面是可能的。这种方法有助于更快速地研究可能的机制，也许更重要的是研究、开发和快速评估干预措施，这些干预措施将能够诱导或促进与CR相似的表型，本质上是CR模拟物。下面是我的实验室与这个项目相关的两个最突出的工作线的描述。