Calorie restriction and aging

热量限制和衰老

• 批准号: 10007344
• 负责人: Rafael de Cabo
• 金额: $ 67万
• 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/10007344
• 关键词: 2 year old; Affect; Age of Onset; Aging; Animals; Biochemical; Blood; Blood Glucose; Body Temperature; Body Weight; Body Weight decreased; Caloric Restriction; Cell Proliferation; Cells; Cellular Metabolic Process; Cessation of life; Chronic Disease; Cognition; Complex; Consumption; Coupled; Data; Data Reporting; Diet; Diet Modification; Dietary Intervention; Disease; Energy Intake; Evaluation; Faculty; Fasting; Fathers; Fatty Liver; Female; Food; Gene Expression; Generations; Genetic; Gerontology; Goals; Growth; Growth Factor; Health; Heritability; Histopathology; Hormones; Hour; House mice; Human; Hybrids; Hypothalamic structure; In Vitro; Incidence; Insulin; Intervention; Investigation; Laboratories; Laboratory Study; Laboratory mice; Long-Term Effects; Longevity; Macronutrients Nutrition; Malignant Neoplasms; Malnutrition; Measurable; Measures; Metabolic; Modeling; Molecular; Monkeys; Morbidity - disease rate; Mouse Strains; Mus; Neurosecretory Systems; Outcome; Pathologist; Pathology; Pathway interactions; Phenotype; Physiological; Pilot Projects; Play; Primates; Process; Protocols documentation; Publishing; Regimen; Role; Scientist; Serum; Severities; Structure of nucleus infundibularis hypothalami; Summary Reports; Testing; Time; Tissues; Urine; age effect; age related; behavior measurement; biological adaptation to stress; blood glucose regulation; cell growth; feeding; follow-up; functional decline; healthspan; improved; male; mimetics; mortality; nonhuman primate; novel strategies; nutrition; offspring; phrases; research and development; response; sex; theories

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. 1.- We are investigating the differential response to CR in male and female F1 offspring of DBA/2J and C57BL/6J mice. In a follow up to our published study 19, we wanted to determine if CR would have the same lifespan and healthspan benefits in the F1 offspring as it did with the parental strains of mice, and further investigate the mechanisms underlying these observations. In order to investigate the role of CR in extending lifespan in laboratory mice, the DBA2 strain, which is classically considered unresponsive to CR, and the standard C57BL6 mouse strain were subjected to 20% or 40% CR, and their response compared to ad libitum (AL)-fed mice 19. We found that male and female DBA2 mice were responsive to CR with maximum lifespan extension at 40% CR. In contrast, male and female C57BL6 mice responded very well to 20% CR, but there was no lifespan extension in 40% CR-fed females when compared to AL-fed C57BL6 mice 19. To test whether there was maternal inheritance, we crossed male and female offspring of DBA/2 dams x C57BL/6 fathers (D2B6F1) and C57BL/6 dams x DBA/2 fathers (B6D2F1) and maintained them on AL, 20% or 40% CR and tracked their survival (Figure 10). The study is still ongoing; however, preliminary results indicate that the B6D2F1 mice are unresponsive to CR, which is in contrast to previously published results 13. D2B6F1 mice respond best to 40% CR, with 20% CR having little to no effect in all F1 hybrids. 2.- We are also determining if the two different diets used in the NHP CR studies have the same outcomes in mice, in terms of longevity and health, and to investigate the underlying mechanism. In a novel approach to characterize the role of macronutrients in primates, we are comparing the short- and long-term effects of NIA and WIS NHP diets fed to mice in AL, pair-fed (PF) and CR regimens. This study is currently ongoing and expected to be finished within the next 3-6 months. In order to further understand the differences in survival and health outcomes and investigate the underlying mechanisms between the NIA and WNPRC diets, we established two pilot studies using mice and NHPs fed the NIA or WNPRC diets ad libitum. We found comparable metabolic effects in terms of bodyweight gain and fasting blood glucose over 3-4mo of diet between mice and monkeys, indicating the dietary effects are conserved across species. From these data, a longevity study was initiated with 4mo-old male C57BL/6J mice. Single-housed mice were started on either the WNPRC or NIA diet, provided AL, 30% CR or restricted to a single isocaloric daily allotment (pairfed, PF) of food of the opposite diet at approximately AL levels in order to control for slight differences in caloric content between diets. CR and PF mice were fed a single daily allotment at approximately 2pm every day. Any food remaining the following day was removed, weighed and recorded to yield an accurate measure of daily energy consumption. Physiological, metabolic and behavioral measurements were collected across the study, including weekly body weights and temperatures, insulin and glucose homeostasis, metabolic cage, blood, and urine. A subset of mice was euthanized at 2 years of age and tissues collected for further analysis. A detailed histopathology assessment of the mice is underway by a board-certified veterinary pathologist. This study is ongoing, We assessed various measures of healthspan, including histopathology, and found important differences in the incidence and type of pathologies that mice died with. Notably, CR and PF protocols were able to delay the onset of pathologies in mice, whereas WIS-fed mice had a higher incidence of fatty liver compared to mice on NIA diet. This demonstrates that diet plays a role in the type of pathologies that an animal will develop, but the age of onset of the pathology and subsequent death are determined by the feeding regimen (CR, PF). This study will be published in September 2018 in Cell Metabolism, a quick summary of the reported data is as follows; Adequate nutrition with reduced caloric intake (CR) delays age-related diseases and extends lifespan in most species. However, CR studies in non-human primates (NHP) have produced divergent outcomes, challenging CRs applicability to humans. Here, we mimicked in male mice the diet compositions and feeding paradigms used in the two NHP studies. Both diets were tested with three paradigms: lifelong CR, ad libitum (AL), and meal-feeding (MF). MF mice gorged, which resulted in extended periods of daily fasting. This extended daily fasting caused a significant improvements in morbidity and mortality compared to AL. These results indicate that merely fasting daily for a few hours improves healthspan and lifespan, regardless of dietary composition, caloric intake, or bodyweight. Extended periods of daily fasting may be much more attainable by humans than lifelong diet modifications, caloric reductions, and weight loss. Consequently, this discovery might have a significant impact on and wide applicability to human health.

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，以识别与这些作用相关的生理机制，并评估可能会改变年龄相关的功能下降的干预措施/分子途径。实验室研究始终表明，在卡路里限制（CR）中，动物的寿命延长，其中总热量摄入量减少了10-40％，但否则可以维持足够的营养。 CR进一步证明，可以延迟与癌症等衰老相关的慢性疾病的发作和严重程度，并扩大重要能力等重要能力的功能健康跨度。 CR可能会引起此类改变的基本机制较少了解。一种理论假设CR的有益作用与神经内分泌对低能量可用性的反应密切相关，下丘脑中的弓形核起着关键作用。 CR诱导几种激素的循环水平和调节细胞生长和增殖的生长因子的可测量变化。从CR动物获得的血清会改变培养物中细胞的生长，增殖和应激反应。我们已经证明，可以使用这种体外方法研究CR的某些方面。这种方法使自己对可能的机制进行了更快速的研究，也许更重要的是，对干预措施的研究，开发和快速评估，这些干预措施能够诱导或促进与CR相似的表型，本质上是CR模拟的。 1.-我们正在研究DBA/2J和C57BL/6J小鼠的男性和雌性F1后代对CR的差异反应。在我们发表的研究19的后续过程中，我们想确定CR在F1后代中是否具有与父母菌株相同的寿命和HealthSpan益处，并进一步研究了这些观察结果的机制。 为了研究CR在实验室小鼠中延长寿命中的作用，DBA2菌株在经典上被认为对CR没有反应，并且标准的C57BL6小鼠菌株受到20％或40％的Cr，并且与Ad litbitum（Al）喂养的小鼠相比，它们的反应19。我们发现与crsementive crsensive cressive crensive crension crension crension crension crension crensive crensive crensept crenspe crensens crensept avterspan上的最高超高为40％。 In contrast, male and female C57BL6 mice responded very well to 20% CR, but there was no lifespan extension in 40% CR-fed females when compared to AL-fed C57BL6 mice 19. To test whether there was maternal inheritance, we crossed male and female offspring of DBA/2 dams x C57BL/6 fathers (D2B6F1) and C57BL/6 dams x DBA/2父亲（B6D2F1）并将其维持在Al，20％或40％Cr上，并跟踪其存活率（图10）。该研究仍在进行中；但是，初步结果表明，B6D2F1小鼠对CR没有反应，这与先前发表的结果相反13.D2B6F1小鼠对40％CR的反应最佳，其中20％Cr在所有F1混合动力车中几乎没有影响。 2.-我们还在确定NHP CR研究中使用的两种不同饮食是否在长寿和健康方面都具有相同的结果，并研究了基本机制。在一种表征大量营养素在灵长类动物中的作用的新方法中，我们比较了NIA和WIS NHP饮食在AL中喂给小鼠的短期和长期作用，配对（PF）和CR方案。这项研究目前正在进行中，预计将在未来3-6个月内完成。 为了进一步了解生存和健康结果的差异，并研究了NIA和WNPRC饮食之间的基本机制，我们使用小鼠和NHP进行了两项试验研究，并喂养了NIA或WNPRC饮食。我们发现，在小鼠和猴子之间的3-4mO饮食中，体重增加和禁食的血糖在3-4MO上的空腹血糖方面存在可比的代谢作用，这表明饮食效应在物种之间是保守的。 从这些数据中，使用4MOGER雄性C57BL/6J小鼠进行了长寿研究。单身小鼠的WNPRC或NIA饮食开始使用，提供了30％的Cr或仅限于相反饮食的单一等量平衡的每日分配（配对，Pf，PF），以控制饮食之间热量含量的轻微差异。 CR和PF小鼠每天大约下午2点喂食一次每日分配。剩下的第二天的任何食物都被去除，称重并记录下来，以产生准确的日常能源消耗量。在整个研究中收集了生理，代谢和行为测量，包括每周体重和温度，胰岛素和葡萄糖稳态，代谢笼，血液和尿液。在2岁时对小鼠的一部分被安乐死，并收集了组织以进行进一步分析。董事会认证的兽医病理学家正在进行对小鼠进行详细的组织病理学评估。 这项研究正在进行中，我们评估了包括组织病理在内的健康状况的各种措施，发现小鼠死亡的病理的发病率和类型存在重要差异。值得注意的是，与NIA饮食中的小鼠相比，CR和PF方案能够延迟小鼠的病理发作，而WIS喂养的小鼠的脂肪肝发病率更高。这表明饮食在动物会发育的病理类型中起作用，但是病理的发作年龄和随后的死亡是由喂养方案（CR，PF）确定的。这项研究将于2018年9月发表在细胞代谢中，对报告的数据进行快速摘要如下；通过减少热量摄入量（CR）延迟与年龄有关的疾病，并延长大多数物种的寿命，足够的营养。但是，非人类灵长类动物（NHP）的CR研究产生了不同的结果，挑战了CRS对人类的适用性。在这里，我们模仿了两种NHP研究中使用的饮食组成和喂养范例。两种饮食都用三个范式进行了测试：终生CR，Ad Adbitum（Al）和进餐（MF）。 MF小鼠gored了，这导致了每日禁食的长时间。与AL相比，这种延长的日常禁食导致发病率和死亡率有了显着改善。这些结果表明，每天仅禁食几个小时，就可以改善健康状态和寿命，而不论饮食成分，热量摄入或体重如何。人类的日常禁食时间比终身饮食修改，减少热量和减肥可能更能实现。因此，这一发现可能对人类健康有重大影响和广泛的适用性。