Mechanisms of Lifespan Modulation by Diet

饮食调节寿命的机制

• 批准号: 8335836
• 负责人: Sige Zou
• 金额: $ 55.72万
• 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/8335836
• 关键词: Accounting; Address; Age; Aging; Anastrepha ludens; Animal Model; Bees; Behavior; Behavioral; Biological Process; Botanicals; Cluster Analysis; Computers; Cranberries; Custom; Deposition; Development; Diet; Dimensions; Disease; Drosophila genus; Eating; Effectiveness; Energy Intake; Engineering; Environmental Risk Factor; Excretory function; Feces; Feeding Methods; Female; Flying body movement; Food; Future; Gene Mutation; Genetic; Geographic Locations; Gerontology; Goals; Greece; Health; Health Benefit; Honey; Human; Individual; Informatics; International; Intervention; Invertebrates; Laboratories; Light; Location; Longevity; Malnutrition; Measurement; Measures; Methods; Mexico; Modeling; Molecular; Monitor; Movement; Musca domestica; National Institute on Aging; Nutraceutical; Nutrient; Oregano spice; Organism; Oxidative Stress; Pathway interactions; Pattern; Pharmacologic Substance; Phytochemical; Population; Publishing; Radioactive Tracers; Records; Reproduction; Research; Resolution; Rest; Source; Supplementation; System; Technology; Time; United States; Vision; Walking; Work; Yeasts; age related; base; dietary restriction; dosage; drinking; egg; feeding; fly; functional genomics; interdisciplinary collaboration; male; middle age; non-genetic; preference; response; software development; tool

Dietary nutrients are among the most potent environmental factors involved in modulating lifespan. Dietary restriction (DR) without malnutrition is well known to increase lifespan and promote health span in divergent species. Our understandings of molecular mechanisms of DR come primarily from studies of genetically amenable systems, including yeast, worms, and flies, where DR has been imposed by either diluting the food source or by using genetic mutations that reduce feeding efficiency. However, a major drawback of these approaches is that it remains substantially uncertain in determining the exact caloric intake of individual organisms under the DR paradigms. It is, therefore, critical to measure food intake in dietary studies in invertebrate models. Further, accurate measurement of food intake is essential to assess the dosage effect of any aging intervention using pharmaceutical and nutraceutical compounds. Several methods have been developed to measure food intake in flies. These methods, however, overlook the amount of the food excreted out of the flies as feces or deposited in eggs. We have developed a feeding method using a radioactive tracer to account for all the ingested food. We have found that most of the ingested food is retained in the fly bodies and 8% is excreted out of the flies as feces and eggs. Under a DR condition, flies increase food intake in volume to compensate for the reduction of calorie content in the diet and also slightly increase the excretion. Under an oxidative stress condition, flies reduce both food intake and excretion. In general, males ingest and excrete 3-5 folds less amount of the food than females. This work has been published in Fly (2011). Taken together, our method provides an accurate way to measure food intake and facilitates studying the mechanisms underlying lifespan extension by DR and pharmaceutical or nutraceutical interventions in invertebrates. Characterization of lifetime behavioral changes is essential for understanding aging and aging-related diseases. However, such studies are scarce partly due to the lack of efficient tools. To this end, we have established an international and interdisciplinary collaboration with biologists, physicists and computer engineers from the United States, Mexico and Greece. We have developed a stereo vision system that automatically classifies and records at an extremely fine scale six different behaviors (resting, micro-movement, walking, flying, feeding and drinking) and 3-dimension location of individual Mexican fruit flies (Mexflies) throughout their lives. Using this system, we have determined for the first time lifetime behavioral changes and location preference of Mexflies under different dietary conditions at a high resolution. In addition, we have developed a behavioral informatics method to perform clustering analyses of daily behavioral patterns of flies, which has revealed three distinct young, middle-aged and old behavioral clusters for flies under different diet conditions. This work has been published in PLoS ONE (2011). Future research and development will be directed to further development of the software and hardware of this behavioral system to allow tracking other invertebrate flying species, such as Drosophila, house flies and honey bees. This technology provides research opportunities for using a behavioral informatics approach to understand the complexity of aging in model organisms. Botanical extracts are rich with phytochemicals and have been shown to exert numerous health benefits. Considering diverse dietary customs among human populations in different geographic regions, it is important to assess the effectiveness of an aging intervention using pharmaceutical and nutraceutical compounds in humans under different dietary condition. To this end, we have investigated the interaction between botanicals and DR, and the age-dependent effect of botanicals on lifespan and reproduction. We previously demonstrated that an oregano-cranberry (OC) mixture could promote longevity in the Mexfly. We have now assessed the effect of OC supplementation on lifespan and reproduction of Mexflies under a DR condition. We have also determined the effect of short-term OC supplementation on lifespan and reproduction by implementing the supplementation at three age intervals--young, middle, and old age. Our findings suggest that OC extends lifespan and promotes reproduction partly through DR-independent pathways. Our results also indicate that short-term supplementation has varied effects on longevity and reproduction depending on the period of supplementation. This work has been published in AGE (2011). Future studies will be directed to determine whether the response to OC supplementation in Mexflies is conserved in D. melanogaster and then investigate the underlying molecular mechanisms in Drosophila, a genetically amenable model organism. Together, these studies should shed light on the interaction between non-genetic and genetic factors in promoting longevity and provide guidance for using botanicals as aging interventions in humans. In summary, we have addressed several issues related to dietary modulation of lifespan in this project. We have developed an accurate method to measure food intake in Drosophila. We have also developed a high resolution system to automatically monitor lifetime behavioral changes in the Mexfly. In addition, we have determined the impact of dietary nutrients and implementing periods on the prolongevity effect of a botanical extract in Mexflies. These studies provide a basis to investigate mechanisms underlying lifespan modulation by dietary nutrients and their interactions with genetic and non-genetic factors. Together, this project should advance the objectives of the Laboratory of Experimental Gerontology and the National Institute on Aging, and provide valuable information for understanding human aging and more importantly for developing efficient aging intervention strategies in humans.

膳食营养素是调节寿命的最有效的环境因素之一。众所周知，在不同物种中，无营养的饮食限制（DR）可以延长寿命和促进健康。我们对DR的分子机制的理解主要来自对遗传可调节系统的研究，包括酵母、蠕虫和苍蝇，在这些系统中，DR是通过稀释食物来源或使用降低摄食效率的基因突变造成的。然而，这些方法的一个主要缺点是，在确定DR范式下个体生物的确切热量摄入方面仍然存在很大的不确定性。因此，在无脊椎动物模型的饮食研究中测量食物摄入量是至关重要的。此外，准确测量食物摄入量对于评估使用药物和营养品化合物进行任何衰老干预的剂量效应至关重要。已经开发了几种方法来测量苍蝇的食物摄入量。然而，这些方法忽略了苍蝇作为粪便排出体外或沉积在卵中的食物量。我们开发了一种喂养方法使用放射性示踪剂来解释所有摄入的食物。我们发现，大部分摄入的食物被保留在苍蝇体内，8%的食物以粪便和卵的形式排出体外。在DR条件下，果蝇增加食物摄入量以弥补饮食中卡路里含量的减少，同时也略微增加了粪便。在氧化应激条件下，苍蝇减少食物摄入和排泄。一般来说，雄性的食物摄取量和排泄量比雌性少3-5倍。这项工作已发表在Fly（2011）上。综上所述，我们的方法提供了一种精确的方法来测量食物摄入量，并有助于研究DR和药物或营养品干预对无脊椎动物寿命延长的机制。