Mechanisms of Lifespan Modulation by Diet

衰老受遗传和环境因素的调节。膳食营养素已被证明是对健康和寿命有重大影响的最有力的环境因素之一。已经确定许多药物和营养品在模式生物中具有长寿效应。以植物为原料制成的营养保健品含有丰富的植物化学物质，具有多种生物活性，具有多种健康益处，包括抗衰老作用。然而，膳食营养素是否以及如何影响促进健康老龄化的干预措施的长寿效果仍然难以捉摸。这是老龄化领域的一个重要问题，要考虑到不同地理来源的人群之间的不同饮食习惯。包括蠕虫和苍蝇在内的无脊椎动物是研究药物和营养品的长寿效应的理想模式生物，至少部分是由于它们的寿命短和丰富的遗传资源。我们总结了使用无脊椎动物模型的长寿营养品的研究进展，并在Oxidative Medicine and Cellular Longevity（2013）上发表了一篇综述。本研究为进一步研究补充营养药物延缓衰老和提高健康寿命的作用机制提供了有价值的指导。 为了研究营养保健品和常量营养素在寿命调节中的相互作用，我们研究了蔓越莓衍生的营养保健品对寿命的影响，并确定了膳食常量营养素组成对蔓越莓在果蝇中的寿命效应的影响。我们已经发现，蔓越莓可以延长喂食适量糖和蛋白质饮食的果蝇的寿命，并且在喂食高糖低蛋白饮食的果蝇中更显着地延长寿命，但不会延长或缩短喂食低糖高蛋白饮食的果蝇的寿命。我们进一步证明了蔓越莓补充剂诱导的寿命延长与一生生殖输出增加和应激反应基因的更高表达有关。我们还表明，蔓越莓可以提高高脂肪饮食喂养的苍蝇的生存率。这项研究揭示了膳食常量营养素在蔓越莓补充剂的长寿效应中的关键作用，并指出在实施促进健康老龄化的干预措施时考虑饮食组成的重要性。这一系列的工作已被接受发表在老年学生物科学杂志（2013年）。未来的工作将更多地致力于了解蔓越莓补充剂的长寿效应及其在调节寿命中膳食常量营养素之间的相互作用的分子机制。这将为促进健康老龄化提供全面的观点，并有助于改善干预措施。 老龄化研究的一个重要问题是评估健康寿命，因为老龄化研究的基本目标不仅是延长寿命，而且通过保护功能显着改善健康寿命。衰老与许多行为变化有关，例如运动活动的逐渐下降，这是健康寿命的一个参数。许多工具可用于测量模型生物和人类的运动活动。然而，与年龄相关的行为变化仍然知之甚少，主要是由于缺乏能够在任何生物体中以高分辨率记录终身行为变化的工具。我们以前已经开发了一个行为监测系统（BMS），可以记录六种类型的行为在墨西哥果蝇（mexflies）的一生中的精细分辨率。墨西哥蝇已被广泛用于人口和老龄化干预研究。与墨西哥的巴勃罗·列多博士、加州大学戴维斯分校的乔安妮·邱和詹姆斯·凯里博士以及彭宁顿的唐纳德·英格拉姆博士合作，我们利用BMS研究了饮食对与年龄相关的运动活动、睡眠数量和质量变化的影响。我们已经发现，营养均衡饮食下的苍蝇几乎没有与年龄相关的活动曲线变化，而次优饮食的苍蝇在老年时活动幅度和睡眠质量显著降低。这一系列工作已发表在Scientific Reports（2013）上。未来的工作将是使用BMS来评估任何长寿干预措施引起的终身行为变化，以阐明衰老干预措施对健康寿命的影响。我们还将开发一种类似的果蝇BMS，以研究终身行为变化的分子机制。 总之，我们已经确定了饮食常量营养素对含蔓越莓的营养品在果蝇中的长寿效应的影响。我们通过分析不同饮食条件下墨西哥苍蝇的终身行为变化来评估饮食对健康寿命的影响。这些发现为我们未来的研究提供了基础，这些研究旨在了解膳食宏量营养素和营养保健品或药物在调节寿命和健康寿命方面相互作用的分子机制。 这些研究应该为开发有效的干预措施以促进人类健康老龄化提供有价值的信息。该项目应推进转化老年学分支的目标和国家老龄研究所的总体使命。

Aging is modulated by both genetic and environmental factors. Dietary nutrients have been shown to be among the most potent environmental factors that have significant impact on healthspan and lifespan. A number of pharmaceuticals and nutraceuticals have been identified to have prolongevity effects in model organisms. Nutraceuticals made from plants are rich in phytochemicals, which possess diverse bioactivities and exert numerous health benefits, including anti-aging effects. However, whether and how dietary nutrients influence the prolongevity effects of interventions for promoting healthy aging remains elusive. This is an important issue in the aging field to address considering diverse dietary customs among human populations of different geographic origins. Invertebrates including worms and flies are ideal model organisms to investigate the prolongevity effect of pharmaceuticals and nutraceuticals at least partially due to their short lifespan and rich genetic resources. We have summarized the research progress on prolongevity nutraceuticals using invertebrate models and published a review in Oxidative Medicine and Cellular Longevity (2013). This work should provide valuable guidance for future mechanistic studies on the effect of nutraceutical supplementation in delaying aging process and improve healthspan. To investigate the interaction between nutraceuticals and macronutrients in lifespan modulation, we have investigated the effect of cranberry-derived nutraceuticals on lifespan and determined the impact of dietary macronutrient composition on the prolongevity effect of cranberry in Drosophila. We have found that cranberry can extend lifespan of flies fed a diet with modest amount of sugar and protein, and increase lifespan more prominently in flies fed a high sugar-low protein diet, but does not extend or shorten lifespan of flies fed a low sugar-high protein diet. We have further demonstrated that lifespan extension induced by cranberry supplementation is associated with increased lifetime reproductive output and higher expression of stress response genes. We have also shown that cranberry can improve the survival of flies fed a high-fat diet. This study reveals the critical role of dietary macronutrients in the prolongevity effect of cranberry supplementation and points out the importance of take into account diet composition in implementing interventions for promoting healthy aging. This line of the work has been accepted for publication in Journal of Gerontology Biological Sciences (2013). Future work will be directed more to understand the molecular mechanisms underlying the prolongevity effect of cranberry supplementation and its interaction between dietary macronutrients in modulating lifespan. This will provide a comprehensive view of and help improve interventions for promoting healthy aging. An important issue in aging studies is to assess healthspan since a fundamental goal of aging research is to not just increase lifespan but significantly improve healthspan through the preservation of function. Aging is associated with numerous behavioral changes, such as gradual decline of locomotor activity, which is a parameter for healthspan. Many tools are available for measuring locomotor activity in model organisms and humans. However, age-related behavioral changes remain poorly understood mainly due to the lack of tools capable of recording lifelong behavioral changes in a high resolution in any organism. We have previously developed a behavior monitor system (BMS) that can record six types of behaviors in a fine resolution over the lifetime of Mexican fruit flies (mexflies). Mexflies have been used extensively in demographic and aging intervention studies. In collaboration with Drs. Pablo Liedo at Mexico, Joanne Chiu and James Carey at UC Davis and Donald Ingram at Pennington, we have taken advantage of the BMS to investigate the impact of diet on age-related changes in locomotor activity, sleep quantity and quality using the high resolution lifelong behavior recording data in mexflies. We have found that flies under a nutritionally balanced diet have little age-related change in activity profile, while flies on suboptimal diet have a significant decrease of activity in amplitude and lower sleep quality at old age. This line of work has been published in Scientific Reports (2013). Future work will be to use the BMS to evaluate lifelong behavioral changes induced by any prolongevity interventions to shed light on the impact of aging interventions on healthspan. We will also develop a similar BMS for Drosophila in order to investigating molecular mechanisms underlying the lifelong behavioral changes. In summary, we have determined the impact of dietary macronutrients on the prolongevity effect of a cranberry-containing nutraceutical in Drosophila. We have assessed the impact of diet on healthspan by analyzing lifelong behavioral changes in mexflies under different dietary conditions. These findings provide the foundation for our future research directed towards understanding the molecular mechanisms underlying the interplay between dietary macronutrients and nutraceuticals or pharmaceuticals in modulating lifespan and healthspan. These studies should provide valuable information for developing efficient interventions for promoting healthy aging in humans. This project should advance the objectives of the Translational Gerontology Branch and overall missions of the National Institute on Aging.