Mechanisms of Lifespan Modulation by Diet

衰老受到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产生重大影响的最有效的环境因素之一。许多药物和营养保健品已被确定对模型生物体具有延长寿命的作用。由植物制成的营养保健品富含植物化学物质，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干预措施的延长效果仍然难以捉摸。这是老龄化领域的一个重要问题，需要考虑不同地理来源人群的多样化饮食习惯。包括蠕虫和苍蝇在内的无脊椎动物是研究药物和营养保健品的延长效应的理想模型生物，至少部分原因是它们的寿命短和丰富的遗传资源。我们总结了利用无脊椎动物模型进行长寿保健品的研究进展，并在 Oxidative Medicine and Cellular Longevity (2013) 上发表了综述。这项工作应该为未来关于营养补充剂延缓衰老过程和改善健康寿命的机制研究提供有价值的指导。 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成分对蔓越莓在果蝇中的长寿作用的影响。我们发现，蔓越莓可以延长饲喂适量糖和蛋白质饮食的果蝇的寿命，并且更显着地延长饲喂高糖低蛋白饮食的果蝇的寿命，但不会延长或缩短饲喂低糖高蛋白饮食的果蝇的寿命。我们进一步证明，蔓越莓补充剂诱导的寿命延长与终生生殖输出的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的果蝇的存活率。这项研究揭示了膳食常量营养素在蔓越莓补充剂的延长作用中的关键作用，并指出在实施促进健康衰老的干预措施中考虑饮食成分的重要性。该系列工作已被《老年学生物科学杂志》（2013 年）接受发表。未来的工作将更多地致力于了解蔓越莓补充剂延长寿命的分子机制及其在调节寿命方面膳食大量营养素之间的相互作用。这将为促进健康老龄化提供全面的视角并有助于改进干预措施。 衰老研究的一个重要问题是评估健康寿命，因为衰老研究的基本目标不仅是延长寿命，而且通过保留功能来显着改善健康寿命。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，这主要是由于缺乏能够在任何生物体中以高分辨率记录终生行为变化的工具。我们之前开发了一种行为监测系统（BMS），可以在墨西哥果蝇（mexflies）的一生中以精细的分辨率记录六种类型的行为。 Mexflies 已广泛用于人口和老龄化干预研究。与博士合作。墨西哥的 Pablo Liedo、加州大学戴维斯分校的 Joanne Chiu 和 James Carey 以及彭宁顿的 Donald Ingram，我们利用 BMS 利用墨西哥果蝇的高分辨率终生行为记录数据来研究饮食对运动活动、睡眠数量和质量等年龄相关变化的影响。我们发现，营养均衡饮食的果蝇在活动方面几乎没有与年龄相关的变化，而饮食不理想的果蝇在老年时活动幅度显着下降，睡眠质量较低。该系列工作已发表在《科学报告》（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生行为变化，以揭示衰老干预措施对健康寿命的影响。我们还将为果蝇开发类似的 BMS，以研究其终生行为变化背后的分子机制。 总之，我们确定了膳食常量营养素对果蝇中含有蔓越莓的营养保健品的延长效果的影响。我们通过分析墨西哥果蝇在不同饮食条件下的终生行为变化，评估了饮食对健康寿命的影响。这些发现为我们未来的研究奠定了基础，旨在了解膳食大量营养素和营养保健品或药物之间在调节寿命和健康方面相互作用的分子机制。 这些研究应该为制定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化研究所的总体使命。

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.