Mechanisms of Lifespan Modulation by Diet

寿命受遗传和环境因素的影响。膳食营养素是调节健康寿命和寿命的最有效的环境因素之一。无营养不良的饮食限制（DR）已被证明可以促进许多物种的健康和寿命。营养保健品含有丰富的植物化学物质，具有多种生物活性，并发挥许多健康益处，包括抗衰老作用。膳食营养素是否以及如何影响衰老干预措施的长寿效果仍然难以捉摸。考虑到不同地理区域人群中的不同饮食习惯，重要的是评估在人类不同饮食条件下使用药物和营养药物化合物的任何衰老干预措施的有效性。 为此，我们使用两种果蝇模型，墨西哥果蝇（Mexfly）和果蝇，研究了营养保健品和膳食常量营养素对健康寿命和寿命之间的相互作用。首先，我们设计了一个营养几何学的方法来确定膳食脂肪，糖，蛋白质和冷冻干燥的aai纸浆之间的相互作用，在调节寿命和繁殖输出的墨西哥苍蝇。Aai是亚马逊河地区的一种水果，含有多种植物化学物质，具有抗氧化，抗炎，抗癌和抗心血管疾病的特性。我们发现，AAI补充剂提高了生存率，但降低了高脂肪和高糖饮食的墨西哥果蝇的终生生殖输出，而不是其他饮食的墨西哥果蝇。这项工作发表在Experimental Gerontology（2012）上。其次，我们确定了白藜芦醇与膳食中的糖，蛋白质和脂肪对果蝇寿命的相互作用。 白藜芦醇是一种多酚化合物，已被证明可以延长不同生物体的寿命。然而，一些证据表明，白藜芦醇在任何培养条件下都不能延长酵母、蠕虫和苍蝇的寿命。我们假设白藜芦醇的长寿效应可能取决于膳食组成，并设计了一个营养几何学研究来验证这一假设。我们发现，白藜芦醇补充剂并不能延长标准、限制或高糖低蛋白饮食喂养的果蝇的寿命。然而，白藜芦醇确实延长了低糖高蛋白或高脂肪饮食的果蝇的寿命。白藜芦醇的寿命延长与参与胰岛素样信号传导和氧化应激反应的基因下调有关。这项工作发表在AGE 2011上。我们在两种不同的果蝇中进行的aai和白藜芦醇研究揭示了营养保健品对寿命的影响，并强调了饮食组成在实施有效的衰老干预措施中的重要性。 实施有效的老龄化干预措施的挑战之一是需要长期干预。因此，重要的是确定任何药物或营养剂在人类中实现期望的长寿效果的关键年龄段。确定这些关键年龄段将大大减少往往是长期干预措施的成本和潜在副作用。我们进行了两项研究，以解决使用营养保健品的衰老干预措施的时间效应。首先，基于我们之前的研究结果，即牛至-蔓越莓混合物（OC）可以延长墨西哥果蝇的寿命，我们确定了短期OC补充剂对寿命的影响。我们发现，只有在中年时期的短期OC补充足以延长墨西哥蝇的寿命。这项工作发表在AGE（2011）上。第二，我们研究了短期补充aai对sod 1基因敲除果蝇（具有高水平氧化损伤）的存活率和减少氧化损伤的影响。我们之前已经证明，终生补充aai可以延长sod 1敲除果蝇的寿命，该研究发表在Experimental Gerontology（2010）上。 我们现在已经证明，在果蝇死亡率开始加速时开始补充aai，足以促进sod 1基因敲除果蝇的存活，减少氧化损伤，增加生殖输出。这项工作发表在AGE（2012）上。OC和AAI研究的结果表明，短期补充营养品可以有效促进健康老龄化。 总之，我们已经确定了饮食营养素对几种果蝇品系（特别是墨西哥果蝇和果蝇）寿命和关键分子途径的影响。更重要的是，我们已经证明，在Mexfly和果蝇模型中，当在中年受试者中开始时，观察到营养品的长寿效应。我们未来的研究将致力于了解营养保健品，膳食营养素和这些干预措施的时机之间相互作用的分子机制。 这些研究应该提供深入了解的机制，饮食营养素的寿命调制及其相互作用与遗传和非遗传因素。该项目应推进实验老年学实验室和国家老龄化研究所的目标，并为了解人类衰老提供有价值的信息，更重要的是为制定有效的人类衰老干预策略，包括在生命周期中这些干预措施的时机。

Lifespan is modulated by both genetic and environmental factors. Dietary nutrients are among the most potent environmental factors in modulating healthspan and lifespan. Dietary restriction (DR) without malnutrition has been shown to promote healthspan and lifespan in numerous species. Nutraceuticals are rich in phytochemicals that possess diverse bioactivities and exert numerous health benefits, including anti-aging effects. Whether and how dietary nutrients influence the prolongevity effects of aging interventions remains elusive. Considering diverse dietary customs among human populations in different geographic regions, it is important to assess the effectiveness of any aging intervention using pharmaceutical and nutraceutical compounds under different dietary conditions in humans. To this end, we have investigated the interactions between nutraceuticals and dietary macronutrients on healthspan and lifespan using two fly models, the Mexican fruit fly (Mexfly) and Drosophila. First, we designed a nutritional geometry approach to determine the interplay among dietary fat, sugar, protein and freeze-dried aai pulp in modulating lifespan and reproductive output in the Mexfly. Aai is a fruit indigenous to the Amazon River region and contains numerous phytochemicals that have anti-oxidant, anti-inflammation, anti-cancer and anti-cardiovascular disease properties. We found that aai supplementation promoted survival, but decreased lifetime reproductive output in Mexflies on diets with high fat and high sugar but not those on other diets. This work was published in Experimental Gerontology (2012). Second, we determine the interaction of resveratrol with dietary sugar, protein and fat on lifespan in Drosophila. Resveratrol is a polyphenolic compound that has been shown to extend lifespan in different organisms. However, several lines of evidence have indicated that resveratrol is not capable of extending lifespan in yeast, worms and flies under any culture conditions. We postulated that the prolongevity effect of resveratrol may depend on dietary composition, and designed a nutritional geometry study to test this hypothesis. We found that resveratrol supplementation did not extend the lifespan of flies fed a standard, restricted or high sugar-low protein diet. However, resveratrol did extend the lifespan of flies fed a low sugar-high protein or a high-fat diet. Lifespan extension by resveratrol was associated with downregulation of genes involved in insulin-like signaling and oxidative stress response. This work was published in AGE 2011. Our aai and resveratrol studies in two different fly species reveal the context-dependent effect of nutraceuticals on lifespan and stress the importance of diet composition in implementing effective aging interventions. One of the challenges in implementing effective aging interventions is the requirement of long-term intervention. Therefore, it is important to determine the age period critical for any pharmaceutical or nutraceutical agents to achieve desired prolongevity effects in humans. Identification of such critical age periods will significantly reduce the cost and potential side-effects of the often long-term interventions. We conducted two studies to address the temporal effects of aging interventions using nutraceuticals. First, based on our previous findings that an oregano-cranberry mixture (OC) can extend the lifespan of the mexfly, we determined the effect of short-term OC supplementation on lifespan. We found that only short-term OC supplementation at the middle age period was sufficient to extend lifespan in Mexflies. This work was published in AGE (2011). Second, we investigated the effect of short-term aai supplementation on promoting survival and reducing oxidative damage in sod1 knockdown flies, which have high levels of oxidative damage. We have previously shown that lifetime supplementation of aai can extend the lifespan of sod1 knockdown flies, which was published in Experimental Gerontology (2010). We have now demonstrated that aai supplementation, initiated at the time when the mortality rate of flies begins to accelerate, is sufficient to promote survival, reduce oxidative damage and increase reproductive output in sod1 knockdown flies. This work was published in AGE (2012). The findings from both the OC and aai studies suggest that short-term supplementation of nutraceuticals can be effective in promoting healthy aging. In summary, we have determined the impact of dietary nutrients on lifespan and critical molecular pathways in several fly lines, specifically the Mexfly and Drosophila. More importantly, we have demonstrated that the prolongevity effects of nutraceuticals in both Mexfly and Drosophila models are observed when initiated in middle aged subjects. Our future research will be directed to understand the molecular mechanisms underlying the interplay between nutraceuticals, dietary nutrients and the timing of these interventions. These studies should provide insight into the mechanisms underlying lifespan modulation by dietary nutrients and their interactions with genetic and non-genetic factors. 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, including the timing of those interventions during the lifespan.