Functional Genomic Study of Aging and Aging Interventions

衰老是一个复杂的生物学过程，受到许多遗传和环境因素的调节。在环境因素中，膳食营养素对调节健康寿命和寿命至关重要。营养不平衡已被证明对人类健康，特别是老年人的健康构成巨大风险。膳食宏量营养素，如糖，蛋白质和脂肪，可以相互作用，对健康有重大影响。因此，在阐明衰老的分子机制和开发促进健康衰老的有效干预措施时，考虑饮食组成至关重要。 线粒体基因已被证明在调节寿命中起关键作用，并与许多与年龄有关的疾病有关，如帕金森病和阿尔茨海默病。然而，线粒体基因如何与膳食常量营养素相互作用来调节寿命和健康寿命仍然没有完全阐明。为此，我们重点研究了ATP合成酶亚基d（ATPsyn-d）在调节果蝇寿命的各种饮食条件下的功能。去年，我们在Cell Reports上发表了一篇论文，报告ATPsyn-d与膳食常量营养素相互作用，至少部分通过TOR信号通路调节寿命。我们已经进一步证明，雷帕霉素，一种已知在包括苍蝇和啮齿动物在内的各种物种中促进长寿的药物，显著降低了苍蝇的寿命，同时降低了ATPsyn-d的表达。这些研究结果强调了在实施促进长寿和健康的干预措施时考虑遗传背景的重要性，并为设计有效的老龄化干预措施提供了一个框架。在本报告周期中，我们扩展了ATPsyn-d在调节寿命方面的工作，并研究了哪些组织对ATPsyn-d对寿命的影响至关重要。我们已经证明，在成年脂肪组织中敲低ATPsyn-d足以延长果蝇的寿命。与普遍存在的ATPsyn-d敲除类似，这种寿命延长取决于饮食的组成，特别是碳水化合物与蛋白质的比例。正在准备一份手稿来描述这些组织特异性发现。 总之，我们在了解衰老和年龄相关疾病的分子机制方面取得了重大进展。我们已经扩展了我们的研究功能的ATP合成酶在调节寿命除了其众所周知的功能，在产生ATP。我们研究了衰老过程中的基因-环境相互作用，这是解决衰老和年龄相关疾病的关键。这些研究对于推进翻译老年学分支的目标和NIA的使命是有价值的，即了解衰老的基本生物学并为人类开发有效的干预措施。

Aging is a complex biological process that is modulated by numerous genetic and environmental factors. Among the environmental factors, dietary nutrients are critical in modulating healthspan and lifespan. Nutrient imbalance has been shown to post great risks to human health, especially to the elderly population. Dietary macronutrients, such as sugar, protein and fat, can interact with each other and have significant impact on health. Therefore, it is critical to take into account diet composition in elucidating molecular mechanisms of aging and in developing effective interventions for promoting healthy aging. Mitochondrial genes have been shown to play a key role in modulating lifespan and are implicated in numerous age-related diseases, such as Parkinsons and Alzheimers diseases. However, how mitochondrial genes interact with dietary macronutrients to modulate lifespan and healthspan remains incompletely elucidated. To this end, we have focused on studying the function of ATP synthase subunit d (ATPsyn-d) in modulating lifespan under various dietary conditions in Drosophila. Last year, we have published a paper in Cell Reports reporting that ATPsyn-d interacts with dietary macronutrients to modulate lifespan at least partially through TOR signaling pathway. We have further demonstrated that Rapamycin, a drug known to promote longevity in various species including flies and rodents, significantly reduces lifespan of flies with reduced expression of ATPsyn-d. These findings stress the importance to take into account the genetic background in implementing interventions for promoting longevity and healthspan and provide a framework for designing effect aging interventions. In this reporting cycle, we have extended this line of work on ATPsyn-d in modulating lifespan and investigated which tissue is critical for the effect of ATPsyn-d on lifespan. We have shown that ATPsyn-d knockdown in adult fat tissue is sufficient to extend lifespan in Drosophila. Similar to ubiquitous ATPsyn-d knockdown, this lifespan extension depends on the composition of the diet, particularly the carbohydrate-to-protein ratio. A manuscript is in preparation to describe these tissue-specific findings. In summary, we have made significant progress towards understanding molecular mechanisms underlying aging and age-related diseases. We have extended our studies on the function of ATP synthase in modulating lifespan besides its well-known function in generating ATP. We have investigated the gene-environment interactions in aging, which is a key to tackle aging and age-related diseases. These studies are valuable for advancing the objectives of the Translational Gerontology Branch and the mission of the NIA to understand the basic biology of aging and develop efficient interventions for humans.