Functional Genomic Study of Aging and Aging Interventions

衰老和衰老干预的功能基因组研究

• 批准号: 8931526
• 负责人: Sige Zou
• 金额: $ 63.32万
• 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/8931526
• 关键词: Accounting; Aging; Aging-Related Process; Alzheimer' s Disease; Biological Process; Biology of Aging; Cells; Collaborations; Complex; Diet; Dietary Factors; Disease; Drosophila genus; Elderly; Environmental Risk Factor; Fatty acid glycerol esters; Genes; Genetic; Gerontology; Goals; Head and Neck Squamous Cell Carcinoma; Health; Human; Immune response; Intervention; Longevity; Macronutrients Nutrition; Malignant Neoplasms; Metabolism; MicroRNAs; Mission; Mitochondria; Mitogen-Activated Protein Kinases; Molecular; NF-kappa B; Nutraceutical; Nutrient; Nutritional; Oxidative Stress; Paper; Parkinson Disease; Pharmaceutical Preparations; Pharmacologic Substance; Play; Population; Proteins; Proteolysis; Publications; Publishing; Reporting; Research; Resistance; Risk; Rodent; Signal Pathway; Signal Transduction; Sirolimus; Stress; Testing; Work; age effect; age related; design; effective intervention; feeding; fly; functional genomics; gene environment interaction; healthy aging; oxidative damage; protein aggregate; sugar

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. We have found that ATPsyn-d interacts with dietary macronutrients to modulate lifespan likely through altering the accumulation of oxidative damage and protein aggregates, the resistance to oxidative stress and the expression of numerous genes involved in metabolism, proteolysis and innate immune response. We have also demonstrated that ATPsyn-d interacts with MAP kinase (MAPK) and TOR signaling pathways to modulate lifespan. This line of research has been accepted for publication in Cell Reports (2014 in press). Our study reveals the unexpected interaction between mitochondrial genes and nutritional factors at least partially through TOR signaling in modulating lifespan. Our findings on the interaction between ATPsyn-d and TOR signaling in aging prompted us to propose that the hypothesis that genetic background is critical for the effect of nutraceuticals and pharmaceuticals in promoting longevity. To test this hypothesis, we have determined the effect of rapamycin on lifespan in wild type and ATPsyn-d knockdown flies. Rapamycin is known to suppress rapamycin and promotes longevity in various species including flies and rodents. We have found that, while rapamycin feeding can extend lifespan of wild type flies, it significantly reduces lifespan of flies with reduced expression of ATPsyn-d. This line of research has been presented in our aforementioned paper accepted for publication in Cell Reports 2014. 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 addition, in collaboration with Drs. Ming Zhan and Bing Yu, we have investigated the regulatory network among microRNA, NF-kappaB and p53 in head and neck squamous cell carcinoma. This line of work has been published in PLoS ONE 2013. This work will be valuable for studying aging-related diseases, including cancer. In summary, we have made significant progress towards understanding molecular mechanisms underlying aging and age-related diseases. We have demonstrated an unexpected 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.

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。我们已经发现，ATPsyn-d与膳食常量营养素相互作用，可能通过改变氧化损伤和蛋白质聚集体的积累、对氧化应激的抵抗以及参与代谢、蛋白水解和先天免疫应答的许多基因的表达来调节寿命。我们还证明了ATPsyn-d与MAP激酶（MAPK）和TOR信号通路相互作用以调节寿命。这一系列研究已被接受发表在Cell Reports（2014年出版）上。我们的研究揭示了线粒体基因和营养因子之间的意外相互作用，至少部分通过TOR信号调节寿命。 我们关于ATPsyn-d和TOR信号在衰老中相互作用的发现促使我们提出遗传背景对营养品和药物促进长寿的作用至关重要的假设。为了验证这一假设，我们已经确定了雷帕霉素对野生型和ATPsyn-d敲低果蝇寿命的影响。已知雷帕霉素抑制雷帕霉素并促进包括苍蝇和啮齿动物在内的各种物种的长寿。我们已经发现，虽然雷帕霉素喂养可以延长野生型果蝇的寿命，但它显著降低了ATPsyn-d表达减少的果蝇的寿命。这一系列的研究已经在我们上述的论文中提出，该论文已被接受发表在Cell Reports 2014上。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。 此外，我们还与詹明和余冰博士合作，研究了头颈部鳞状细胞癌中microRNA、NF-κ B和p53之间的调控网络。这一系列的工作已经发表在PLoS ONE 2013上。这项工作对于研究与衰老有关的疾病，包括癌症，将是有价值的。 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。我们已经证明了一个意想不到的功能，ATP合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。