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: 9147284
• 负责人: Sige Zou
• 金额: $ 67.35万
• 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/9147284
• 关键词: Accounting; Adult; Aging; Aging-Related Process; Alzheimer' s Disease; Biological Process; Biology of Aging; Carbohydrates; Cells; Complex; Diet; Dietary Factors; Disease; Drosophila genus; Elderly; Environmental Risk Factor; Fatty acid glycerol esters; Genes; Genetic; Gerontology; Goals; Health; Human; Intervention; Longevity; Macronutrients Nutrition; Manuscripts; Mission; Mitochondria; Molecular; Nutrient; Paper; Parkinson Disease; Pharmaceutical Preparations; Pharmacologic Substance; Play; Population; Preparation; Proteins; Publishing; Reporting; Risk; Rodent; Signal Pathway; Sirolimus; Stress; Tissues; Work; age effect; age related; design; effective intervention; fly; functional genomics; gene environment interaction; healthy aging; 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. 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.

衰老是一个复杂的生物过程，受到众多遗传和环境因素的调节。在环境因素中，膳食营养素对于调节健康和寿命至关重要。营养失衡已被证明会给人类健康带来巨大风险，特别是对老年人群。膳食大量营养素，如糖、蛋白质和脂肪，可以相互作用，对健康产生重大影响。因此，在阐明衰老的分子机制和制定促进健康衰老的有效干预措施时，考虑饮食成分至关重要。 线粒体基因已被证明在调节寿命方面发挥着关键作用，并与许多与年龄相关的疾病有关，例如帕金森病和阿尔茨海默病。然而，线粒体基因如何与膳食大量营养素相互作用以调节寿命和健康寿命仍未完全阐明。为此，我们重点研究果蝇 ATP 合酶亚基 d (ATPsyn-d) 在不同饮食条件下调节寿命的功能。去年，我们在 Cell Reports 上发表了一篇论文，报告称 ATP​​syn-d 与膳食大量营养素相互作用，至少部分通过 TOR 信号通路调节寿命。我们进一步证明，雷帕霉素（Rapamycin）是一种已知可促进包括果蝇和啮齿动物在内的多种物种寿命的药物，它可通过减少 ATPsyn-d 的表达而显着缩短果蝇的寿命。这些发现强调了在实施促进长寿和健康寿命的干预措施时考虑遗传背景的重要性，并为设计有效的衰老干预措施提供了框架。在本报告周期中，我们扩展了 ATPsyn-d 在调节寿命方面的工作范围，并研究了哪些组织对于 ATPsyn-d 对寿命的影响至关重要。我们已经证明，成年脂肪组织中 ATPsyn-d 的敲低足以延长果蝇的寿命。与普遍存在的 ATPsyn-d 敲除类似，这种寿命的延长取决于饮食的成分，尤其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的发现。 总之，我们在理解衰老和年龄相关疾病的分子机制方面取得了重大进展。除了众所周知的产生 ATP 的功能外，我们还扩展了对 ATP 合酶在调节寿命方面的功能的研究。我们研究了衰老过程中基因与环境的相互作用，这是解决衰老和与年龄相关的疾病的关键。这些研究对于推进转化老年学分支的目标和 NIA 的使命非常有价值，即了解衰老的基本生物学并为人类开发有效的干预措施。

项目成果

Drop coating deposition Raman spectroscopy of fluorescein isothiocyanate labeled protein.

• DOI: 10.1366/000370210792973497
• 发表时间: 2010-10
• 期刊: Applied spectroscopy
• 影响因子: 3.5
• 作者: Zhang D;Vangala K;Jiang D;Zou S;Pechan T
• 通讯作者: Pechan T

Sensitive carbohydrate detection using surface enhanced Raman tagging.

• DOI: 10.1021/ac102284x
• 发表时间: 2010-12-15
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Vangala, Karthikeshwar;Yanney, Michael;Hsiao, Cheng-Te;Wu, Wells W.;Shen, Rong-Fong;Zou, Sige;Sygula, Andrzej;Zhang, Dongmao
• 通讯作者: Zhang, Dongmao

Gender-specific prandial response to dietary restriction and oxidative stress in Drosophila melanogaster.

果蝇对饮食限制和氧化应激的性别特异性膳食反应。

• DOI: 10.4161/fly.5.3.15572
• 发表时间: 2011
• 期刊: Fly
• 影响因子: 1.2
• 作者: Zeng,Chaoyang;Du,Yanping;Alberico,Thomas;Seeberger,Jeanne;Sun,Xiaoping;Zou,Sige
• 通讯作者: Zou,Sige

Acid cleavable surface enhanced raman tagging for protein detection.

用于蛋白质检测的酸可裂解表面增强拉曼标记。

• DOI: 10.1039/c0an00708k
• 发表时间: 2011
• 期刊: The Analyst
• 作者: Zhang,Dongmao;Vangala,Karthikeshwar;Li,Shaoyong;Yanney,Michael;Xia,Hao;Zou,Sige;Sygula,Andrzej
• 通讯作者: Sygula,Andrzej

Ratiometric Raman spectroscopy for quantification of protein oxidative damage.

比例分析拉曼光谱法，用于定量蛋白质氧化损伤。

• DOI: 10.1016/j.ab.2009.05.019
• 发表时间: 2009-08-15
• 期刊: Analytical biochemistry
• 影响因子: 2.9
• 作者: Zhang D;Jiang D;Yanney M;Zou S;Sygula A
• 通讯作者: Sygula A