Prebiotic Regulation of Longevity

 美国老年人（65岁及以上）的数量将增加一倍以上，从2010年的4030万增加到2050年的8850万。老年人口的迅速增长大大增加了慢性病和退行性疾病的发病率，对公共卫生提出了巨大挑战。为了应对这一挑战，我们的研究旨在确定生物活性营养化合物，通过调节微生物-宿主相互作用促进生物体的寿命和健康，并进一步表征其潜在的调控机制。微生物群是宿主体内不同种类微生物的集合，其稳态与宿主健康密切相关，并受到饮食和遗传因素的严格调节。饮食驱动的微生物群组成变化与老年人的健康改善有关，然而，在哺乳动物系统中，识别和验证特定的促进长寿的生物活性饮食因子仍然具有技术挑战性。在我们对秀丽隐杆线虫的初步研究中，我们确定了一种促进长寿的多糖，colanic acid（CA），它是从细菌中分泌出来的，作为一种益生元来改善宿主线粒体动力学。我们的研究进一步表明，CA促进进化上遥远的宿主生物的长寿，并在不同的微生物环境中有效。这些研究表明，CA作为一种新型的生物活性营养化合物，以改善微生物群的稳态，促进宿主的代谢健康和健身。本研究旨在通过以下具体目标来剖析CA在调节宿主寿命中的益生元功能：1）阐明CA介导的调节宿主寿命的微生物因子; 2）揭示CA提高宿主寿命的分子机制。3)评估CA在促进哺乳动物宿主健康和长寿方面的保守作用。在这些研究中，我们将应用多学科的方法，并利用强大的原核生物，无脊椎动物和脊椎动物模型系统的优势。我们与不同领域的科学家建立了独特的合作关系。这些研究的成功完成将为改善晚年生活质量提供一种新的益生元治疗策略，并将对营养科学和衰老生物学领域的研究产生重大影响。

 DESCRIPTION (provided by applicant): The number of elderly people (aged 65 and older) in the U.S. will be more than doubled, from 40.3 million in 2010 to 88.5 million in 2050. This rapid growth of the older population dramatically increases the incidence of chronic and degenerative diseases, and presents a grand challenge for public health. To tackle this challenge, our research aims to identify bioactive nutrient compounds that promote organismal longevity and fitness through modulating microbiota-host interactions, and to further characterize their underlying regulatory mechanisms. The microbiota is a collection of diverse species of microorganisms that reside in the host, and its homeostasis is strongly associated with host health and is tightly regulated by both dietary and genetic factors. Diet-driven microbiota compositional changes have been linked to health improvement among the elderly, however identification and validation of specific longevity-promoting bioactive dietary factors remain technically challenging in mammalian systems. During our preliminary studies in Caenorhabditis elegans, we identified a longevity-promoting polysaccharide, colanic acid (CA), which is secreted from bacteria and functions as a prebiotic to improve host mitochondrial dynamics. Our studies further revealed that CA promotes longevity in evolutionarily distant host organisms and is effective in diverse microbial environments. These studies suggest CA as a novel bioactive nutrient compound to improve microbiota homeostasis and to promote host metabolic health and fitness. This proposal seeks to dissect the prebiotic function of CA in the regulation of host longevity through the following specific aims: 1) Elucidate CA-mediated microbial factors that regulate host longevity; 2) Reveal the molecular mechanisms by which CA improves host longevity. 3) Assess the conserved role of CA in promoting host health and longevity in mammals. In these studies, we will apply multidisciplinary approaches and take advantages of powerful prokaryotic, invertebrate and vertebrate model systems. We have established unique collaborations with scientists in diverse areas. Successful accomplishment of the proposed studies will provide a new strategy of prebiotic therapies to improve the quality of later life, an will have significant impacts on research in the fields of nutritional science and aging biology.