The relationship between protein intake, gut microbiome, inflammaging and loss of mobility in older adults

这份K01申请是为了让Samaneh Farsijani博士在营养流行病学和 掌握整合组学(肠道微生物组)和非组学(饮食摄入量)数据的技能，以实现她的长期目标 在《精确营养》中制定针对年龄的饮食建议，取代目前的一刀切 办法，促进健康老龄化。这项提议源于候选人在营养学方面的广泛训练 以及生物学和流行病学的跨学科研究背景。建议的培训目标是有针对性的 提高应聘者在1)衰老和营养流行病学；2)高级生物统计学；3)肠道微生物组； 4)职业发展。所获得的技能将应用于拟议的科学目标，以确定 老年人蛋白质摄入量、肠道微生物群、炎症和活动能力丧失之间的关系。老龄化是 与食物蛋白质利用效率低下有关，这是由于合成代谢抵抗，这可能导致 功能性损失。此外，高达50%的美国老年人没有达到推荐的膳食津贴(RDA) 蛋白质(0.8g/kg体重/d)。因此，较高的蛋白质摄入量，高于RDA(1.0-1.2g/kg/d) 建议用来补偿蛋白质代谢的变化，并在衰老过程中保持肌肉健康。然而， 由于来自Small和Short的非决定性证据，这一策略尚未纳入饮食指南。 术语研究，无法显示蛋白质之间的潜在机制和因果关系 老年人的摄取和活动功能。肠道菌群失调(即肠道微生物群的变化)和炎症 (即，衰老过程中的低级别慢性炎症)与老年人的虚弱有关。因为饮食起着关键作用 在塑造肠道微生物群和炎症方面的作用，可以推测蛋白质摄入量对 运动功能是通过生物失调和炎症的改变来调节的。我们的核心假设是： I)高蛋白质摄入量通过改善炎症降低行动能力受限的风险；ii)不同的蛋白质 摄取指标与肠道微生物群和炎症独立相关；以及iii)肠道生态失调 与老年人的行动能力障碍有关。该提案将利用来自健康、老龄化和身体的数据 组成(健康ABC)和肌肉、活动和衰老研究(Somma)队列，以解决三个目标： 目的1：用Health ABC队列模拟一项实用的临床试验，以确定1)蛋白质的作用 摄入量对活动受限的风险，以及ii)其通过改善炎症而引起的调解。目标2：a) 描述蛋白质摄入量的不同指标(即数量、来源和日内摄入量)之间的关系 分布模式)、肠道微生物组组成和粪便代谢物；以及b)确定相关性 在索玛的肠道生物失调和发炎之间。目标3：确定横截面关联 老年人肠道微生物组成和粪便代谢物与活动能力(即步速)之间的关系 索玛。这个项目将拓宽我们对蛋白质摄入量对肠道的影响的洞察力，蛋白质摄入量是一个可修改的因素。 微生物群，发炎，和肌肉健康与衰老的最终目标是驱动特定年龄的饮食建议。

This K01 application is for Dr. Samaneh Farsijani to establish a research career in Nutritional Epidemiology and acquire skills to integrate omics (gut microbiome) and non-omics (dietary intake) data towards her long-term goal in “Precision Nutrition” to develop age-specific dietary recommendations, replacing the current one-size-fits-all approach, to promote healthy aging. The proposal is derived from the candidate’s extensive training in nutrition and interdisciplinary research background in biology and epidemiology. The proposed training goals are directed to advance candidate’s skills in 1) aging & nutritional epidemiology; 2) advanced biostatistics; 3) gut microbiome; and 4) career development. Acquired skills will be applied toward the proposed scientific goal to determine the relationships between protein intake, gut microbiome, inflammation, and mobility loss in older adults. Aging is associated with inefficient utilization of dietary proteins, due to anabolic resistance, which potentially leads to functional losses. Also, up to 50% of US older adults fail to meet the Recommended Dietary Allowance (RDA) for protein (0.8 g/kg body weight/d). Therefore, a higher protein intake, above the RDA (1.0-1.2 g/kg/d), has been suggested to compensate for changes in protein metabolism and to maintain muscle health in aging. However, this strategy has not been incorporated into dietary guidelines due to inconclusive evidence from small and short- term studies, which were unable to show the underlying mechanisms and causal relationships between protein intake and mobility function in older adults. Gut dysbiosis (i.e., changes in gut microbiome) and inflammaging (i.e., low-grade chronic inflammation in aging) have been linked to frailty in older adults. Since diet plays a key role in shaping the gut microbiome and inflammation, it may be speculated that the effects of protein intake on mobility function are mediated through alterations of dysbiosis and inflammaging. Our central hypotheses are: i) high protein intake reduces the risk of mobility limitation by ameliorating inflammaging; ii) different protein intake metrics are independently associated with gut microbiome and inflammaging; and iii) gut dysbiosis is associated with mobility impairment in older adults. This proposal will leverage data from Health, Aging & Body Composition (Health ABC), and Study of Muscle, Mobility & Aging (SOMMA) cohorts to address three Aims: Aim 1: To simulate a pragmatic clinical trial using the Health ABC cohort to determine i) the effect of protein intake on the risk of mobility limitation, and ii) its causal mediation by amelioration of inflammaging. Aim 2: a) To characterize the associations between different metrics of protein intake (i.e., quantity, source and within-day distribution pattern), gut microbiome composition, and fecal metabolites; and b) to determine the association between gut dysbiosis and inflammaging in SOMMA. Aim 3: To determine the cross-sectional associations between gut microbial composition and fecal metabolites with mobility (i.e., gait speed) in older adults from SOMMA. This project will broaden our insights into the influence of protein intake, as a modifiable factor, on gut microbiome, inflammaging, and muscle health in aging with the ultimate goal to drive age-specific dietary advice.