相同能量下不同膳食结构对寿命的影响及其动态代谢组学通路研究

Diet is an important factor affecting the incidence of chronic diseases and life expectancy. Calorie restriction can extend the lifespan of different species such as nematode, drosophila, mice and rats, which has been recognized as the most ideal and effective means to prolong the lifespan. With the development of diet research, dietary patterns has been reported to affect the lifespan in animal experiments as well, and some studies reported that reasonable dietary patterns may be better to extend the lifespan than calorie restriction. However, the results about relationship between different dietary patterns and lifespan presented in most of the studies were inconsistent, which might be due to energy intake was not well controlled during the experiment. Therefore, we speculate that different dietary pattern may also affect the lifespan with the same energy intake. The aim of our study is to investigate the effect of different dietary patterns with the same energy intake on the lifespan of rats, clarify the biomarkers related to lifespan, and elucidate the effect and mechanisms of different dietary pattern on energy metabolism, gene expression profiles and the discovered biomarkers related to lifespan. Furthermore, the biomarkers related to lifespan in rats will be validated for the first time in human trial, and the effect of different dietary pattern under same energy on the biomarkers related to lifespan will be analyzed in a population based cohort study. The project would provide scientific guide for daily dietary guidance and intervention on the basis of controlling total energy intake.

饮食是影响慢性病发病与寿命的重要因素。控制能量摄入能够延长多种系如线虫、果蝇、小鼠、大鼠等的寿命，也是公认的有效延长寿命的手段。随着饮食研究的深入，动物研究发现膳食结构也可影响寿命，甚至有研究认为膳食结构可能比能量控制更有利于延长寿命。但目前大多数有关膳食结构和寿命的研究结果并不一致，其最主要原因可能是没有考虑到能量摄入这一因素。我们推测在控制能量相同的前提下，膳食结构的调整也可能延长寿命。为此本课题研究相同能量摄入下不同膳食结构（正常、高蛋白、高脂、高碳水化合物膳食）对大鼠寿命的影响，明确与衰老相关的生物标志物，确定不同膳食结构对大鼠机体能量代谢、基因表达谱图及其衰老生物标志物的作用及机制。在此基础上首次利用人群试验验证并确定与人类衰老相关的生物标志物，研究相同能量摄入下，不同膳食结构对衰老生物标志物的影响，进而确定不同膳食结构对寿命的影响，为居民日常的膳食习惯的指导和干预提供理论依据。

饮食是影响慢性病发病与寿命的重要因素。控制能量和膳食结构均能影响寿命，而能量控制可能是导致膳食结构和寿命研究中的主要混杂因素。为此本课题利用动物及人群试验研究了相同能量摄入下不同膳食结构对寿命的作用及机制。.1.相同能量下高脂肪膳食（IHF）延长大鼠及果蝇的作用及机制。研究结果发现IHF能够显著延长大鼠和果蝇的寿命，延缓大鼠肿瘤的发生及衰老相关的病理损伤，改善大鼠的记忆行为能力。其机制可能是下调游离脂肪酸合成代谢，上调分解代谢进而降低血清和多种组织中FFAs的含量。特别是显著降低软脂酸，上调PPARG /PPRC1的表达，最终导致氧化应激和炎症的改善以及寿命的延长。蛋白质组学发现通过调节经典的寿命相关的营养敏感信号通路、下调氧化应激和炎症以及脂肪酸合成来发挥作用的。代谢组学发现IHF能够使老年大鼠的代谢图谱向年轻化转移。.2.相同能量不同膳食结构对大鼠肠道菌群的影响。门水平上高脂肪组的Firmicutes水平显著升高，高碳水化合物组中Firmicutes富集程度最低。属水平发现高脂肪组拥有最多的Lactobacillus和Clostridium_sensu_stricto_1数量，而高蛋白质组拥有最高的Christensenellaceae_R-7_group水平。总之，随着年龄的增长其肠道菌群群落多样性与群落丰富度显著下降。相同能量下高脂肪膳食肠道内微生物组成更加均衡多样并且有较多的益生菌。.3.相同能量不同膳食结构对健康人群寿命影响的代谢组学研究。非靶向代谢组学发现与年龄相关的标志物18个。高碳水化合物组与年龄负相关的生物标志物除 LysoPC(20:4)、LysoPE(18:2/0:0)和甘氨胆酸外，其余生物标志物均明显降低；而高脂肪组中仅血清素离子明显升高。总之，高蛋白和高碳水化膳食氨基酸、脂质以及三羧酸循环代谢均向促进衰老的方向发展，而高脂肪膳食代谢无明显影响。