The role of diet and gastrointestinal microbes in animal ageing and metabolism

有很多证据表明，一般来说，饮食会影响衰老。饮食也影响许多主要疾病，有一个数十亿美元的产业，生产膳食补充剂，以改善人类健康的目标。人类饮食中有大量的成分，因此评估每种成分对衰老的影响是一项艰巨的任务。研究实验室动物的衰老可以更快，更好地控制实验。微小的线虫，秀丽隐杆线虫，寿命只有几个星期，是一种成熟的实验室动物，用于研究衰老的生物学。蠕虫的寿命可以通过破坏蠕虫中的一些基因而大大延长，其中一些基因在人类中有明确的对应物。例如，破坏与人类对胰岛素反应所需的基因相似的基因，会导致蠕虫活得更长。在小鼠身上的实验表明，这一发现也与哺乳动物有关。动物的消化道中有许多微生物，主要是细菌，这些微生物以多种方式帮助营养。除了帮助吸收营养外，肠道细菌还能产生动物宿主无法产生的必需氨基酸和维生素等化合物。有人认为肠道微生物的变化会导致肥胖。在实验室中，我们保持C。elegans对单一种活细菌的作用，一种无害的E.大肠杆菌，来源于人体肠道。这种菌株提供食物，但需要活着才能提供良好的营养。我们发现了一株E.大肠杆菌，当喂养蠕虫时，使它们活得更长。我们发现，这种突变体使动物寿命延长的原因是叶酸合成减少。所有细胞都需要叶酸，用于各种目的，特别是细胞生长，但叶酸只在微生物和植物中产生，因此动物必须依赖它们的饮食。我们的实验表明，吃突变细菌的蠕虫的寿命延长，因为它们比正常细菌的蠕虫获得更少的叶酸。此外，细菌含有较少的叶酸来支持自身的新陈代谢，这也有助于减缓吃它们的蠕虫的衰老。我们还不知道叶酸的减少是如何导致这种效果的，但我们知道这不是因为额外的叶酸是有毒的。E.大肠杆菌可能是研究得最好的生物体，因为60多年来，它一直被用来了解细胞的基本运作和代谢。E.大肠杆菌具有大约4000个基因，并且存在3909个菌株的集合，其中来自集合中的每个菌株的单个基因被破坏。这项提议的目的是用这些突变株中的每一种来喂养蠕虫，并寻找长寿的蠕虫和生长缓慢的蠕虫。我们希望找到几个E。增加蠕虫寿命和/或影响营养的大肠杆菌突变体。首先，我们应该找到破坏叶酸代谢相关基因的突变体。这些基因的身份将有助于我们了解叶酸的作用机制。其次，我们还应该找到新的突变体，导致C。elegans活得更长，我们将使用C. elegans衰老和E.大肠杆菌代谢来了解这些突变体是如何工作的。我们将联合收割机的突变，看看我们是否可以使动物活得更长。我们还将使用C的突变体。elegans影响衰老，以了解动物如何应对E.大肠杆菌突变体。这些研究揭示了饮食、寿命和肠道微生物之间的基本关系。我们的发现可以在小鼠等高等动物中进行后续研究，希望能为人类提供药物和饮食干预，以减缓衰老和减少肥胖。这项研究的结果也将激发讨论，并帮助我们理解一个与我们所有人都有关的话题：吃什么才能健康地活到老年？

There is much evidence that in general, diet affects ageing. Diet also impacts many major diseases and there is a multibillion-dollar industry that produces dietary supplements with the goal of improving human health. There are a vast number of constituents of the human diet, so assessing the effect of each them on ageing is a monumental task. Studying ageing in laboratory animals allows for quicker and better-controlled experiments. The tiny nematode worm, Caenorhabditis elegans, with a lifespan of only a few weeks, is a well-established lab animal for investigating the biology of ageing. The lifespan of the worm can be extended considerably by the disruption of some genes in the worm, several of which have clear human counterparts. For example disruption of genes similar to those needed to respond to insulin in humans, causes the worm to live longer. Experiments in mice have shown that this finding is also relevant to mammals. The digestive tracts of animals are populated by numerous microbes, mainly bacteria and these microbes assist nutrition in many ways. As well as assisting uptake of nutrients, gut bacteria produce compounds such as essential amino acids and vitamins that can't be made by the animal host. It has been suggested that changes in gut microbes can cause obesity. In the lab we maintain C. elegans on a single species of live bacteria, a harmless strain of E. coli, derived from the human intestine. This strain provides food but needs to be alive to provide good nutrition. We have discovered a mutant strain of E. coli, which when fed to worms makes them live considerably longer. We have found that the reason why this mutant causes the animals to live longer is a decrease in the synthesis of folic acid. Folic acid is needed in all cells for a variety of purposes, especially for cell growth, but folic acid is only made in microbes and plants so animals have to rely on their diet. Our experiments show that the lifespan of the worms eating the mutant bacteria is extended because they are receiving less folic acid than worms on the normal bacteria. In addition, the fact that the bacteria have less folic acid to support their own metabolism also contributes to the slowed ageing of the worms that eat them. We don't yet understand how reduced folic acid causes this effect but we know that is not because extra folic acid is toxic. E. coli is probably the best studied organism there is, because for over 60 years it has been used to understand the basic workings and metabolism of cells. E. coli has around 4000 genes and there is a collection of 3909 strains in which a single gene has been disrupted from each strain in the collection. The aim of this proposal is to feed worms on each of these mutant strains and look for long-lived worms and worms that grow slowly. We expect to find several E. coli mutants that increase worm lifespan and/or affect nutrition. Firstly, we should find mutants that disrupt genes related to folic acid metabolism. The identity of these genes will help us understand how the folic acid effect works. Secondly, we should also find new mutants that cause C. elegans to live longer and we will use the accumulated knowledge of C. elegans ageing and E. coli metabolism to understand how these mutants work. We will combine mutants to see if we can make the animals live longer still. We will also use mutants of C. elegans that affect ageing to understand how the animal responds to changes caused by E. coli mutants. Together these studies reveal fundamental relationships between diet, lifespan and intestinal microbes. Our findings can be followed up in higher animals such as mice, hopefully leading to pharmaceutical and dietary interventions for humans both to slow ageing and decrease obesity. The results of this study will also stimulate discussion and help our understanding of a topic that concerns us all: What to eat to live to a healthy old age?