GEroscience and Multi-Morbidity: identifying targets for intervention (GEMM)

GEroscience 和多种发病率：确定干预目标 (GEMM)

• 批准号: MR/V005030/1
• 负责人: Claire Joanne Steves
• 金额: $ 12.84万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV005030%2F1
• 关键词: GEroscience; Multi; Morbidity; identifying; targets

Currently medicine tends to treat distinct diseases individually. We are increasingly aware that people do not suffer from one disease in isolation. Current treatment means that many people are taking multiple medications, which increases side-effects and can lead to harmful drug interactions.We now know that groups of diseases tend to cluster together, such that an individual with one disease is more likely to have others in the cluster. We think this is because there are underlying mechanisms which are root causes of many diseases at the same time.Age is the major risk factor for getting many diseases. Biologists have studied ageing in model organisms and humans for many years. This body of work is called Geroscience. Geroscience has now identified key mechanisms which occur in ageing and contribute to changes in physiology and health. We want to investigate how these processes relate to the development of disease clusters. By understanding the mechanisms behind the development of these disease clusters we aim to develop strategies to combat the root causes, thereby preventing or treating multiple diseases at once.Geroscience has identified three key changes which occur with ageing and contribute to health problems: cell senescence (where old cells do not die but remain in tissues secreting molecules which upset healthy cells); changes in nutrient sensing (where the cell system inappropropriately assesses the balance between growth and health), and altered autophagy (problems recycling proteins in the cells such that they accumulate and affect cell function). All three of these mechanisms have possible therapies which could be used to stop the underying process. Importantly, some of these therapies are drugs like metformin or lifestyle changes such as diet alterations which are already used in humans and known to be relatively safe.Our consortium contains internationally recognised expertise across five universities with experts from discovery science, ageing biology, computational biology, clinical trial design, and medicine who will work together to develop a new strategy for treatment. Our vision is to bring a paradigm shift in the clinical management of age-related multimorbidity, via modulation of the upstream drivers of the major disease clusters, replacing the current approach of treating diseases separately.The overarching aim of our proposal is to build a multidisciplinary collaborative to identify whether these ageing mechanisms underpin the development of distinct multimorbidity clusters. The consortium is led by doctors and will involve clinical trial experts to keep us focused on developing new treatment strategies quickly. Our plan is to use data from large cohorts which already have many biological and health measures characterised, to investigate the biology behind multimorbidity clusters. We will start with the TwinsUK cohort which has had molecular biology assayed in detail, from genes, to expression of genes, proteins, metabolites and cell subsets. In the first six-month consolidation phase, we will construct the clusters in this dataset and look at the relationships between biology and the clusters. We will also extend the team to involve additional scientific experts. In the consortium phase we will extend this to other cohorts and perform experiments on cells derived from participants and then in clinical studies to demonstrate cause and effect, and investigate how we can modify and treat multiple diseases safely (Figure 1). Combining this understanding with our collaborative's expertise in novel clinical trial designs, we will develop protocols for testing treatments targeting the identified mechanisms in people suffering from multiple diseases.

目前的医学倾向于个别治疗不同的疾病。我们日益认识到，人们不会孤立地患上一种疾病。目前的治疗意味着许多人正在服用多种药物，这增加了副作用，并可能导致有害的药物相互作用。我们现在知道，疾病的群体往往聚集在一起，这样一个患有一种疾病的人更有可能在集群中拥有其他疾病。我们认为，这是因为有一些潜在的机制，这些机制是许多疾病的根源，而年龄是患上许多疾病的主要风险因素。多年来，生物学家一直在研究模式生物和人类的衰老。这项工作被称为老年科学。老年科学现在已经确定了衰老过程中发生的关键机制，并有助于生理和健康的变化。我们想研究这些过程如何与疾病群的发展相关。通过了解这些疾病集群发展背后的机制，我们的目标是制定战略，以打击根源，从而预防或治疗多种疾病一次。老年科学已经确定了三个关键的变化，发生与老龄化，并有助于健康问题：细胞衰老（老细胞不会死亡，而是留在组织中，分泌扰乱健康细胞的分子）;营养感知的变化（细胞系统不适当地评估生长和健康之间的平衡），以及改变的自噬（细胞中蛋白质的回收问题，使它们积累并影响细胞功能）。所有这三种机制都有可能的治疗方法，可以用来阻止潜在的过程。重要的是，其中一些治疗药物，如二甲双胍，或生活方式的改变，如饮食改变，已经用于人类，并且已知是相对安全的。我们的联盟包含国际公认的专业知识，来自五所大学的专家，来自发现科学，衰老生物学，计算生物学，临床试验设计和医学，他们将共同努力开发新的治疗策略。我们的愿景是通过调节主要疾病集群的上游驱动因素，取代目前单独治疗疾病的方法，为年龄相关性多发性硬化症的临床管理带来范式转变。我们提案的总体目标是建立多学科协作，以确定这些衰老机制是否支持不同多发性硬化症集群的发展。该联盟由医生领导，并将涉及临床试验专家，以使我们专注于快速开发新的治疗策略。我们的计划是使用已经有许多生物和健康措施特征的大型队列的数据，以调查多发病集群背后的生物学。我们将从TwinsUK队列开始，该队列已经进行了详细的分子生物学分析，从基因到基因表达，蛋白质，代谢物和细胞亚群。在前六个月的整合阶段，我们将构建此数据集中的聚类，并查看生物学和聚类之间的关系。我们还将扩大该小组，吸收更多的科学专家。在联盟阶段，我们将把这一点扩展到其他队列，并对来自参与者的细胞进行实验，然后在临床研究中证明因果关系，并研究我们如何安全地修改和治疗多种疾病（图1）。将这一理解与我们在新型临床试验设计方面的专业知识相结合，我们将制定针对患有多种疾病的人的已确定机制的治疗方案。

项目成果

Biological mechanisms of aging predict age-related disease co-occurrence in patients.

• DOI: 10.1111/acel.13524
• 发表时间: 2022-04
• 期刊: Aging cell
• 影响因子: 7.8

Systematic identification of the role of gut microbiota in mental disorders: a TwinsUK cohort study

• DOI: 10.1038/s41598-024-53929-w
• 发表时间: 2024-02-13
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Delanote，Julie;Correa Rojo，Alejandro;Ertaylan，Goekhan
• 通讯作者: Ertaylan，Goekhan

The composition of the gut microbiome differs among community dwelling older people with good and poor appetite.

• DOI: 10.1002/jcsm.12683
• 发表时间: 2021-04
• 期刊: Journal of cachexia, sarcopenia and muscle
• 作者: Cox NJ;Bowyer RCE;Ni Lochlainn M;Wells PM;Roberts HC;Steves CJ
• 通讯作者: Steves CJ

Tackling immunosenescence to improve COVID-19 outcomes and vaccine response in older adults Comment

解决免疫衰老问题以改善老年人的 COVID-19 结果和疫苗反应

• 发表时间: 2020
• 期刊: LANCET HEALTHY LONGEVITY
• 影响因子: 13.1
• 作者: Cox Lynne S.

Tackling immunosenescence to improve COVID-19 outcomes and vaccine response in older adults.

• DOI: 10.1016/s2666-7568(20)30011-8
• 发表时间: 2020-11
• 期刊: The lancet. Healthy longevity
• 作者: Cox LS;Bellantuono I;Lord JM;Sapey E;Mannick JB;Partridge L;Gordon AL;Steves CJ;Witham MD
• 通讯作者: Witham MD