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

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.

Although age is the major risk factor for multimorbidity, the role of biological ageing mechanisms is not known. This limits our ability to tackle the primary drivers of multi-morbidity clusters and maintains the status quo of treating component diseases individually, resulting in polypharmacy. The Geroscience hypothesis advocates interventions that target core ageing processes, such as cell senescence, to treat age-related diseases and their clustering. Tractable pathways which already have therapeutic agents available to accelerate the potential impact of the study include: 1) Nutrient sensing (diet & metformin); 2) Senescence (senolytics); 3) Proteostasis (spermidine).

The overarching aim of this proposal is to build a multidisciplinary collaborative to identify ageing mechanisms that underpin the development of distinct multimorbidity clusters. The consortium is led by geriatricians working closely with discovery scientists. This will ultimately deliver our vision of achieving 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.

Our plan in the consolidation phase is to use data from large and deeply phenotyped cohorts to characterise and validate multimorbidity clusters. We will start with the TwinsUK cohort and its associated multi-omic datasets to identify likely mechanisms underlying the clusters. These will be further tested in the consortium phase using other cohorts, clinical studies, ex-vivo experiments, and animal models (Figure 1), to confirm pathways and modifiability. We will then use these data and our collaborative's expertise in novel clinical trial designs to develop protocols for testing interventions targeting the identified mechanisms in multimorbid patients.