Following on from our Seed funding awards focussed on the topic of ‘the Ageing Immune System’, in late 2022 we invited the submission of project grant proposals on the same theme.
Proposals were required to align to the Trust’s key principles for research and develop our knowledge on at least one of the following topics:
- The influence of the ageing immune system on the development of frailty – including, but not limited to, the mechanisms, the effects of gender and/or other characteristics etc.
- The influence of the ageing immune system on cognitive decline and vice versa.
- The influence of the ageing immune system on the gut microbiome and vice versa – including, but not limited to, any links to age-related issues.
N.B: holders of seed funding awards were exempt from the above topics provided their project grant proposals followed-on from their seed funding award.
Proposals were peer-reviewed, and applicants were able to provide a rebuttal to the peer reviewer feedback. Further assessment was then carried out by a Panel comprising independent experts and suitably qualified members of the Research Grants Committee.
The Panel/Committee members were:
- Dr Mariana Borsa (University of Oxford)
- Professor Arthur Butt (University of Portsmouth)
- Professor Andrew Clegg (University of Leeds)
- Dr Roel De Maeyer (University of Oxford)
- Professor Andrew Devitt (Aston University)
- Professor Felicity Gavins (Brunel University London)
- Professor Stuart Gray (University of Glasgow)
- Professor Carmel Hughes (Queen’s University Belfast, Chair of the Expert Panel and Dunhill Medical Trust Research Grants Committee)
- Dr Catherine Lawrence (University of Manchester)
- Dr Carmen Martin-Ruiz (Newcastle University)
- Dr Katie Mylonas (University of Edinburgh)
- Dr Aimée Parker (Quadram Institute)
- Dr Nicholas Rattray (University of Strathclyde)
Thank you to those who applied, we appreciate the time and effort that goes in to making an application. We also appreciate the large amount of time and effort that goes into assessing grant proposals, and we wouldn’t be able to keep funding high-quality research without the help of reviewers, panellists, and committee members. We’d therefore like to take this opportunity to thank all those who contributed to the assessment of these proposals.
25 applications were received with 6 awards being made (equating to a success rate of 24%). Details of the funded projects can be found below.
Please expand any of the project titles below to read more information, including the lay summary:
Lead applicant: Chrissy Hammond (University of Bristol)
Award amount: £396,885
Duration: 36 months
Summary:
Osteoporosis causes bones to become fragile and fracture (called a fragility fracture). 3 million people are living with osteoporosis in the UK, resulting in half a million fractures annually. Fragility fractures and musculoskeletal frailty cause long-term pain, mobility problems and social isolation, and cost the UK £4.4 billion every year.
People with osteoporosis and frailty often have weakened immune systems which are less able to respond to injuries. This means fractures in older people don’t heal as well. Current therapies to prevent or treat fragility fractures are limited. Therefore, there is an urgent need for more research to identify new treatments for people living with osteoporosis.
The ability of bone to repair after fracture depends on multiple factors. Neutrophils, a type of white blood cell, are known to be important in the earliest stages, where they help to prevent infection and kickstart repair. Recent research in mice and fish suggests that neutrophils may also help to stabilise fractures by making an emergency scaffold to support damaged bone; when neutrophils are slow to arrive at the fracture then repair can fail. We predict that neutrophils from older people are affected by ageing and frailty, and that this can impact their ability to respond well to skeletal damage. We want to test this with studies in zebrafish where we can watch cell behaviour in the living fish, as well as studies of human neutrophils collected from older people with frailty to allow us to test that findings from the fish are relevant to humans.
Zebrafish are good models for studying fracture, as their bones are maintained by the same cells as humans. As zebrafish fins are translucent and contain bones which can fracture; we have developed a way to study fractures over time, in a way which can’t be done in mice or other models. Additionally, different combinations of medicines are easily given to zebrafish via the water in the fish tank. We have seen that aged fish are less able to repair fractures. We see something similar in fish when we give them drugs to reduce the number of neutrophils that come to the fracture. In this project, which follows-on from our earlier DMT-funded seed award, we will compare what the neutrophils are doing at the fracture site in fish when repair succeeds compared to when it fails, then using neutrophils from the blood of frail and healthy older people, test if the same is true in humans.
Lead applicant: Catarina Henriques (University of Sheffield)
Award amount: £399,467
Duration: 36 months
Summary:
As we age, we are more likely to become ill. Why is that? Ageing of the gut is an often-neglected aspect of old age that we know can actually contribute to multiple illnesses across the body, including the brain. Therefore, if we could understand how the different elements of the gut become damaged with ageing, perhaps if we can prevent or undo this, we can improve health across our bodies, including our brains, throughout our whole life. An important aspect of gut function relies on its ability to heal, and this requires communication between different types of cells, such as stem cells and immune cells. In this project we will use a combination of animal models and “mini-guts” grown in vitro, on a petri dish, from both human and zebrafish, to test specific mechanisms involved in gut regeneration. Our ultimate aim is to find ways to help tissue rejuvenation, to foster good overall health throughout our whole lifespan.
Lead applicant: Robert Knight (King’s College London)
Award amount: £366,873
Duration: 36 months
Summary:
Muscle weakness in ageing is a critical driver of frailty and results in a less active lifestyle. The immune system regulates muscle strength and function in part through modulating the function of muscle stem cells (muSCs). These cells are important for repairing muscle after injury and maintaining muscle strength. In ageing the immune system is affected and is thought to act inappropriately on the muSCs, so preventing them from repairing muscle effectively. Although this relationship is well established, it is not clear exactly how age-associated changes to immune cells alters their interaction with muSCs. This is because it is not possible to observe how cells respond to one another during muscle repair in a living animal or in people. Zebrafish offer a powerful and tractable system for understanding how cells are controlled in living animals during regeneration: they swiftly repair damaged tissue, genes can be easily manipulated and tissues are transparent so cells with fluorescent tags can be observed. We have carefully optimised a method to obtain precise measures of cell responses during muscle regeneration in zebrafish larvae and are now evaluating how these are affected by ageing.
This project therefore aims to identify age-associated factors such as genes or molecules that alter how immune cells control muSCs after injury. By showing how these ageing factors affect these cells during regeneration we can then start considering how to intervene to promote a healthier muscle environment. This may be through clinically approved drugs or chemicals that could readily be redeployed, or by other interventions such as exercise or dietary supplements. We will therefore investigate how age-associated factors that alter immune cell interactions with muSCs in zebrafish function in human cells to identify candidates for interventions.
As muscle weakness affects the vast majority of older people, our findings would be of interest to physicians and carers looking to promote greater mobility and independence. Identifying which age-associated factors affect the role of immune cells in muscle would have large implications for many areas of age-related research, as it is poorly understood how ageing affects cell behaviour. Our findings showing how altered immune cell function affect resident stem cells in muscle are relevant for ageing in other tissues, such as the liver, pancreas and heart. Therefore, outputs from this work will have a much broader impact across a range of ageing associated conditions.
Lead applicant: Alexi Nott (Imperial College London)
Award amount: £314,730
Duration: 36 months
Summary:
As we age, low-level inflammation in the brain can lead to cognitive decline, which can increase the risk of age-related brain disorders. Researchers have found that the major immune cells of the brain, called microglia, are affected by age, and also have sex differences in humans. Interestingly, some age-related brain disorders have a higher incidence in females, like Alzheimer’s.
We and others have discovered that genetic risk variants for brain disorders are mainly found in non-coding parts of our DNA called enhancers (the parts that control how genes work). We have found that these variants are linked to the function of the brain’s immune cells. By studying the epigenome of ageing brain immunity, we may be able to identify risk factors that could lead to cognitive decline.
We will test whether differences in the way male and female brain immune cells age can influence the likelihood of cognitive decline and if there are genetic factors that could explain why this happens.
Aim 1 is to look at how the brain’s immunity changes with age, and how it is different between males and females. We will look at human brain tissue from 30-40 year-olds and 60-70 year-olds to see how enhancers differ between sexes and with age using a technique called chromatin-immunoprecipitation.
Aim 2 is to look at how changes in the brain due to ageing and sex can impact the genes in microglia. We will use a technique called promoter-capture Hi-C to look at how enhancers interact with genes in the brain. We will use this information to figure out which genes are impacted by ageing and sex. We will look at the pathways these genes are involved in to see how ageing and sex affect brain immunity.
Aim 3 is to study how brain disorders are impacted by ageing of the immune system by using genetic risk data. We will use computational tools to identify which brain disorders are affected by immune ageing, and which gene regulatory networks are impacted. We will use genetic tools in microglia to test whether our computational findings can be seen in a living cell. Overall, this research investigates how ageing affects brain immunity and how this can lead to brain disorders. It will provide a better understanding of how sex can influence how our brains age, and how this can lead to different brain disorders. This will help guide future drug designs.
Lead applicant: Natalie Riddell (University of Surrey)
Award amount: £353,674
Duration: 36 months
Summary:
Chronic stress, increased sympathetic nervous system (SNS) activity, and high adrenaline levels are linked to cognitive decline (decreased ability to think and learn), and age-related diseases such as cardiovascular disease. SNS activity, chronic stress and adrenaline are also known to increase inflammation and reduce immune protection to infections. Increased inflammation and decreased immune protection are key features of the aged immune system. This immune ageing can cause illness in older people. We have shown that stimulating cells in the laboratory with adrenaline can cause immune cells to become aged, which we call senescence.
The primary aim of this work is to determine if SNS activity and adrenaline are linked to immune ageing in humans. We will achieve this by comparing the immune system in individuals with high SNS activity and high adrenaline levels to people with low SNS activity and low adrenaline levels. We will also see if the effect of high or low SNS activity and adrenaline on immunity is the same in young compared to older individuals. Finally, we will test if high SNS activity and adrenaline, increased immune ageing, and cognitive decline are linked. Understanding the relationship between adrenaline, ageing of the immune system, and cognitive decline will help us to design interventions to improve healthy lifespan.
This work will determine if high SNS activity and adrenaline is linked to immune ageing and cognitive decline. This data is critical to demonstrate the need for clinical trials assessing: 1) the immunological benefits of stress and SNS reduction interventions on immunological health, cognitive function and ageing; and 2) whether stopping the actions of adrenaline using beta-blockers in older adults may improve immune responses, for example to vaccination. Additionally, the work will follow-on from our earlier DMT-funded seed award and support the training and career development of several early career researchers.
Lead applicant: Kerrin Small (King’s College London)
Award amount: £208,826
Duration: 30 months
Summary:
The 20th century saw brilliant improvements to the life expectancy of humans. However, for many, this does not mean a long and healthy life. Indeed, increasing numbers of people are spending a higher proportion of their life in ill health. This is thought to be partly attributable to the deterioration of the immune system but studying this is far from trivial. There is a great need for biomarkers to measure age-related changes to the immune system which could indicate disease risk.
In 1961, Mary Lyon discovered that in every female cell where there are two X chromosomes one of them is silenced. This is termed Chromosome X Inactivation (XCI), and which X gets silenced in each cell is selected at random, and so, just like flipping a coin, each chromosome should be silenced in 50% of cells. However, as females age, some develop a “skewed” pattern of XCI in the immune cells of their blood, which is very different from the expected 50:50 ratio.
We previously carried out a study in 1,575 female twins from the TwinsUK cohort – one of the largest biobanks in the world – and found that people with this skewed pattern in their blood were at higher risk of developing cancer and cardiovascular disease. Fascinatingly, we also found 27% of identical twins had a different XCI pattern to each other – where the immune cells from one twin, but not the other, had become skewed – despite them having the same genetic makeup and being perfectly matched for age.
Our proposal will study the differences between the immune cells of these identical twins to define how changes to the immune system, which is tagged by the skewed XCI pattern, increases the risk of developing age-related diseases. To do this, we will use state-of the-art technology which generates read-outs from thousands of individual immune cells from each person. We will also use the 1,575 people on whom we have previously measured XCI, to test whether a skewed pattern in immune cells correlates with measures of deteriorating cognition, strength, and general health.
This work could be the first step to creating a routine blood test offered to females as they age to measure XCI. This could act as a proxy for the health of their immune systems and could help target those who would benefit from preventative lifestyle measures to reduce their risk of developing age-related diseases.