In June 2021 we launched our call for seed funding proposals focussing on The Ageing Immune System as part of our new thematic approach to funding.
The ageing immune system was identified by the British Society for Research on Ageing as an underfunded area of great importance and thus, applications were invited for projects that would generate vital data to support larger grant applications in the future. We plan to allocate funding to support larger research project grant applications on this theme in the future, and are working with other funders and initiatives in this area such as the CARINA (CAtalyst Reducing ImmuNe Ageing) Network funded by the Medical Research Council (MRC) and the Biotechnology and Biological Sciences Research Council (BBSRC).
Proposals for our seed funding call were peer-reviewed and then assessed by a panel comprising independent experts, which included some early career researchers, as well as suitably qualified members of our Research Grants Committee. The panel members were:
- Professor Bernard Conway (Chair of the Expert Panel and Dunhill Medical Trust Research Grants Committee)
- Professor Andrew Devitt (Aston University)
- Professor Deborah Dunn-Walters (University of Surrey)
- Dr Katie Mylonas (University of Edinburgh)
- Dr Kylie Belchamber (University of Birmingham)
- Dr Madhvi Menon (University of Manchester)
- Dr Mariana Borsa (University of Oxford)
- Dr Nicholas Rattray (University of Strathclyde)
- Dr Sian Henson (Queen Mary University of London)
- Professor Simon Milling (University of Glasgow)
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 extend a huge thank you to all those who contributed to the assessment of these proposals.
We received 28 applications and the following nine were successful (equating to a success rate of 32%).
Please expand any of the project titles below to read more information, including the lay summary:
Lead applicant: Dr Alice Denton (Imperial College London)
Award amount: £30,052
Duration: 12 months
Summary: Advancing age is associated with the decline in the functions of many body systems, and this includes the immune system. This can be easily seen with the recent coronavirus pandemic, where older people are substantially more likely to become very ill, or die, from SARS-CoV-2 infection, and we see similar pathology with other infections, such as influenza. The coronavirus pandemic has also shown us that vaccinations, when available, are very effective at limiting bad outcomes from infection, however this is not always the case with older people. Some older people don’t respond very well to vaccines, meaning they are less protected from infection, and we don’t really understand why this is the case. If we could better understand why vaccines don’t work in older people then we could engineer vaccines that can target what’s wrong to get a better response from the vaccine. This would mean that older people are better protected from severe infections and can lead healthier lives.
My laboratory is trying to understand why older people do not respond well to vaccines. We have recently found, using mice, that the environment to which immune cells are exposed has a significant impact on how well they can generate a vaccine response: young immune cells aren’t very good at responding to vaccines when they are in an old environment. We have also found that the lymph node environment seems to become non-responsive with increasing age, and we now think that this may be an important reason as to why vaccines sometimes don’t work well in older people. In this project, I want to extend these findings and determine whether the environment of human lymph nodes is similarly affected by age, and whether this impacts on the vaccine response. This study will determine whether the lymph node environment is switched off (“senescent”) with advancing age, and whether this impairs the immune response. These proof-of-concept findings will form the basis for future studies, which will delve into why the aged environment cannot support the immune response. Ultimately, this research will inform ways to improve vaccine design in order to elicit better vaccine responses in at-risk older people.
Lead applicant: Professor Andrew Devitt (Aston University)1
Award amount: £49,990
Duration: 10 months
Summary: Non-healing (chronic) wounds such as abscesses and ulcers are a great health burden, both financially and personally, and are a significant and increasing challenge within an ageing society. Estimates suggest that each year 3.8 million patients are managed by the NHS for wounds at a total cost of £8.3 billion and 80+% of this is incurred in community care, including over 130 million patient visits from healthcare staff. Chronic wounds are difficult to treat. In a recent study, up to 55% of them failed to heal within the year of study. It is clear that there is a pressing need for new approaches to wound management and therapy.
Wound healing involves the immune system promoting a defence response (to clear infection and damaged tissue) and subsequently, a repair response is initiated. This involves macrophages (an important immune cell) which switch their function from defence to repair (wound healing) responses. This switch is impaired in older people and leads to chronic wounds becoming ‘stalled’. However, we do not understand the mechanism that is affected by ageing. This programme of work will address this gap in our knowledge directly.
Over recent years, stem cells and small membrane bags (Extracellular Vesicles : EV) that they release have been shown to promote repair responses and wound healing. However, stem cells and EV are less able to promote repair as we age and our work will define why this is the case.
Our work reveals that EV from stem cells carry a family of crucial inflammation-controlling enzymes that can both promote and inhibit inflammation. Consequently, the precise balance of these family members within EV will decide the outcome: beneficial wound repair or detrimental chronic inflammation. We call these enzyme-carrying EV ‘active EV’. Our preliminary work reveals that EV from stem cells of older people carry more enzyme activity, and we hypothesise that the precise enzyme composition of EV changes during ageing, causing impaired wound healing. By studying stem cells and their vesicles from older and younger people, we will understand how EV changes alter macrophage repair responses. This work therefore aims to reveal the repair pathway from stem cells that becomes defective as we age so that therapies can be designed to overcome the defects. Consequently, this work will pave the way for novel therapeutic approaches for hard to treat and debilitating conditions associated with ageing such as chronic non-healing wounds.
Lead applicant: Dr Chrissy Hammond (University of Bristol)
Award amount: £48,815
Duration: 10 months
Summary: Osteoporosis is a disease which 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 cause long-term pain, mobility issues and social isolation, and cost the UK £4.4 billion every year; as the ageing population grows, the cost of osteoporosis will rise significantly.
As well as being age-related, osteoporosis can be caused by steroid medicines used to treat inflammatory diseases like arthritis. These people often have weakened immune systems which are less able to respond to injuries. This means fractures in aged and immunosuppressed 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 immune cell, are known to be important in the earliest stages, where they help to prevent infection and kickstart repair. Recent research suggests that neutrophils may also help to stabilise fractures by making an emergency scaffold to support damaged bone. We want to better understand the role of neutrophils in bone repair, and whether the neutrophil response to fracture is affected by ageing.
Zebrafish are good models for studying fracture, as their bones are maintained by the same cells as humans. We can study bone repair over time in zebrafish, because their tails are transparent and contain bones which are easily fractured. The low cost compared to mice makes them a preferred model for studying the effect of aging on bone repair. Additionally, different combinations of drugs are easily given to zebrafish via their tank water.
Our research shows that zebrafish get more fractures as they age. We have also developed a method for studying fractures over time. We will use this method in young and old zebrafish, to study how neutrophils behave after fracture. We will test whether reduced neutrophil function, often seen in older or immunocompromised people, affects bone repair. Finally, we will test whether drugs which affect neutrophils alter fracture repair in zebrafish. Our experiments will reveal more about the role of neutrophils in bone ageing and repair. We will determine whether neutrophils should be researched further as a target for treating fragility fractures in older patients.
Lead applicant: Dr Dianne Cooper (Queen Mary, University of London)
Award amount: £46,820
Duration: 12 months
Summary: Advanced age is a major risk factor for most chronic diseases and infections in humans, yet the reasons why this occurs are not fully understood. We now know that the body makes protective molecules as part of a normal healthy response to infection or inflammation, however this process becomes defective with ageing. One of these protective molecules is called Annexin A1, which instructs white blood cells to destroy bacteria during infections. We hypothesise that the amount of Annexin A1 produced by our body declines with age and that if we supplement these levels, we will be able to restore normal white blood cell function and subsequently reduce the risk of infections and chronic illness and improve the quality of life in elderly individuals.
For this study, we will use a small amount of blood from healthy young and old people to compare the levels of AnnexinA1 on white blood cells; we will also explore how these cells communicate and influence other cells via tiny packages termed microvesicles. This is important as multiple cell types are involved in the immune response to infection or inflammation therefore monitoring their cross-talk is vital for obtaining a full overview of the health status of these cells.
Lead applicant: Dr Dinis Calado (The Francis Crick Institute)
Award amount: £49,145
Duration: 12 months
Summary: As individuals age, changes in the immune system often mean that older individuals lack long-term protective immunity following infection or vaccination, as recently shown for COVID-19. This problem is undoubtedly multifactorial and complex. In this proposal we will focus primarily on the study of plasma cells, also known as antibody-producing cells. Plasma cells are formed during the course of an immune response and the antibody produced by these cells is essential for long-term protection from infection. However, current knowledge does not provide in-depth longitudinal information on the impact of age in the plasma cell population nor on the cellular composition and properties of other cells that interact with plasma cells and that contribute for their survival.
Our laboratory generated a new system in the mouse that allows to specifically trace plasma cells over-time after an immune response. We will use this model to investigate the impact age has on both plasma cells and cells that support plasma cell survival. The overall expectation is to gather age related biological data on plasma cell survival and devise ways of intervention that offer enhanced longer-term protective immunity to older individuals.
Lead applicant: Dr Emma Chambers (Queen Mary, University of London)
Award amount: £47,230
Duration: 12 months
Summary: Inflammageing is the process whereby as we get older we have an increased amount inflammatory proteins circulating in blood. This increase in inflammatory proteins is associated with worsening immunity, poor vaccine responses and quite shockingly increased risk of death. Thereby identifying therapeutic targets to block this inflammation is desperately needed to improve the health of older adults.
Although there are many potential origins of inflammageing, there is one cell type which has been ignored, despite the fact it has the potential to drive inflammatory protein production and thus inflammageing – is a monocyte. Monocytes are circulating white blood cells which predominantly live in the blood and respond to pathogen and inflammageing signals with a large increase in inflammatory protein production. Monocytes are known to exist in three different subtypes (flavours) and they are known as either classical, intermediate and non-classical. It has been observed by myself and others that there is a significant increase in the number of non-classical monocytes in the blood of older (≥65 years) adults as compared to younger (<35 years).
The majority of research to date on the effect of age on monocyte function has focussed on the classical monocytes, actively excluding the non-classical monocytes. I have observed that when monocytes from older adults are cultured in a plate with a combination of two different stimuli, there is significantly more inflammatory protein production as compared to younger monocytes. This increase in inflammatory proteins is due to the increased number of inflammatory non-classical monocytes. However, further research is needed to understand if this is a general inflammatory defect in the older non-classical monocytes or whether its specific to the stimulation conditions I used.
The overarching aim of this grant is to perform in depth analysis of older monocyte populations and compared them to younger monocytes. I will be using culturing techniques as well as an exciting new technique called proteomics which looks at protein levels within the cell, to assess if there are any differences between young and old. The ultimate aim of this research is to identify different proteins within older monocytes which drive inflammatory protein production, which in turn can be blocked with drugs and improve immunity and health of older adults.
Lead applicant: Dr Iwan Evans (University of Sheffield)
Award amount: £49,995
Duration: 12 months
Summary: As we age our bodies become increasingly prone to infection and take longer to repair following injury. We contain many different types of white blood cell, including cells known as macrophages. These immune cells play important roles protecting us against infection and mediating repair. Consequently, understanding how these cells change their behaviour as we age is a critical question. Unsurprisingly, given the diverse roles they play, there are many kinds of macrophages within our bodies: different types of macrophages are found within different organs. Adding to this diversity, macrophages also change their behaviour, or become “activated”, depending on the precise job they need to do. Unfortunately, macrophages can worsen many human diseases via overenthusiastic responses, leading to excessive amounts of inflammation. Inflammation contributes to diseases of old age, such as neurodegenerative disorders, cancer and chronic lung disease. At the same time, failure of immune responses involving macrophages leaves us exposed to infection.
In this study, we want to understand the contributions different types of macrophages make to ageing and whether their manipulation can improve age-related declines in how we deal with infections. To do this, we will use fruit flies, an organism used in biomedical research for >100 years that has played vital roles in discovering many of biology’s central ideas. Like us, flies contain a variety of macrophage-like cells. The genetic tractability of flies means we can easily manipulate numbers of different macrophages within this organism and understand the role different populations play during ageing. Flies are an especially good organism for this as they are short-lived, but still experience old age becoming increasingly frail and more likely to die as they age. Critically, they contain their own versions of the majority of human disease genes, while fly experiments are cheaper and less ethically challenging than using longer-lived, more sentient creatures like mice. Their small size also makes it easier to image immune cells within intact animals – in their proper environment – during ageing.
This work will tell us how different types of macrophages influence ageing and whether changing which particular macrophages are present can improve the weakened immune responses we see in old age. Furthermore, we will analyse which genes are turned on as an organism’s immune system ages. This work thus has the potential to identify new drug targets to improve health in old age and help us understand how immune systems change as we age.
Lead applicant: Dr Kylie Belchamber (University of Birmingham)2
Award amount: £49,042
Duration: 12 months
Summary: Every day we breath in millions of particles from the air. Some particles will be harmful viruses, bacteria and pollutants which can damage the lungs and cause lung infections. Our immune system is made up of different cells that work together to prevent infections and then promote lung healing. As we age, our immune system does not work as well during infections. This means older people suffer with more lung infections, such as pneumonia, and the consequences of those infections are more severe, including hospital admission and death. By understanding why the immune system becomes less effective with age, we can find new ways to support the immune system and improve the health of older adults.
Macrophages are one of the immune cells that fight infection. They are found in blood, but enter the lungs and other organs where they phagocytose or ‘eat’ bacteria, killing them. We know that macrophages do not work as well as they should in some lung diseases, but we don’t know if they work normally as we grow older. Studies in mice and rats have suggested that macrophages work less well in older animals, but these studies have not been repeated in humans. Humans can remain healthy as they age, but for many people, old age is associated with frailty and poor health. If we can understand changes in macrophages function as healthy and frail humans age, we might be able to find new treatments to reduce the increased risk of infection and improve outcomes for older people with infections.
To do this, we will take blood samples from young people (under the age of 35), and healthy and frail older people (over the age of 60), with their consent. We will study macrophages including whether they can eat bacteria normally and find out what may be making them work less well. This includes looking at factors in the blood that we know change during unhealthy ageing, and looking at the bacteria in the throat that macrophages are exposed to, by taking a swab of the throat (similar to a COVID-19 test).
This study will identify why older people are more likely to get lung infections, and have poorer outcomes, especially those with frailty. It will identify where new drugs might be used to improve how these immune cells work, and help people live healthier for longer.
Lead applicant: Dr Natalie Riddell (University of Surrey)
Award amount: £49,977
Duration: 12 months
Summary: Normal immune function is vital for good health. The correct balance between immune activation, for protection against cancers and infections, and immune restraint, to prevent inflammation, is essential to our wellbeing. Immune balance is maintained by communication between the nervous, endocrine (hormonal) and immune system. The sympathetic nervous system regulates immune function by releasing the stress hormone adrenaline. Adrenaline decreases our immune protection to infections and cancers and may reduce the effectiveness of vaccinations. The aim of this work is to see how adrenaline alters immune cell function. Importantly, this work will find out whether the aged immune system is more vulnerable to adrenaline regulation. The results will help us understand how the release of adrenaline that fluctuates daily, and is seen in psychological stress, anxiety, sleep disruption, and is altered during ageing, may reduce immunity.
Alterations to how our immune cells respond to adrenaline will change the way the immune system works. Over time our immune cells increase the number of adrenergic receptors present upon the surface of the cell. This means that the cells become sensitive to adrenaline, and this could result in altered cell function. We have found that this increase in adrenergic receptors does results in increased sensitivity of immune cells to adrenaline, and that this causes a loss of normal immune responses. As the number of adrenergic receptors increases upon our immune cells over time, we predict that immune cells from old individuals will be more sensitive to adrenaline than immune cells of young people. If this is proved to be true, then adrenaline may cause a further reduction in immune protection in old people. The main aim of this work is to find out whether the aged immune system is more sensitive to adrenaline when compared to the young.
We will use a technique that allow us to study the many different types of immune cells found in the circulating blood. We will obtain blood from young (<35 years) and old (>65 years) individuals and examine how cells respond to adrenaline in the laboratory by changing how they function e.g., changes to the cells ability to divide into two.
The results of this work may provide evidence that adrenaline can reduce immunity in old adults. This means that drugs which prevent the actions of adrenaline (e.g. β-blockers) may be used to promote immune responses in old people, such as when receiving a vaccine.
Congratulations to each of the successful applicants and we look forward to seeing how the work develops. We hope that the unsuccessful applicants found the detailed feedback provided to each of them helpful.
Notes:
The usual strict rules regarding conflicts of interest were applied and our general guidance for peer reviewers can be found here for your information.
- Professor Andrew Devitt was a member of the Research Grants Committee and Expert Panel at the time of the award but was neither involved in the decision regarding the award of a grant to him nor the final ranking of proposals.
- Dr Kylie Belchamber was a member of the Expert Panel at the time of the award but was neither involved in the decision regarding the award of a grant to her nor the final ranking of proposals.