helsi bites 2024

People are spending increasingly long lengths of time in a state of ill-health, particularly in older age. One key cause of this is the syndrome of frailty. Frailty can be defined as deterioration of organ systems and reduced internal reserve, though the exact causes of frailty are not fully understood. Frailty typically manifests as exhaustion, weight loss, muscle weakness and reduced/slowed activity. Although this may not appear immediately life-threatening, people with frailty have a greater risk of infections, injuries and falls and are more likely to die from common infections and minor procedures. Additionally, those frail individuals who do survive are less likely to fully recover from these insults. 

Although frailty affects over half of people aged over 85, not all old people are frail and not all frail people are old. Therefore, ageing alone cannot be pinpointed as the sole driver of frailty. Research primarily in cells have shown that as cells accumulate damage, some cells transition into a state termed senescence. Senescent cells survive indefinitely and release damaging agents which promotes degradation of tissues and encourage surrounding cells to also become senescent. Accumulation of senescent cells in mice has been linked to the onset of frailty and selective elimination of these senescent cells with drugs that target a senescent state, have alleviated the symptoms of frailty. This suggests that senescence may be a targetable solution to the onset and recovery from frailty.

However, there is limited research in humans. The next steps are to determine whether the relationship between senescence and frailty in humans is the same as that in mice. With the goal of targeting senescence as a therapeutic treatment for frailty, we aim to increase the number of years a person lives in a healthy and independent state, in turn reducing strain on health and social care requirements. 

An ageing population brings many challenges, with the increase in complex medical conditions prominent among them. While advances have been made in the last 50 years in tackling short-term illnesses, research is desperately needed to tackle the vast number of long-term, age-related conditions such as arthritis, diabetes, and Alzheimer’s disease. Many of these ageing-associated conditions are at least in part associated with the accumulation of senescent cells, a consequence of natural ageing. These senescent cells promote a highly inflammatory state in the surrounding tissue, which is detrimental to general tissue health. The secretions of these cells also encourage surrounding healthy cells to become senescent, further promoting the build-up of senescent cells in the body. As such, drugs are being developed to either eliminate senescent cells (senolytics) or neutralise the pro-inflammatory secretions from these senescent cells (senomorphics). However, new senescence detection and quantification methods are required to validate whether these drugs are effective.

Extracellular vesicles are small membrane-bound bubbles of biological information released by cells as a way of achieving cell-to-cell communication. These vesicles also allow for the removal of some waste products produced by cells, and have been of interest to researchers since the 1990s. Extracellular vesicles have been identified as a potential biomarker source for the detection of senescence. Extracellular vesicles are a particularly promising biomarker for detecting senescence non-invasively due to their prevalence in saliva. The identification of a specific, sensitive, and reliable biomarker of senescence would enable the development of technology to screen for senescence and accelerate the development of drugs targeting senescent cells. Here, we are developing a new type of sensor to detect extracellular vesicles released from senescent cells in saliva. This technology would facilitate the move away from treating people when they become sick, towards keeping people healthy into older age.

One of the main contributors to ageing is damage to our DNA. In order to understand this relationship further, we use zebrafish as a model to study the role of DNA damage in frail ageing. Zebrafish can experience some of the same ageing processes as humans, such as scoliosis, cancer and cataract. Using these ageing traits we are grouping our old fish into two groups: healthy old fish and frail old fish.  Between these two groups we see that the frail old fish have a decreased ability to remove RNA molecules, which are almost identical to DNA, from its DNA. Having these molecules in the DNA is a common practice for our cells, as it simplifies other cellular processes. However, if the RNA is not removed after being placed, they can cause a break in DNA, damaging it. By further understanding how this decreased ability of the cells to remove RNA is linked to ageing unfavourably, we aim to be able to find ways to reduce disease in ageing so that we can live longer and healthier.  

Increasing levels of patient health data is being stored in Electronic Health Records, with a significant portion of this being free-text records written by clinicians. This free-text data has been shown to contain information that cannot be found in other, more structured, sections of the records. However, due to privacy concerns, the data required to train the models need to process reports is difficult to obtain in the quantities required. Our approach explores the ways that modern Large Language Models can be used to create synthetic free text records from the structured data that is easier to anonymise and so more easily available. Additionally, we evaluate whether this data can be effectively used to train models that can identify multimorbidity in patients and make predictions about outcomes.

My research is all about inflammation that won’t stop, i.e., chronic inflammation. This research specifically looks at people who have two or more chronic inflammatory disorders at once, these people are described as having a ‘multimorbidity’. My aim is to develop new treatments which can be used for people suffering from multimorbidity, to help reduce the impacts of both diseases using one treatment. To do this, I’m going to be targeting a specific white blood cell called neutrophils. White blood cells are the main defensive arm of the immune system, capable of capturing and killing harmful materials such as bacteria. Neutrophils are an essential part of the immune system, being the first cells to respond to harmful materials. Neutrophils can kill bacteria in several ways, they can engulf and digest bacteria, or release materials capable of killing bacteria into the surrounding area in order to kill bacteria and other pathogens. Following the removal of bacteria, neutrophils themselves die by a natural and beneficial process called ‘apoptosis’, resolving inflammation as a result. However, in some cases this apoptosis does not occur, meaning neutrophils live for longer than needed. This process can result in the neutrophils continuously releasing materials capable of killing bacteria into host tissues (i.e., the lungs). This can cause significant damage to the hosts tissues, meaning the host is negatively impacted by this process. My research aims to develop drugs which are able to stop neutrophils releasing harmful materials into host tissues (thereby reducing the impact of neutrophils not undergoing apoptosis), whilst also developing drugs which are able to induce apoptosis in neutrophils. The aim of this is to: 1) Reduce the damage caused by neutrophils in those with chronic inflammatory diseases, and 2) To induce neutrophil apoptosis to cleanly remove neutrophils from sites of inflammation.