University College LondonNov 15 2024

The aging and failure of cells that occurs when the liver is damaged can spread to other organs, suggests a new study in mice and humans from researchers at UCL, the University of Edinburgh and the CRUK Scotland Institute.

In the study, published in Nature Cell Biology, scientists demonstrate for the first time that the deterioration of cells in a damaged liver can activate a process associated with ageing and impaired function, which then transmits to otherwise healthy organs elsewhere in the body.

The team also identified a key protein that could potentially be manipulated to prevent this multi-organ failure.

The authors of the study say the findings could have major implications for our understanding of how diseases in different parts of the body interact with each other, and what happens as people age.

Our findings provide the first insight into why severe liver injury results in the failure of other organs, such as the brain and kidneys, and death.

We were able to validate these new and exciting observations in patients, providing a route to develop blood biomarkers that can be measured to identify those at risk, and new therapies to treat severe liver disease."

Professor Rajiv Jalan, study author from UCL Division of Medicine

As the body gets older, cells become tired and stop working effectively. This process - called cell senescence - is a common effect of ageing but can also be triggered by diseases at any stage of life.

Senescence of liver cells following acute severe liver disease - which can be caused by a number of diseases including viral infections or toxins such as paracetamol overdose - can cause irreparable damage, leading to liver failure and can often lead to multi-organ failure.

The study observed that once a large enough number of liver cells were damaged in mice with sudden liver failure, senescence started to appear in other organs, including the kidneys, lungs and brain, causing them to fail.

The researchers identified a key biological pathway involving TGFβ, a protein linked to the immune system, which when blocked prevented liver cell senescence from spreading to other organs in mice.

In the future, treatments to block this pathway could prevent multi-organ failure in patients with severe liver injury, experts say.

Levels of liver cell senescence were also a powerful indicator of disease outcome in patients with severe liver damage.

The study team examined liver tissue biopsies from 34 people with acute severe liver disease. High levels of liver cell senescence early in disease were linked to an increased risk of multi-organ failure and the need for liver transplantation.

There is currently no test to predict how sudden liver failure will progress when it begins. Monitoring liver cell senescence could help to identify those most at risk, including those likely to need a liver transplant, the research team says.

The study's principal investigator, Professor Tom Bird of the University of Edinburgh's Centre for Inflammation Research and the CRUK Scotland Institute, said: "The implications of the findings are potentially very profound. This may be a means by which severe disease, even in a single organ, can snowball into the failure of many organs in the body.

"But it can also teach us about ways to prevent this happening, both in sudden disease and potentially in a range of diseases occurring over years or even decades as we age."

Morag Foreman, Head of Discovery Researchers at Wellcome, said: "This is an exciting set of findings, unlocking crucial new insights with the potential to transform our understanding of multi-organ failure. This opens new avenues of research into how our cells break down that could help us treat and prevent sudden, or even age-related, disease.

"We are pleased to have supported Professor Bird and team. This study marks a culmination of years of work, underlining the importance of long-term, discovery research and finding insights into life, health and wellbeing."

This research was principally funded by Wellcome and Cancer Research UK.

University College London

Journal reference:

Kiourtis, C., et al. (2024). Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ. Nature Cell Biology. doi.org/10.1038/s41556-024-01543-3.