A team of scientists, including researchers from UCL, has uncovered crucial insights that could revolutionize the treatment of cancer, fibrosis, and age-related conditions.
Their research, recently published in Nature Cell Biology and led by the Laboratory of Medical Sciences (MRC-LMS), reveals a promising target for a class of drugs designed to eliminate harmful senescent cells that trigger inflammation.
These drugs, known as senolytics, focus on removing senescent cells—often referred to as “zombie” cells. Senescent cells cease to replicate in response to cellular damage or aging, yet they continue to release proteins that provoke inflammation in the body.
Normally, the immune system eliminates senescent cells, but factors like aging and diseases can disrupt this process, allowing these cells to accumulate and contribute to chronic inflammation and tissue damage.
This continuous cycle of accumulating senescent cells exacerbates the aging process and the development of diseases.
Senolytics aim to break this cycle by eliminating senescent cells, thus restoring tissue stability and potentially improving the outcomes of various age-related diseases.
While pre-clinical studies have shown promise, there are currently no senolytic drugs on the market, and those in clinical trials have limitations. This has led to a call for more effective options to be developed.
Lead author Professor Jesus Gil, head of the Senescence Research Group at LMS, stated, “In a previous study, we showed the potential of repurposing existing drugs, but there are only limited drugs to choose from.
In this study, we greatly expanded our selection pool by seeking targets in over 7,000 ‘druggable’ genes. We were thrilled to reveal previously unknown vulnerabilities of senescent cells. This opens up new possibilities for treating age-related diseases.”
The research team employed a technique called RNA interference (RNAi) to investigate the molecular pathways affecting the survival of senescent cells. RNAi prevents the production of proteins by reducing gene expression.
They screened RNAi molecules targeting more than 7,000 genes and identified RNAi molecules that selectively killed senescent cells without harming normal cells.
Their discovery pinpointed a senolytic target pathway called coat protein complex I (COPI), responsible for transporting proteins within cells.
Inhibiting this pathway led to the death of senescent cells. Moreover, targeting this pathway improved outcomes in mouse models of cancer and fibrosis.
Co-author Professor J.P. Martinez-Barbera from UCL Great Ormond Street Institute of Child Health shared, “When we tested these senolytics in preclinical models of a pediatric brain tumor called craniopharyngioma, we were amazed to see that the majority of the senescent cells had been killed.
These results have encouraged us to explore these drugs further as potential treatments against these aggressive tumors.”
Building on these findings, the researchers explored drug candidates that target the COPI pathway. While some existing drugs directly interfere with the COPI pathway, their short lifespan in the bloodstream limits their clinical utility.
To overcome this limitation, the LMS team collaborated with Prof Edward Tate at Imperial College London and Myricx Bio, an Imperial spin-off, to investigate a different class of drugs known as N-myristoyltransferase inhibitors (NMTi).
These drugs indirectly inhibit the COPI pathway and demonstrated potent senolytic effects, improving cancer and fibrosis outcomes in mouse models.
Lead author Prof Jesus Gil concluded, “This work defines a novel class of senolytic drugs that expand the possibilities to treat a wide range of diseases associated with senescence, including cancer, idiopathic pulmonary fibrosis (IPF), or non-alcoholic steatohepatitis (NASH).”
This groundbreaking research opens up new avenues for drug development, offering hope in the fight against cancer, fibrosis, and other age-related conditions.
The team is now poised to embark on further research and potential clinical trials, marking a promising advancement in the pursuit of healthier aging.
If you care about cancer, please read studies about A common blood thinner can help fight cancer and findings of Heavy alcohol drinking is common in cancer patients.
For more information about cancer prevention, please see recent studies about nutrient in fish that can be a poison for cancer, and results showing this daily vitamin is critical to cancer prevention.
The research findings can be found in Nature Cell Biology.
Copyright © 2023 Knowridge Science Report. All rights reserved.
