Buck Scientists Discover First Non-Invasive Biomarker to Verify Efficacy of Senolytics

The lipid-metabolite biomarker Oxylipin is released when senescent cells are forced to die and is detectable in blood and urine. This makes it possible to track and verify the efficacy of senolytics in a non-invasive way which will facilitate research and clinical trials of drugs that target multiple diseases.

Researchers at the Buck Institute have discovered a novel, non-invasive biomarker to measure and track performance of senolytics. This landmark discovery is important to many areas of medical research including senescence, aging, cancer, inflammation, and metabolism and is expected to play a major role in efforts to develop treatments to treat many conditions including arthritis, cardiovascular disease, lung disease, Alzheimer’s, Parkinson’s, fatty liver disease,?cancer metastasis, diabetic complications, cataracts, and glaucoma. A paper on the discovery Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis was published today in Cell Metabolism.

The researchers discovered that the lipid-metabolite biomarker Oxylipin is released when senescent cells are forced to die and is detectible in blood and urine, making non-invasive testing possible.?They are also developing a non-invasive biomarker test that can be used to measure and track performance of senolytics. With a growing list of senolytic drugs in development, detecting this metabolite via a companion test could verify performance of senolytic candidates.

Authors

The authors of the paper are Christopher D. Wiley, Judith Campisi, Rishi Sharma, Sonnet S. Davis, Jose Alberto Lopez Dominguez, Kylie P. Mitchell, Samantha Wiley, Fatouma Alimirah, Dong Eun Kim, Therese Payne, Andrew Rosko, Eliezer Aimontche, Sharvari M. Deshpande, Francesco Neri, and Chisaka Kuehnemann. Other co-authors include Marco Demaria, European Research Institute for the Biology of Aging, Groningen, Netherlands and Arvind Ramananathan, Institute for Stem Cell Science and Regenerative Medicine, Bengaluru, Karnataka, India.??

“The list of age-related diseases definitively linked to cellular senescence keeps growing, as does the number of biotech companies racing to develop drugs to eliminate senescent cells. The lack of a simple biomarker to measure and track efficacy of these treatments has been a hindrance to progress.?We are excited to bring this new biomarker to the field and look forward to it being used in the clinic. We hope that identifying and including these bioactive lipids as part of the SASP will encourage researchers working in a broad range of fields to take a new look at cellular senescence. The fact that one of these lipids ends up being a simple non-invasive biomarker for tracking the efficacy of treatments is a huge plus for those of us working to stem the ravages of age-related disease.”

Judith Campisi, PhD, Buck professor and senior scientist in this study

Senescent Cells Accumulate

Senescent cells accumulate over time and make proteins that negatively affect surrounding cells. This causes chronic inflammation that leads to many age-related diseases such as dementia, atherosclerosis, cancer, and arthritis. Diabetes and obesity are associated with accumulation of senescent cells in fat and other tissues. Many researchers are working to develop interventions that selectively target senescent cells. Removing senescent cells may delay, prevent, and maybe even reverse age-related diseases. Some of the most advanced research in this area is focused on?cell repair mechanisms and cell reprogramming.

Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis ( Image source Christopher Wiley, PhD)

"This work provides a new way of understanding and studying senescence-driven pathology. Oxylipins are implicated in many inflammatory conditions including cardiovascular disease and pain response.?Many commonly used drugs, such as aspirin and ibuprofen, act by preventing oxylipin synthesis."

Christopher Wiley, PhD, is an author on this paper and former assistant research professor at the Buck. He is now?at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University

Highlights from the Buck Study

The Buck study, which was performed in human cell culture and mice, shows that senescent cells synthesize a large array of oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids. Researchers identified one of these fatty acids as unique to senescent cells. It accumulates inside senescent cells and is released when the cells die. In this study, mice were given chemotherapy which induces widespread senescence, followed by a senolytic drug. The biomarker was only detected in the blood and urine of mice treated with both chemotherapy and the senolytic, but not with either on its own, confirming specificity for senolysis. Researchers also showed that dihomo-15d-PGJ2 had a functional role in senescence.?Addition of dihomo-15d-PGJ2 to non-senescent cell drove them into senescence by activating RAS, a cancer-promoting gene that is also known to cause senescence.?

This discovery will be useful in many areas of medical research. Two major uses for this biomarker are 1) showing that a drug is working when people are being treated with a senolytic for diseases driven by senescence and 2) as a companion assay for clinical trials using new senolytics. This discovery will accelerate clinical trials and help scientists develop new treatments to save lives.

Citation:??Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis??

DOI:?10.1016/j.cmet.2021.03.008

Authors: Christopher D. Wiley, Judith Campisi, Rishi Sharma, Sonnet S. Davis, Jose Alberto Lopez Dominguez, Kylie P. Mitchell, Samantha Wiley, Fatouma Alimirah, Dong Eun Kim, Therese Payne, Andrew Rosko, Eliezer Aimontche, Sharvari M. Deshpande, Francesco Neri, and Chisaka Kuehnemann.

Other co-authors include: Marco Demaria, European Research Institute for the Biology of Aging, Groningen, Netherlands and Arvind Ramananathan, Institute for Stem Cell Science and Regenerative Medicine, Bengaluru, Karnataka, India.??

Acknowledgments: This work was supported by grants from the National Institutes of Health and the Science and Engineering Research Board of India.?

?About the Buck Institute for Research on Aging

The Buck aims to end the threat of age-related diseases for this and future generations. The most capable and passionate scientists from a broad range of disciplines are studying mechanisms of aging to identify therapeutics that slow down aging. Their goal is to increase human health span which are the healthy years of life. Located just north of San Francisco, the Buck is globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious diseases including Alzheimer’s, Parkinson’s, cancer, macular degeneration, heart disease, and diabetes. The Buck wants to help people live better longer.?Success will ultimately change healthcare.?

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Copyright ? 2021 Margaretta Colangelo. All Rights Reserved.

This article was written by?Margaretta Colangelo.?Margaretta is a leading AI analyst based in San Francisco. She serves on the advisory board of the AI Precision Health Institute at the University of Hawai?i?Cancer Center.?

Twitter?@realmargaretta