Tag Archives: #senolyticdrugs

The First Non-invasive Biomarker to Track and Verify Efficacy of Senolytic Drugs (Medicine)

The discovery and development of a lipid-metabolite biomarker is expected to facilitate research and clinical trials of drugs that target multiple age-related diseases

Buck Institute researchers have discovered and are developing a novel, non-invasive biomarker test that can be used to measure and track performance of senolytics: a class of drugs that selectively eliminate senescent cells. The discovery is expected to play a major role in efforts to develop treatments that would battle a myriad of chronic age-related conditions that range from arthritis to lung disease to Alzheimer’s disease and glaucoma. This biomarker is a unique signaling lipid metabolite, normally exclusively intracellular, but is released when senescent cells are forced to die. This metabolite is detectible in blood and urine, making non-invasive testing possible. With a growing list of senolytic drugs in development, detecting this metabolite via a companion test could verify performance of senolytic candidates.

“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,” said Buck professor Judith Campisi, PhD, senior scientist on the study. “While the field has never been more promising, 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.”

Understanding senescence and identifying lipids as a new and potent component of the SASP

During cellular senescence, stressed or damaged cells permanently stop dividing, a putative mechanism to safeguard against cancer. Senescent cells are not dead – they spew out a stew of bioactive molecules that promote wound healing and chronic inflammation, the latter playing a major role in many age-related diseases as the cells accumulate over time. This bioactive stew is known as the SASP (senescence-associated secretory phenotype); its composition, and deleterious effects have been well-studied.

This work, performed in human cell culture and mice, shows that senescent cells also synthesize a large array of oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids. “Lipid components of the SASP have been vastly understudied,” says lead scientist Christopher Wiley, PhD, a former assistant research professor at the Buck, now at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston. “The biosynthesis of these signaling lipids promotes segments of the SASP and reinforces the permanent growth arrest of senescent cells. This work provides a new way of understanding and studying senescence-driven pathology,” he said. 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.

The biomarker is exclusive to senescent cells and may be of interest in cancer research

Wiley says senescent cells change their fatty acid metabolism and they do it in such a way that free polyunsaturated fatty acids accumulate inside the arrested cells where they are used to manufacture oxylipins. Researchers identified one of these fatty acids, 15-deoxy-delta-12, 14-prostaglandin J2 (dihomo-15d-PGJ2), 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. Inhibiting its synthesis allowed a subset of cells to escape senescence and continue dividing, and had a less inflammatory SASP profile. 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.

“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,” said Campisi. “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.”

Featured image: Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis © Christopher Wiley, PhD

Reference: Christopher D. Wiley, 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, Chisaka Kuehnemann, Marco Demaria, Arvind Ramanathan, Judith Campisi, Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis, Cell Metabolism, 2021, , ISSN 1550-4131, https://doi.org/10.1016/j.cmet.2021.03.008. (https://www.sciencedirect.com/science/article/pii/S1550413121001157)

Provided by Buck Institute for Research on Aging

Preclinical Research Shows Senescent Cell Removal Improves Cognitive Function (Medicine)

Mayo Clinic research findings indicate that the removal of senescent cells in aging mice improves cognitive ability in animals that already show signs of dementia. The results of these tests using senolytic drugs in aging mice appear in Aging Cell.

Senescent cells are those cells in the body that have ignored the order to expire. These cells exist in a suspended state. They are powerful enough to avoid the body’s signal to die, but they are not powerful enough to keep dividing. Instead, they linger, spewing out toxic chemicals. The cells and their toxic chemicals often are grouped together as senescence.

Many physical states, such as chronic inflammation, are linked to human cognitive decline. But recent studies also have examined the link between cognitive impairment and senescence. In this paper, Mayo researcher Diana Jurk, Ph.D., member of the Robert and Arlene Kogod Center on Aging, and her colleagues used a two-pronged approach to explore whether cognitive decline can be reversed. One approach focused on the genetic response to a drug ― pharmacogenomics ― while the other examined the problem from the perspective of drug administration ― pharmacologic.

Dr. Jurk’s Biology of Aging and Age-Related Diseases Laboratory at Mayo Clinic investigates the cellular and molecular mechanisms that lead to aging and age-related disorders, such as dementia, Type-2 diabetes and nonalcoholic fatty liver disease. This photo was taken prior to the COVID-19 pandemic, and masking and social distancing requirements. © Mayo Clinic

While senescent cells have been previously identified in the brain, it is still unknown which cell types in the brain become senescent during aging. To answer this question, Dr. Jurk and her team used single-cell RNA sequencing, which provides gene expression information from thousands of cells. Using this method, they identified that during aging, senescence is more pronounced in microglia and oligodentrocyte progenitor cells.

They then aged genetically modified mice ― INK-ATTAC mice ― and used two senolytic methods to clear senescent cells: AP20187, which eliminates p16positive senescent cells or the cocktail of dasatinib and quercetin. Both methods significantly improved cognitive function in the mice, based on before and after tests.

The authors write that this finding in mice provides a proof of concept for future studies on senescent cell removal as a potential therapy for age-related cognitive impairment in patients. This finding also reinforced a 2018 Nature paper by Mayo Clinic authors which showed that clearance of senescent cells improved cognitive decline in a mouse model of Alzheimer’s disease, as well as previous work by Dr. Jurk and colleagues on senescent cells and anxiety.

Still to be explored are the questions of:

  • Mechanistically, how do senescent cells contribute to aging of the brain?
  • Which senescent cells were targeted since the therapy was systemic?
  • What effect did this intervention have on immune cells in the genetically modified model?

The authors note that additional tests of cognitive function would further validate their findings.

The research was supported by grants from Glenn Foundation for Medical Research, the National Institute on Aging and other National Institutes of Health agencies, the Biotechnology and Biological Sciences Research Council, the Ted Nash Long Life Foundation, The Academy of Medical Sciences, the Conner Group, Robert J. and Theresa W. Ryan, and the Noaber Foundation. The full author list can be found in the Aging Cell article.

Provided by Mayo Clinic