MDNews - Cleveland-Akron-Canton

January/February 2018

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" Our work now establishes that cell senescence is an important mechanism that causes bone loss with aging. The fact that this is a common aging mechanism across tissues offers the possibility of a novel therapeutic approach that targets the fundamental aging mechanisms and could help affect multiple age-related comorbidities." SUNDEEP KHOSLA, MD, PROFESSOR OF MEDICINE, MAYO CLINIC COLLEGE OF MEDICINE mice. These genetically engineered mice have a well-validated suicide transgene within their senescent cells, and the administration of AP20187 causes the cells to self-destruct without a" ecting normal cells. "These cells provided proof of concept that if you kill or reduce the burden of these senescent cells in aging mice, you could alter age- related bone loss," says Sundeep Khosla, MD, Professor of Medicine, Mayo Clinic College of Medicine, and senior and co-corresponding author of the study. In the second phase of the study, researchers administered a com- bination of dasatinib and quercetin (D+Q) — two senolytic agents that co-corresponding author Dr. Kirkland has found in previous research to destroy senescent cells without a" ecting healthy cells. To complete the third part of the study, researchers administered a Janus kinase inhibitor, which did not destroy the senescent cells but rather inhibited their ability to produce the SASP. At the end of the study, the 20-month-old INK-ATTAC mice that received injections of AP20187 experienced a 50 percent increase in bone mass at the spine. The mice treated with the other approaches experienced 30 percent increases in spinal bone mass, according to Dr. Khosla. As a control, researchers also administered these three approaches to younger mice with no e" ect. "The fact that [the interventions] worked in the old mice but not in young mice provides strong support that they were really targeting mechanisms related to and specifi c for aging," Dr. Khosla says. The treatment duration of the senolytic D+Q compound, which mice received monthly for four months, also has causal implications. "Even though this senolytic drug combination was only present in the mice for a couple of hours, it eliminated senescent cells and had a long-lasting e" ect," Dr. Kirkland said in a Mayo Clinic News Network release discussing the fi ndings. "This is another piece of the mounting evidence that senolytic drugs are targeting basic aging processes and could have widespread application in treating multiple chronic diseases." A FOUNTAIN OF YOUTH? One exciting potential of this research is the ability to treat a variety of age-related comorbidities, such as osteoporosis, heart disease and frailty, with one senolytic agent that targets senescent cells instead of multiple drugs that target disease-specifi c pathways, according to Dr. Khosla. Moving forward at the basic science level, researchers plan to investigate which specifi c cell types become senescent and why senescent cells have detrimental e" ects on bone. On a translational level, Drs. Khosla and Kirkland are initiating early-phase trials to test the combination of D+Q in humans. Pilot studies examining new compounds that, like D+Q , eliminate senescent cells are also in development to investigate whether these compounds lower cell senescence in humans and whether they affect bone a long with other tissues. Dr. Bunta agrees that cell senescence is a worthwhile avenue of research but warns physicians not to jump to conclusions or overlook the value of current treatments. "Would it be wonderful if we had [these] drugs? Yes," he says. "But we have no idea how well any drug would do when measured against the anabolic agents or bisphosphonates [already on the market]." ■ 1 1 M D N E W S . C O M /// M D N E W S C L E V E L A N D /A K R O N / C A N T O N ■ J A N U A R Y/ F E B R U A R Y 2 018

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