The new research was published March 9 online ahead of print by the journal Aging Cell.
The scientists coined the term “senolytics” for the new class of drugs.
“We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders,” said TSRI Professor Paul Robbins, PhD, who with Associate Professor Laura Niedernhofer, MD, PhD, led the research efforts for the paper at Scripps Florida. “When senolytic agents, like the combination we identified, are used clinically, the results could be transformative.”
“The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging,” said Mayo Clinic Professor James Kirkland, MD, PhD, senior author of the new study. “It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time.”
Finding the Target
Senescent cells—cells that have stopped dividing—accumulate with age and accelerate the aging process. Since the “healthspan” (time free of disease) in mice is enhanced by killing off these cells, the scientists reasoned that finding treatments that accomplish this in humans could have tremendous potential.
The scientists were faced with the question, though, of how to identify and target senescent cells without damaging other cells.
The team suspected that senescent cells’ resistance to death by stress and damage could provide a clue. Indeed, using transcript analysis, the researchers found that, like cancer cells, senescent cells have increased expression of “pro-survival networks” that help them resist apoptosis or programmed cell death. This finding provided key criteria to search for potential drug candidates.
Using these criteria, the team homed in on two available compounds—the cancer drug dasatinib (sold under the trade name Sprycel®) and quercetin, a natural compound sold as a supplement that acts as an antihistamine and anti-inflammatory.
Further testing in cell culture showed these compounds do indeed selectively induce death of senescent cells. The two compounds had different strong points. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall.
Next, the team looked at how these drugs affected health and aging in mice.
“In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan,” said Niedernhofer, whose animal models of accelerated aging were used extensively in the study. “Remarkably, in some cases, these drugs did so with only a single course of treatment.”
In old mice, cardiovascular function was improved within five days of a single dose of the drugs. A single dose of a combination of the drugs led to improved exercise capacity in animals weakened by radiation therapy used for cancer. The effect lasted for at least seven months following treatment with the drugs. Periodic drug administration of mice with accelerated aging extended the healthspan in the animals, delaying age-related symptoms, spine degeneration and osteoporosis.
The authors caution that more testing is needed before use in humans. They also note both drugs in the study have possible side effects, at least with long-term treatment.
The researchers, however, remain upbeat about their findings’ potential. “Senescence is involved in a number of diseases and pathologies so there could be any number of applications for these and similar compounds,” Robbins said. “Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects.”
The co-first authors of the study, “Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs,” are Yi Zhu and Tamara Tchkonia of the Mayo Clinic.
In addition to Robbins, Niedernhofer and Kirkland, other authors include Sara J. McGowan, Heike Fuhrmann-Stroissnigg, Aditi Gurkar, Jing Zhao, Debora Colangelo, Akaitz Dorronsoro, Yuan Yuan Ling, Amira Barghouthy, Diana Navarro and Tokio Sano of TSRI; Yuji Ikeno and Gene Borden of The University of Texas Health Science Center; Adam Gower and Marc Lenburg of Boston University; Yi Zhu (co-first author), Tamara Tchkonia (co-first author), Tamar Pirtskhalava, Husheng Ding, Nino Giorgadze, Allyson Palmer, Steven O’Hara, Nicholas LaRusso, Carolyn Roos, Jordan Miller, Carolyn Roos, Grace Verzosa, Nathan LeBrasseur, Joshua Farr, Sundeep Khosla and Michael Stout of Mayo Clinic; and Jonathan Wren of Oklahoma Medical Research Foundation. See http://onlinelibrary.wiley.com/doi/10.1111/acel.12344/abstract
The work was supported by the National Institutes of Health (grants AG013925, AG041122, AG031736, AG044396, DK050456, HL111121 and AG043376), the Glenn Foundation and the Clinical & Translational Science Awards (grant UL1-TR000157).
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the world’s largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates—work toward their next discoveries. The institute’s graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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