Mayo Clinic researchers have uncovered three new agents that aim to delay the onset of aging by targeting senescent cells. A recent study of human cell cultures shows that the drugs fisetin and two BCL-XL inhibitors – A1331852 and A1155463 – cleared senescent cells in vitro. The findings appear online in Aging.
Senescent cells contribute to frailty and other age-related conditions. “These cells accumulate with age and at sites of multiple chronic conditions, such as fat tissue in diabetes, the lungs in chronic pulmonary diseases, the aorta in vascular disease, or the joints in osteoarthritis,” says James Kirkland, M.D., Ph.D. (GIM ’07), Division of General Internal Medicine and director of the Robert and Arlene Kogod Center on Aging. “At Mayo Clinic, we discovered the first senolytic drugs – agents that selectively eliminate senescent cells while leaving normal cells unaffected. These senolytic agents alleviated a range of age- and disease-related problems in mice. We used the hypothesis-driven approach that we used to discover the first senolytic drugs – two published in early 2015 and another later in 2015 – to discover these three new senolytic drugs.”
Mayo Clinic researchers, working in collaboration with the University Medical Center Groningen and the Scripps Research Institute, induced senescence in human cell cultures by radiating human primary preadipocytes, human umbilical vein endothelial cell cultures and IMR90 cell cultures. Then, using an ATPLite and crystal violet assay, researchers measured cell viability and demonstrated that fisetin and BCL-XL inhibitors A1331852 and A1155463 cleared senescent cells in vitro.
In addition to fisetin and BCL-XL inhibitors, previously reported senolytics include dasatinib, quercetin, navitoclax (ABT263) and piperlongumine. Dr. Kirkland and collaborators are hopeful that fisetin, which is present in low concentrations in many fruits and vegetables, and the BCL-XL inhibitors may be better candidates for eventual translation into clinical interventions than some other senolytics due to their low toxicity levels.