Senolytic drugs boost key protective protein

Senolytics developed at Mayo Clinic and given once clear the bloodstream of senescent or "zombie" cells. These cells contribute to multiple diseases and negative aspects of aging. This study shows that the removal of senescent cells significantly boosts the production of a protective protein called a-klotho.

"We show that there is an avenue for an orally active, small-molecule approach to increase this beneficial protein and also to amplify the action of senolytic drugs," says James Kirkland, M.D., Ph.D., a Mayo Clinic internist and senior author of the study.

The researchers first showed that senescent cells decrease levels of a-klotho in three types of human cells: umbilical vein endothelial cells, kidney cells and brain cells. They also demonstrated that using the senolyitics desatinib plus quercitin in three types of mice that a-klotho was increased. And then after administering desatinib plus quercitin in clinical trial participants with idiopathic pulmonary fibrosis, that a-klotho also increased.

"We also are first to link the potential impact of fat-resident senescent cells on brain a-klotho," says Yi Zhu, Ph.D., a Mayo Clinic physiologist and biomedical engineer, and first author of the study. "This may open another avenue to investigate the impact of peripheral senescent cells on brain aging."

The protein a-klotho is important to maintaining good health, as it tends to decrease with age, and especially decreases in multiple diseases, including Alzheimer's, diabetes and kidney disease. Animal studies have shown that decreasing a-klotho in mice shortens life span and increasing a-klotho in mice by inserting a gene that causes its production increases life span by 30%.

Discovering ways to increase a-klotho in humans has been a major research goal, but that has been difficult because of its size and instability. Introducing it directly is problematic, as it would have to be administered into a vein instead of by mouth.

This study shows that senolytics, which can be administered orally, increase a-klotho in humans with idiopathic pulmonary fibrosis, a senescence-associated disease that leads to frailty, serious breathing difficulties and death.

The study was supported by the National Institute of Health, the Translational Geroscience Network, Robert and Arlene Kogod, the Connor Group, Robert J. and Theresa W. Ryan, and the Noaber Foundation.

The other authors are Yi Zhu, Ph.D.; Larissa Prata, Ph.D.; Erin Wissler Gerdes; Jair Machado Espindola Netto, Ph.D.; Tamar Pirtskhalava, Ph.D.; Nino Giorgadze; Utkarsh Tripathi; Christina Inman; Kurt Johnson; Ailing Xue; Allyson Palmer, M.D., Ph.D.; Tingjun Chen, M.D., Ph.D.; Kalli Schaefer; Jun Chen, Ph.D.; Sundeep Khosla, M.D.; Diana Jurk, Ph.D.; Marissa Schafer, Ph.D.; and Tamar Tchkonia, Ph.D. -- all of Mayo Clinic -- and Jamie Justice, Ph.D., and Stephen Kritchevsky, Ph.D., Wake Forest School of Medicine, and Anoop Nambiar, M.D., and Nicolas Musi, M.D., University of Texas.