As the human body ages, cellular changes can drive a host of age-related diseases and conditions. The appearance of aging cells, also called senescent cells, in age-related diseases has spurred the search for drug compounds, or senolytics, that can target aging cells in tissues.
But not all senescent cells are the same. A fundamental challenge with the current discovery approach is the inability to isolate senescent cells from actual diseased tissue so they can be screened for specific targets. This technical barrier has impeded researchers from identifying compounds that precisely target senescent cell types that might differ across organs and diseases.
UCSF researchers have now developed a new drug pipeline technique where senescent cells can be directly isolated from diseased tissue and organs. They focused on fibrotic lung tissues, which have become thickened or scarred. In a mouse model, the researchers used a novel genetic reporter that allowed them to isolate and quantify senescent p16Ink4a+ cells in fibrotic lung tissues. This enabled the investigators to perform screens against senescent cells that are specific to the fibrotic lung. The research team identified XL888, a HSP90 inhibitor, as a potent senolytic in tissue fibrosis.
In the study published May 1, 2024 in the Journal of Clinical Investigation, first author Jinyoung Lee, PhD, a post-doctoral researcher in the UCSF lab of Tien Peng, MD, described the new screening pipeline and demonstrates that XL888 treatment eliminated senescent lung fibroblasts and improved preclinical endpoints in a mouse model of lung fibrosis. In addition, XL888 preferentially targeted senescent human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), a deadly age-related lung disease.
“This study provides proof of concept for a platform where senescent cells are directly isolated from diseased tissues. This allows us to identify compounds that precisely target disease-causing senescent cells, rather than cells that are innocent bystanders,” said Peng, senior study author, UCSF associate professor of Medicine and investigator in the UCSF Bakar Aging Research Institute. “The goal of our research is to spur academic-industry collaborations to help bring effective anti-aging therapeutics to the clinics.”
Authors: Jin Young Lee, Nabora S. Reyes, Supriya Ravishankar, Minqi Zhou, Maria Krasilnikov, Christian Ringler, Grace Pohan, Chris Wilson, Kenny Kean-Hooi Ang, Paul J. Wolters, Tatsuya Tsukui, Dean Sheppard, Michelle R. Arkin, and Tien Peng
Funding: Please see the study.
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