Blocking a Protein May Reduce Buildup of Harmful Aging Cells
Cedars-Sinai Investigators Identify Possible Target for Therapies to Help Remove These Cells and Prevent Age-Related Health Problems
A team led by Cedars-Sinai Health Sciences University investigators has identified a protein that may hide aging cells from the body’s immune system, allowing them to build up and contribute to age-related health problems.
The findings, published in Cell Metabolism, suggest that the protein, called PD-L2, could serve as a target for treatments designed to remove harmful aging cells or as a blood marker that helps researchers track them.
“Our findings suggest that PD-L2 may help aging cells stay in the body when they would normally be removed by the immune system,” said Selim Chaib, PhD, research assistant professor of Medicine at Cedars-Sinai and first and co-corresponding author of the study.
These harmful aging cells, called senescent cells, become damaged and stop dividing but do not die. The cells remain in tissues and release substances that promote inflammation and interfere with the function of nearby cells. Their buildup has been linked to age-related health problems.
Investigators found that in laboratory mice, removing or blocking PD-L2 reduced the number of aging cells and levels of the inflammatory substances they produce. The mice were better able to process sugar and could grip objects with greater strength.
Investigators also found that human aging cells produced more PD-L2 than younger cells, and levels of the protein increased in some human tissues with age.
“If we can find a way to block this protein, we may be able to help the immune system get rid of these cells and potentially improve health problems linked with aging,” said James Kirkland, MD, PhD, director of the Center for Advanced Gerotherapeutics and senior author of the study.
Future research will explore whether blocking PD-L2 can safely produce health benefits in human patients and help researchers better understand its role in age-related diseases.
Additional Cedars-Sinai authors include Larissa Langhi Prata, Masayoshi Suda, Andres Sola, Jia Nie, Hyungsoo Kim, Tamar Pirtskhalava, Nino Giorgadze, Nicolas Musi, Ze’ev Ronai, and Tamara Tchkonia.
Other authors include Thomas Mitchell, Zacharias Anastasiadis, Hawley Kunz, Stella Victorelli, Ricardo Lozano Flores, Moritz Weigl, Shimpei Kawamoto, Ken Uemura, Binsheng Wang, Christina Inman, Ailing Xue, Kurt Johnson, Jair Espindola-Netto, Sonja Suvakov, Jennet Hatamova, Erik Parker, Davyn Benitto Hartono, Vagisha Kulshreshtha, Jose Alberto Lopez-Dominguez, Aaron Deisinger, Allyson Palmer, Yi Zhu, Megan Weivoda, Anne Gingery, Robert Hromas, Vesna Garovic, João Passos, David Allison, Eiji Hara, Michael Jensen, Stefan Tullius, Manuel Serrano, Ming Xu, Ian Lanza, and Yuji Ikeno.
Funding: Work in the J.L.K. laboratory was supported by the US National Institutes of Health (NIH; grants R37AG013925, R33AG061456, and P01AG062413), the Connor Fund, Robert J. and Theresa W. Ryan, the Hevolution Foundation, and the Noaber Foundation. Y.I. was supported by the San Antonio Nathan Shock Center Pathology Core (NIH Grant P30AG13319), San Antonio Claude D. 445 Pepper Center (NIH P30 AG044271), and NIH grants R01AG070034 and R56AG057785. M.D.J.’s studies were supported by NIH grants DK-45343 and DK-40484. H.E.K. was supported by an NIH musculoskeletal research training grant (T32AR56950) and NIH grant K01DK134765. S.K. was supported by the Japan Science and Technology Agency (JST) JPMJFR2308 and Japan Society for the Promotion of Science (JSPS) JP23K06481. L.G.P.L.P was supported by NIH grant 1K01AG090692. The clinical trial (NCT03350906) was supported by grants UL1TR002377 from the National Center for Advancing Translational Sciences (NCATS) and NIH R01AG054454. Y.Z. was supported by the Hevolution Foundation. J.F.P. was supported by NIH grants R01AG068048, R01AG82708, and UG3CA268103 and the Glenn Foundation for Medical Research. S.V.G. is supported by a Robert and Arlene Kogod Center on Aging Career Development Award and a c-SiG Pilot and Feasibility Award. A.G. was supported by NIH grant R01AR076347. M.X. is supported by a Hevolution/AFAR New Investigator Award in Biology and Geroscience Research. This work was supported in part by NIH P30AG050886.
Disclosures: S.C. holds patents or pending patents on PD-L2 at Mayo Clinic and Spanish National Cancer Research Center, some of which had been licensed to Rejuveron Senescence Therapeutics. M.S. is a shareholder of Senolytic Therapeutics, Life Biosciences, Rejuveron Senescence Therapeutics, and Altos Labs. T.T., Y.Z., A.K.P., T.P., N.G., and J.L.K. have a financial interest related to this research, including patents and pending patents covering senolytic drugs and their uses that are held by Mayo Clinic.
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