PD-L2 May Help Harmful Aging Cells Evade the Immune System, Study Finds
Researchers at Cedars-Sinai University of Health Sciences have identified a protein that may allow harmful aging cells to escape detection by the immune system. The protein, known as PD-L2, may help senescent cells remain in the body instead of being removed. Their accumulation may contribute to inflammation and age-related health problems.
The findings identify PD-L2 as a potential target for future treatments designed to eliminate harmful senescent cells. The protein may also serve as a blood marker, offering a possible way to detect and monitor these cells.
“Our findings suggest that PD-L2 may help retain senescent cells in the body that are normally removed by the immune system,” said Dr. Selim Chaib, assistant professor of medical research at Cedars-Sinai University and first co-corresponding author of the study.
How senescent cells evade the immune system
As cells age or become damaged, some enter a state known as cellular senescence. These cells stop dividing but remain alive in tissues instead of being eliminated. Over time, they can release substances that promote inflammation and disrupt the normal activity of nearby cells.
The accumulation of senescent cells is associated with several health problems that become more common with age. Understanding why these cells persist could help scientists develop ways to reduce their harmful effects.
In the study, researchers found that PD-L2 may help senescent cells evade immune clearance, allowing them to remain in the body.
Blocking PD-L2 reduced senescent cells in mice
To investigate the protein’s role, scientists used laboratory mice in which PD-L2 was removed or blocked. Both approaches reduced the accumulation of senescent cells and lowered levels of inflammatory substances released by those cells.
The effects extended beyond cellular changes. Mice with reduced PD-L2 activity were better able to process sugar and had improved grip strength. These results suggest that targeting PD-L2 could affect physical functions associated with aging.
The researchers also studied human cells and tissues. They found that older human cells produced more PD-L2 than younger cells, while levels of the protein increased with age in certain human tissues. The findings suggest that the mechanisms observed in mice may also be relevant to human aging.
Could PD-L2 become a target for age-related diseases?
The results raise the possibility that blocking PD-L2 could help the immune system recognize and eliminate harmful senescent cells. In turn, this approach might help alleviate some health problems linked to the accumulation of these cells.
“If we can find a way to block this protein, we may be able to help the immune system eliminate these cells and potentially reverse health problems associated with aging,” said James Kirkland, MD, director of the Center for Advanced Geriatrics and senior author of the study.
However, the findings are preliminary. More research is needed before PD-L2-blocking treatments can be considered for use in people. Future studies will examine whether targeting the protein is safe, whether it provides meaningful health benefits in humans, and how PD-L2 contributes to age-related diseases.
Study contributors
Cedars-Sinai researchers who contributed to the study also included Larissa Langhi Plata, Masayoshi Suda, Andres Sola, Jia Ni, Hyun-Soo Kim, Tamar Piltskarava, Nino Giorgadze, Nicolas Musi, Ze’ev Ronai, and Tamara Cikonia.
Other contributors include Thomas Mitchell, Zacharias Anastasiadis, Holly Kuntz, Stella Victorelli, Ricardo Lozano Flores, Moritz Weigl, Shinpei Kawamoto, Ken Uemura, Bingsheng Wang, Christina Inman, Ayling Xue, Kurt Johnson, Jair Espindra-Netto, Sonya Svakov, Jennette Hatamova, Eric Parker, Davin Beni Hartono, Vagisha Krushlesta, Jose Alberto López-Dominguez, Aaron Dysinger, Allison Palmer, Yi Zhu, Megan Wivoda, Anne Gingery, Robert Lomas, Vesna Galovic, Joan Passos, David Allison, Eiji Hara, Michael Jensen, Stefan Tullius, Manuel Serrano, Ming Xu, Ian Lanza, and Yuji Ikeno.
Funding
Research in the JLK laboratory was supported by the National Institutes of Health (NIH, grants R37AG013925, R33AG061456, and P01AG062413), the Connor Foundation, Robert J. and Teresa W. Ryan, the Evolution Foundation, and the Noaber Foundation. YI was supported by the San Antonio Nathan Shock Center Pathology Core (NIH grant P30AG13319), the San Antonio Claude D. 445 Pepper Center (NIH P30 AG044271), and NIH grants R01AG070034 and R56AG057785. MDJ’s research was supported by NIH grants DK-45343 and DK-40484. HEK was supported by NIH Musculoskeletal Research Training Grant T32AR56950 and NIH Grant K01DK134765. SK was supported by Japan Science and Technology Agency (JST) JPMJFR2308 and Japan Society for the Promotion of Science (JSPS) JP23K06481. LGPLP was supported by NIH grant 1K01AG090692. This clinical trial (NCT03350906) was supported by grants UL1TR002377 and NIH R01AG054454 from the National Center for the Advancement of Translational Sciences (NCATS). YZ was supported by the Hevolution Foundation. JFP was supported by NIH grants R01AG068048, R01AG82708, UG3CA268103, and the Glenn Medical Research Foundation. SVG is supported by a Robert and Arlene Kogod Senior Center Career Development Award and a c-SiG Pilot and Feasibility Award. AG was supported by NIH grant R01AR076347. MX is supported by a Hevolution/AFAR New Investigator Award in Biology and Geriatrics Research. This research was supported in part by NIH P30AG050886.
Disclosure
SC holds patents or pending patents for PD-L2 at the Mayo Clinic and Spain’s National Cancer Research Center, some of which have been licensed to Rejuveron Senescent Therapeutics. MS is a shareholder in Senolytic Therapeutics, Life Biosciences, Rejuveron Senense Therapeutics, and Altos Labs. TT, YZ, AKP, TP, NG, and JLK have financial interests related to this research, including patents and pending applications covering senolytic agents and their use held by the Mayo Clinic.
Source: www.sciencedaily.com