Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction.

Selim Chaib, Larissa G P Langhi Prata, Masayoshi Suda, Andres Sola, Thomas J Mitchell, Zacharias P Anastasiadis, Hawley E Kunz, Jia Nie, Stella G Victorelli, Ricardo Lozano Flores, Moritz Weigl, Shimpei Kawamoto, Ken Uemura, Hyungsoo Kim, Binsheng Wang, Christina L Inman, Tamar Pirtskhalava, Nino Giorgadze, Ailing Xue, Kurt O Johnson, Jair M Espindola-Netto, Sonja Suvakov, Jennet Hatamova, Erik S Parker, Davyn Benitto Hartono, Vagisha Kulshreshtha, Jose Alberto Lopez-Dominguez, Aaron M Deisinger, Allyson K Palmer, Yi Zhu, Megan M Weivoda, Anne Gingery, Robert Hromas, Vesna D Garovic, João F Passos, David B Allison, Eiji Hara, Michael D Jensen, Nicolas Musi, Stefan G Tullius, Ze'ev A Ronai, Manuel Serrano, Ming Xu, Ian R Lanza, Yuji Ikeno, Tamara Tchkonia, James L Kirkland

Center for Advanced Gerotherapeutics, Cedars-Sinai Medical Center and Cedars-Sinai Health Sciences University, Los Angeles, CA, USA; Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center and Cedars-Sinai Health Sciences University, Los Angeles, CA, USA. Electronic address: [email protected] for Advanced Gerotherapeutics, Cedars-Sinai Medical Center and Cedars-Sinai Health Sciences University, Los Angeles, CA, USA; Division of Endocrinology, Diabetes & Metabolism, Cedars-Sinai Medical Center and Cedars-Sinai Health Sciences University, Los Angeles, CA, USA. Electronic address: [email protected]. · pubmed

Paper

Abstract

Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.

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Research summary

Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction by restoring immune clearance. This paper is relevant because it identifies a specific immune checkpoint mechanism (PD-L2) that allows senescent cells to evade clearance, offering a novel therapeutic target to remove the root cause of age-related dysfunction rather than just treating symptoms.

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