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Transplanting old organs promotes senescence in young recipients.

Authors: Jasper Iske|||Maximilian J Roesel|||Friederike Martin|||Andreas Schroeter|||Tomohisa Matsunaga|||Ryoichi Maenosono|||Utkarsh Tripathi|||Yao Xiao|||Yeqi Nian|||Barbara J Caldarone|||Florian W R Vondran|||Peter T Sage|||Haruhito Azuma|||Reza Abdi|||Abdallah Elkhal|||Tamar Pirtskhalava|||Tamara Tchkonia|||James L Kirkland|||Hao Zhou|||Stefan G Tullius

Journal: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Tr

Publication Type: Journal Article

Date: 2024

DOI: NIHMS1942803

ID: 37913871

Affiliations:

Affiliations

    Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Klinik für Herz-, Thorax-, und Gefäßchirurgie, Deutsches Herzzentrum der Charité, Berlin, Germany; Berlin Institutes of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Klinik für Herz-, Thorax-, und Gefäßchirurgie, Deutsches Herzzentrum der Charité, Berlin, Germany.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Surgery, CVK/CCM, Charité Universitätsmedizin Berlin, Berlin, Germany.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Regenerative Medicine and Experimental Surgery, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan.|||Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan.|||Department of Physiology and Biochemical Engineering Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Institute of Transplant Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, China.|||Mouse Behavior Core, Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.|||Regenerative Medicine and Experimental Surgery, Department of General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.|||Transplant Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Department of Urology, Osaka Medical and Pharmaceutical University, Osaka, Japan.|||Transplant Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||NAD+ Immunology Laboratory, Huntington Medical Research Institutes, Pasadena, California, USA.|||Department of Physiology and Biochemical Engineering Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA.|||Department of Physiology and Biochemical Engineering Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA.|||Department of Physiology and Biochemical Engineering Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA; Division of General Internal Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.|||Division of Transplant Surgery, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: stullius@bwh.harvard.edu.

Abstract

In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce senescence in naïve cells. We hypothesized that the engraftment of old organs may induce senescence in younger recipients, promoting age-related pathologies. When performing isogeneic cardiac transplants between age-mismatched C57BL/6 old donor (18 months) mice and young and middle-aged C57BL/6 (3- or 12- month-old) recipients , we observed augmented frequencies of senescent cells in draining lymph nodes, adipose tissue, livers, and hindlimb muscles 30 days after transplantation. These observations went along with compromised physical performance and impaired spatial learning and memory abilities. Systemic levels of the senescence-associated secretory phenotype factors, including mitochondrial DNA (mt-DNA), were elevated in recipients. Of mechanistic relevance, injections of mt-DNA phenocopied effects of age-mismatched organ transplantation on accelerating aging. Single treatment of old donor animals with senolytics prior to transplantation attenuated mt-DNA release and improved physical capacities in young recipients. Collectively, we show that transplanting older organs induces senescence in transplant recipients, resulting in compromised physical and cognitive capacities. Depleting senescent cells with senolytics, in turn, represents a promising approach to improve outcomes of older organs.


Chemical List

    Senotherapeutics|||DNA

Reference List

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