Local senolysis in aged mice only partially replicates the benefits of systemic senolysis

Joshua N. Farr, Dominik Saul, Madison L. Doolittle, Japneet Kaur, Jennifer L. Rowsey, Stephanie J. Vos, Mitchell N. Froemming, Anthony B. Lagnado, Yi Zhu, Megan Weivoda, Yuji Ikeno, Robert J. Pignolo, Laura J. Niedernhofer, Paul D. Robbins, Diana Jurk, João F. Passos, Nathan K. LeBrasseur, Tamara Tchkonia, James L. Kirkland, David G. MonroeSundeep Khosla

Producción científica: Articlerevisión exhaustiva

16 Citas (Scopus)

Resumen

Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allowed for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes. By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclast and marrow adipocyte numbers. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide proof-of-concept evidence that local senolysis has health benefits in the context of aging, but, importantly, that local senolysis only partially replicates the benefits of systemic senolysis. Furthermore, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging.

Idioma originalEnglish (US)
Número de artículoe162519
PublicaciónJournal of Clinical Investigation
Volumen133
N.º8
DOI
EstadoPublished - abr 17 2023

ASJC Scopus subject areas

  • General Medicine

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