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Local senolysis in aged mice only partially replicates the benefits of systemic senolysis
Joshua N Farr 1, Dominik Saul 2, Madison L Doolittle 2, Japneet Kaur 2, Jennifer L Rowsey 1, Stephanie J Vos 2, Mitchell N Froemming 2, Anthony B Lagnado 3, Yi Zhu 4, Megan M Weivoda 5, Yuji Ikeno 6, Robert J Pignolo 4, Laura J Niedernhofer 7, Paul D Robbins 7, Diana Jurk 4, João F Passos 2, Nathan K LeBrasseur 8, Tamara Tchkonia 4, James L Kirkland 4, David G Monroe 2, Sundeep Khosla 4
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 allows 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 osteoclasts and marrow adipocytes. 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 the first proof-of-concept evidence that local senolysis has health benefits in the context of aging, but importantly, local senolysis only partially replicates the benefits of systemic senolysis. Further, we establish that SnCs, through their 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.