It has long been suspected that removing senescent cells locally is insufficient to treat age-related conditions in which the pro-inflammatory signaling produced by senescent cells contributes to pathology. These signals enter the bloodstream and are carried widely about the body. While the effect of a distant senescent cell on local pathology is more dilute than that of a local senescent cell, there are a lot more distant senescent cells than there are local senescent cells. This issue is likely why Unity Biotechnology's initial clinical trial of localized removal of senescent cells in osteoarthritic knee joints failed to produce sufficiently large beneficial effects in patients to proceed.
In today's open access paper, researchers demonstrate this issue in mice, in the context of the age-related loss of bone density that leads to osteoporosis. Bone tissue is constantly remodeled through the actions of osteoblast cells, depositing extracellular matrix, and osteoclast cells, breaking down extracellular matrix. Chronic inflammatory signaling generated by senescent cells helps to tip the balance away from osteoblast activity, leading to a steady loss in bone density over time. At least in mice, clearing senescent cells locally doesn't help to prevent this issue to anywhere near as great a degree as clearing senescent cells globally.
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 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.