Robert and Arlene Kogod Center on Aging.
Division of Endocrinology.
J Clin Invest. 2023 Apr 17;133(8):e162519. doi: 10.1172/JCI162519.
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.
衰老细胞（SnC）的清除可以预防几种与年龄相关的病理，包括骨丢失。然而，SnC 在介导组织功能障碍方面的局部和全身作用仍不清楚。因此，我们开发了一种小鼠模型（p16-LOX-ATTAC），该模型允许以细胞特异性的方式诱导 SnC 消除（衰老细胞清除），并使用骨骼作为原型组织比较衰老过程中局部与全身衰老细胞清除的效果。特异性去除衰老的成骨细胞可预防与年龄相关的脊柱骨丢失，但不能预防股骨骨丢失，其通过改善骨形成而不影响破骨细胞或骨髓脂肪细胞来实现。相比之下，全身性衰老细胞清除可预防脊柱和股骨的骨丢失，不仅改善了骨形成，还减少了破骨细胞和骨髓脂肪细胞的数量。将衰老细胞移植到年轻小鼠的腹腔中会导致骨丢失，并在远处的宿主成骨细胞中诱导衰老。总的来说，我们的研究结果提供了概念验证证据，证明局部衰老细胞清除在衰老背景下具有健康益处，但重要的是，局部衰老细胞清除仅部分复制了全身性衰老细胞清除的益处。此外，我们还证实衰老细胞通过其衰老相关分泌表型（SASP）导致远处细胞衰老。因此，我们的研究表明，优化衰老细胞清除药物可能需要针对全身而不是局部的衰老细胞，以延长健康的衰老。
