Macrophage depletion during disease induction attenuates disease severity in old and young mice. Periodontal disease was induced in old and young mice (n = 6/group) for a period of 7 d. Macrophages were depleted via treatment with PLX3397 throughout the induction period. After the 7-d induction period, the maxillae were isolated and analyzed. PLX3397 treatment resulted in a significant decrease in macrophage quantity within the periodontium of old and young mice (A). PLX3397 treatment also resulted in significant decrease in tartrate-resistant acid phosphatase–positive (TRAP+) osteoclast cell surface/bone surface and TRAP+ osteoclast number per bone surface in the periodontium of old and young mice (B, C). Attenuation of disease severity was demonstrated in both old and young mice via treatment with PLX3397. Similarly, across both age groups, PLX3397 resulted in significantly decreased proinflammatory cytokine expression within the gingiva of old mice as measured by quantitative real-time polymerase chain reaction (D, E) and significantly greater bone volume fraction (BV/TV) and bone mineral density (BMD) as measured by micro–computed tomography (CT) (F, G). Representative micro-CT images demonstrate the effect of PLX3397 treatment in old and young mice (H–K). Data presented as mean ± SD and mean ± SEM for D and E. *P < 0.05. **P < 0.01.