Abstract Periodontal disease or periodontitis is characterized with inflammation and bone loss due to oral infection. Importantly, growing evidence suggests that chronic periodontal inflammation is an important risk factor for diabetes, heart diseases, oral cancer, and other systemic diseases. Increased periodontitis is associated with aging, and it represents a significant public concern in the aging population. The mouse model of periodontitis suggests that aging promotes microbial colonization, disease susceptibility, periodontal inflammation and bone loss. However, how aging affects the onset and progression of periodontitis is not fully understood. Peroxisome proliferator-activated receptor γ coactivators 1α (PGC-1α; encoded by Ppargc1α, also known as Pgc-1α) is a master regulator of mitochondrial biogenesis and oxidative metabolism in skeletal muscle, liver, brain and the heart. PGC-1α has been shown to interplay with the NF-κB pathway in skeletal muscle and cardiac cells. During the last funding period, we showed that the immune transcription factor nuclear factor kappa B (NF-κB) played a critical role in bone loss of periodontitis and osteoporosis. Although it is well known that loss of PGC- 1α is associated with increased ROS, aging and chronic inflammation, its role in periodontal inflammation and bone homeostasis is largely unexplored. Therefore, we explored the role of PGC-1α in periodontitis and osteoporotic bone loss. Unexpectedly, we found that PGC-1α was abundantly expressed in monocytes and macrophages, but its expression levels were downregulated with aging. Importantly, genetic studies revealed that loss of PGC-1α significantly increased periodontal inflammation and alveolar bone loss induced by oral infection. Additionally, we found that loss of PGC-1α intrinsically enhanced the expression of pro-inflammatory cytokines in macrophages and osteoclastogenesis by enhancing NF-κB activation in vitro. Based on these exciting novel discoveries, in this competing renewal, we hypothesize that PGC-1α plays a critical role in control of periodontal inflammation and alveolar bone loss in periodontitis by inhibiting NF-κB. Loss of PGC-1α not only promotes the expression of inflammatory mediators, but also enhances osteoclastogenesis and bone resorption. To test our hypothesis, we propose the following three specific aims: 1) Determine whether loss of PGC-1α in monocytes/macrophages exacerbates periodontal inflammation and alveolar bone loss in periodontitis by enhancing NF-κB; 2) Determine if induction of PGC-1α can attenuate periodontal inflammation and alveolar bone loss in periodontitis by inhibiting NF-κB; and 3) Explore the molecular mechanisms by which PGC-1α regulates periodontal inflammation and osteoclastogenesis through NF-κB. New findings from our studies may identify a novel factor that regulates periodontal inflammation and bone loss in periodontitis, and have important implications in the prevention and treatment of periodont...