Insofar as either type 1 diabetes or type 2 diabetes increase the burden of senescent cells, we might say that the condition literally accelerates aging. The accumulation of lingering senescent cells is a contributing cause of aging; these errant cells disrupt tissue function and produce the characteristic profile of chronic inflammation known as inflammaging via a potent mix of secreted molecules and vesicles. Diabetic patients suffer more and worse gum disease, periodontitis, than their healthy peers, and researchers here show that hyperglycemia leads to increased numbers of senescent cells in gum tissue, causing all of the expected downstream consequences resulting from inflamed gums.

Inflammaging was recently affiliated with the progression of diabetic complications. Local cellular senescence together with senescence-associated secretory phenotype (SASP) are the main contributors to inflammaging. However, little is known about their involvement in diabetic periodontitis. Gingiva is the first line of host defense in the periodontium, and macrophages are key SASP-carrying cells. Here, we explored the molecular mechanism by which hyperglycemia drives the inflammaging in the gingival tissue of diabetic mice and macrophages.

We demonstrated that hyperglycemia increased the infiltrated macrophage senescence in gingival tissue of diabetic mice. Simultaneously, hyperglycemia elevated the local burden of senescent cells in gingival tissue and induced the serum secretion of SASP factors in vivo. Moreover, in vitro, high glucose induced macrophage senescence and SASP factors secretion through phosphorylation of NLRC4, which further stimulated the NF-κB/Caspase-1 cascade via IRF8-dependent pathway.

Deletion of NLRC4 or IRF8 abolished hyperglycemia-induced cellular senescence and SASP in macrophages. In addition, we found that treatment with metformin inhibited NLRC4 phosphorylation and remarkably decreased cellular senescence and SASP in the context of hyperglycemia. Our data demonstrated that hyperglycemia induces the development of inflammaging in gingival tissue and suggested that NLRC4 is a potential target for treatment of diabetes-associated complications.