Targeting senescence with 5-methyltetrahydrofolate: a novel strategy to attenuate periodontitis.

Introduction: 5-methyltetrahydrofolate (5-MTHF), the biologically active form of folate, possesses well-characterized anti-inflammatory and antioxidant properties that are closely implicated in the regulation of cellular senescence. Accordingly, this study aimed to investigate whether 5-MTHF attenuates periodontitis by mitigating cellular senescence. Methods: We performed a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 to evaluate the association between serum 5-MTHF levels and periodontitis. Weighted multivariable regression models were applied, and exploratory mediation analysis assessed the contribution of biological aging. In vitro experiments examined the anti-senescence effect of 5-MTHF on lipopolysaccharide (LPS)-induced human gingival fibroblasts (HGFs). An in vivo mouse model of experimental periodontitis was used to evaluate alveolar bone loss. Results: Among 6,245 adults, higher serum 5-MTHF levels were significantly associated with lower odds of periodontitis, reduced clinical attachment loss, and shallower probing depth. Biological aging mediated 5.5%-17.3% of these associations. Mechanistically, 5-MTHF treatment attenuated LPS-induced cellular senescence in HGFs, as shown by decreased SA-β-gal activity, downregulation of p16, p21, and senescence-associated secretory phenotype genes. Correspondingly, local administration of 5-MTHF significantly alleviated alveolar bone resorption in mice with periodontitis. Discussion: 5-MTHF is associated with improved periodontal health, partly through attenuating cellular senescence. Our findings suggest that targeting senescence with 5-MTHF may represent a novel mechanism-based strategy for preventing and treating periodontitis.