Upregulation of senescence-associated gene expression levels in human gingival tissue affected by periodontitis

Abstract

Background: Accumulation of senescent cells is increasingly recognized as a mechanism of aging and is considered an attractive therapeutic target for various age-associated diseases. The prevalence and severity of periodontitis increase with age, and preclinical studies have demonstrated that senescent cells could be a potential therapeutic target for age-associated periodontitis. However, clinical data linking cellular senescence and periodontitis are limited. Methods: Gingival tissues affected with periodontitis and healthy controls were collected from patients with or without periodontitis in a cross-sectional study. RNA isolated from these samples was analyzed for senescence gene expression by quantitative polymerase chain reaction (qPCR) assays. The associations of the gene expression levels with periodontal diagnosis, presence or absence of attachment loss or bleeding on probing, and age were examined. Additionally, we analyzed the expression of senescence genes in the gingival tissues of mice with or without ligature-induced periodontitis. Results: A total of 54 human gingival tissue samples were included in the study. Among the genes analyzed, p16, TP53, MMP2, and MMP14 exhibited significantly higher expression in the periodontitis group compared to the control group. Furthermore, these genes were associated with clinical signs of periodontitis, such as bleeding score and attachment loss at diagnosis. There were no statistically significant positive correlations between gene expression levels and age. The ligature-induced periodontitis significantly increased expression levels of p16 and other senescence genes in mouse gingival tissues. Conclusion: Gene expression analysis indicates the accumulation of senescent cells in gingival tissue affected with periodontitis, supporting the concept that senotherapeutics could be effective in treating periodontitis. Plain language summary: Biological stressors cause cells to age, known as cellular senescence. These senescent cells play a significant role in age-related diseases and are considered a key target for treatment. Periodontitis, a gum disease, damages the tissues that support teeth and is a leading cause of tooth loss worldwide. When people get older, they have a higher chance of being affected by periodontitis. Studies using animal models have shown that the accumulation of senescent cells may be driving periodontitis in older individuals. Therefore, targeting senescent cells may be a potential treatment approach for periodontitis. However, clinical evidence showing the accumulation of senescent cells in gum tissue affected with periodontitis is limited. This study aimed to investigate whether periodontitis is accompanied by senescent cell accumulation in the gum tissue by examining gene expression in tissues with and without periodontitis. A total of 54 human gum tissues (27 healthy and 27 diseased) were collected during gum surgeries. Our analysis found that four genes related to cellular senescence (p16, TP53, MMP2, and MMP14) were significantly higher in samples affected with periodontitis. This indicates that senescent cells accumulate in diseased gum tissue. Additionally, results from an animal experiment suggested that being affected with gum disease may be a mechanism accelerating cellular aging in the gum tissue. The findings support the concept that targeting senescent cells would be an effective approach to treat gum disease.