Senescence-associated secretory phenotype and its impact on oral immune homeostasis

Abstract

The senescence-associated secretory phenotype (SASP), which accumulates over the course of normal aging and in age-related diseases, is a crucial driver of chronic inflammation and aging phenotypes. It is also responsible for the pathogenesis of multiple oral diseases. However, the pathogenic mechanism underlying SASP has not yet been fully elucidated. Here, relevant articles on SASP published over the last five years (2017-2022) were retrieved and used for bibliometric analysis, for the first time, to examine SASP composition. More than half of the relevant articles focus on various cytokines (27.5%), growth factors (20.9%), and proteases (20.9%). In addition, lipid metabolites (13.1%) and extracellular vesicles (6.5%) have received increasing attention over the past five years, and have been recognized as novel SASP categories. Based on this, we summarize the evidences demonstrating that SASP plays a pleiotropic role in oral immunity and propose a four-step hypothetical framework for the progression of SASP-related oral pathology-1) oral SASP development, 2) SASP-related oral pathological alterations, 3) pathological changes leading to oral immune homeostasis disruption, and 4) SASP-mediated immune dysregulation escalating oral disease. By targeting specific SASP factors, potential therapies can be developed to treat oral and age-related diseases.

Keywords: age-related disease; cellular senescence; oral homeostasis; oral-systemic disease; senescence-associated secretory phenotype.

Figure 1

Keyword co-occurrence network visualization. (A) The proportion of different SASP factors in articles published in recent 5 years. Demonstrated as a pie plot. The inner are different types of SASP factors. The outer are most cited SASP factors of each type. (B) The keyword co-occurrence network shows the relationship between different types of SASP factors and different types of cells. Each node is a concentric circle, and the thickness of each layer of the concentric circle represents the frequency of use of this keyword in a certain year. The color of each line represents the year of the first co-occurrence between the two keywords. The thickness of each line represents the frequency of co-occurrence between the two keywords.

Figure 2

The molecular mechanism of senescence-associated secretory phenotype production. The formation of senescence-associated secretory phenotype (SASP) networks in cells is regulated by a complex molecular mechanism. The DNA damage response is related to senescence activation and SASP expression. SASP protein expression is regulated at both the transcription and post-transcriptional levels. Additionally, epigenetic changes regulate SASP gene expression.

Figure 3

The four proposed layers of how senescence-associated secretory phenotype impacts oral diseases. Senescence-associated secretory phenotype (SASP) (including cytokines, chemokines, growth factors, and proteases) secreted by oral senescent cells, as well as circulating SASP, constitute the aging microenvironment of oral cavity. As an important mediator, SASP accelerates oral pathological alterations including senescence re-enforcement, recruitment of immune cells, matrix remodeling and fibrosis. Then, the SASP-induced dysregulation of immune homeostasis can be divided into three categories: mucosal immunity, bone immunity, and tumor immunity. These destroy the structure and function of different oral tissues. When age-related tissue damage accumulates, it manifests as age-related diseases.

Figure 4

The central role of senescence-associated secretory phenotype in natural aging, inflammation, and cellular senescence. With natural aging, there is a progressive loss in tissue and organ functions, and accumulated senescence-associated secretory phenotype (SASP) can contribute to this process. Depending on the triggers, including infection or injury, the inflammatory response has different pathological consequences. The inflammatory response can be amplified via the secretion of inflammatory cytokines. Various cells (such as epithelial cells, dental pulp cells, fibroblasts, and macrophages) in the oral cavity undergoing senescence release SASP to the local microenvironment under the induction of natural aging and stress.