Aging is characterized by progressive degeneration, which is influenced by alterations in the oxidation-reduction status and inflammatory responses triggered by oxidative stress (8). This results in an increased production of reactive oxygen species (ROS) within the body, leading to abnormal levels of oxidative stress. Specific increases in the levels of ROS are hypothesized to serve an important role in initiating and perpetuating the cellular aging processes. The accumulation of ROS can result in DNA damage and subsequent cell cycle arrest (9). DNA damage can further lead to telomere shortening, DNA methylation, histone deacetylation and mitochondrial dysfunction, thereby instigating transcriptome alterations that are associated with aging (10,11).

Mitochondrial dysfunction is a hallmark of aging (12). Mitochondrial autophagy, vital for maintaining mitochondrial quality control, eliminates dysfunctional mitochondria to maintain cellular homeostasis. It can modulate the cellular senescence phenotype by suppressing transcription of SASP-associated genes (13). The accumulation of lipofuscin is a distinctive feature of senescent cells, and oxidative stress-induced DNA damage during senescence promotes its accumulation (14). Moreover, it is associated with impaired mitochondrial autophagy function, exhibiting a positive association with the expression levels of cell aging markers p16 and p21 (11,15,16). Oxidative stress-induced senescence (SIPS) is implicated in the pathogenesis of age-associated macular degeneration and is known to increase secretion of SASP-associated proteins (15,16). In periodontal tissue, increases in the SIPS levels have detrimental effects that are comparable to inflammatory factors and promote the secretion of SASP-associated proteins (17). Targeting mitochondrial autophagy pathways in mesenchymal stem cells in various degenerative conditions, such as intervertebral disc degeneration (IVDD) and osteoarthritis (OA), may enhance cartilage repair and regeneration capabilities (18–20).

Aging is associated with alterations in the composition of microbial communities. For example, in the gut, the microbiota can influence the aging of gut cells by regulating the intestinal epithelial barrier, gut immune system and gut metabolism. In the skin, the microbiota can influence skin cell senescence by regulating the integrity of the stratum corneum, the skin immune system and skin metabolism. Previous studies reveal a shift in the microbiome with age, demonstrating a positive association between aging and the presence of gram-negative bacteria such as Porphyromonas gingivalis (21,22). Furthermore, aging is characterized by an increased responsiveness of periodontal cells to the oral microbiota and mechanical stress (23). A previous study indicates that bacterial lipopolysaccharides (LPS) can induce cellular senescence and increase expression levels of SASP-associated genes (24). Prolonged exposure to P. gingivalis LPS can prompt periodontal cell senescence due to the activation of the cell cycle arrester molecule p53 (25). LPS also mediate microglia activation and ischemic brain injury via the NF-κB signaling pathway (26). Additionally, LPS from Escherichia coli is indicated to increase the activity of senescence-associated β-galactosidase, increase the expression levels of cell cycle inhibitor proteins p21 and p53, and impede human pulp stem cell growth (25,27,28). Increased expression of LPS by P. gingivalis may stimulate NF-κB activation in periodontal ligament stem cells (PDLSCs), exacerbate the high glucose microenvironment and increase the expression of proinflammatory cytokines (namely, ILs, TNF and INF) and matrix metalloproteinases (MMPs) such as MMP-1 (29,30). LPS can also trigger the downstream NF-κB pathway via Toll-like receptor 4, prompting the release of inflammatory cytokines such as TNF-α, IL-6 and IL-1β that contribute to cellular damage. Activation of NF-κB also results in an increased expression of p53 and p21 in the PDLSC nucleus, which is pivotal in promoting cellular aging (31,32).

A potential feedback loop exists between inflammatory cytokines and cellular senescence, which could hasten the progression of the senescence of inflammatory cell (33). Senescent cells are more vulnerable to harm from external stimuli, including proinflammatory factors and bacterial virulence factors. The NOD-like receptor pyrin domain-containing protein 3 inflammasome recognizes pathogen-associated molecular patterns or damage-associated molecular patterns, activating cysteinyl aspartate specific proteinases-1 (Caspase-1) (34). Caspase-1 cleaves the protein Gasdermin D, which then converts the precursor forms of IL-1β and IL-18 into mature forms, thereby initiating pyroptosis (35,36). IL-1β can promote paracrine cellular senescence and NF-κB activation, activating a cascade of an inflammatory-induced senescence (37). The accumulation of pyroptotic macrophages (MΦs) in gingival tissue under high-glucose conditions can stimulate IL-1β secretion and paracrine senescence in neighboring cells (38). Furthermore, proinflammatory cytokines (such as ILs, TNF and INF) generate the ROS themselves and then the ROS induce epithelial cell senescence, the ROS activate the Eotaxin-1/CCL11 pathway leading to fibroblast senescence (39,40).

Senescent cells, with a SASP, release various proinflammatory factors (such as IL-1α, IL-1β, IL-6 and IL-8), growth factors (such as hepatocyte growth factor, TGF-β and granulocyte macrophage colony-stimulating factor), chemokines [such as chemokine (C-X-C motif) ligand (CXCL)-1/3 and CXCL-10] and MMP-8 and MMP-9. The SASP can promote chronic inflammation through paracrine effects, affecting neighboring stem cells, fibroblasts, immune cells, epithelial cells and endothelial cells via paracrine and autocrine signaling mechanisms (41). In the aging heart, MMP-9 activates the transition of the MΦ phenotype to the proinflammatory M1 subtype can induce inflammation due to its increased secretion of TNF-α, IL-1β, IL-6 and other inflammatory factors (42). Activation of the SASP initiates a milieu of chronic inflammation in addition to the age-induced stressors, leading to a self-perpetuating cycle of senescent cell accumulation (43).

PDLSCs possess self-renewal and multi-directional differentiation capabilities, which are important for periodontal tissue regeneration and osteogenic differentiation (44). The senescence of PDLSCs reduces their osteogenic potential, leading to periodontal tissue destruction via inflammation and the induction of the SASP (Fig. 2). This process reduces the regenerative capacity of periodontal tissues in periodontitis. In patients with diabetes, oxidative stress induces telomere dysfunction and PDLSC senescence, reducing periodontal bone tissue regeneration and increasing bone loss in periodontitis (45–47).

Aging impacts the proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs), with senescent cells involved in senile osteoporosis-related bone loss (48). Sirtuin (SIRT), a NAD-dependent deacetylase family member, is a potential therapeutic target for age-related diseases (49). SIRT1, an upstream regulator of mitochondrial autophagy, can inhibit age-related degenerative changes in IVDD and OA (18,50). The SIRT1/PTEN-induced kinase 1/Parkin pathway-mediated mitophagy activation reduces renal tubular epithelial cell senescence (51). The balance between osteoblast and osteoclast activity maintains bone mass, and osteoblasts are important in bone formation through matrix synthesis, substance secretion and tissue mineralization. Upregulation of SIRT1 expression levels activates the PI3K/Akt/mTOR pathway to promote mitophagy, enhancing osteoblast proliferation and viability (52).

Inhibition of micro (mi)RNA-96-5p expression levels in osteoblasts markedly downregulates the mRNA of alkaline phosphatase (the bone differentiation factor), which indicates that miRNA-96-5p promotes osteoblast senescence, leading to decreased bone differentiation. miRNA-96-5p is likely crucial in regulating osteoblast degenerative changes during aging (53,54). The accumulation of senescent cells in the alveolar bone can stimulate the secretion of SASP-associated protein, which exerts a potent paracrine effect on osteoblasts, inhibiting their function and reducing bone regeneration in periodontitis (23,55). Inflammatory bone loss in periodontitis, characterized by osteoclast activity, is exacerbated by aging, which enhances osteoclast production (56). Osteoblast-secreted osteoprotegerin (OPG) mitigates bone loss by inhibiting the receptor activator of NF-κB (RANK) ligand/RANK pathway. However, the reduction in osteoblast numbers with aging reduces OPG levels, contributing to osteoclast-induced bone loss (57,58). These findings underscore the causal role of senescent cells and their SASPs in alveolar bone loss and suggest that targeting senescent cells could increase the alveolar bone remodeling capabilities.

Gingival fibroblasts (GFs) are predominant cells within the gingival connective tissue and serve an important role in regulating periodontal inflammation. The proliferative capacity of GFs and the mitotic activity of PDLSCs may reduce with age. This reduction is associated with increased mRNA levels of MMP-2 and MMP-8, leading to the increased degradation of the extracellular matrix (59). Chronic bacterial assaults can induce a reduction in the amount of epithelial growth, compromising the integrity of the epithelial barrier (60). Once this barrier is breached, bacteria and their virulence factors such as endotoxin and exotoxin, can penetrate deeper connective tissues, exacerbating periodontal tissue damage (61).

Neutrophils are important for pathogen clearance in the immune response to periodontitis. Age-related neutrophil dysfunction may disrupt the neutrophil homeostasis in periodontal tissues, impairing bacterial clearance and resulting in subsequent damage to periodontal tissues (62). Previous studies demonstrate developmental endothelial locus-1 mRNA and protein expression levels are downregulated in the periodontal tissue of aged mice compared with that of young mice (63,64). This downregulation leads to an excessive recruitment of neutrophils and inflammatory bone resorption. Furthermore, in elderly hosts aged >65 years, excessive or dysregulated PI3K activity impairs the accuracy of neutrophil migration (65,66). Aging mice have a deficiency in autophagy-related protein 5, resulting in decreased autophagy levels and impaired release of neutrophil extracellular traps (NETs) (67–69). This impairment hinders the clearance of pathogenic bacteria and their metabolites in the gingival sulcus by NETs. In summary, cellular senescence reduces the clearance of existing periodontal bacteria, compromising the integrity of the epithelial barrier and exacerbating local periodontal inflammation.

MΦs serve an important role in the innate immunity as the initial defense against pathogenic microorganisms. Monitoring periodontitis activity may rely on the phenotypic polarization of MΦs in order for them to modulate the immune response to the subgingival biofilm and mitigate alveolar bone loss (70). Aging-related M1 to M2 repolarization failure can lead to an increase in osteoclast activation, a reduction in osteoblast formation, an increase in bone resorption and a decrease in bone formation. Senescent MΦs are implicated in perpetuating chronic inflammation during bone remodeling, as well as inducing a senescent state in young BMSCs and diminishing their osteogenic potential (71). MΦ M1 polarization is associated with PDLSC senescence in diabetic periodontitis microenvironments. By contrast, M2 polarization potentially increases the expression levels of osteogenesis-related cytokines, such as runt-related transcription factor 2, alkaline phosphatase and osteocalcin, exerts anti-aging effects and facilitates the osteogenic differentiation of PDLSCs (72,73). Additionally, the paracrine factors released by PDLSCs can stimulate the expression of CD163, a surface marker associated with M2-MΦs, which contributes to macrophage M2 polarization (74).

Dendritic cells (DCs) represent a diverse cell population and inhibiting their function results in reduced responses of the adaptive immune system as well as an increased susceptibility to periodontal disease. A previous study indicates that the quantity of DCs in the peripheral blood fluctuates with age, potentially contributing to the increased vulnerability of older patients to infection compared with younger patients (75). Furthermore, alterations in the functionality of DCs contribute to immune dysregulation and the onset of chronic inflammation. In vitro, infection of DCs by the non-living oral pathogen P. gingivalis triggers activation of the SASP and subsequent bone loss (76).

Langerhans cells (LCs), a subset of DCs located in the oral mucosal epithelium, likely serve a role in initiating and perpetuating periodontal diseases (77). A decrease in the number of epithelial LCs and their dendritic structures in elderly individuals aged >75 years with periodontitis, which are distinct compared with those in adults, may compromise their removal of pathogenic bacteria (78,79). Reducing LCs in the aging epidermis impairs the immunoregulatory functions of the skin and compromises barrier integrity, antimicrobial defenses and overall cell protection capabilities (80,81). Consequently, immune cell senescence may disrupt the homeostasis of periodontal defense mechanisms.