Cellular Senescence and Periodontal Diseases: An Overview

Aging is an intricate physiological process that impacts organ system function. It is considered a significant risk factor for several geriatric and chronic conditions [1-3]. Aging can augment age-related bone disorders including osteoporosis, rheumatoid arthritis, and periodontitis [3]. Bone tissue is a scaffold composed of collagen, minerals, water, and non-collagenous proteins. Trabecular bone constitutes 20% of the total bone mass and cortical bone accounts for the remaining 80%. Aging causes a decline in trabecular and cortical bone masses, changes in bone tissue components, and a decline in bone’s biological and mechanical characteristics. Ulti mately, this increases the susceptibility to age-related bone diseases in the elderly population.

The incidence of rheumatoid arthritis increases with age, and it is recognized as a model of premature senescence [3]. In the same context, a strong association between osteoporosis, cellular senescence, and inflammaging was reported [4]. Osteoporosis is characterized by a reduction in bone minerals and damage in bone microstructure which reduces the bone’s strength, and raises the risk of fractures. Osteoarthritis, a deterioration of articular cartilage that eventually leads to physical function impairment, is characterized by an increased number of senescent chondrocytes [5]. Periodontitis is associated with chronic inflammation, alveolar bone loss and gingival recession. Interestingly, the severity and prevalence of periodontitis tends to increase with advanced age [6]. Prior studies demonstrated age-related changes in periodontium including decreased wound healing, increased senescent cell population, and increased pro-inflammatory cytokine gene expression [7]. However, the exact mechanism is not clearly elucidated. Therefore, expanding our knowledge in age-related changes in the periodontium can offer mechanistic insights and help in developing strategies to improve oral health in geriatric patients.

Aging and immune respons

Several aging mechanisms, including mitochondrial dysfunction, protein imbalance, epigenetic alterations, telomere damage, unstable genomes, and cellular senescence were reported. Although each mechanism plays a role in certain aspects of the aging process, cellular senescence plays a central role in aging and inflammatory processes [3, 8]. Hayflick, et al. proposed the concept of cellular senescence in 1961. It refers to a progressive degradation in cellular function and complexity that ultimately leads to a gradual and irreversible decline in the cellular proliferative capacity [9-10]. Growth arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) are hallmarks of cellular senescence and are thought to be major drivers for chronic, age-related diseases [11- 12]. DNA damage can trigger cellular senescence via a prolonged DNA damage response and growth arrest [13-16]. If the damage is severe, cells may undergo apoptosis to maintain the integrity of the host genome. To maintain homeostasis, apoptotic and senescent cells are regularly removed by the immune system. However, aging decreases our immune system’s ability to remove senescent and apoptotic cells. Walford RL, introduced the term immunosenescence to reflect age-related modulation of the immune system [17]. This multifactorial phenomenon impacts both innate and adaptive immunity [18]. The concept of immunosenescence and accumulation of senescent cells have been linked to various pathologies including cardiovascular diseases, age-related bone diseases, cancer, and increased susceptibility to infections.

While acute inflammation is an essential component of the natural immune response against insults, chronic inflammation can slowly lead to tissue and organ damage. Neves, et al. (2020) demonstrated that chronic inflammation is a key player in the manifestation of several age-related pathologies [19]. Francesch, et al. (2000) introduced the concept of ‘inflammaging’ characterized by a chronic low-grade ‘sterile’ inflammatory state [20]. This persistent low-grade chronic inflammation accelerates aging, which in turn exacerbates the inflammation process, creating a self-perpetuating cycle [3]. Senescent cells have been widely implicated in the promotion of inflammaging [21-22].

Although senescent cells exhibit growth arrest, they maintain their metabolic viability through their SASP complex which includes secretion of a variety of proinflammatory chemokines, cytokines, growth factors, and proteases. This modulates tissue regeneration, repair, chronic inflammation, and progression of age-related dysfunction [23-25]. Deursen, et al. (2014) suggest that senescent cells utilize the SASP complex to attract immune cells and induce local inflammation [26]. In the periodontium, senescent cells can facilitate an environment that fosters inflammation which accelerates the deterioration of alveolar bone [27].

The immune system can be divided into innate immunity which includes neutrophils, monocytes and natural killer cells, and adaptive immunity which involves the B and T lymphocytes. Innate and adaptive immunity can be affected by the aging process. Neutrophils are the most common leukocytes in our body, and they confer the initial protection against invading microbes [28]. Neutrophils mediate the host immune response via several mechanisms including phagocytosis, degranulation of antimicrobial proteins, and releasing neutrophil extracellular traps (NETs) [2]. Immunosenescence can decrease the immunoprotective activity of neutrophils via impairing phagocytosis, degranulation, and decreasing the NETs [2]. In the monocyte/macrophage population, age-related decline in phagocytic capacity and dysregulation of the inflammatory cytokines were also reported.

The adaptive immune system includes a humoral immune response mediated by B-lymphocytes and antibodies as well as a cell-mediated immune response mediated by T-lymphocytes [2]. T lymphocytes are further subdivided into CD4+ T-helper (Th) cells and CD8+ cytotoxic T cells. Upon activation, naïve CD4+ helper T-cells differentiate into different effector T cell lineage including Th1, Th17, and others; each with a unique function in orchestrating the immune response [29, 30]. Effector cytotoxic T cells induce cell death to clear intercellular pathogens. Immunosenescence downregulates the effector T-cell response through reducing the production of naïve T cells and defective T-cell signal transduction. On the other hand, senescent T cells upregulate the production of proinflammatory cytokines which contribute to immune dysregulation and inflammaging [2]. Similar age-related decline in B cell function and the associated humoral immune response were also reported [31].

Pro-inflammatory cytokines and chemokines play a central role in inflammaging and immunosenescence. With the aim of discovering immunological markers associated with aging, several studies investigated the association between pro-inflammatory mediators and aging. In a study that included 2111 participants with a mean age of 62.9 years, Lima-Silva, et al. (2024) reported a significant positive association between aging and upregulated interleukin (IL)-2, IL-4, IL-6, IL-17, tumor necrosis factor-α (TNF-α) as well as chemokine ligand-10 (CXCL10) levels [32]. CXCL10 is secreted following induction by interferon-gamma, and acts as a chemoattractant and a mediator for the inflammatory process. In agreement, Ravalet, et al. (2023) previously demonstrated the upregulation of CXCL10 level with advanced age [33]. IL-2 is a growth factor that is essential for T-lymphocyte development and maturation. IL-6, IL-17, and TNFα are proinflammatory cytokines that can mediate proinflammatory responses and play a role in inflammaging. Interestingly, Adriaensen, et al. (2015) selected IL-6 as a prognostic inflammaging biomarker that can be correlated with adverse health outcomes in elderly patients [34].

The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) was upregulated in age-related chronic inflammation [35]. Tavenier, et al. (2020) proposed that elevated basal NF-κB activity in monocytes may contribute to inflammaging [36]. Moreover, NF-κB inhibition was beneficial in reducing DNA damage and delaying cellular senescence [37]. NF-κB is pivotal in activating proinflammatory pathways, resulting in altered cytokine and chemokine expressions, as well as the secretion of anti-apoptotic factors, which collectively impede the clearance of senescent cells [38]. Chien, et al. demonstrated the regulatory function of NF-κB in the SASP complex. Simply put, localized inflammation dysregulates NF-κB signaling which in turn triggers SASP. As previously discussed, the secretion of SASP recruits immune mediators to inflammation site, establishing a self-perpetuating and growing cycle of inflammatory mediator recruitment [11, 39]. Taken together, accumulating evidence has demonstrated the association between inflammatory cytokines, aging, and pathogenesis of age-related chronic inflammatory disorders [35-42].

Aging and periodontitis

Gingival and periodontal diseases are inclusive terms that encompass a wide variety of conditions affecting the tooth-supporting structures [43]. Periodontitis is a multifactorial sustained inflammatory process of the periodontium that may extend to the jaw bones. Smoking, genetics, several systemic diseases and advanced age are among risk factors contributing to its development [44]. With a prevalence of 19% among the adult population worldwide, severe periodontitis is a significant global oral health challenge [45]. In the United States, the prevalence of severe periodontitis is estimated to hover around 7.8% of the adult population [46]. Severe untreated periodontitis may damage the tooth supporting structures leading to tooth loss, aggravation of other systemic diseases and consequentially negatively impacting the quality of life.

Periodontitis is characterized by a dysregulated immune response towards dysbiotic bacteria leading to gingival detachment, deepening of the subgingival crevice, degradation of the periodontal ligament, and loss of the alveolar bone [47, 48]. Disease progression occurs upon the dysregulation of the immuno-inflammatory response towards bacterial challenge, resulting in uncontrolled host reactions involving both innate and adaptive immunity. Moreover, breakdown products from host tissues facilitate the growth and persistence of dysbiotic microbiota which further generates a self-perpetuating pathogenic cycle. Due to its direct proximity to teeth, the subgingival crevice serves as the primary locus for harboring complex bacterial species [49]. Neutrophils, macrophages, T-lymphocytes and other immune cells contribute to the defense mechanism against periodontal pathogens and their dysregulation contribute to the development of periodontitis. Following successful combat against infection, the pro-inflammatory process is downregulated, and immune cells exit the infection site and re-enter the vascular system (a phenomenon known as reverse migration). This process not only contributes to the proper resolution of infection but also prevents localized damage to periodontal tissue [50].

For instance, dysfunction of neutrophil reverse migration can amplify the inflammatory response and contribute to the development of periodontitis. In addition, the declining function of neutrophils with aging leads to lower antimicrobial activity and negatively impacts the wound healing process [2, 51]. In the same context, altered Th17 cells and regulatory T-cell ratio with aging leads to altered cytokine expression and imbalanced pre-inflammatory/anti- inflammatory immune response [52]. Cytokines are fundamental mediators to maintain the intricate balance between homeostasis and inflammation. Positioned at barrier sites, like the subgingival crevice, they orchestrate sophisticated communication between connective tissue cells, immune cells, and other accessory cell populations [53, 54]. For instance, IL-8 is a potent chemoattractant that facilitates the extravasation of neutrophils into the subgingival crevice, and beta-2 integrins play pivotal roles in the immunological processes including leukocyte trafficking, phagocytosis, ROS production, and T-cell activation [55, 56]. On the other hand, accumulating evidence demonstrated the role of several cytokine families in the pro-inflammatory process activation, stimulation of the bone-resorbing osteoclasts, and the progression of periodontitis [57]. Polymorphisms in genes encoding IL-1A, IL-1B, IL-6, and IL- 10 are significantly associated with an increased risk for periodontitis. In addition, the amplification of the inflammatory cascade mediated by Th17, IL-17 and related cytokines lead to excessive recruitment of neutrophils, which orchestrate immunopathological processes that eventually lead to bone loss [58].

The prevalence and severity of periodontitis increases with advanced age [6]. Senescent cells present with a gradual decline in functionality and can release pro-inflammatory cytokines that contribute to tissue damage. For instance, the periodontal ligament stem cells present with declining proliferative and osteogenic-differentiation capacity with age [35]. Increased SASP levels including but not limited to TNF-α, interferon-gamma (INF-γ), IL-1, IL-6, and IL-8 were detected in the gingival crevicular fluid. These pro-inflammatory cytokines contribute to dysregulated immune response, tissue damage and enhance alveolar bone loss in periodontitis. Loss of alveolar bone occurs due to an imbalance between bone formation and resorption. Yamashita, et al. demonstrated that NF-κB can significantly enhance osteoclast differentiation and maturation downstream of receptor activator of NF-κB ligand (RANKL) [59]. Similarly, TNF-α plays a crucial role in osteoclastogenesis and periodontal tissue destruction. Jain, et al. demonstrated a positive correlation between increased serum levels of TNF-α and periodontitis [60]. Taken together, the increased secretion of pro-inflammatory associated with aging will contribute to inflammaging in the periodontium and enhance the osteoclasts activity leading to imbalanced bone remodeling and subsequent bone loss. In addition, the ongoing inflammatory process in the periodontium will upregulate the secretion of IL-6 which will consequently activate osteoclastic activity and promote alveolar bone loss [3]. Therefore, in addition to its prognostic value in inflammaging, IL-6 plays an important role in the development of periodontal diseases as well as other immune disorders [34, 61, 62].

Aging, dysbiotic microbiota, and multiple environmental factors including tobacco smoking can all increase oxidative DNA damage, thereby accelerating the accumulation of senescent cells and SASP. At the same time, the aged immune system becomes less efficient in removing senescent and apoptotic cells. This can plausibly contribute to the development of age-related chronic diseases. It is however unclear whether the rise in senescent cells with age is due to a greater number of cells becoming senescent or an impaired clearance of senescent cells due to immunosenescence, or a combination of both [26]. Nevertheless, in response to heightened senescent cell population, Zhou, et al. elucidated that aging is also associated with increased immune cell populations [63]. Immune cells proliferation enhances the expression of proinflammatory mediators, potentially accelerating the progression of age-related diseases. This altered immune response will contribute to an aggravated state of low-grade chronic inflammation or inflammaging which may exacerbate periodontal health and contribute to the development of severe periodontitis.

This research did not receive any source of funding

None.

The authors declare no conflict of interest.

1. Guo J, Huang X, Dou L, Yan M, Shen T, et al. (2022) Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct Target Ther 7: 391.
2. Santoro A, Bientinesi E, Monti D (2021) Immunosenescence and inflammaging in the aging process: age-related diseases or longevity? Ageing Res Rev 71: 101422.
3. Bi J, Zhang C, Lu C, Mo C, Zeng J, et al. (2024) Age-related bone diseases: Role of inflammaging. J Autoimmun 143: 103169.
4. Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco RJ (2012) Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res 91(10): 914-920. CDC Periodontal Disease Surveillance workgroup: James Beck, Gordon Douglass, Roy Page.
5. Pignolo RJ, Law SF, Chandra A (2021) Bone Aging, Cellular Senescence, and Osteoporosis. JBMR Plus 5: e10488.
6. Liu Y, Zhang Z, Li T, Xu H, Zhang H (2022) Senescence in osteoarthritis: from mechanism to potential treatment. Arthritis Res Ther 24: 174.
7. Da Costa JP, Vitorino R, Silva GM, Vogel C, Duarte AC, et al. (2016) A synopsis on aging-Theories, mechanisms and future prospects. Ageing Res Rev 29: 90-112.
8. Kim YG, Lee SM, Bae S, Park T, Kim H, et al. (2021) Effect of Aging on Homeostasis in the Soft Tissue of the Periodontium: A Narrative Review. J Pers Med 11: 58.
9. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25: 585-621.
10. Goldberger AL, Amaral LA, Hausdorff JM, Ivanov PCh, Peng CK, et al. (2002) Fractal dynamics in physiology: alterations with disease and aging. Proc Natl Acad Sci U S A 99:2466-2472.
11. Campisi J, d'Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8: 729-740.
12. Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, et al. (2015) JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A. 112: E6301-10.
13. d'Adda di Fagagna F (2008) Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer 8: 512-522.
14. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, et al. (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11: 973-979.
15. Chatterjee N, Walker GC (2017) Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen 58: 235-263.
16. Huang W, Hickson LJ, Eirin A, Kirkland JL, Lerman LO (2022) Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol 18: 611-627.
17. Walford RL (1964) The immunologic theory of aging. Gerontologist 4: 195-197.
18. Hajishengallis G (2014) Aging and its Impact on Innate Immunity and Inflammation: Implications for Periodontitis. J Oral Biosci 56: 30-37.
19. Neves J, Sousa Victor P (2020) Regulation of inflammation as an anti-aging intervention. FEBS J 287: 43-52.
20. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, et al. (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908: 244-254.
21. López Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153: 1194-217.
22. Bleve A, Motta F, Durante B, Pandolfo C, Selmi C, et al. (2023) Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases. Clin Rev Allergy Immunol 64: 123-144.
23. Fang CL, Liu B, Wan M (2023) "Bone-SASP" in Skeletal Aging. Calcif Tissue Int 113: 68-82.
24. van Vliet T, Varela Eirin M, Wang B, Borghesan M, Brandenburg SM, et al. (2021) Physiological hypoxia restrains the senescence-associated secretory phenotype via AMPK-mediated mTOR suppression. Mol Cell 81: 2041-2052.e6.
25. Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, et al. (2014) An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31: 722-733.
26. Van Deursen JM (2014) The role of senescent cells in ageing. Nature 509: 439-446.
27. Chen S, Zhou D, Liu O, Chen H, Wang Y, et al. (2022) Cellular Senescence and Periodontitis: Mechanisms and Therapeutics. Biology (Basel) 11: 1419.
28. Lehman HK, Segal BH (2020) The role of neutrophils in host defense and disease. J Allergy Clin Immunol 145: 1535-1544.
29. Kumar BV, Connors TJ, Farber DL (2018) Human T Cell Development, Localization, and Function throughout Life. Immunity 48: 202-213.
30. Wan YY, Flavell RA (2009) How diverse--CD4 effector T cells and their functions. J Mol Cell Biol 1: 20-36.
31. Frasca D, Diaz A, Romero M, Garcia D, Blomberg BB (2020) B Cell Immunosenescence. Annu Rev Cell Dev Biol 36: 551-574.
32. Lima Silva ML, Torres KCL, Mambrini JVM, Brot NC, Santos SO, et al. (2024) A nationwide study on immunosenescence biomarkers profile in older adults: ELSI-Brazil. Exp Gerontol 191: 112433.
33. Ravalet N, Guermouche H, Hirsch P, Picou F, Foucault A, et al. (2023) Modulation of bone marrow and peripheral blood cytokine levels by age and clonal hematopoiesis in healthy individuals. Clin Immunol 255: 109730.
34. Adriaensen W, Matheï C, Vaes B, van Pottelbergh G, Wallemacq P, et al. (2015) Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: A regression and CART approach in the BELFRAIL study. Exp Gerontol 69: 53-61.
35. Zhu L, Tang Z, Hu R, Gu M, Yang Y (2023) Ageing and Inflammation: What Happens in Periodontium? Bioengineering (Basel) 10(11): 1274.
36. Tavenier J, Rasmussen LJH, Houlind MB, Andersen AL, Panum I, et al. (2020) Alterations of monocyte NF-κB p65/RelA signaling in a cohort of older medical patients, age-matched controls, and healthy young adults. Immun Ageing 17(1): 25.
37. Tilstra JS, Robinson AR, Wang J, Gregg SQ, Clauson CL, et al. (2012) NF-κB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest 122(7): 2601-12.
38. Chung HY, Kim DH, Lee EK, Chung KW, Chung S, et al. (2019) Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept. Aging Dis 10(2): 367-382.
39. Pawlikowski JS, Adams PD, Nelson DM (2013) Senescence at a glance. J Cell Sci 126: 4061-7.
40. Mohammadi Shahrokhi V, Ravari A, Mirzaei T, Zare Bidaki M, Asadikaram G, et al. (2018) IL-17A and IL-23: plausible risk factors to induce age-associated inflammation in Alzheimer's disease. Immunol Invest 47(8): 812-822.
41. Xia S, Zhang X, Zheng S, Khanabdali R, Kalionis B, et al. (2016) An Update on Inflamm-Aging: Mechanisms, Prevention, and Treatment. J Immunol Res 2016: 8426874.
42. Shen CY, Lu CH, Wu CH, Li KJ, Kuo YM, et al. (2021) Molecular Basis of Accelerated Aging with Immune Dysfunction-Mediated Inflammation (Inflamm-Aging) in Patients with Systemic Sclerosis. Cells 10(12): 3402.
43. Martínez-García M, Hernández-Lemus E (2021) Periodontal Inflammation and Systemic Diseases: An Overview. Front Physiol 12: 709438.
44. Van Dyke TE, Sheilesh D (2005) Risk factors for periodontitis. J Int Acad Periodontol 7(1): 3-7.
45. Zhang X, Wang X, Wu J, Wang M, Hu B, et al. (2024) The global burden of periodontal diseases in 204 countries and territories from 1990 to 2019. Oral Dis. 30(2): 754-768.
46. Eke PI, Thornton-Evans GO, Wei L, Borgnakke WS, Dye BA, et al. (2018) Periodontitis in US Adults: National Health and Nutrition Examination Survey 2009-2014. J Am Dent Assoc 149(7): 576-588.e6.
47. Hajishengallis G, Chavakis T, Lambris JD (2020) Current understanding of periodontal disease pathogenesis and targets for host-modulation therapy. Periodontol 2000 84(1): 14-34.
48. Hajishengallis G, Korostoff JM (2017) Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later. Periodontol 2000 75(1): 116-151.
49. Winning TA, Townsend GC (2000) Oral mucosal embryology and histology. Clin Dermatol 18(5):499-511.
50. Xu Q, Zhao W, Yan M, Mei H (2022) Neutrophil reverse migration. J Inflamm (Lond). 19(1): 22.
51. Sabbatini M, Bona E, Novello G, Migliario M, Renò F (2022) Aging hampers neutrophil extracellular traps (NETs) efficacy. Aging Clin Exp Res 34(10): 2345-2353.
52. Schmitt V, Rink L, Uciechowski P (2013) The Th17/Treg balance is disturbed during aging. Exp Gerontol 48(12): 1379-1386.
53. Pan W, Wang Q, Chen Q (2019) The cytokine network involved in the host immune response to periodontitis. Int J Oral Sci 11(3): 30.
54. Baumeister SE, Holtfreter B, Lars Reckelkamm S, Hagenfeld D, Kocher T, et al. (2023) Effect of interleukin-17 on periodontitis development: An instrumental variable analysis. J Periodontol 94(5): 616-621.
55. Dutzan N, Konkel JE, GreenwellWild T, Moutsopoulos NM (2016) Characterization of the human immune cell network at the gingival barrier. Mucosal Immunol 9(5): 1163-1172.
56. Zhou M, Graves DT (2022) Impact of the host response and osteoblast lineage cells on periodontal disease. Front Immunol 13: 998244.
57. da Silva MK, de Carvalho ACG, Alves EHP, da Silva FRP, Pessoa LDS, et al. (2017) Genetic Factors and the Risk of Periodontitis Development: Findings from a Systematic Review Composed of 13 Studies of Meta-Analysis with 71,531 Participants. Int J Dent 2017:1914073.
58. Ikeuchi T, Moutsopoulos NM (2022) Osteoimmunology in periodontitis; a paradigm for Th17/IL-17 inflammatory bone loss. Bone 163:116500.
59. Yamashita T, Yao Z, Li F, Zhang Q, Badell IR, et al. (2007) NF-kappaB p50 and p52 regulate receptor activator of NF-kappaB ligand (RANKL) and tumor necrosis factor-induced osteoclast precursor differentiation by activating c-Fos and NFATc1. J Biol Chem 282(25): 18245-18253.
60. Jain P, Ved A, Dubey R, Singh N, Parihar AS, et al. (2020) Comparative Evaluation of Serum Tumor Necrosis Factor α in Health and Chronic Periodontitis: A Case-Control Study. Contemp Clin Dent 11(4): 342-349.
61. Mazurek Mochol M, Bonsmann T, Mochol M, Poniewierska Baran A, Pawlik A (2024) The Role of Interleukin 6 in Periodontitis and Its Complications. Int J Mol Sci 25: 2146.
62. Moreira PR, Lima PM, Sathler KO, Imanishi SA, Costa JE, et al. (2007) Interleukin-6 expression and gene polymorphism are associated with severity of periodontal disease in a sample of Brazilian individuals. Clin Exp Immunol 148: 119-126.
63. Zhou D, Borsa M, Simon AK (2021) Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells. Aging Cell 20: e13316.