The rosetta stone of successful ageing: does oral health have a role?

Abstract

Ageing is an inevitable aspect of life and thus successful ageing is an important focus of recent scientific efforts. The biological process of ageing is mediated through the interaction of genes with environmental factors, increasing the body's susceptibility to insults. Elucidating this process will increase our ability to prevent and treat age-related disease and consequently extend life expectancy. Notably, centenarians offer a unique perspective on the phenomenon of ageing. Current research highlights several age-associated alterations on the genetic, epigenetic and proteomic level. Consequently, nutrient sensing and mitochondrial function are altered, resulting in inflammation and exhaustion of regenerative ability.Oral health, an important contributor to overall health, remains underexplored in the context of extreme longevity. Good masticatory function ensures sufficient nutrient uptake, reducing morbidity and mortality in old age. The relationship between periodontal disease and systemic inflammatory pathologies is well established. Diabetes, rheumatoid arthritis and cardiovascular disease are among the most significant disease burdens influenced by inflammatory oral health conditions. Evidence suggests that the interaction is bi-directional, impacting progression, severity and mortality. Current models of ageing and longevity neglect an important factor in overall health and well-being, a gap that this review intends to illustrate and inspire avenues for future research.

Keywords: Ageing; Centenarians; Hallmarks of ageing; Inflammation; Oral health; Successful ageing.

Fig. 1

Current model for host bacteria interaction in the pathogenesis of Periodontitis. Extensive biomass drives a proportionate immune response resulting in gingivitis. Without the removal of the biofilm an increase in pathogenicity occurs, resulting in tissue destruction and periodontitis. PMNs polymorphonuclear neutrophils, AMPs antimicrobial peptides, fMLP N-formylmethionyl-leucyl-phenylalanin, LPS lipopolysaccharide, GCF gingival crevicular fluid, DAMPs damage-associated molecular patterns, MMPs matrix metalloproteinases (Schmalz and Ziebolz 2020)

Fig. 2

Periodontitis and systemic implications. Periodontitis occurs as a consequence of the imbalance between the subgingival microbiota and the host immune response (Gondo et al. ; Arnold et al. ; Hajishengallis 2021). The commensal bacteria population shifts into a pathogenic dysbiotic state (Dyke et al. 2020), stimulating an inflammatory response. This results in a local accumulation of leucocytes, specifically neutrophiles (Gondo et al. 2006). They contribute to the tissue destruction through the secretion of Matrix-Metalloproteinases (MMPs) and reactive oxygen species (ROS) (Lamont et al. ; Curtis et al. 2000). The failure to control the dysbiotic environment leads to tissue penetration of bacteria. Through the interaction with macrophages and dendritic cells an increased production of cytokines, e.g. Interleukin 1 (IL1), Interleukin 6 (IL6) and tumor necrosis factor alpha (TNF ⍺) occurs. Furthermore, proinflammatory cytokines promote chemotaxis, increasing immune cell recruitment and aggravating the inflammatory process (Curtis et al. ; Hajishengallis and Hajishengallis 2014). 1) In periodontitis the risk of bacteraemia and systematic dissemination of bacteria is increased (Hajishengallis 2014). a In addition, further dissemination occurs through survival in phagocytic host cells. Consequently, periodontal bacteria can be found in atherosclerotic lesions, possibly aggravating the process (Pelletier et al. 2010). 2) The local inflammatory response consisting of IL 1, IL6 and TNF ⍺ can enter the circulation and possibly induces changes in the b liver. Thus, leading to metabolic dysfunction expressed as insulin resistance (Gondo et al. ; Schenkein et al. 2000) and potentially triglyceride accumulation (Carrion 2012). This process aggravates atherogenesis. Additionally, circulation cytokines may induce an acute phase reaction in the liver, which in turn is marked by elevated levels of C reactive Protein, Fibrinogen and Serum Amyloid A, furthering the atherosclerotic processes. 3) The swallowing of large quantities of bacteria present in periodontitis, is known to influence the gut microbiome, c leading to dysbiosis (Gondo et al. ; Jepsen et al. 2000). Altered gut microbiota has been linked to increased gut permeability and endotoxaemia due to an induced downregulation of tight junction proteins (Arimatsu et al. ; Yamazaki et al. ; Cani et al. Kashiwagi et al. 2021), further promoting a systemic inflammatory state (Jepsen et al. 2000). Dysbiosis has been related to changes in metabolites produced by the microbiota, which may increase insulin resistance independent of the effect of proinflammatory cytokines induced by the endotoxaemia (Arimatsu et al. 2014)

Fig. 3

Interconnections between ageing related processes and the potential role of oral health. 1) In ageing, multiple factors within a variety of systems are in a state of dynamic change. These links have been established between inflammation, immune function, endocrine changes, genetics/epigenetics and metabolic changes. 2) Beneficial behavioral patterns e.g. frequent exercise have multiple positive effects. In the case of exercise; reduced inflammation, improved immune function, enhanced hormonal health, engaged epigenetic mechanisms improving memory function and better insulin sensitivity have been reported. Similar links exist for several other behavioral patterns e.g. social support, diet, purposeful living and spirituality. Oral health has an important role in preventing age related decline. 3) Oral disease is associated with reduced masticatory function, leading to an impaired nutrient intake, especially protein. Periodontal disease increases the risk of T2DM and prediabetes in non-diabetics and has been linked to poorer glycemic control and a higher complication rate in diabetic patients. The presence of a proinflammatory state, characterized by interleukine-1beta and tumor necrosis factor-alpha, potentially influences autoimmune disease e.g. rheumatoid arthritis and immune senescence. Bacterial antigens and cytokines trigger changes in the cell metabolism of myeloid cells, leading to epigenetic changes, which ultimately enhance the inflammatory response. Recent research suggests that ageing is not only expressed on the macroscopic scale but also on the molecular level, providing possible targets for pro longevity interventions

Fig. 4

Ageing: balance and imbalance. The human body seeks a homeostatic state. 1) Stressors (symbolized by weights) influence the biological state. Normally the organism has the capability to maintain balance. 2) Insults e.g., disease, injuries, famine, etc. force the system out of its equilibrium. The impact of the stressing event has been symbolized by the amplitude A₁. In the young resilient body, a conservation of a relative state of balance is often possible, offering the opportunity to regain an equilibrium e.g., fight disease, heal injuries, refeeding. 3) Ageing increases the length of the lever, thus reducing resilience and leaving the organism more susceptible to insults. *Genetics, good dietary habits, exercise, purposeful living and social support can act as pillars of support, counteracting the increased vulnerability and enhancing the organisms´ compensatory capacity. 4) Due to the increased susceptibility, the same insult results in a much larger negative impact (amplitude A₂ > A₁). This leads to a state of imbalance, exceeding the capacity of compensatory mechanisms. This results in incomplete recovery, chronic disease, frailty or death