In the absence of telomerase or when this enzyme is expressed at very low levels, DNA synthesis during cell division results in the progressive shortening of telomeric DNA. This erosion eventually compromises telomere integrity, triggering cellular senescence and blocking further cell replication. (7) 
 
Telomere Length, Oxidative Stress and Ageing.
 
It was the Russian biologist Alexei Olovnikov who in the late 1960s first predicted the shortening of telomeres as an explanation for finite cell division in cells grown in culture. It took more than 20 years to show experimentally that telomeric DNA declines with the ageing of human fibroblasts. 

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Oxidative stress and shortened telomere length have been shown to have important implications for the onset of other age related systemic diseases such as cardiovascular disease, hypercholesterolemia, diabetes mellitus and chronic inflammation (8). Kurtz et al (9) demonstrated that long-term exposure of human endothelial cells to mild oxidative stress caused by disruption of the glutathione redox-cycle results in accelerated telomere erosion, loss of telomeric integrity and the premature onset of cell senescence and apoptosis. This confirmed the results of an earlier study, indicating that oxidative stress can induce or accelerate the development of cell senescence and ageing (10).

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Implications For Periodontal Health.
 
Over the last ten years the impact of periodontal disease on systemic health has been established, with research showing an increasing association between periodontal inflammation and cardiovascular disease (11), diabetes (12), rheumatoid arthritis (13) and impaired lung function (14). The association between periodontal inflammation and systemic disease has yet to be fully understood. It appears to be based on systemic inflammation and elevated levels of pro-inflammatory cytokines in the general circulation (15).  Other risk factors include the presence of C Reactive Protein (CRP) (16), intrinsic genetic factors and lifestyle factors such as stress, smoking and the absence of health enhancing behaviour (17). All of these factors collectively may increase the risk of inflammatory disease and reduce the inflammation pro-resolving mechanisms of the body, thus increasing the risk of systemic disease.

This latest piece of research from Masi et al (1) has found that telomere length is inversely associated with periodontitis and this also correlates with systemic inflammation and oxidative stress.
 
The protective enzyme TERT in human cells extends both the lifespan of the cell and telomere length to those typical of young cells (18).  Inflammation is also thought to contribute to telomere attrition in the cells of the immune system through increasing the rate of leucocyte turnover. An increased expression of pro-inflammatory cytokines has been shown to adversely affect telomerase activity and telomere length (19). In addition, research has demonstrated that increased generation of reactive oxygen species (ROS) stimulates  the loss  of the protective enzyme TERT from the nucleus of the cell, thus increasing the rate of cell senescence and subsequently apoptosis (20).

Could these factors be part of the causal link that could explain the association between periodontitis and chronic inflammatory diseases? It may be that the critical shortening of telomeres triggers inflammation in a bi-directional manner.  Are there any preventive measures that could be taken to attenuate oxidative stress and degradation of telomere length?

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Lifestyle Influences on Telomere Length. 

 

There is evidence that telomere degradation, chronic inflammation and oxidative stress may be attenuated by modulating certain lifestyle factors such as nutrition, smoking, stress and obesity(21) . Ornish et al (22) conducted a 3 months comprehensive lifestyle intervention program, (including nutrition and physical activity) in 24 low-risk prostate cancer patients and demonstrated an increase of 29% in peripheral blood mononuclear cell telomerase activity. This suggests that telomere attrition is not genetically determined but can be attenuated by modification of lifestyle factors.   

 

Micronutrient Status   

 

 An increasing body of evidence suggests that several micronutrients, such as antioxidant vitamins and minerals, can modulate the states of oxidative stress and chronic inflammation and therefore may affect telh. These include vitamin C (23), alpha tocopherol (24) vitamin D (25) and Omega three fatty acids (26). Multivitamin supplements contain large amounts of many vitamins and minerals and therefore represent a major source of micronutrient intake.      

 

Xu et al (27) examined whether multivitamin use was associated with increased telomere length among 586 women from the Sister Study The researchers found that after age and other potential confounders were adjusted for, multivitamin use was associated with longer telomeres. In the analysis of micronutrients, higher intakes of vitamins C and E from foods were each associated with longer telomeres, even after adjustment for multivitamin use. Furthermore, intakes of both nutrients were associated with telomere length among women who did not take multivitamins. Intervention studies are required to further determine the evidence base for dietary and/or supplemental intake of these nutrients as a potential long term preventive strategy.  

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Glutathione and the redox cycle.

 

There is an increasing body of evidence demonstrating the effect of nutrition on antioxidant status and periodontal health. Research has suggested that low levels of the endogenous antioxidant reduced glutathione (GSH) may be implicated in the susceptibility and progression of chronic periodontal disease (28). The researchers have suggested that high concentrations of GSH in health may represent an important anti-inflammatory defence system in the progression of inflammatory periodontal disease.   

 

 The effect of N- acetylecysteine (NAC) on telomere length has also been investigated. NAC can elevate glutathione synthesis, a key component of the glutathione redox cycle. The glutathione redox cycle is an endogenous antioxidant enzyme system, which plays a pivotal role in the protection of the cell membrane from oxidative damage (29). Haendler et al (30) found that NAC reduced intracellular ROS formation and prevented mitochondrial DNA damage. NAC also reduced the loss of TERT from the cell and inhibited cellular senescence. They suggested that the prevention of intracellular reactive oxygen species (ROS) activity and loss of TERT from the cell, also prevents telomere shortening and subsequent cell senescence. Similar effects were reported by the authors with statins (Atorvastatin). The results with statins were dose dependant with lower concentrations able to delay the onset of senescence, and higher concentrations increasing ROS formation in endothelial cells.   

 

 NAC has been used for about thirty years as a mucolytic in patients with broncho- pulmonary diseases (31) . Other therapeutic uses of GTH and NAC appear to be mainly employed in the treatment of paracetamol overdose (32), inflammatory diseases of the lung (33), and in HIV and AIDS therapy (34) . NAC is  well absorbed, readily passes through cellular membranes, resists enzymatic breakdown and stimulates glutathione production in the cells (35) . It appears to be well tolerated and does not raise blood or tissue levels above the desired ranges (36) . The case for NAC as an important inhibitor of the pro inflammatory transcription factor NFkB, as a potential glutathione-preserving therapy for periodontitis, was first proposed by Chapple in 1996 (37) . The use of NAC as an adjunctive therapy in the treatment of chronic periodontal disease has yet to be established and provides an intriguing basis for further investigation and clinical trials.

 

Obesity and Smoking

 

Obesity and cigarette smoking are important risk factors for many age-related and inflammatory diseases. Both factors are associated with increased oxidative stress, inflammation and periodontal disease (38). 

Obesity

Obesity has been associated with the development of periodontal disease (39). An association between obesity, periodontal infections and diabetes has been suggested as being mediated by increased levels of tumour necrosis factor (TNF) which may lead to a systemic inflammatory state, thereby increasing susceptibility to inflammatory periodontal disease (40). 

Research has also shown an association between shorter telomere length in obesity, with lean individuals (BMI <20) having significantly longer telomeres than obese (BMI>30) individuals (41). Consistent with earlier studies, particularly amongst women, Kim et al (42) demonstrated an inverse association between BMI and telomere length. Shorter telomere length was associated with higher hip and waist circumferences. In addition higher BMI at ages 30-49, adult weight gain and frequent weight cycling were also inversely associated with telomere length.

Exploring the possibility of a bi-directional effect between elevated levels of circulating pro inflammatory mediators and telomere attrition may therefore, provide additional insight into the incidence of periodontal disease in obese individuals and subsequent supportive treatment protocols. 

 

Smoking   

 

 As dental professionals we are only too aware of the effects of smoking on the periodontium and oral mucosa. Smoking is recognised as a major factor in the aetiology of periodontitis (43). Smoking is typically associated with increased inflammation, oxidative stress and telomere attrition (44) . Valedes et al (41) reported that cigarette smoking enhances telomere loss and subsequent telomere shortening. A dose dependent relationship with smoking was recorded, with each pack year smoked, equivalent to an additional 18% loss of telomere length when compared to the rest of the cohort. Individuals who had never smoked had longer age adjusted telomeres than former smokers and both had longer telomeres than current smokers. Smoking a pack per day for 40 years corresponded to an additional 7.4 years of ageing. This was also confirmed by Moria et al (45) in patients with chronic obstructive pulmonary disease (COPD). This may provide further insight into the effect of smoking on the periodontal tissues and subsequent systemic disease. 

   

Stress   

 

The effects of stress on periodontal health, is now widely recognized as having a significant physiological effect on the periodontal tissues via the activity of the stress hormones adrenaline and cortisol. Stress is recognized as a contributing risk factor in both the incidence of periodontal disease (46)  and negative outcome of periodontal treatment (47).     

 

More recently psychological and life stress have been shown to be significantly associated with higher levels of oxidative stress, lower telomerase activity and increased leukocyte telomere attrition(48). An early study from Epel and Blackburn et al (49) reported accelerated telomere shortening as a biological response to chronic life stress and more recently in women who have experienced chronic stress related to intimate partner violence (50) . The modification of lifestyle factors has been suggested as having a buffering effect on chronic stress and telomere attrition (51) .    

  

Oestrogen and Telomere Length   

 

There is a substantial body of evidence linking oestrogen status and the onset of menopause with an increased risk of periodontal disease and alveolar bone loss (52, 53). Clinical observations include more frequent and  more exaggerated responses to oral bacteria, which initiate gingival and periodontal lesions and includes bleeding on probing or with tooth brushing, inflamed gingivae, hyperplastic gingivae, pyrogenic granuloma, tooth mobility and bone loss (54). These clinical observations coupled with tissue specificity of hormone localisation, have strongly suggested that periodontal tissues are targets for androgens (55), oestrogen's (56) and progesterone (57).   

 

Earlier investigations have shown that the risk of tooth loss during menopause is smaller in women using HRT (58)  and that circulating levels of oestrogen influence alveolar bone density (53) . 

 

More recent research has shown decreasing numbers of Porphyromonas gingivalis and Tannerella forsythia in periodontal pocketswith HRT use (59) . In addition a significant association between the levels of oestrogen and telomerase activity has been shown under physiological conditions (60) . Decreased leukocyte telomere length has also been associated with osteoblast senescence, decreased bone mineral density and osteoporosis (61).   

 

Taking into account the known associations between periodontal bacteria and systemic diseases coupled with the anti-inflammatory effects of oestrogen (62), the role of this steroid hormone in telomere length, periodontal inflammation and systemic disease deserves some attention.   

 

Menopause usually begins at approximately 45-55 years of age, unless accelerated by hysterectomy or ovariectomy. At this stage there is a dramatic decrease of oestrogen and progesterone production. Whereas the pre menopausal woman has cycling plasma levels of oestrodiol and progesterone of 50 – 500 pg/ml and 0.5- 20 ng/ml respectively, the post menopausal woman has non cycling, circulating levels of 5 – 25pg/ml and 0.5ng/ml respectively (63).   

 

Oestrogen has been linked to leukocyte telomere length through anti-inflammatory and antioxidant effects and its ability to stimulate TERT (64) . Oestrogen lowers the production of pro inflammatory cytokines including TNF (65)  and stimulates the activity of mitrochondrial superoxide dismutase (SOD) and glutathione peroxidase (Gpx) (66), two powerful antioxidant enzyme systems. It has been suggested that oestrogen may stimulate telomerase expression and exert some of its antioxidant effects through the same cellular pathways (67).   

 

Sato et al (68) were able to show that the administration of exogenous oestradiol in hepatic cells can attenuate telomere shortening by up-regulation of telomerase activity, thereby prolonging the lifespan of these cells. A concentration dependent increase in TERT protein expression by oestradiol induction was observed. The fact that women exhibit a significantly lower rate of age-dependent telomere attrition compared with men (69) may possibly be due to the stimulating properties of oestrogen on telomerase.   

 

It may also be possible that the anti-inflammatory and antioxidant effects of oestrogen may have an additional effect on the periodontal tissues , thus preserving telomere length. A drop in oestrogen production consistent with the onset of menopause may therefore alter leukocyte telomere attrition and affect periodontal inflammation. This may further add to our understanding of menopause as a risk factor for periodontal disease, alveolar bone loss and chronic inflammation.  Further research in required to establish whether the modification of nutrition and lifestyle factors relative to oestrogen status, may also provide significant attenuation of chronic inflammation and bone loss of the periodontal tissues.      

 

 

Conclusion

 

Chronic inflammation is involved in the pathogenesis of many systemic diseases and involving the release of pro-inflammatory mediators that may cause persistence of the disease process. Periodontal disease is highly prevalent in the population and therefore presents a marked inflammatory burden in this regard.  Over the last ten years there has been increasingly more evidence establishing an association between inflammatory periodontal disease and other age related inflammatory diseases such as CVD, rheumatoid arthritis, diabetes and COPD. The causal link between these diseases is poorly understood and remains to be established. Oxidative stress and chronic inflammation are a feature of all these diseases. More recently telomere attrition has also been implicated in age related, inflammatory diseases, including periodontal disease. 

 

The glutathione redox cycle is pivotal to the protection of the cell from ROS and oxidative stress. Research has confirmed that GSH concentrations are inversely related to the inflammatory periodontal diseases. NAC increases glutathione availability for the redox cycle and prevents telomere shortening and subsequent cell senescence.

 

 

The rate of telomere attrition is significantly affected by diet and lifestyle choices. A growing body of evidence supports the clinical effectiveness of lifestyle changes including a diet enhanced with key nutrients to minimise oxidative stress and inflammation and thus telomere attrition. 

 

More research and clinical trials are needed to draw together and continue to asses the effects of nutrition and lifestyle intervention as a supportive therapy in the treatment of periodontal disease. Would supporting  the glutathione redox cycle with supplemental glutathione precursors (such as NAC) in addition to dietary antioxidants provide a therapeutic/preventive measure in attenuating telomere loss and oxidative stress. If so can we now begin to draw together nutritional protocols as supportive therapy in the treatment of chronic inflammatory diseases including periodontal disease.

 

This paper was presented at Europerio 7 Vienna 2012.

 

Declaration

 

The author has no conflicts of interest or commercial relationships to declare.

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