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A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy on 7-8 April 2009. One lecture from that Symposium by G. Campisi, L. Ginaldi and F. Licastro is summarized. Ageing is a complex process which negatively impacts on the development of various bodily systems and its ability to function. A long life in a healthy, vigorous, youthful body has always been one of humanity’s greatest dreams. Thus, a better understanding of the pathophysiology of age-related diseases is urgently required to improve our understanding of maintaining good health in the elderly and to program possible therapeutic intervention.

Background

A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy on 7-8 April 2009. Elderly patients constitute a very heterogeneous group with a wide range of cultural, social and educational backgrounds. A worldwide phenomenon of the increasing number of elderly people has been recognized, with older people comprising a larger proportion of the population. This demographic phenomenon is related to an increase in chronic and at times debilitating diseases, associated with advancing age and an exponential growth in health costs. In some cases, a modification to life-style can reduce the so-called ‘indirect’ and ‘intangible’ costs of diseases in terms of public health. Thus, a better understanding of the pathophysiology of age-related diseases is urgently required to improve our understanding of maintaining good health in the elderly and to program possible therapeutic intervention.

Section 1: Giuseppina Campisi and Rosario Guiglia – Systemic diseases in the elderly: relationships between hard and soft oral tissues

Oral health in the elderly

The demographic changes described above could have a dramatic impact on mucosal and dental health: the elderly are at greater risk of oral diseases since gains in longevity result in more medically compromising conditions or systemic diseases, together with several oral-related manifestations.

Ageing affects oral tissues in addition to other parts of the human body, and oral health (the health of the mouth, teeth and associated structures, and their functional activity) is an integral component of general health. Indeed, oral diseases can have a profound impact on general health, as documented by the World Health Organization, whilst problems relating to general health can, and frequently do, manifest themselves in the mouth. This relationship has been extensively treated in the literature, by scientific societies and Journals dedicated to this area of specialization.

The most common oral conditions in the elderly are: dental caries, gingivitis, periodontitis, xerostomia, candidosis, denture stomatitis and oral cancer, while the most common systemic chronic diseases in this age group are arthritis and osteoporosis, Alzheimer’s disease (AD), metabolic syndrome with diabetes mellitus, and cardiovascular diseases with myocardial infarction (MI). Furthermore, these latter conditions have potential sequelae in the oral district, particularly in older people and in medically-compromised adults. Finally, the treatment of these diseases with medication, chemotherapy, and radiotherapy has severe implications for the maintenance of oral health.

In such a context, it is worth noting that the relationship is not only in one direction (from ageing and systemic diseases towards to oral health), but more interestingly from the oral towards systemic diseases and potentially to unsuccessful ageing. Age-related oral changes are based on the same pathological dynamics as those generally recognised in all tissues: from tissue desiccation to diminished reparative ability, from reduced elasticity to altered cell permeability.

Older patients are more susceptible to root caries due to inadequate oral hygiene, infrequent dental examinations and cleaning, salivary gland dysfunction, an insufficient use of fluoride-containing oral hygiene products and removable partial dentures, which can trap plaque around the teeth and create an environment encouraging the formation of caries. External tooth changes include discoloration (from yellow to brown) and loss of enamel due to abrasion, erosion or occlusal attrition. Thinning around the neck of teeth, often related to the use of hard-bristled toothbrushes over many years of improper tooth brushing, is frequent. Severe dental caries and periodontitis can lead to tooth extraction. Tooth loss impairs chewing, swallowing, and speaking, leading to nutritional deficiencies, social isolation, and depression.

Infections of the oral cavity constitute another important area in clinical dental practice. In elderly patients, atrophy of the oral mucosal epithelium occurs with aging but it may be more probably related to extrinsic factors (e.g. dentures) or disorders (e.g. vitamin B12/folate deficiency). This thinner and weaker oral mucosa may be more vulnerable to local irritation, resulting in a greater risk of candidal infection and/or reactivation of the varicella-zoster infection.

Pathological Modification of oral flora in the elderly

Candidal infections are the most common of diseases due to an increased prevalence of salivary gland dysfunction, the use of removable prostheses, drugs that alter oral flora or the immune function (e.g. antibiotics, anti-neoplastic, corticosteroid and immuno-suppressing drugs), diabetes mellitus, malnutrition, and other immuno-compromising conditions. Oral candidosis may present itself as: a) acute pseudomembranous (commonly labeled ‘thrush’), characterized by white plaques or patches that may cause pinpoint bleeding when scraped; b) being hyperplastic, with confluent leukoplakic plaques that cannot be scraped away; c) atrophic, characterized by painful erythematous mucosal lesions, frequently located beneath dentures; or d) angular cheilitis, characterized by leukoplakic and erosive lesions on the lip commissures.

Oral zoster is caused by the reactivation of a latent varicella-zoster virus infection. Precipitating factors include thermal, inflammatory, radiological or mechanical trauma, immuno-compromising states including cancer, Hodgkin’s and non-Hodgkin’s lymphoma, and physiological or emotional stress. Since these conditions are more prevalent in elderly people, herpes zoster is likely to an issue. Its appearance is characterized by a painful segmental eruption of small vesicles which rupture to form confluent ulcers. Vesicles appear on the skin and oral mucous membranes, occurring unilaterally along the ophthalmic, maxillary, or mandibular divisions of the trigeminal nerve. Post-herpetic neuralgia can last for months after the vesicles have erupted and cause considerable pain and neuralgia.

As a consequence of these infective events, dysphagia (i.e. difficulty in swallowing) or xerostomia can occur. The latter two are not considered as ‘diseases’ but conditions that give rise to a nutritional deficiency and reduced salivation respectively. Dysphagia and xerostomia in the elderly may also be caused by a variety of medical conditions, such as immunological (e.g. arthritis, diabetes), neurological (e.g. Parkinson’s disease) or psychological disorders (e.g. depression, dementia), or by various types of medication (e.g. anticholinergic, antipsychotic, antihypertensive drugs).

Oral cancer and potentially malignant lesions are concomitant with ageing. Indeed, exposure to oncogenetic factors (i.e. tobacco smoking, alcohol consumption, exposure to ultraviolet radiation, high risk human papilloma virus) as well as the inflammatory burden involved in onco-pathogenesis, increase during a person’s lifetime and could determine the occurrence of oral cancer precursors.

Periodontal disease as a model of inflamm-aging

However, periodontal disease (PD) is, as a model of chronic inflammatory disease, able to influence the general status of health and the quality of ageing. PDs are a heterogeneous group of diseases that affect the supporting structures of the teeth (gingiva, root cement, alveolar bone and periodontal ligament). Generically, it is possible to distinguish gingivitis, as an early stage of the disease which does not involve tooth attachment and which displays irritated gums, from periodontitis, which affects all the tissue surrounding the tooth, concluding with regrettable dental loss. Its aetiology is complex, clinical manifestations are various and several classifications have been proposed. In 1999, the American Academy of Periodontology successfully classified PD in relation to its aetiology in an International Workshop for the Classification of Periodontal Diseases and Conditions.

The chronic stimulation of inflammation sustained by the Gram-negative anaerobic bacteria of dental plaque has been correlated with various systemic diseases, such as pre-term and low birth- weight, atherosclerosis and cardiovascular diseases, worsening control over diabetes and the slow healing of wounds, aspiration pneumonia and osteoporosis.

Different models of the aetiopathogenetic mechanisms of oral bacteria exist:

1) Common susceptibility involves a genetically determined phenotype. In the presence of periodontal pathogens, a susceptible patient develops PD. This same person would also be susceptible to atherosclerosis, diabetes or pulmonary infections but, in this model, PD does not cause a systemic condition;

2) at present, a more complex model is accredited, in which direct and indirect dynamics as well as innate, endogenous and exogenous factors are involved. Local adaptive immunity reacts to produce cytokines which are capable of altering vessel permeability, thereby enabling monocytes to penetrate the inflamed tissue. The chronic stimulation of inflammation by bacterial plaque involves several cell populations and several networks of cytokines, facilitating detachment and the formation of bone defects, since the cell populations amplify the inflammatory reaction and activate the effector mechanism, which is responsible for tissue destruction. At the same time, bacteria reaches the blood circulation directly or by means of their lipopolysaccharides;

3) this model offers the basic rationale for the documented link between local effects and various related systemic diseases. Specifically, a bi-directional relationship has been reported to exist for many diseases, the latter which could be reciprocally influenced. Of these, diabetes is one of the most reported diseases with a very precise pathological dynamic: the higher susceptibility of diabetics to periodontitis. The latter enhances insulin resistance and complicates glycaemic control, in addition to determining a more severe case of periodontitis, leading to defining periodontitis as the sixth complication of diabetes.

The second bidirectional condition is the presence of osteoporosis (primary and secondary one), which is correlated with the loss of alveolar bone and teeth. Hence, osteoporosis involves the same percentage of the stomatognathic apparatus as with the skeleton, and in numerous studies it has been correlated with a loss of alveolar bone and teeth (see the next paragraph). This model had previously been established in relation to unidirectional pathogenesis (from osteoporosis forward to PD), but today the same dynamics for osteoporosis have also been hypothesised as for diabetes, based on the release of cytokines at the onset of PD. The latter induces an uncoupling of normal bone homeostasis, an increase in osteoclastic activity and decrease in bone mineral density.

Recently new links have been hypothesized between PD and renal disease, obesity, dysmetabolic syndrome and pancreatic cancer. However, possibly the most interesting link suggested to date is that with Alzheimer’s disease (AD), a chronic age-related disease depending on systemic and local inflammation. The invasion of the brain by oral bacteria was posited as recently as 2002: of the periodontal bacteria, various species such as Actinobacillus Actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola and Fusobacterium nucleatum have been found to be capable of invading the brain, modifying the cytokine milieu and possibly contributing to existing pathological mechanisms. In particular, Treponema species, including T. denticola, have been detected in 14/16 AD and 4/18 non-AD brains. Moreover, AD specimens have displayed a greater number of Treponema species than the controls.

Two mechanisms may be involved in the PD-induced onset/progression of AD:

1) inflammatory; and 2) bacterial mechanisms. The first mechanism implies that PD-derived inflammatory molecules increase brain inflammation. The interaction between periodontal bacteria and host response results in the locally increased production of inflammatory molecules, including interleukin (IL)-1β, IL-6, IL-8, Tumor Necrosis Factor (TNF)-α, and C-reactive protein (CRP).

The host response to subgingival periodontal pathogens engages both innate and instructive immune responses, resulting in the alteration of local vasculature, generation of an inflammatory response, immune cell priming, and the secretion of pro-inflammatory cytokines. The bacteria and host response of a patient in good periodontal health are in equilibrium. In cases of gingivitis, the bacterial challenge elicits an innate immune response in the adjacent gingival tissue, which is capable of limiting a bacterial-induced pathology. When periodontitis has been diagnosed, the balance between bacteria and host response is disrupted, thereby resulting in an increased inflammatory infiltrate and the production of pro-inflammatory cytokines. Tissue destruction occurs mainly by the activation of osteoclasts, matrix metalloproteinases, and other proteinases by the host inflammatory response.

In cases of severe PD, these pro-inflammatory molecules may induce a systemic inflammation and may, therefore, access the brain via systemic circulation. Pro-inflammatory molecules, derived locally from periodontal tissue, may stimulate trigeminal nerve fibers, leading to an increase in the number of brain cytokine. These cytokines may act on the already primed glial cells, resulting in an amplified reaction and possible progression of AD. A test for this hypothesis would entail examining whether PD affects the progression of AD, which clinically presents as earlier onset or as a more severe stage of the disease.

The second mechanism by which PD could contribute to brain inflammation is direct, through bacteria and/or bacterial products. Several bacteria, including oral bacteria, have been hypothesized as being implicated in the pathogenesis of AD. The mechanism by which periodontal bacteria access the brain is unknown. However, the mechanisms described for other bacteria accessing the brain via systemic circulation is possible. Orally-originated bacteriaemia occurs relatively frequently during dental and non-dental manipulations. A further route by which bacteria may reach the brain is via the peripheral nerves. Riviere’ studies have demonstrated that spirochete species were detected in the trigeminal ganglia, thereby suggesting the ability of oral spirochetes to invade the central nervous system via the peripheral nerves. However, the simple presence of periodontal bacteria in the systemic circulation or in the territory of peripheral nerve fibers does not imply access to the brain. Additional co-factors may be required, such as age, the presence of inflammatory cytokines or other infection. Although it is most probable that infections are not causative in these types of diseases, their possible role as aggravating co-factors in patients with susceptible genetic backgrounds should be seriously considered. Consequently, every chronic peripheral infection may contribute to the global infectious/inflammatory burden and participate in the aetiopathogenesis of relevant diseases.

Several related cross-sectional studies and various longitudinal studies have demonstrated that patients with dementia are more likely to have poor oral health. For example, the Nun Study, a longitudinal study of ageing and AD, provided an opportunity to study oral health and cognitive function. The authors of this study confirmed that fewer teeth increased the risk of a higher prevalence and incidence of dementia (also in patients without the Apo-E4 allele), albeit without conclusive evidence regarding the ‘causal or casual’ role played by each factor .

In conclusion, evidence-based data regarding the association of PD with neurodegenerative disorders are still lacking. However, it seems plausible that there is an increase in the number of brain cytokines activating the neurodegenerative pathway via a contribution to systemic/brain inflammation.