*2.1. Edentulism*

Edentulism is a pathological condition characterized by multiple missing teeth; it can be partial or total. The etiology of tooth loss includes factors such as predisposition, diet, hormonal status, coexisting diseases, hygiene habits, and use of dental clinics. Additionally, edentulism may result from an unsuccessful periodontal treatment or important carious lesions [37,38]. Dental disease and loss of teeth are not part of normal aging, but if this occurs, it is probably a result of neglected oral hygiene and/or an inadequate treatment [39,40]. Edentulism is exacerbated when masticatory function is not restored with dental prostheses [41]. Tooth loss affects the individual ability to chew determining an alteration of food choices [42]. Indeed, edentulous people are at greater risk of malnutrition than dentate or partially dentate individuals [43], and, consequently, with an increased susceptibility to sarcopenia and frailty [25]. Tooth loss is also a risk factor for disability, since it impedes self-sufficiency and worsens the quality of life [42].

#### *2.2. Dry Mouth*

Saliva is pivotal for bolus formation and consequently is also related to the sensory and textural experience. Xerostomia is a clinical condition characterized by an excessive sensation of dryness in the mouth, which is not necessarily linked to salivary gland hypofunction [30,44]. Xerostomia is estimated to affect 25–50% of older individuals [45]. Etiologic factors include polypharmacy (especially with antihypertensives, antidepressants, and antipsychotics) [46], diseases, poor general health, female sex, and older age [47,48]. Furthermore, radiation for head and neck cancers can damage salivary glands, leading to permanent xerostomia [49]. With aging, there is also a reduced salivary flow in salivary glands, which cannot be explained only on the basis of medications [50]. In fact, salivary hypofunction and xerostomia are two distinct constructs that are frequently improperly used interchangeably [33].

However, it has been reported that nearly one third of older adults complaining of xerostomia do not present any reduction of the salivary flow or saliva secretion. This suggests a psychological component may be involved when reporting the symptom [30]. Nonetheless, hyposalivation may seriously compromise chewing function and early digestive process. A reduced quantity of saliva can, in fact, affect the preparation of the alimentary bolus and the swallowing [51].

#### *2.3. Periodontal Disease*

Periodontitis is described as a chronic inflammatory disease that affects the supporting tissues of the teeth, leading to a progressive destruction of the periodontium [52]. It can also cause mobility and displacement of the remaining teeth and is often linked to difficulty in chewing. Prevalence of periodontal disease, considering a periodontal index score of 4 (deep pockets), ranges from approximately 5% to 70% among older people [53]. Periodontitis is a cumulative disease; therefore, it becomes increasingly severe as the person ages [30]. Poor oral hygiene is a critical determinant of periodontitis since it leads to the formation of dental plaque containing microorganisms [54]. Systemic risk factors for periodontal disease also include other behaviors, such as smoking, medical conditions (i.e., poorly controlled diabetes, obesity, stress, osteopenia), and inadequate dietary consumption of calcium and vitamin D [55]. Since periodontitis share some characteristics with other systemic inflammatory diseases, a relationship between periodontitis and other inflammatory pathologies (i.e., diabetes, cardiovascular diseases, adverse pregnancy outcomes, and rheumatoid arthritis) has been proposed [56].

In recent years, the role of the diet in periodontitis has been highlighted. To date, it has been documented that a diet poor in fruit and vegetables and therefore in micronutrients may lead to a greater inflammatory response of periodontal tissues that support the tooth. Interestingly, a recent systematic review of the relationship between dietary intake and periodontal health in community-dwelling older adults, reported positive associations between periodontal disease and lower intakes of docosahexaenoic acid, vitamin C, vitamin E, β-carotene, milk, fermented dairy products, dietary fiber, fruits and vegetables, and higher intakes of omega-6/omega-3 ratio and saturated fatty acids [57]. Additionally, micronutrient deficiencies can negatively affect healing following periodontal surgery [58]. At the same time, the loss of dental elements due to periodontitis can negatively affect the nutritional status of the patient, resulting in a discomfort during chewing and leading to a selection of soft and easy-to-chew foods.

#### *2.4. Dental Caries*

Dental caries is a multifactorial infectious disease characterized by the demineralization and destruction of the dental substance: enamel, in fact, is susceptible to acid dissolution over time. The pathological changes of the dental structure may have serious consequences, ultimately leading to the breakdown of the teeth themselves [59]. The prevalence of dental caries varies between 20% and 60% in community-dwelling older people and 60% and 80% in care home settings [60–64]. Various predisposing conditions to dental caries have been reported, including carbohydrate (especially simple sugars) consumption, diabetes, and poor socioeconomic conditions [60,65–68].

With increasing age, people may experience physical and cognitive decline, which may result in poor oral hygiene, leading to an increased incidence of caries. Over time, small lesions already filled can need a larger dental restoration, that can lead to a tooth fracture or an endodontic treatment [30]. Endodontic therapy (also known as root canal treatment) is a necessary procedure in case of inflamed or infected dental pulp. It consists in the removal of the pulp, both in the coronal and radicular part of the tooth, and in its replacement with a gutta-percha permanent filling (a substance of vegetable origin such as natural rubber). Xerostomia is closely related to a higher risk for developing caries since loss of saliva may lead to an increased acidity of the mouth. This leads to different situations that may contribute to the development of the dental caries: the proliferation of bacteria, the loss of minerals from the tooth surfaces, and the loss of lubrication [69].

#### *2.5. Impact of Oral Health on Nutritional Status*

Nutrition is a key modulator of health in older persons. Inadequate intake of nutrients is a well-known contributing factor in the progression of many diseases. This also has a significant impact in the complex etiology of sarcopenia and frailty [70–72]. Due to a decline in many functions, including poor oral status, dietary intake is often compromised in older people and the risk of malnutrition is increased. Particularly, acute and chronic illnesses and medications as well as poor dentition can exacerbate anorexia [5,70,73]. Oral problems in older individuals are associated with modifications in food selection and, therefore, in nutrient intake [25]. Deterioration of oral health can ultimately lead to the development of chronic conditions such as diabetes [74] and cardiovascular problems [75–77]. Masticatory performance is affected by the number of teeth in functional occlusion [78–80], the maximal biting force [81,82], denture wearing [83] and xerostomia [84]. The functional occlusion during mandibular closure is provided by the even and simultaneous contact of all remaining teeth (at least 20 with 10 contiguous teeth in each arch) [85].

Tooth loss has been implicated in the reduction of chewing ability and in difficulties in bolus formation [86]. To date, it has been reported that as number of remaining teeth decrease, the bolus size increases leading to a dysfunctional swallowing [87]. Edentulous individuals, even when using well-made dentures, may experience more chewing di fficulties than dentate people [88]. Therefore, they may be considered as the group more prone to changing their diet [89,90]. Older people who experience dental problems frequently avoid harder foods such as meats, fruits, and vegetables which are typically major sources of proteins, fiber, vitamins, and minerals [41,88,91]. The lack of these latter key nutrients may expose older individuals to an increased risk for malnutrition, frailty, and sarcopenia [24,92]. In addition, it is well established that micronutrient deficiencies, even subtle, may lead to oxidative stress and consequently to inflammation. Therefore, these processes can further exacerbate sarcopenia and frailty and become a clear risk factor for periodontitis. Nutritional deficiencies may also negatively affect the mineralization process, increasing the susceptibility to dental caries [93]. Furthermore, undernutrition can exacerbate the severity of oral infections [94]. Indeed, with advancing age, people show a tendency to select soft foods due to di fficulty and fatigue of chewing [10,95]. However, these latter are frequently processed foods that are high in fat and sugar and with a poor content of vitamins and minerals, leading to fat deposition, oxidative stress, inflammation, and, consequently, increased risk of cardiovascular disease and metabolic syndrome [88,95–97]. In fact, it is well established that obesity leads to chronic low-grade inflammation, increasing the susceptibility to dental caries, periodontal disease, and tooth loss [98]. The excess of energy is stored in adipocytes and leads to both hypertrophy and hyperplasia, resulting in an abnormal adipocyte function. This may increase mitochondrial stress and altered endoplasmatic reticulum function. Furthermore, adipocyte-associated inflammatory macrophages can also induce oxidative stress [99]. On the other hand, it is widely recognized that an excessive consumption of simple sugars is a major risk factor for dental caries [100,101].

Large epidemiological studies, such as the UK National Diet and Nutrition Survey (NDNS) [102] and the US National Health and Nutritional Examination Surveys (NHANES) [103,104], reported an association between poor dental status and inadequate dietary intake in older people. In particular, they reported that edentulous subjects, with and without prosthesis, consumed less fruits and vegetables. Moreover, decreased protein and micronutrient intake, together with increased carbohydrate consumption, has been reported in people with less than 21 teeth [104].

#### **3. Sarcopenia and Oral Status**

Sarcopenia, defined as the progressive and accelerated loss of muscle mass and function, is a major determinant of several adverse outcomes including frailty, disability, and mortality [13,105]. Although sarcopenia is a condition commonly observed with the aging process, it can also occur earlier in life [106]. Since 2016, sarcopenia has been recognized as an independent condition with an International Classification of Disease, 10th Revision, Clinical Modification (ICD-10-CM) Diagnosis Code [107]. Recently, the European Working Group on Sarcopenia in Older People (EWGSOP) [106] updated their consensus on definition and diagnosis (EWGSOP2). In this revised consensus, low muscle strength is considered a key characteristic of sarcopenia, and poor physical performance is identified as indicative of severe sarcopenia. Moreover, EWGSOP2 have recommended specific cut-off points to identify and characterize the sarcopenic condition, and provide an algorithm that can be used for case-finding.

Sarcopenia has a complex multifactorial pathogenesis, which involves lifestyle habits (i.e., malnutrition, physical inactivity), disease triggers, and age-dependent biological changes (i.e., chronic inflammation, mitochondrial abnormalities, loss of neuromuscular junctions, reduced satellite cell numbers, hormonal alterations) [108,109]. Sarcopenia is a whole-body process, affecting not only lower extremities, but also muscles dedicated to breathing, mastication, and swallowing [14,18–22]. In particular, swallowing is a complex mechanism involving several head and neck muscles simultaneously and in conjunction to coordinate the entire process [110]. Several age-related changes, such as as reduction of tissue elasticity, changes of the head and neck anatomy, reduced oral and pharyngeal sensitivity, and impaired dental status, may contribute to di fferent degrees to a subtle swallowing impairment, the so called "presbyphagia". It is usually an asymptomatic condition in which swallowing function is preserved, but tends to slowly worsen as the aging process advances [16,111]. Presbyphagia may increase the risk of dysphagia and aspiration in older people, especially during acute illnesses and other stressors [112]. Moreover, reductions in muscle mass of the geniohyoid, pterygoid, masseter, tongue, and pharyngeal muscles have been documented in older individuals [20,113–115]. Several authors also reported a decline in the strength of the swallowing muscles with aging or sarcopenia [116]. Maximal tongue strength decreases with aging [116–119], and there is some evidence that aging leads to a decreased jaw-opening force in older men. Several authors also reported an association between tongue strength and handgrip strength [120,121]. A decrease in tongue strength has been associated with a decline of activities of daily living [122], and a reduced tongue thickness has been noted in people with low body weight [20].

Lip function is also important for feeding. In fact, poor lip muscle closure may cause leakage through the corners of the mouth [123]. Additionally, decreased lip strength has been suggested to occur due to sarcopenia and to be related to difficulties in eating and drinking (i.e., dysphagia) [117]. Lip force has been associated with hand grip strength and lip pendency has been associated with aging [117,124].

Indeed, since it has been shown that skeletal muscle mass and strength decline may affect both swallowing and general muscle groups, a new condition, called "sarcopenic dysphagia" has been coined [22,124,125]. Swallowing muscles are characterized by a high percentage of type II fibers, which are more easily affected by malnutrition and sarcopenia than type I muscle fibers [22]. However, some cranial muscles, including the jaw-closers, are very different in fiber-type composition than other skeletal muscle groups (i.e., limbs or abdomen). For instance, the masseter muscle, which originates from the zygomatic arch, contains both type I and type II fibers, but shows a predominance of type I muscle fibers, which are more strongly affected by inactivity rather than aging [126,127]. Given that the meal texture of older people frequently becomes softer, less power of tongue movement and of masseter muscle is required, which may result in decreased activity of these muscles.

Interestingly, poor oral health may predispose one to a chronic low-grade inflammatory state through periodontal disease, which is a well-known risk factor for frailty and sarcopenia [25,128,129]. In fact, the detrimental effects of periodontitis are not confined solely to the oral cavity, but extend systemically, leading to metabolic alterations [130], including insulin resistance [131], diabetes [131,132], arthritis [133], and heart disease [134]. Furthermore, alterations in mitochondrial function leading to oxidative stress through the production of reactive oxygen species (ROS) have also been reported to mediate both oral and systemic pathologies (i.e., sarcopenia) [108,135–137]. Given their regulatory role as signaling molecules in autophagy, it has been speculated that elevated ROS production in periodontal disease could lead to autophagic alterations [138]. Bullon et al. [139] found high levels of mitochondrial-derived ROS, accompanied by mitochondrial dysfunction in peripheral blood mononuclear cells from patients with periodontitis. Moreover, oral gingiva seems to be highly responsive to the lipopolysaccharides (LPS), which are bacterial endotoxins prevalent in periodontal disease. In fact, gingival fibroblasts, which play an important role in remodeling periodontal soft tissues, may directly interact with LPS. In particular, LPS from *Porphyromonas gingivalis* enhances the production of inflammatory cytokines [140]. *Porphyromonas gingivalis* has been found to be responsible for high mitochondrial ROS and coenzyme Q10 levels, and for mitochondrial dysfunction, given its influence on the amount of respiratory chain complex I and III [138,139]. Indeed, LPS-mediated mitochondrial dysfunction could explain the oxidative stress onset in patients with periodontitis. Furthermore, Hamalainen et al. [29] reported an association between periodontitis and quicker declines in handgrip strength.

On the other hand, as discussed in the previous section, the variety of dental problems experienced by older people can lead to a decline in general health through poor nutrient intake, pain, and low quality of life [25]. Poor oral status has been reported to affect 71% of patients in rehabilitation settings [141] and 91% of people in acute-care hospitals [142], and has been associated with malnutrition, dysphagia, and reduced activities of daily living [17]. Hence, poor oral status may lead to sarcopenia through poor nutrient intake. Moreover, inflammation further contributes to malnutrition through various mechanisms, such as anorexia, decreased nutrient intake, altered metabolism (i.e., elevation of resting energy expenditure), and increased muscle catabolism [143]. Chronic inflammation is a common underlying factor, not only in the etiology of sarcopenia, but also for frailty. In fact, sarcopenia and frailty are closely related and show a remarkable overlap especially in the physical function domain [144–146]. The presence of oral problems, alone or in combination with sarcopenia, may thus represent the biological substratum of the disabling cascade experienced by many frail individuals.
