Oral frailty and systemic health including lifestyle-related diseases: a narrative review

Abstract

Oral health is defined as being free from oral diseases and dysfunction and absence of interference with systemic health. Oral frailty is an intermediary stage in the decline of this function. Oral frailty has been reported to be associated with lower physical activity. Changes in food preferences due to decreased chewing and swallowing functions are associated with malnutrition. Epidemiological studies have shown that oral frailty is also associated with decreased cognitive function, decreased renal function, and decreased bone mineral density. However, a high community periodontal index value is associated with future oral frailty. Specifically, periodontopathogenic bacteria and inflammatory cytokines induced by periodontal disease affect the whole body hematogenously from the gingival region, which is associated with lifestyle-related diseases such as diabetes and cerebrovascular diseases. In addition to this mechanism, malnutrition resulting from oral frailty may exacerbate periodontal disease-derived lifestyle-related diseases by weakening the immune system. Since recent animal experiments revealed that periodontal diseases affect the gut microbiota, oral frailty with periodontal disease may hypothetically affect hypertension and dyslipidemia, which are associated with gut microbiota alterations. In addition to reviewing epidemiological studies on oral frailty published in the past five years, this study also hypothesized the involvement of gut microbiota in the relationship among oral frailty, periodontal disease, and lifestyle-related diseases.

 Definition of Oral Frailty

The concept of “oral frailty” was first proposed in Japan in 2013¹⁾. The Japanese Society of Gerodontology proposed the term “oral frailty syndrome” for oral hypofunction in old age, and the following year, it was changed to “oral frailty” in a report by the Japanese Ministry of Health, Labour and Welfare¹⁾. This concept is defined as “a designation for the intermediate state between normal and impaired oral function in old age.” However, given the wide range of stages from oral health to disability, the Japanese Society of Gerodontology described the new concept of oral hypofunction in a position paper in 2018²⁾. Specifically, oral health is divided into four stages from health to disability: “decline of oral literacy,” resulting from dental caries, periodontal disease, and tooth loss; “oral frailty,” characterized by decreased articulation, slight choking or spillage while eating, and an increase in the number of unchewable foods; “oral hypofunction,” characterized by three and more symptoms as decreased tongue–lip motor function, decreased tongue pressure, reduced occlusal force, poor oral hygiene, oral dryness, decreased masticatory function, and deterioration of swallowing function; and “oral dysfunction,” characterized by eating/swallowing or mastication disorder. In this position paper, oral frailty was defined as follows: “for dental medicine, oral frailty is a relatively new concept that can be associated with gradual oral function loss in relation to aging.”

However, currently, no worldwide agreement exists on the concept of oral frailty. For example, Iwasaki et al.³⁾ proposed that “in the Kashiwa study, oral frailty was first operationally defined as the presence of 3 or more of the following components: (i) low number of remaining teeth, (ii) low masticatory performance, (iii) low articulatory oral motor skill, (iv) low tongue pressure, and subjective difficulties in (v) eating and (vi) swallowing.” Conversely, Shiraishi et al.⁴⁾ defined oral frailty as “the accumulation of a slightly poor status of oral conditions and function, strongly predicts physical frailty, dysphagia, malnutrition, need for long-term care, and mortality in community-dwelling older adults.” Alternatively, Parisius et al.⁵⁾, after evaluating the full text of 47 articles from 1,528 articles screened in their review article, stated that “oral frailty is described with a different number and combination of characteristics, resulting in a lack of conceptual consistency.” Thus, the present review proposed a new conceptual definition, that is, “oral frailty is the lifestyle-related functional decline of orofacial structures,” because current definitions of oral frailty are not considered good conceptual definitions. Although oral frailty refers to a decline in oral function, this concept is still under consideration.

 Evaluation Items for Oral Frailty

Of the 83 articles searched for “oral frailty” in PubMed from 2018 to September 2023, 14 articles were cross-sectional studies, four were longitudinal studies, and one was a randomized controlled trial. Table 1 shows the results of aggregating each article for the same evaluation items. Of the 19 papers, items evaluated were as follows: 15 for swallowing function, 13 for masticatory function, 11 for tongue and lip motor skill (oral motor skill), 9 for oral dryness, 9 for number of teeth, 8 for tongue pressure, and 4 for frequency of tooth brushing. Some evaluation items are commonly used in each paper, whereas others are used only in one article. Considering which items should be assessed regarding the definition of oral frailty may be important. Even for evaluation methods commonly used in various articles, if many of them are continuously published by the same research group, the systematic analysis may have a bias toward a particular study. Therefore, alternative methods that are simple, quick, and cost-effective are necessary for evaluation items that can be commonly used by different research groups and items that cannot be evaluated without expensive dental-specific instruments in epidemiological studies that are large enough to target residents. In a systematic review by Dibello et al.⁶⁾, quantitative meta-analysis may not be reliable because of the heterogeneity of different variables in oral health assessment and assessment of various adverse health-related outcomes.

Table 1.Evaluation items of each oral frailty study

Authors	Evaluation
Nomura et al. (20207), 20218)) Kuo et al. (2022)9) Kusunoki et al. (2023)10)	1: Harder to eat hard food than half a year ago 2: Sometimes, choked by tea or soup 3: Use of denture 4: Minding about oral dryness 5: Less frequent going out times than half a year ago 6: Capable of chewing hard food such as pickled radish or shredded and dried squid 7: Brushing teeth at least twice a day 8: Attending dentist at least once a year
Nakai et al. (2023)11)	1: Harder to eat hard food than half a year ago 2: Sometimes, choked by tea or soup 3: Minding about oral dryness 4: Number of teeth 5: Brushing teeth at least twice a day
Ichikawa et al. (2018)12)	1: Occlusal force 2: Moisture of the oral mucosa
Suzuki et al. (2021)13)	1: Harder to eat hard food than half a year ago 2: Sometimes, choked by tea or soup 3: Minding about oral dryness
Doi et al. (2023)14)	Subjective oral frailty symptoms 1: Harder to eat hard food than half a year ago 2: Sometimes, choked by tea or soup
Hihara et al. (2019)15)	1: I have dental problems than before 2: I am aware of saliva problems more than before 3: I bite my cheek and tongue more than before 4: I drop foods while eating more than before 5: I feel the difficulty to chew more than before 6: I feel nonsmoothness of tongue actions than before 7: I am aware of swallowing action than before
Iwasaki et al. (202016), 202117)) Komatsu et al. (2021)18) Shirobe et al. (2022)19) Yamamoto et al. (2022)20) Nagatani et al. (2023)21) Nishimoto et al. (2023)22)	1: Number of natural teeth 2: Chewing ability as an indicator of general masticatory performance 3: Maximum tongue pressure 4: Articulatory oral motor skill (“ta” sound) 5: Subjective difficulties in eating hard foods 6: Subjective difficulties in swallowing
Satake et al. (2019)23)	1: Tongue pressure 2: Oral diadochokinesis 3: Number of teeth 4: (CPI)
Lin et al. (2022)24)	1: Dysphagia 2: Xerostomia 3: Masticatory performance 4: EI (indicating occlusal support) 5: Oral diadochokinetic rate 6: Silness–Löe plaque index (representing oral hygiene)
Hiltunen et al. (2021)25)	1: Salivation as normal or dry mouth 2: Presence of food residues (on the teeth surface, etc.) 3: Inability to keep mouth open during the examination 4: Unclear speech 5: Pureed or soft food diet 6: Painfulness (expression of pain during oral examination, etc.)

 Oral Frailty and Its Relationship to Physical Frailty

Of the 19 papers, 7 investigated the relationship between oral and physical frailty (Table 2). Since the diagnostic criteria for physical frailty²⁶⁾ include a decrease in walking speed and muscle strength, many studies have evaluated the relationship between these indicators and oral frailty as an outcome. Cross-sectional studies by Iwasaki et al.¹⁶⁾ and Komatsu et al.¹⁸⁾ reported that oral frailty was associated with decreased walking speed. Furthermore, in a cross-sectional study, Kusunoki et al.¹⁰⁾ evaluated the relationship between muscle mass and oral frailty and reported that lower cystatin C-related indices such as Cr/CysC and eGFRcys/eGFRcre were associated with lower skeletal muscle mass and higher risk of oral frailty. Contrastingly, in a 6-year longitudinal study, Doi et al.¹⁴⁾ reported that the hazard ratio for adverse health outcomes such as disability and death due to oral frailty was 1.39.

Table 2.Summary of recent epidemiological studies on the relationship between oral and physical frailty.

Authors	Methods	Participants	Main results
Komatsu et al. (2021)18)	Cross-sectional	308 people aged ≥64 years	Decreased gait speed is an important indicator of oral frailty development.
Iwasaki et al. (2021)16)	Cross-sectional	1,082 people aged ≥70 years	Oral frailty was associated with slower gait speed and shorter stride and step length.
Kusunoki et al. (2023)10)	Cross-sectional	251 people aged ≥65 years	Cr/CysC and eGFRcys/eGFRcre were significantly lower in the high-risk group for oral frailty.
Doi et al. (2023)14)	Longitudinal (6 years)	3,564 people aged 75, 80, 85, and 90 years	The hazard ratio for adverse health outcomes in the presence of subjective symptoms of oral frailty is 1.39.
Ichikawa et al. (2018)12)	Cross-sectional	225 participants	Grip strength is associated with occlusal force.
Kuo et al. (2022) 9)	Cross-sectional	308 people aged ≥75 years	Physical frailty was significantly associated with oral frailty subdomains of difficulty eating hard food, choking, denture use, and inability to chew hard food.
Satake et al. (2019)23)	Cross-sectional	467 people aged ≥60 years	Tongue pressure was positively associated with muscle index and number of teeth.

Regarding the relationship between the individual components of oral frailty and physical frailty, a cross-sectional study by Ichikawa et al.¹²⁾ showed that decreased bite strength was associated with decreased grip strength. A cross-sectional study by Kuo et al.⁹⁾ indicated that difficulty consuming hard foods, swallowing, and denture use were associated with physical frailty, and they reported an odds ratio (OR) of 3.03 for oral frailty versus physical frailty among older adults aged ≥75 years. In a cross-sectional study by Satake et al.,²³⁾ tongue pressure negatively correlated with age and positively correlated with muscle index and number of teeth.

A systematic review of the relationship between tongue pressure and frailty, based on a meta-analysis of 24 articles, Sakai et al.²⁷⁾ indicated that a tongue pressure of -6.80 kPa was associated with frailty from the mean value and -5.40 kPa was associated with sarcopenia. In addition, in a systematic review of 39 articles on the relationship between the individual components of oral frailty and frailty, Dibello et al.²⁸⁾ found that fewer teeth (29%) were most closely associated with physical frailty, followed by reduced oral motor skills (27%) and saliva disorders (20%). Despite the strong relationship between oral frailty and physical frailty, since different researchers assess different items, no clear answer remains as to which of the individual oral function item decline is associated with frailty.

 Oral Frailty and Its Association with Nutrient Intake

Of the 19 papers on the relationship between oral frailty and nutrients, one was a longitudinal study, and two were cross-sectional studies. A 2-year longitudinal study of 466 adults aged ≥70 years, Iwasaki et al.¹⁶⁾ reported that oral frailty worsened nutritional assessment by Mini Nutritional Assessment Short-Form (adjusted OR, 2.24; 95% confidence interval [CI] 1.08–4.63). In a cross-sectional study of 701 individuals aged ≥50 years, Nomura et al.⁷⁾ showed a relationship between oral health behaviors such as frequency of brushing or regular dental visits and nutrient intake, particularly vitamins, using a brief-type self-administered diet history questionnaire; however, no relationship was found between the number of remaining teeth and nutrient intake. In a cross-sectional study of 240 subjects aged ≥40 years, Suzuki et al.¹³⁾ indicated that lower intakes of potassium, calcium, magnesium, and phosphorus were associated with lower bone mineral density as measured by the osteo-sono assessment index (OSI) when accompanied by oral frailty. Although studies on the relationship between oral frailty and nutrient intake are still scarce, all studies speculate that changes in food preferences, such as avoidance of hard foods, may be related to changes in nutrient intake as oral frailty progresses. In addition, the results of the review by de Sire et al.²⁹⁾, who proposed the concept of poor oral health as being related to low nutrition, sarcopenia, dysphagia, and sarcopenic dysphagia, suggested the relationship between oral frailty and malnutrition as an area for further study.

 Oral Frailty, Periodontal Disease, and Their Association with Cognitive Function

Of the 19 papers on the relationship between oral frailty and cognitive function, only one was a longitudinal study. In a longitudinal study of 1,410 participants aged ≥65 years, Nagatani et al.²¹⁾ found that the hazard ratio (95% CI) for new mild cognitive impairment (MCI) after 9 years was 1.76 (1.11–2.8) when both oral and physical frailty were present at baseline. In addition, they reported that among the components of oral frailty, those associated with new MCI were related to a decrease in the number of remaining teeth, low tongue pressure, and difficulty eating hard foods. In the relationship between oral frailty and cognitive decline, a review by Dibello et al.³⁰⁾ proposed the bidirectional pathway in which periodontal disease is directly related to cognitive decline, and periodontal disease and cognitive decline are associated with oral frailty, which affects dementia through malnutrition and physical frailty.

Mechanisms by which periodontal disease affects Alzheimer’s disease (AD) has been elucidated primarily in animal experiments. In an experiment by Miklossy et al.³¹⁾, mammalian glial cells and neurons were exposed in vitro to the periodontopathogenic bacterium spirochetes, and after 2–8 weeks, morphological changes similar to amyloid deposition in the brain in AD were observed, and cultured cells treated with spirochetes or lipopolysaccharide and Western blotting of extracts of the spirochetes or lipopolysaccharide-treated cultured cells revealed increased levels of β-amyloid precursor protein and phosphorylated tau., Poole et al.³²⁾ also reported that infections in the oral cavity of ApoE-/- mice with a predominant periodontopathogenic bacterium led to the detection of the active invasion of Porphyromonas gingivalis in the brain and infection-induced complement activation with bystander neural injury. Conversely, Oue et al.³³⁾ compared mice with molar extraction and without extraction and showed that tooth loss did not change the amount of amyloid-beta in the hippocampus but decreased the number of pyramidal cells, suggesting that a mechanism other than the amyloid hypothesis may cause cognitive dysfunction. At present, only a few animal studies have demonstrated that tooth loss and periodontal disease are associated with dementia, and a few epidemiological studies have shown that a combination of oral and physical frailty is associated with MCI; thus, further research on this relationship is expected.

 Oral Frailty and Its Relationship to Other Systemic Functions

In a cross-sectional study of 400 participants aged ≥40 years, Nakai et al.¹¹⁾ indicated that in the oral frailty group, bone mineral density loss as indexed by the OSI was a significant independent variable for renal function decline as indexed by eGFR (OR, 0.001; 95% CI, 0.000, 0.110: p = 0.006). However, in the nonoral frailty group, the OSI was not a significant variable for eGFR. In a cross-sectional study of patients with chronic kidney disease, Kosaka et al.³⁴⁾ reported that decreased oral diadochokinesis was associated with lower eGFR (OR, 0.68; 95% CI, 0.47–0.98, p = 0.038), whereas chewing and swallowing were not associated with eGFR. Since periodontopathogenic bacteria and cytokines have been associated with a hematogenous decrease in renal function^35,36), a similar association may be observed when periodontal disease is involved in the cause of oral frailty. However, since only a few studies have reported on the relationship between oral frailty and renal function, the direct association between oral frailty with periodontal disease and renal function must be investigated.

In a cross-sectional study of 1100 adults aged ≥65 years, Lin et al.²⁴⁾ indicated an OR of 36.81 for oral frailty when the 15-item Geriatric Depression Scale was used as a measure of depression. Since depression in old age is thought to be related to a decline in physical function^37,38), oral frailty may be similarly involved in this process. However, since depression has many possible causes, the effects of these factors must be excluded, and the extent to which oral frailty is involved in depression examined.

 Future Perspectives: Hypotheses on the Involvement of the Gut Microbiota in the Relationship among Oral Frailty, Periodontal Disease, and Lifestyle-Related Diseases

Regarding the reciprocal relationship between oral functions, a cross-sectional study by Satake et al.²³⁾ indicated that a decrease in tongue pressure was associated with a decrease in the number of teeth. In a cross-sectional study of 210 adults aged ≥60 years, Baba et al.³⁹⁾ reported a relationship between the presence or absence of oral Candida carriage and the number of teeth, and poor chewing and swallowing function. In addition, in a 6-year longitudinal study of 1,234 adults aged ≥65 years, Nishimoto et al.²²⁾ enrolled and used the community periodontal index (CPI) as an indicator of periodontal disease, reported that a group with a CPI of ≥4 at baseline was significantly more likely than a group with a CPI of ≤3 to experience a new onset of oral frailty (hazard ratio, 1.42; (95% CI, 1.12–1.81). Thus, oral frailty may be related to interrelated declines in individual oral functions and factors such as oral bacteria and periodontal disease. For example, discussions appear lacking about the order in which oral function deteriorates.

Tooth loss resulting from periodontal disease can cause a decline in chewing function. In addition, periodontopathogenic bacteria and inflammatory cytokines affect the entire body hematogenously from the gingival localization in the bloodstream and are associated with lifestyle-related diseases such as diabetes^40,41), cerebrovascular disease^40,42), and dementia^21,31,32). However, the decline in chewing and swallowing caused by oral frailty can lead to malnutrition^13,16). Since malnutrition decreases immune function^29,43), if bacteremia is caused by periodontal disease, it may exacerbate the symptoms.

Recent research has suggested that periodontal disease may be related to the intestinal microbiota. According to Nagao et al.⁴⁴⁾, when periodontal pathogenic bacteria from patients with periodontal disease were introduced into the intestines of mice, periodontal pathogenic bacteria were taken up from Peyer’s patches of the intestines, and Th17 cells, which respond to periodontal pathogenic bacteria, were activated in the intestines. Furthermore, this study reported that Th17 cells migrate from the gut to the gingiva, which is infected with periodontopathogenic bacteria, leading to the onset and severity of periodontal disease. In an animal experiment by Sato et al.⁴⁵⁾, feces from obese mice were transplanted into recipient mice and fed a normal or high-fat diet. The high-fat diet group showed greater alveolar bone destruction and increased uric acid levels, which suggests that obesity and increased uric acid production are mediated by abnormal gut flora. This study hypothesizes that increased production of uric acid, mediated by obesity and intestinal microflora abnormalities, may increase the risk of periodontal disease. Therefore, animal experiments have shown that periodontal disease and intestinal microflora may be reciprocally affected. Reviews by Sansores-España et al.⁴⁶⁾, Byrd et al.⁴⁷⁾, and Lam et al.⁴⁸⁾ have described the hypothesis that periodontopathogenic bacteria reach the gut by swallowing and are associated with inflammatory bowel disease. Furthermore, in an animal study by Lu et al.⁴⁹⁾, forced oral administration of saliva samples from patients with periodontitis to mice for 2 months impaired cognitive function and increased β-amyloid accumulation and neuroinflammation, in addition to gut microbiota abnormalities, proinflammatory responses in the gut, gut barrier dysfunction, and subsequent worsening of systemic inflammation coincided, suggesting that periodontitis-associated salivary microbiota may exacerbate AD etiology through the cross-talk between the gut and the brain. Since animal experiments have primarily focused on the relationship between periodontal disease and gut microbiota, epidemiological studies in humans are needed to prove this hypothesis.

On the contrary, in epidemiological studies on gut microbiota and systemic diseases, a cross-sectional study by Nagase et al.⁵⁰⁾, who investigated the relationship among salt intake, hypertension, and gut microbiota, showed that even in the low salt intake group with hypertension, the relative abundance of Blautia, Bifidobacterium, Escherichia-Shigella, Lachnoclostridium, and Clostridium sensu stricto in the restoration of gut microbiome homeostasis is important to prevent hypertension. In addition, an epidemiological study by Miyajima et al.⁵¹⁾, who used a linear non-Gaussian acyclic model to analyze the relationship between dyslipidemia and gut microbiota, revealed that Prevotella 9 and Bacteroides were associated with changes in the levels of low- and high-density lipoprotein cholesterol in men, and Akkermansia and Escherichia/Shigella have a presumed causal relationship with lipid profiles in women. Therefore, periodontopathogenic bacteria may be related to various systemic diseases by affecting the gut microbiota.

We hypothesized that oral frailty with periodontal disease would have a greater systemic effect than periodontal disease or oral frailty alone and that gut microbiota abnormalities would further exacerbate systemic diseases (Fig. 1). Although the relationship between oral frailty presumably associated with periodontal disease and lifestyle-related diseases has been indirectly investigated in dementia²¹⁾ and chronic kidney disease^11,34), the direct effects of oral frailty, periodontal disease, gut microbiota, and systemic condition have rarely been evaluated. It is necessary to conduct a large prospective study to prove these hypotheses.

Fig. 1.  Hypotheses on the involvement of the gut microbiota in the relationship among oral frailty, periodontal disease, and lifestyle-related diseases.

 Limitation

Since this review focused on trends in epidemiologic studies on oral frailty over the last five years, the results may not be consistent with a systematic evaluation of a larger number of articles.

 Conclusions

Oral frailty is an intermediate stage of decline in oral function. Epidemiological studies on oral frailty over the last 5 years have described its association not only with physical frailty but also with changes in food preferences, malnutrition, dementia, depression, and declining renal function. Oral frailty with periodontal disease may have exaggerated effects on systemic health. Furthermore, the gut microbiota was hypothesized to be involved in the relationship among oral frailty, periodontal disease, and lifestyle-related diseases. It has been a decade since the oral frailty concept was first proposed, promising to become an increasingly attractive field.

 Acknowledgments

The authors thank all the staff at the Department of Geriatric Dentistry, Ohu University School of Dentistry, and the Department of Hygiene and Public Health, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University.

 Author Contributions

Conceptualization: F.S. and H.N.; Funding acquisition: F.S.; literature search: F.S., K.H., H.T., A.H., and H.N.; Visualization: F.S.; Writing—original draft: F.S.; Writing–review & editing: K.H., H.T., A.H., and H.N.

 Funding

This study was funded by an individual research grant from Ohu University.

 Conflict of Interest

The authors declare no conflicts of interest.

References

• 1.    Hirano  H. Management of oral-frailty in elderly. Ronen Shika Igaku 31; 400–404: 2017.
• 2.    Minakuchi  S,  Tsuga  K,  Ikebe  K, et al. Oral hypofunction in the older population: position paper of the Japanese Society of Gerodontology in 2016. Gerodontology 35; 317–324: 2018. DOI: 10.1111/GER.12347.
• 3.    Iwasaki  M,  Hirano  H. Decline in oral function and its management. Int Dent J 72; S12–S20: 2022.
• 4.    Shiraishi  A,  Wakabayashi  H,  Yoshimura  Y. Oral management in rehabilitation medicine: oral frailty, oral sarcopenia, and hospital-associated oral problems. J Nutr Health Aging 24; 1094–1099: 2020. DOI: 10.1007/S12603-020-1439-8.
• 5.    Parisius  KGH,  Wartewig  E,  Schoonmade  LJ, et al. Oral frailty dissected and conceptualized: a scoping review. Arch Gerontol Geriatr 100; 104653: 2022.
• 6.    Dibello  V,  Lobbezoo  F,  Lozupone  M, et al. Oral frailty indicators to target major adverse health-related outcomes in older age: a systematic review. GeroScience 45; 663: 2023. DOI: 10.1007/S11357-022-00663-8.
• 7.    Nomura  Y,  Ishii  Y,  Suzuki  S, et al. Nutritional status and oral frailty: a community based study. Nutrients 12; 2886: 2020. DOI: 10.3390/NU12092886.
• 8.    Nomura  Y,  Ishii  Y,  Chiba  Y, et al. Structure and validity of questionnaire for oral frail screening. Healthcare (Basel) 9; 45: 2021. DOI: 10.3390/healthcare9010045.
• 9.    Kuo  YW,  Lee  JD. Association between oral frailty and physical frailty among rural middle-old community-dwelling people with cognitive decline in Taiwan: a cross-sectional study. Int J Environ Res Public Health 19; 2884: 2022. DOI: 10.3390/IJERPH19052884.
• 10.    Kusunoki  H,  Ekawa  K,  Kato  N, et al. Association between oral frailty and cystatin C-related indices-A questionnaire (OFI-8) study in general internal medicine practice. PLOS ONE 18; e0283803: 2023. DOI: 10.1371/JOURNAL.PONE.0283803.
• 11.    Nakai  S,  Suzuki  F,  Okamoto  S, et al. Association between bone mineral density and oral frailty on renal function: findings from the Shika study. Healthcare (Basel) 11; 314: 2023. DOI: 10.3390/HEALTHCARE11030314.
• 12.    Ichikawa  T,  Goto  T,  Hihara  T, et al. OSC46: a quantitative evaluation of oral frailty-physical frailty relationship model based on covariance structure analysis. J Indian Prosthodont Soc 18 Suppl 1; S28: 2018. DOI: 10.4103/0972-4052.244639.
• 13.    Suzuki  F,  Okamoto  S,  Miyagi  S, et al. Relationship between decreased mineral intake due to oral frailty and bone mineral density: findings from Shika study. Nutrients 13; 1193: 2021. DOI: 10.3390/NU13041193.
• 14.    Doi  T,  Fukui  M,  Yoshioka  M, et al. The relationship between subjective oral frailty and adverse health outcomes or medical and dental expenditures in the latter-stage older adult: a 6-year longitudinal study. Clin Exp Dent Res 9; 349–357: 2023. DOI: 10.1002/CRE2.717.
• 15.    Hihara  T,  Goto  T,  Ichikawa  T. Investigating eating behaviors and symptoms of oral frailty using questionnaires. Dent J (Basel) 7; 66: 2019. DOI: 10.3390/DJ7030066.
• 16.    Iwasaki  M,  Motokawa  K,  Watanabe  Y, et al. A two-year longitudinal study of the association between oral frailty and deteriorating nutritional status among community-dwelling older adults. Int J Environ Res Public Health 18; 213: 2020. DOI: 10.3390/IJERPH18010213.
• 17.    Iwasaki  M,  Watanabe  Y,  Motokawa  K, et al. Oral frailty and gait performance in community-dwelling older adults: findings from the Takashimadaira study. J Prosthodont Res 65; 467–473: 2021. DOI: 10.2186/jpr.JPR_D_20_00129.
• 18.    Komatsu  R,  Nagai  K,  Hasegawa  Y, et al. Association between physical frailty subdomains and oral frailty in community-dwelling older adults. Int J Environ Res Public Health 18; 2931: 2021. DOI: 10.3390/IJERPH18062931.
• 19.    Shirobe  M,  Watanabe  Y,  Tanaka  T, et al. Effect of an oral frailty measures program on community-dwelling elderly people: a cluster-randomized controlled trial. Gerontology 68; 377–386: 2022. DOI: 10.1159/000516968.
• 20.    Yamamoto  T,  Tanaka  T,  Hirano  H, et al. Model to predict oral frailty based on a questionnaire: a cross-sectional study. Int J Environ Res Public Health 19; 13244: 2022. DOI: 10.3390/IJERPH192013244.
• 21.    Nagatani  M,  Tanaka  T,  Son  BK, et al. Oral frailty as a risk factor for mild cognitive impairment in community-dwelling older adults: Kashiwa study. Exp Gerontol 172; 112075: 2023.
• 22.    Nishimoto  M,  Tanaka  T,  Hirano  H, et al. Severe periodontitis increases the risk of oral frailty: a six-year follow-up study from Kashiwa cohort study. Geriatrics (Basel) 8; 25: 2023. DOI: 10.3390/GERIATRICS8010025.
• 23.    Satake  A,  Kobayashi  W,  Tamura  Y, et al. Effects of oral environment on frailty: particular relevance of tongue pressure. Clin Interv Aging 14; 1643–1648: 2019. DOI: 10.2147/CIA.S212980.
• 24.    Lin  YC,  Huang  SS,  Yen  CW, et al. Physical frailty and oral frailty associated with late-life depression in community-dwelling older adults. J Pers Med 12; 459: 2022. DOI: 10.3390/JPM12030459.
• 25.    Hiltunen  K,  Saarela  RKT,  Kautiainen  H, et al. Relationship between Fried’s frailty phenotype and oral frailty in long-term care residents. Age Ageing 50; 2133–2139: 2021. DOI: 10.1093/AGEING/AFAB177.
• 26.    Fried  LP,  Tangen  CM,  Walston  J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56; M146: 2001. DOI: 10.1093/GERONA/56.3.M146.
• 27.    Sakai  K,  Nakayama  E,  Yoneoka  D, et al. Association of oral function and dysphagia with frailty and sarcopenia in community-dwelling older adults: a systematic review and meta-analysis. Cells 11; 2199: 2022. DOI: 10.3390/cells11142199.
• 28.    Dibello  V,  Zupo  R,  Sardone  R, et al. Oral frailty and its determinants in older age: a systematic review. Lancet Healthy Longev 2; e507–e520: 2021.
• 29.    de  Sire A,  Ferrillo  M,  Lippi  L, et al. Sarcopenic dysphagia, malnutrition, and oral frailty in elderly: a comprehensive review. Nutrients 14; 982: 2022. DOI: 10.3390/NU14050982.
• 30.    Dibello  V,  Lozupone  M,  Manfredini  D, et al. Oral frailty and neurodegeneration in Alzheimer’s disease. Neural Regen Res 16; 2149: 2021. DOI: 10.4103/1673-5374.310672.
• 31.    Miklossy  J,  Kis  A,  Radenovic  A, et al. Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes. Neurobiol Aging 27; 228–236: 2006. DOI: 10.1016/J.NEUROBIOLAGING.2005.01.018.
• 32.    Poole  S,  Singhrao  SK,  Chukkapalli  S, et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE-/- mice brains. J Alzheimers Dis 43; 67: 2015. DOI: 10.3233/JAD-140315.
• 33.    Oue  H,  Miyamoto  Y,  Okada  S, et al. Tooth loss induces memory impairment and neuronal cell loss in APP transgenic mice. Behav Brain Res 252; 318–325: 2013. DOI: 10.1016/J.BBR.2013.06.015.
• 34.    Kosaka  S,  Ohara  Y,  Naito  S, et al. Association among kidney function, frailty, and oral function in patients with chronic kidney disease: a cross-sectional study. BMC Nephrol 21; 357: 2020. DOI: 10.1186/S12882-020-02019-W.
• 35.    Kapellas  K,  Singh  A,  Bertotti  M, et al. Periodontal and chronic kidney disease association: a systematic review and meta-analysis. Nephrology (Carlton) 24; 202–212: 2019. DOI: 10.1111/NEP.13225.
• 36.    Kitamura  M,  Mochizuki  Y,  Miyata  Y, et al. Pathological characteristics of periodontal disease in patients with chronic kidney disease and kidney transplantation. Int J Mol Sci 20; 3413: 2019. DOI: 10.3390/IJMS20143413.
• 37.    Maștaleru  A,  Abdulan  IM,  Ștefăniu  R, et al. Relationship between frailty and depression in a population from North-Eastern Romania. Int J Environ Res Public Health 19; 5731: 2022. DOI: 10.3390/IJERPH19095731.
• 38.    Borges  MK,  Aprahamian  I,  Romanini  CV, et al. Depression as a determinant of frailty in late life. Aging Ment Health 25; 2279–2285: 2021. DOI: 10.1080/13607863.2020.1857689.
• 39.    Baba  H,  Watanabe  Y,  Miura  K, et al. Oral frailty and carriage of oral Candida in community-dwelling older adults (check-up to discover health with Energy for senior residents in Iwamizawa; CHEER Iwamizawa). Gerodontology 39; 49–58: 2022. DOI: 10.1111/GER.12621.
• 40.    Liccardo  D,  Cannavo  A,  Spagnuolo  G, et al. Periodontal disease: a risk factor for diabetes and cardiovascular disease. Int J Mol Sci 20; 1414: 2019. DOI: 10.3390/IJMS20061414.
• 41.    Genco  RJ,  Graziani  F,  Hasturk  H. Effects of periodontal disease on glycemic control, complications, and incidence of diabetes mellitus. Periodontol 2000 83; 59–65: 2020. DOI: 10.1111/PRD.12271.
• 42.    Priyamvara  A,  Dey  AK,  Bandyopadhyay  D, et al. Periodontal inflammation and the risk of cardiovascular disease. Curr Atheroscler Rep 22; 28: 2020. DOI: 10.1007/S11883-020-00848-6.
• 43.    Strasser  B,  Wolters  M,  Weyh  C, et al. The effects of lifestyle and diet on gut microbiota composition, inflammation and muscle performance in our aging society. Nutrients 13; 2045: 2021. DOI: 10.3390/NU13062045.
• 44.    Nagao  J,  Kishikawa  S,  Tanaka  H, et al. Pathobiont-responsive Th17 cells in gut-mouth axis provoke inflammatory oral disease and are modulated by intestinal microbiome. Cell Rep 40; 111314: 2022. DOI: 10.1016/j.celrep.2022.111314.
• 45.    Sato  K,  Yamazaki  K,  Kato  T, et al. Obesity-related gut microbiota aggravates alveolar bone destruction in experimental periodontitis through elevation of uric acid. mBio 12; e0077121: 2021. DOI: 10.1128/mBio.00771-21.
• 46.    Sansores-España  LD,  Melgar-Rodríguez  S,  Olivares-Sagredo  K, et al. Oral-gut-brain axis in experimental models of periodontitis: associating gut dysbiosis with neurodegenerative diseases. Front Aging 2; 781582: 2021. DOI: 10.3389/FRAGI.2021.781582.
• 47.    Byrd  KM,  Gulati  AS. The “Gum-Gut” axis in inflammatory bowel diseases: a hypothesis-driven review of associations and advances. Front Immunol 12; 620124: 2021. DOI: 10.3389/FIMMU.2021.620124.
• 48.    Lam  GA,  Albarrak  H,  McColl  CJ, et al. The oral-gut axis: periodontal diseases and gastrointestinal disorders. Inflamm Bowel Dis 29; 1153–1164: 2023. DOI: 10.1093/IBD/IZAC241.
• 49.    Lu  J,  Zhang  S,  Huang  Y, et al. Periodontitis-related salivary microbiota aggravates Alzheimer’s disease via gut-brain axis crosstalk. Gut Microbes 14; 2126272: 2022. DOI: 10.1080/19490976.2022.2126272.
• 50.    Nagase  S,  Karashima  S,  Tsujiguchi  H, et al. Impact of gut microbiome on hypertensive patients with low-salt intake: Shika Study results. Front Med (Lausanne) 7; 475: 2020. DOI: 10.3389/FMED.2020.00475.
• 51.    Miyajima  Y,  Karashima  S,  Ogai  K, et al. Impact of gut microbiome on dyslipidemia in Japanese adults: assessment of the Shika-machi super preventive health examination results for causal inference. Front Cell Infect Microbiol 12; 908997; 2022. DOI: 10.3389/FCIMB.2022.908997.