Does Periodontitis Affect the Association of Biological Aging with Mortality?

Abstract

The prevalence of periodontitis is increasing with the aging of the global population. Periodontitis has been suggested to accelerate aging and increase mortality. The present nationwide prospective cohort study aimed to determine whether periodontitis could modify the association of biological aging with all-cause and cause-specific mortality in middle-aged and older adults. Participants ≥40 y of age from the Third National Health and Nutrition Examination Survey (NHANES III) were included (n = 6,272). Phenotypic age acceleration (PhenoAgeAccel) was used to evaluate the biological aging process. Moderate/severe periodontitis was defined using a half-reduced Centers for Disease Control and Prevention and American Academy of Periodontology case definition. Multivariable Cox proportional hazard regression was conducted to estimate the association between PhenoAgeAccel and mortality risk, followed by effect modification analysis to test whether periodontitis modified the association. During a median follow-up of 24.5 y, 3,600 (57.4%) deaths occurred. The positive relationships between PhenoAgeAccel and all-cause and cause-specific mortality were nonlinear. After adjusting for potential confounders, the highest quartile of PhenoAgeAccel was associated with increased all-cause mortality in individuals with no/mild periodontitis (hazard ratio for Q4 vs. Q1 [HR_Q4vs.Q1] = 1.789; 95% confidence interval [CI], 1.541–2.076). In contrast, the association was enhanced in patients with moderate/severe periodontitis (HR_Q4vs.Q1 = 2.446 [2.100–2.850]). Periodontal status significantly modified the association between PhenoAgeAccel and all-cause mortality (P for interaction = 0.012). In subgroup analyses, the modifying effect of periodontitis was observed in middle-aged adults (40–59 y), females, and non-Hispanic Whites. Although cause-specific mortality showed a similar trend, the PhenoAgeAccel × periodontitis interaction did not reach statistical significance. In conclusion, periodontitis might enhance the association of biological aging with all-cause mortality in middle-aged and older adults. Hence, maintaining and enhancing periodontal health is expected to become an intervention to slow aging and extend life span.

Keywords

periodontal diseases risk factors epidemiologic effect modifier prospective studies

Introduction

In an ever-increasing aging society, promoting healthy aging has become a public health priority. Accelerated aging is differentiated from normal aging, leading to an increased risk of mortality (Ferrucci et al. 2020). Numerous studies have reported that unhealthy modifiable lifestyle factors could enhance the impact of accelerated aging on mortality, including smoking, unhealthy diets, physical inactivity, and obesity (Zillikens et al. 2009; Tajuddin et al. 2017; Loprinzi and Loenneke 2018; Kresovich and Bulka 2022). In contrast, healthy lifestyles can reduce the mortality risk in the elderly population by promoting healthy aging (Jin et al. 2022). Periodontitis is suggested as a modifiable risk factor for age-related diseases (Lee et al. 2017, 2022). Of note, patients with moderate/severe periodontitis were associated with 47% increased odds of shorter leukocyte telomere length, a molecular marker of aging, when compared with controls (Song et al. 2021). The relationship between periodontitis and biological aging is bidirectional (Baima et al. 2022). One of the underlying mechanisms is related to inflammaging, a low-grade chronic inflammatory process (Ebersole et al. 2016). The molecular mechanisms of inflammaging primarily involve oxidative stress, senescence-associated secretory phenotypes (SASPs), telomere attrition, and autophagy (Franceschi et al. 2017).

Several measurements were developed based on the above mechanisms to calculate biological age, such as epigenetic clocks, leukocyte telomere length, metabolic age score, and phenotypic age acceleration (PhenoAgeAccel) (Hertel et al. 2016; Liu et al. 2018; Drew 2022; Nguyen et al. 2022). Among these aging measures, PhenoAgeAccel represents the manifestations of multiple hallmarks of aging at the cellular and intracellular levels based on a series of biomarkers (Levine et al. 2018; Liu et al. 2018). There has been immense interest in finding modifiable risk factors that could delay aging and extend life span. Since periodontitis could trigger inflammaging and increase mortality risk, treating periodontitis or maintaining periodontal health might be a plausible prevention for aging. However, few studies have reported on the modifying effect of periodontitis on the biological aging–mortality association.

We hypothesized that middle-aged and older patients with moderate/severe periodontitis would be more susceptible to the aging–life span effect than individuals with no/mild periodontitis. Therefore, this study aims to 1) investigate the associations of accelerated biological aging (measured by PhenoAgeAccel) with all-cause and cause-specific mortality in middle-aged and older adults and 2) identify whether these associations were enhanced by periodontitis.

Methods

Study Population

Data on middle-aged and older adults (≥40 y of age) participating in the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) were investigated in this prospective cohort study. The National Center for Health Statistics (NCHS) conducted NHANES III to collect data on the health and nutritional status of noninstitutionalized US civilians. The NHANES survey included an in-home interview and various medical and laboratory examinations at a mobile examination center. The NCHS Ethics Review Board (ERB) approved all NHANES protocols and testing procedures. All the participants were included after signing informed consent forms (Ezzati et al. 1992). We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (Appendix Table 1) for reporting cohort studies (von Elm et al. 2008). The phenotypic age algorithm excluded the oldest elderly (≥85 y old) (Liu et al. 2018). Therefore, participants aged 40 to 84 y with data for periodontal status, aging measures, and mortality were included in this study.

Assessment of Phenotypic Aging

Phenotypic age was regarded as an exposure variable in the present study. A series of clinical biomarkers were previously used as the expected age predictors to calculate phenotypic age among NHANES participants (Levine et al. 2018; Liu et al. 2018). The predictors included chronological age and 9 biomarkers (albumin, g/L; creatinine, µmol/L; glucose, mmol/L; C-reactive protein [CRP], mg/dL; lymphocyte percentage, %; mean cell volume [MCV], fL; red blood cell distribution width, %; alkaline phosphatase, U/L; and white blood cell [WBC] count, 1,000 cells/µL). The equation of phenotypic age was used in a study by Liu et al. (2018, 2019):

\begin{array}{l} Phenotypic age = 141.50 \\ + \frac{\ln [- 0.00553 \times \ln (1 - 1 - \exp (\frac{- 1.51714 \times \exp (x b)}{0.0076927}))]}{0.09165}, \end{array}

where

\begin{array}{l} x b = - 19.907 - 0.0336 \times Albumin + 0.0095 \times \\ Creatinine + 0.1953 \times Glucose + 0.0954 \times \ln (CRP) - 0.0120 \times \\ Lymphocyte percent + 0.0268 \times MCV + 0.3306 \\ \times Red cell distribution width + \\ 0.00188 \times Alkaline phosphatase + \\ 0.0554 \times WBC count + 0.0804 \times Chrononological age \end{array}

PhenoAgeAccel was defined as the residual regressing phenotypic age on chronological age according to a linear model. PhenoAgeAccel was developed to determine whether an individual was phenotypically older or younger than their chronological age (Liu et al. 2018), with a negative value of PhenoAgeAccel indicating a younger phenotypic age (Appendix Fig. 1).

Assessment of Periodontal Status

Dental examiners from the NHANES, trained by the National Institute of Dental Research (NIDR), assessed the periodontal status. The dentists performed a periodontal examination on random half-mouths (1 upper and 1 lower quadrant) and a dental examination to determine the number of teeth (excluding third molars). In addition, attachment loss (AL) and probing pocket depth (PPD) were measured from the buccal and mesial-buccal aspects of each tooth. Since NHANES III applied the partial-mouth periodontal examination protocol, we used a half-reduced case definition by the Centers for Disease Control and Prevention (CDC)/American Academy of Periodontology (AAP) to assess the severity of periodontitis (Tran et al. 2014). The half-reduced definition was applied to NHANES participants in our previous work (Li, Chen, van der Sluis, et al. 2021; Li et al. 2022). When a participant was defined as a moderate/severe periodontitis case, they were assigned to the moderate/severe periodontitis group (moderate: ≥1 interproximal site with ≥4 mm AL or ≥1 interproximal site with ≥5 mm PPD; severe: ≥1 interproximal site with ≥6 mm AL and ≥1 interproximal site with ≥5 mm PPD). In the absence of moderate/severe periodontitis signs, the participant was assigned to the no/mild periodontitis group. In brief, the participants were categorized into 2 groups: no/mild periodontitis versus moderate/severe periodontitis.

Mortality

The primary and secondary outcomes of this study were all-cause and cause-specific mortalities, thst is, cardiovascular disease (CVD) mortality and cancer mortality. The mortality data of NHANES III participants were obtained by linking to the National Death Index from the NCHS. The linked mortality files contain mortality data and information about the underlying causes of death variables. CVD-specific death included deaths induced by cardiac and cerebrovascular diseases. The follow-up started from the interview date to the date of death or December 31, 2019.

Covariates

We used sociodemographic variables, lifestyle variables, and health- related factors at baseline as covariates. Sociodemographic variables included chronological age, sex (male and female), race/ethnicity (non-Hispanic White and others), educational level (less than high school, high school, and college or more), and annual family income (<$20,000 and ≥$20,000). Healthy lifestyle factors included smoking status (never, former, and current smoker), time since last dental visit (<1 y and ≥1 y), body mass index (BMI), and healthy eating index. Self-reported diseases included hypertension, diabetes, heart disease, stroke, cancer, and arthritis. More detailed information on covariates has been described in our previous study (Li, Chen, Schuller, et al. 2021). In addition, the counts of systemic diseases were calculated.

Statistical Analyses

Baseline characteristics were summarized using descriptive statistics. Continuous variables were presented as the means (SD) or medians (interquartile range [IQR]) for nonnormally distributed data, with categorical variables as numbers (percentages). Cox proportional hazard regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) to explore the association between PhenoAgeAccel and the risks of all-cause and cause-specific mortality. Restricted cubic splines were performed by multivariable Cox regression with 3 knots located at the 10th, 50th, and 90th percentiles of PhenoAgeAccel to understand possible dose–response associations between PhenoAgeAccel and mortality risk. Given the detected nonlinearity, we categorized PhenoAgeAccel as quartiles (categorical variable) in the following analyses. Multivariable Cox regression models were adjusted for chronological age, sex, race/ethnicity, education, income, smoking status, dental visit, healthy eating index, BMI, tooth number, hypertension, diabetes, heart disease, stroke, cancer, and arthritis. We conducted effect modification analysis and tested interaction terms (PhenoAgeAccel × periodontitis) in multivariable models to examine whether periodontal status modified the relationship between PhenoAgeAccel and all-cause and cause-specific mortality (Appendix Fig. 2). The effect modification on the PhenoAgeAccel–mortality association was repeatedly stratified by age (40–59 vs. ≥60 y old), and sex (male vs. female), race/ethnicity (non-Hispanic Whites vs. others).

We conducted several sensitivity analyses to test the findings’ robustness. First, we excluded the first 3 y of follow-up to minimize potential reverse causation bias. Second, sensitivity analyses were conducted to exclude patients with heart disease, stroke, or cancer. Third, we conducted further sensitivity analyses to adjust the counts of systemic diseases to detect the confounding effect of comorbidities. Fourth, the frailty phenotype was considered a functional aging measure (Fried et al. 2001). We analyzed whether the effect of frailty on mortality risk differed in the presence of moderate/severe periodontitis. NHANES III provided the data for frailty phenotype among older adults (≥60 y). The details of the frailty phenotype are described in the Appendix Methods. Given the small amount of missing data (<5%), a complete case analysis was performed, excluding participants with missing values for any covariate. Statistical significance was defined at P < 0.05 in 2-sided testing. All statistical analyses were performed using SPSS 26 (SPSS, Inc.) and R Project (version 4.2.1).

Results

Population Characteristics

Appendix Figure 3 demonstrates the population inclusion flowchart. Among the participants aged 40 to 84 y (n = 9,620), edentulous patients (n = 768) and those without data on periodontal status (n = 1,991) were excluded. Then, participants without data on biomarkers to estimate phenotypic age were excluded (n = 274), and participants with no data on mortality and survey weight (n = 4) were excluded. A total of 6,272 middle-aged and older participants from the NHANES III study were included in this prospective cohort study. In addition, we extracted the subgroup population with data on frailty for sensitivity analysis (n = 2,541).

During a median follow-up of 24.5 y, 3,600 (57.4%) deaths were recorded, with 1,317 due to CVD and 819 due to cancer. The mean (SD) age of all the participants was 57.77 (12.56) y, 3,323 (53.0%) were female, and 2,903 (46.3%) were non-Hispanic Whites. In the study population, the prevalence of none/mild and moderate/severe periodontitis was 55.2% and 44.8%, respectively. Appendix Table 2 presents the baseline population characteristics by quartiles of PhenoAgeAccel. Participants with lower PhenoAgeAccel (representing a biologically younger person) tended to be White females with higher income, higher healthy eating index, more frequent dental visits, and lower BMI. Appendix Tables 3 and 4 shows the population characteristics stratified by periodontal and frail statuses.

Effect Modification of Periodontitis on the PhenoAgeAccel–Mortality Link

Figure 1A–C shows the statistically significant relationships of PhenoAgeAccel with all-cause, CVD, and cancer mortality risks (P < 0.001). These associations were nonlinear (P < 0.05). Figure 1D–F shows that cumulative mortality rates increased among participants during the follow-up years. Cumulative all-cause, CVD, and cancer mortality rates among participants with the highest quartile of PhenoAgeAccel (Q4) increased significantly in the first quartile of PhenoAgeAccel (Q1). After adjusting for confounding factors, the risk of all-cause mortality increased by 109.7% with PhenoAgeAccel (HR_Q4vs.Q1 = 2.097; 95% CI, 1.887–2.331) (Fig. 2A). The adjusted HR_Q4vs.Q1 for CVD and cancer mortality was 2.087 (95% CI, 1.753–2.485) and 1.910 (95% CI, 1.529–2.386), respectively (Fig. 2D, G).

The association between PhenoAgeAccel and all-cause mortality was significantly modified by periodontal status (P for interaction = 0.012, Fig. 2B, C). The highest quartile of PhenoAgeAccel was associated with increased all-cause mortality in the participants with no/mild periodontitis (HR_Q4vs.Q1 = 1.789; 95% CI, 1.541–2.076; Fig. 2B). In contrast, the effect of PhenoAgeAccel on all-cause mortality was increased in patients with moderate/severe periodontitis (HR_Q4vs.Q1 = 2.446; 95% CI, 2.100–2.850; Fig. 2C). Similarly, patients with moderate/severe periodontitis had stronger associations of PhenoAgeAccel with CVD mortality (HR_Q4vs.Q1 = 2.508; 95% CI, 1.942–3.238; Fig. 2F) and cancer mortality (HR_Q4vs.Q1 = 2.317; 95% CI, 1.688–3.179; Fig. 2I). However, the interactions did not reach statistical significance (CVD mortality: P for interaction = 0.118; cancer mortality: P for interaction = 0.110).

Subgroup and Sensitivity Analyses

In the subgroup analysis, moderate/severe periodontitis significantly modified the association between PhenoAgeAccel and all-cause mortality in middle-aged adults (40–59 y), females, and non-Hispanic Whites (P for interaction < 0.05; Fig. 3). In addition, the impact of PhenoAgeAccel on CVD and cancer mortality was remarkably stronger among females and non-Hispanic Whites with moderate/severe periodontitis (Figs. 4 and 5). Sensitivity analysis, excluding the first 3 y of follow-up, showed results consistent with the main findings (Appendix Table 5). Excluding patients with heart disease, stroke, or cancer had a nonsignificant impact on the results (Appendix Table 6). The results remained consistent after further adjustment for the counts of systemic diseases (Appendix Table 7). As shown in Appendix Table 8, prefrail/frail was significantly associated with all-cause mortality risk (HR = 1.184; 95% CI, 1.075–1.304). In contrast, the HR of CVD or cancer mortality did not increase with the frailty phenotype. Compared with individuals with non/mild periodontitis, the impact of prefrail/frail on all-cause and cause-specific mortality was relatively increased in patients with moderate/severe periodontitis. However, the frailty phenotype × periodontitis interaction was not significant (Appendix Table 8).

Discussion

Up to a 31-y follow-up period, this prospective cohort study demonstrated that periodontitis might exacerbate the effect of biological aging on mortality among a nationally representative sample of US middle-aged and older adults. Patients with moderate/severe periodontitis in the highest PhenoAgeAccel quartile exhibited 144.6%, 150.8%, and 131.7% higher risks of all-cause, CVD, and cancer mortality than those in the lowest quartile, respectively. In the subgroup analyses, the modifying effect of periodontitis on the association between PhenoAgeAccel and all-cause mortality was statistically significant in middle-aged adults (40–59 y), females, and non-Hispanic Whites. The consistency of the results in the sensitivity analyses supported the robustness of our findings.

Our findings are consistent with earlier evidence that periodontitis increased the risk of all-cause mortality in the older population in Sweden and Denmark and in hypertensive patients (Hansen et al. 2016; Bengtsson et al. 2021; Larvin et al. 2022). Nevertheless, it is not easy to compare these studies, as they applied slightly different definitions for periodontitis. Furthermore, epidemiological studies have traditionally focused on chronological age, emphasizing that inflammaging and immunosenescence impair periodontal defenses (Ebersole et al. 2016). In contrast, our findings measured phenotypic age instead of chronological age, suggesting that associations may vary by different periodontal conditions. The modifying effect of periodontitis in subgroup analyses was maintained in females. Recently, sex differences in biological aging and cellular senescence have drawn interest (Ng and Hazrati 2022). Despite evidence suggesting that estrogen inhibits senescence regulatory proteins, a lower capacity for DNA damage repair during aging was found in females than in males (Rall-Scharpf et al. 2021). Following UV irradiation, female cells preferentially undergo cellular senescence, while male cells undergo apoptosis (Malorni et al. 2008). To the best of our knowledge, this is the first report indicating that periodontal status modifies the association between biological aging and mortality through phenotypic age.

Several potential explanations are available for the observed interrelationship between periodontitis, aging, and mortality. First, aging is accompanied by “inflammaging,” which describes the chronic, low-grade inflammation that develops with age and is suspected of laying the ground for all known major age-related diseases, including periodontitis (Franceschi et al. 2017; Baima et al. 2022). Second, periodontitis is an age-related disease characterized by increased SASPs, such as interleukin 1, interleukin 6, and tumor necrosis factor α (Coppé et al. 2010; Li et al. 2020). Periodontitis might increase SASPs, consequently accelerating the onset of aging. Moreover, persistent gram-bacterial infection might also be associated with a relationship between periodontitis and aging–mortality. Since periodontal bacteria are associated with the risk of periodontitis, a study on US adults aged >40 y suggested that increased disease and mortality risk could be transmittable via the transfer of oral microbiota (Chiu et al. 2016). A study showed that after alveolar osteocytes were treated with bacteria-derived lipopolysaccharide (LPS), the expression of various senescence and SASP markers and the hallmarks of cellular senescence increased (Aquino-Martinez et al. 2020).

Our findings may have clinical relevance. Promoting periodontal health might contribute to reducing systemic inflammation and cardiometabolic risk (Orlandi et al. 2022; Simpson et al. 2022). A population-based prospective cohort study showed that adopting healthy lifestyles promoted healthy aging to extend the life span in middle-aged adults (Zhou et al. 2021). A long-term follow-up cohort study recently reported that restoring functional dentition could significantly enhance the protective effect of healthy lifestyles on life span in edentulous elderly patients (Dai et al. 2022). In this study, non-Hispanic Whites may be more susceptible to periodontal intervention for preventing aging-related mortality. Since non-Hispanic Whites have less accelerated aging than other races (Forrester et al. 2021), they are prone to reverse or slow the aging process by modifiable risk factors. However, future large-scale randomized controlled trials are needed to confirm the beneficial effect of periodontal health care and treatment of periodontitis on delaying the aging process and reducing death rates in the middle-aged and older population.

The main strength of this study was the use of both serological markers of biological aging and functional characterization, which are relatively more comprehensive than a single indicator. The present study, with a long-term follow-up of up to 31 y, provides ample opportunity to investigate all-cause and cause-specific mortality, better depicting the long life course from aging to death. However, several limitations must be discussed. First, we cannot assess the changes in biological aging over the follow-up period since the baseline information was collected cross-sectionally. Future studies should repeatedly measure aging parameters during follow-ups. Second, we considered the partial periodontal examination protocol used in NHANES III and thus applied a half-reduced CDC/AAP definition of periodontitis. Although the definition can reduce the underestimation of periodontitis severity, the modifying effect of periodontitis should be validated further in cohort studies where full-mouth periodontal examination protocol is used. Third, instead of exploring biological aging at cellular or molecular levels, the present study only investigated aging using clinical markers such as phenotypic age and frailty. Fourth, we focused on the middle-aged and elderly population. Therefore, our findings might not be generalized to the whole population.

Conclusion

In conclusion, this study demonstrated the effect of periodontitis on the aging–mortality association. Moderate/severe periodontitis may increase the impact of biological aging on mortality in middle-aged and older adults. Periodontal health condition shows promise as a potential target to attenuate the effect of aging on death. However, further research is necessary to determine causality and explore the underlying mechanism for our findings.

Author Contributions

Y. Liu, contributed to conception, data interpretation, drafted the manuscript; S. Xu, contributed to data conception and design, critically revised the manuscript; Q. Cai, Y. Chen, contributed to data analysis, critically revised the manuscript; P. Zhu, M. Du, contributed to data interpretation, critically revised the manuscript; A. Visser, contributed to conception and design, data interpretation, critically revised the manuscript; A. Li, contributed to conception and design, data acquisition and interpretation, drafted and critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.

Supplemental Material

sj-docx-1-jdr-10.1177_00220345231179117 – Supplemental material for Does Periodontitis Affect the Association of Biological Aging with Mortality?

Supplemental material, sj-docx-1-jdr-10.1177_00220345231179117 for Does Periodontitis Affect the Association of Biological Aging with Mortality? by Y. Liu, S. Xu, Q. Cai, Y. Chen, P. Zhu, M. Du, A. Visser and A. Li in Journal of Dental Research

Footnotes

Acknowledgements

The authors thank the NHANES III staff and investigators. A special thanks to the participants involved in the NHANES study for making this research possible through their participation.

A supplemental appendix to this article is available online.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The present study was supported by the Science Research Cultivation Program of Stomatological Hospital, Southern Medical University, China (No. PY2021007); Clinical Research Initiation Plan of Stomatological Hospital, Southern Medical University, China (grant number: KQIIT2021001); and Guangdong Basic and Applied Basic Research Foundation (grant number: 2022A1515110379).

ORCID iDs

M. Du

A. Li

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