樱花视频

Skip to main content
Download PDF
  • Research
  • Published:

Association between physical multimorbidity in middle adulthood and mortality: findings from two large cohort studies in Japan

樱花视频 volume听25, Article听number:听92 (2025) Cite this article

Abstract

Background

While previous literature suggests that multimorbidity is linked to a higher risk of mortality, evidence is scarce among individuals in middle adulthood. We aimed to examine the association between physical multimorbidity and all-cause mortality among individuals aged 40鈥�64 years at baseline in Japan.

Methods

Data were obtained from two cohort studies, the Japan Public Health Center-based Prospective Study (JPHC) and the Japan Epidemiology Collaboration on Occupational Health Study (J-ECOH). The study participants were 144,774 individuals aged 40鈥�64 years at baseline who were followed up for a maximum of 29 and 10 years in the JPHC and J-ECOH, respectively. Multimorbidity was defined as the presence of 鈮モ��2 of 10 morbidities or conditions based on self-reported information. A Cox proportional hazards model was used to examine the association in relation to all-cause mortality. We calculated pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) using a random-effects meta-analysis model. Cause-specific analysis was performed using the JPHC dataset, which provided a sufficient number of events for mortality due to physical disorders, mental disorders/suicide, and unintentional injuries.

Results

During a follow-up of 2,304,375 person-years in the JPHC and 311,637 person-years in the J-ECOH, 23,611 and 275 deaths were recorded, respectively. Participants with vs. without physical multimorbidity at baseline were more likely to die prematurely in both cohorts with a pooled HR of 1.61 (95%CI鈥�=鈥�1.29鈥�2.01). Cause-specific analyses among the JPHC participants revealed that physical multimorbidity at baseline was linked with mortality due to physical disorders, mortality due to mental disorders/suicide, and mortality due to unintentional injuries.

Conclusions

Physical multimorbidity in middle adulthood is associated with an increased risk of all-cause mortality in Japan.

Peer Review reports

Background

Multimorbidity is commonly defined as the presence of two or more diseases or conditions [1]. As populations age, the prevalence of chronic conditions has increased, leading to a rise in multimorbidity [2]. Given that secondary care services have generally been single-disease focused (as is epidemiological research), the study of multimorbidity has gained significant attention over the past decade [3,4,5].

Previous studies suggest that multimorbidity is associated with a variety of subsequent poor health conditions [6,7,8,9,10], including mortality [6, 7]. For example, a systematic review of 26 studies by Nunes et al. [6] reported that those with multimorbidity had a 1.44-fold higher risk of all-cause mortality (95% confidence interval [CI]鈥�=鈥�1.34鈥�1.55) than those without multimorbidity; they also showed that the number of morbidities was linked with a 1.20-fold higher risk of all-cause mortality (95%CI鈥�=鈥�1.10鈥�1.30).

Despite these previous studies, several issues remain unaddressed. First, most of the earlier studies examined the association between multimorbidity and mortality among individuals in their late adulthood (i.e., 65 years and older), and comparatively little is known about the situation in middle adulthood [11,12,13,14,15,16]. This is a significant omission, given that evidence among younger individuals will facilitate efforts to mitigate the disease burden associated with multimorbidity. Additionally, the current evidence might have been subject to a selection bias because of the focus on individuals who survived until late adulthood. Second, cause-specific analyses have rarely been conducted. As exemplified by some previous studies suggesting that chronic conditions may increase the risk of depression [17], suicidal behaviors [9, 18], and unintentional injuries [19,20,21], multimorbidity may also increase the risk of mortality due to causes other than those that compose the multimorbidity at baseline. Third, most previous research originated in Western countries, and only a handful of studies have examined this association in Asian countries (e.g., China [15, 16, 22, 23] and Japan [24]). Given that the prevalence of obesity, an underlying condition for various morbidities, is much lower in Asian countries than in countries where previous studies were conducted, the magnitude of the association may be different in Asian settings. For example, the prevalence of obesity, defined as a body mass index [BMI]鈥夆墺鈥�30.0听kg/m2 in Japan (i.e., our study location) was estimated to be 5.0% for men and 3.9% for women [25], which were markedly lower than the estimates for Americans and Europeans [26].

Against this backdrop, we aimed to examine the association of physical multimorbidity with all-cause mortality and cause-specific mortality (i.e., mortality due to physical disorders, mental disorders and suicide, and unintentional injuries) among individuals aged 40鈥�64 years at baseline in Japan. We also examined the association between the number of morbid conditions at baseline and the risk of all-cause mortality to determine whether a dose-response relationship existed.

Methods

Study populations

Data was obtained from two eligible cohort studies that participate in the Japanese National Center Cohort Collaborative for Advancing Population Health (NC-CCAPH), which is a research consortium among six national centers for advanced and specialized medicine in Japan (6NC) [27]. More specifically, we used data collected from the Japan Public Health Center-based Prospective Study (JPHC) [28] and the Japan Epidemiology Collaboration on Occupational Health Study (J-ECOH) [29, 30].

The JPHC is a population-based cohort study of residents living in the catchment areas of 11 public health centers across Japan. A self-administered questionnaire survey was conducted between 1990 and 1993 (Cohort I, residents in the catchment area of five centers) and 1993 and 1994 (Cohort II, residents in the catchment area of the remaining six centers) [31]. Residence and vital status were monitored using a residential registry for a maximum of 29 years. Of 140,420 participants, 113,398 provided questionnaire information. We then excluded individuals who were in their late adulthood (aged鈥夆墺鈥�65 years) at baseline (n鈥�=鈥�8,865), individuals with missing information on physical multimorbidity (n鈥�=鈥�1,673) and covariates (n鈥�=鈥�2,855), and individuals without follow-up information (n鈥�=鈥�73). The remaining 99,932 individuals were included in subsequent analyses. The excluded individuals were more likely to be male (57.4% vs. 46.7%) and older (51.2 years vs. 50.1 years) compared to those included in the analytic sample.

The J-ECOH is a company-based cohort study conducted in several large-scale companies with headquarters in the Kanto and Tokai regions of Japan. Information on annual health check-ups was collected via full-time corporate occupational physicians at each company. A study-specific registry was launched in April 2012 to collect information on mortality among participating companies. The participants were followed up for a maximum of 10 years. Of the 94,809 participants who were working for a company that provided information on a set of morbid conditions to define physical multimorbidity (described below), we excluded individuals aged鈥�<鈥�40 or 鈮モ��65 years (n鈥�=鈥�39,129) at baseline, those with missing information on physical multimorbidity (n鈥�=鈥�869) and covariates (n鈥�=鈥�5,081), and individuals without any information to define the follow-up period (n鈥�=鈥�4,888), leaving 44,842 individuals in the subsequent analysis. The excluded participants had a lower proportion of males compared to the analytic sample (80.3% vs. 84.2%), and they were also older on average (52.7 years vs. 49.7 years).

The study protocol was approved by the Institutional Review Board of the National Cancer Center (NCC), Japan (approval number 2018鈥�194), with specific approval obtained at NCC (2001-021) and National Center for Global Health and Medicine (NCGM-S-001140). Informed consent was assumed on the voluntary response to the JPHC questionnaire and if the participants did not opt out of the in-company bulletin board for the J-ECOH. Participants were informed that they could withdraw their participation at any time.

Outcome (mortality)

While the JPHC linked records with vital statistical data from the Ministry of Health, Labour and Welfare with permission and defined the causes of death, the J-ECOH used information provided by occupational physicians and registered in the study-specific registry [32]. The follow-up period ended on different dates: for the JPHC, December 2009 for Katsushika, December 2012 for Suita, and December 2018 for the remaining sites; for the J-ECOH, March 2016 for site 12, March 2017 for site 9, March 2018 for site 11, and March 2022 for the others. In both studies, the International Classification of Diseases 10th Revision (ICD-10) was used to code the diagnoses.

The primary outcome measure was the all-cause mortality. We also examined the association between physical multimorbidity and the following specific secondary outcomes among JPHC participants given that J-ECOH participants did not have enough events that allow us to conduct the cause-specific analysis: (1) mortality due to physical disorders (other than those specified below), (2) mortality due to mental disorders and suicide (ICD-10: F00-F99, X60-X84), and (3) mortality due to unintentional injuries (injury/accident) (S00-T98, V01-Y98 but not X60-84).

Exposure (physical multimorbidity)

The self-reported information on morbid conditions collected from both datasets was harmonized to generate the following 10 sets of morbid conditions: cancer, heart disease, stroke, hypertension, diabetes, dyslipidemia, excess body weight, kidney disease, liver disease, and asthma. The available information varied across cohorts and within each study site. For example, 鈥榟eart disease鈥� definitions ranged from being narrowly defined as 鈥榤yocardial infarction鈥� in some sites to including a broader range of ischemic heart diseases, such as angina pectoris, in others. These variations are listed in Supplementary Table 1. Except for the information on excess body weight (BMI鈥夆墺鈥�25.0听kg/m2) for the J-ECOH study, which was based on measured height and weight, the information was collected via self-report.

We defined physical multimorbidity when a participant had two or more conditions at baseline. We also counted the number of morbid conditions and categorized the participants as 0, 1, 2, 3, and 鈮モ��4.

Covariates

Information on demographic variables (age and sex) and lifestyle parameters (smoking and alcohol consumption) were collected in both studies using a questionnaire. Smoking status was categorized as never, former, and current smoker. Alcohol consumption was assessed using information on alcohol consumption frequency and the amount of alcohol consumed per occasion; we then categorized participants into: did not drink; drank鈥�<鈥�1 go; drank 1-1.9 go; and drank 2 go or more (go is a Japanese traditional unit containing approximately 23听g ethanol).

Statistical analysis

Person-years were calculated as the difference between the date of baseline (i.e., the date of the baseline survey for the JPHC and the date of launch of the disease registry for the J-ECOH [April 1, 2012]) and either the date of death, the date on which study participants were no longer under observation (e.g., due to moving abroad for the JPHC and resigning/retiring from the company for the J-ECOH), or the end of follow-up, whichever occurred first. In the cause-specific analyses, participants were also censored on the date of death due to causes other than those of interest.

A Cox proportional hazards model was applied to each study separately to examine the association between physical multimorbidity at baseline and all-cause mortality while accounting for clustering at the study sites. Model 1 was adjusted for age and sex and Model 2 was further adjusted for smoking status and alcohol consumption. The results are shown as hazard ratios (HRs) and the corresponding 95% confidence intervals (CI). We checked the proportional hazards assumption regarding physical multimorbidity using Schoenfeld residual and graphical assessment using log-log plots.

To calculate the pooled HRs and corresponding 95%CI, we aggregated the HRs obtained in each study using a random-effects meta-analysis model. This model was chosen given the significant differences between the two cohorts in terms of the study population, timing of the baseline survey, and available information to define exposure. Heterogeneity was assessed using the I2-statistics and Cochran鈥檚 Q-statistics.

We also examined (i) the association between the number of morbid conditions and all-cause mortality to test whether a dose-response relationship existed; (ii) the association between physical multimorbidity and all-cause mortality among those without cancer, heart disease, or stroke at baseline to ascertain whether the observed association was exclusively influenced by these severe health conditions at baseline; (iii) whether the association between physical multimorbidity and all-cause mortality differed between individuals aged 40鈥�54 years vs. 55鈥�64 years at baseline, and (iv) whether the association between physical multimorbidity and all-cause mortality differed between sex.

Statistical analyses were performed using the Stata ver. 15.0 (College Station, TX, USA) for the JPHC and Stata ver. 17.0 for the J-ECOH and meta-analysis (College Station, TX, USA).

Results

Table听1 shows the basic characteristics of the study participants in each cohort. The mean age of both cohorts was approximately 50 years, with a higher proportion of male participants in the J-ECOH than in the JPHC group. Current smokers accounted for 29.2% and 32.4% of the JPHC and J-ECOH participants, respectively, whereas the corresponding figures for alcohol drinkers were 50.2% and 71.6%, respectively. The prevalence of morbid conditions did not differ significantly between the two cohorts, except for dyslipidemia (JPHC, 2.9%; J-ECOH, 12.4%). Those with physical multimorbidity accounted for 12.5% and 17.9% of the JPHC and J-ECOH participants, respectively.

Table 1 Basic characteristics of study participants, shown using study cohort and physical multimorbidity status at baseline
Full size table

In the JPHC study, Schoenfeld residual tests produced p-values of <鈥�0.001 for all-cause mortality, 0.28 for mortality due to physical disorders, <鈥�0.001 for mortality due to mental disorders or suicide, and 0.96 for mortality due to injuries or accidents, suggesting potential assumption violations in some models. However, visual inspection of log-log survival plots (Supplementary Fig.听1) revealed no substantial deviations from proportionality. Given the possibility that the large sample size could generate small p-values that overstate assumption violations, we retained the current model for its interpretability. In contrast, in the J-ECOH study (all-cause mortality), both Schoenfeld residual tests (p鈥�=鈥�0.55) and log-log plots (Supplementary Fig.听2) demonstrated no evidence of proportional hazards violations.

During a follow-up of 2,304,375 person-years in the JPHC and 311,637 person-years in the J-ECOH, 23,611 and 275 deaths were recorded, respectively. Specific causes of death are detailed in Supplementary Table 2. Table听2 shows the results of a Cox proportional hazards model that examined the association between physical multimorbidity and risk of all-cause mortality. Compared to individuals without physical multimorbidity at baseline, those with physical multimorbidity were at a higher risk of all-cause mortality in both cohorts; the HRs (95%CIs) for the age- and sex-adjusted models (Model 1) were 1.44 (1.38鈥�1.50) for JPHC and 1.86 (1.45鈥�2.39) for J-ECOH with their pooled estimate being 1.59 (1.24鈥�2.02). When the model was further adjusted for smoking and alcohol consumption, these associations did not change materially.

Table 2 Results of the Cox proportional hazards model examining the association between physical multimorbidity and the risk of all-cause and cause-specific mortality in Japan
Full size table

In cause-specific analyses among JPHC participants, physical multimorbidity was associated with a higher risk of mortality due to physical disorders (Model 2: HR鈥�=鈥�1.51, 95% CI鈥�=鈥�1.44鈥�1.57) (Table听3). Additionally, physical multimorbidity at baseline was significantly associated with mortality due to mental disorders (pooled HR鈥�=鈥�1.25, 95% CI鈥�=鈥�1.05鈥�1.48) and mortality due to unintentional injuries (HR鈥�=鈥�1.14, 95% CI鈥�=鈥�1.02鈥�1.28).

Table 3 Results of the Cox proportional hazards model examining the association between physical multimorbidity and the risk of cause-specific mortality among participants in the Japan Public Health Center-based prospective study (JPHC)
Full size table

In the analysis examining the association between the number of morbid conditions and the risk of all-cause mortality, we found a dose-response relationship (Table听4). We also confirmed that physical multimorbidity at baseline was associated with a higher risk of all-cause mortality in individuals without cancer, heart disease, or stroke at baseline (Supplementary Table 3).

Table 4 Results of the Cox proportional hazards model examining the association between the number of morbid conditions and the risk of all-cause mortality in Japan
Full size table

When we examined the association between physical multimorbidity and all-cause mortality according to baseline age category (i.e., 40鈥�54 and 55鈥�64 years), we found that the association was more pronounced among individuals aged 40鈥�54 years vs. 55鈥�64 years (Table听5). More specifically, the pooled HR was 1.83 (1.43鈥�2.35) for individuals aged 40鈥�54 years while the corresponding figure for individuals aged 55鈥�64 years was 1.39 (1.34鈥�1.45). We did not find any evidence of significant interaction between sex and physical multimorbidity (Supplementary Table 4).

Table 5 Results of the Cox proportional hazards model examining the association between physical multimorbidity and the risk of all-cause mortality in Japan, stratified according to age categories at baseline
Full size table

Discussion

Using information collected from two large-scale cohort studies in Japan, we found that baseline physical multimorbidity measured in middle adulthood was associated with a higher risk of all-cause mortality. In the cause-specific analysis among the JPHC participants where a sufficient number of events were observed for each cause, we found that physical multimorbidity was associated with an increased risk of mortality due to physical disorders, mortality due to mental disorders/suicide, and the mortality risk from unintentional injuries.

Our finding of a higher risk of all-cause mortality associated with baseline physical multimorbidity is consistent with the findings reported in the meta-analysis by Nunes et al. [6] (HR鈥�=鈥�1.44). We initially hypothesized that the HR might be lower than that found in Western studies considering the lower prevalence of obesity compared to these countries. This hypothesis stemmed from the observation that the HRs reported in studies from Japan [24] and China [22] were comparatively lower albeit with difference in multimorbidity definitions (i.e., HR鈥�=鈥�1.07 in a study by Kato et al. of individuals in late adulthood in Japan [24], and HR鈥�=鈥�1.12 in a study by Su et al. of those aged鈥夆墺鈥�65 years in China [22]). However, this association was relatively more substantial in our study participants, aligning closely with the effect size reported in a referenced meta-analysis. [6]

One possible interpretation of our results, as suggested by prior research [11, 14], is that the magnitude of the association may be more pronounced due to the younger age of the study population compared with older cohorts. For example, Jani et al. [11] reported that having鈥夆墺鈥�4 long-term conditions vs. none was associated with a 4.61-fold higher risk of all-cause mortality among male participants aged 37鈥�49 years while the corresponding figure was 2.47 for male participants aged 60鈥�79 years. Given this, our study findings should perhaps be interpreted within the context of the participants鈥� average age, rather than as a direct comparison between Western and Asian populations. Our stratified analysis according to age categories also supports this supposition. The early onset of multimorbidity may reflect and accelerate biological aging within the body, potentially leading to a stronger association with mortality [33].

In a series of cause-specific analyses among the JPHC participants, we found the association in relation to mortality due to physical disorders was statistically significant. While evidence of its biological mechanisms remains scarce, it is possible that multiple chronic conditions can interact and exacerbate each other, leading to an increased risk of mortality [34]. Even if morbid conditions at baseline are not a direct cause of death, they can cause more severe physical disorders. This assumption was supported by our sensitivity analysis in which we confined our study participants to those without cancer, heart disease, or stroke at the baseline. In addition, some cardiometabolic risk factors are known to be a risk factor for cancer [35,36,37] as well as CVD [38].

We also found a significant association between physical multimorbidity at baseline and mortality due to mental health/suicide in the JPHC study. This association has not been extensively studied, but our findings are in line with those of previous studies suggesting that psychological or financial burdens associated with the diagnosis of a disease can cause mental health problems [39,40,41].

The significant association between physical multimorbidity and the risk of mortality due to unintentional injuries was in line with some studies suggesting that multimorbidity is linked to an elevated risk of falls (i.e., one type of unintentional injury) [42, 43], and several studies have linked individual health conditions to the risk of unintentional injuries or related outcomes (e.g., diabetes [44], cancer [45], and self-rated health [46]), albeit with some exceptions [47]. Previous research has also suggested that individuals with and without multimorbidity are more likely to experience worsening physical performance (e.g., gait [48, 49], balance [48], and lower extremity muscle function [48]), both of which can serve as risk factors for unintentional injuries. Collectively, our study and the existing research indicate a potentially increased risk of mortality from unintentional injuries in individuals with multimorbidity, meriting further investigation.

In this study, we used data collected from two prospective cohort studies in Japan, which differed in several ways, as reflected in the high I虏 values indicating substantial heterogeneity. For example, whereas the JPHC is a population-based study that collected baseline information using a questionnaire, the J-ECOH is a company-based occupational cohort study that uses information routinely collected in an occupational health setting. The differences in study settings may have led to different types of bias in each study (described below). In addition, there were methodological differences between the two cohorts, e.g., the set of specific information on morbid conditions with which we defined the exposure, the duration of the follow-up period (JPHC: 29 years; J-ECOH: 10 years), the method of outcome data collection (JPHC: national registry; J-ECOH: study-specific registry that did not account for post-retirement mortality, potentially underestimating the hazard ratio), and the year in which the baseline information was collected (JPHC: 1991鈥�1993; J-ECOH: 2011).

Despite these differences, we consistently observed an association between physical multimorbidity and all-cause mortality in two representative settings (the community and workplace), which suggests the robustness of the findings. It should be also of note that while the JPHC provides robust evidence of the association between multimorbidity and mortality, the J-ECOH offers valuable insights into this relationship within a working population, a group often underrepresented in national health surveys. We believe that combining data from these two cohorts strengthens our study by offering a more comprehensive view of the population.

This study has several limitations. First, while we harmonized the information collected in the two cohorts, the set of information used to define exposure differed between them. One notable difference is that we used information on medication use (lipid-lowering drugs) to define the morbid condition of dyslipidemia in the JPHC, but used self-reported diagnosis and/or medication use in the J-ECOH to define the same condition. It should also be noted that the differences in the baseline years between the two studies might be associated with variations in medication availability or diagnostic techniques, both of which could potentially affect our capacity to accurately identify each morbid condition. Second, the criteria for defining morbid conditions varied slightly in terms of severity across cohort studies and study sites within each study. For instance, while some sites defined heart disease exclusively as myocardial infarction, others included a broader spectrum of ischemic heart diseases, encompassing conditions such as angina pectoris. Third, our study did not differentiate the potential impact of each condition on mortality, and quantified multimorbidity by simply counting the number of morbid conditions. Fourth, apart from the height and weight measurements in the J-ECOH study, we relied on self-reported data to define physical multimorbidity, which is likely to result in measurement errors. Fifth, the number of events registered might have been insufficient for cause-specific analysis, which prevented us from conducting cause-specific analysis among the J-ECOH. Sixth, competing risks may pose a challenge when conducting cause-specific analyses in the JPHC study. However, given that mortality due to physical disorders, where the strongest associations were observed, tends to occur later in life compared to mortality from mental health issues/suicide, or unintentional accidents, we believe it is unlikely that our study falsely identified an association where none exists. The average age at death was 71.9 years for mortality due to physical illness, 64.4 years for mortality due to mental illness or suicide, and 68.8 years for mortality due to accidents in the JPHC, while in the J-ECOH, it was 54.7 years, 49.7 years, and 51.4 years, respectively. Seventh, some variables were not available that would have helped better understand the association between physical multimorbidity and mortality (e.g., socioeconomic status, living arrangement, and detailed lifestyle parameters). Only a subset of participants in the JPHC study had information on educational attainment available. Eighth, we conducted the analysis based on the proportional hazard assumption, but the actual hazard may change over time. Future studies may employ a discrete-time hazard model, accounting for time-varying hazards. Finally, the study participants might not have been fully representative of the Japanese people of this age group. Both cohort studies faced selection bias; for example, the healthy volunteer effect was reported for the JPHC [50, 51] and the healthy worker effect can also exist in the J-ECOH. In addition, the J-ECOH was conducted in relatively large companies; thus, workers from small- and medium-sized corporations were underrepresented.

Conclusions

In conclusion, using large-scale data collected from two prospective cohort studies in Japan, we observed that physical multimorbidity assessed in middle adulthood was significantly associated with an elevated risk of all-cause mortality. We also found significant associations between physical multimorbidity and the risk of mortality due to physical disorders, mental disorders/suicide, and unintentional injuries in one of the study cohorts where the sample size was large enough to do the cause-specific analysis, which warrants further investigation.

Data availability

The data from the JPHC and J-ECOH studies are not publicly available due to restrictions related to research participant privacy. The informed consent obtained for the JPHC study and the contracts with study companies for the J-ECOH study do not include provisions for public data sharing. Researchers interested in accessing the JPHC data and/or biospecimens can find detailed application instructions at https://epi.ncc.go.jp/en/jphc/805/8155.html. For inquiries regarding the J-ECOH study, please contact Dr. Tetsuya Mizoue at mizoue@hosp.ncgm.go.jp.

Abbreviations

BMI:

Body mass index

CI:

Confidence interval

CVD:

Cardiovascular diseases

HR:

Hazard ratio

ICD-10:

The International Classification of Diseases 10th Revision

J-ECOH:

The Japan Epidemiology Collaboration on Occupational Health Study

JPHC:

The Japan Public Health Center-based Prospective Study

NC:

National centers for advanced and specialized medicine in Japan

NCC:

National Cancer Center of Japan

NC-CCAPH:

National Center Cohort Collaborative for Advancing Population Health (NC-CCAPH)

NCGM:

National Center for Global Health and Medicine

References

  1. Johnston MC, Crilly M, Black C, Prescott GJ, Mercer SW. Defining and measuring multimorbidity: a systematic review of systematic reviews. Eur J Pub Health. 2019;29:182鈥�9.

    听 听

  2. Technical Series on Safer Primary Care. Multimorbidity. . Accessed 10 Apr 2022.

  3. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012;380:37鈥�43.

    听 听 听

  4. Guthrie B, Payne K, Alderson P, McMurdo MET, Mercer SW. Adapting clinical guidelines to take account of multimorbidity. BMJ. 2012;345:e6341.

    听 听 听

  5. Ong KY, Lee PSS, Lee ES. Patient-centred and not disease-focused: a review of guidelines and multimorbidity. Singap Med J. 2020;61:584鈥�90.

    听 听

  6. Nunes BP, Flores TR, Mielke GI, Thum茅 E, Facchini LA. Multimorbidity and mortality in older adults: a systematic review and meta-analysis. Arch Gerontol Geriatr. 2016;67:130鈥�8.

    听 听 听

  7. Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, et al. Association of Cardiometabolic Multimorbidity with Mortality. JAMA. 2015;314:52鈥�60.

    听 听

  8. Multiple long-term conditions (multimorbidity): making sense of the evidence. NIHR Evidence. 2021. . Accessed 10 Apr 2022.

  9. Stickley A, Koyanagi A, Ueda M, Inoue Y, Waldman K, Oh H. Physical multimorbidity and suicidal behavior in the general population in the United States. J Affect Disord. 2020;260:604鈥�9.

    听 听 听

  10. Makovski TT, Schmitz S, Zeegers MP, Stranges S, van den Akker M. Multimorbidity and quality of life: systematic literature review and meta-analysis. Ageing Res Rev. 2019;53:100903.

    听 听 听

  11. Jani BD, Hanlon P, Nicholl BI, McQueenie R, Gallacher KI, Lee D, et al. Relationship between multimorbidity, demographic factors and mortality: findings from the UK Biobank cohort. 樱花视频 Med. 2019;17:74.

    听 听 听 听

  12. Dugravot A, Fayosse A, Dumurgier J, Bouillon K, Rayana TB, Schnitzler A, et al. Social inequalities in multimorbidity, frailty, disability, and transitions to mortality: a 24-year follow-up of the Whitehall II cohort study. Lancet Public Health. 2020;5:e42鈥�50.

    听 听 听

  13. Hanlon P, Jani BD, Nicholl B, Lewsey J, McAllister DA, Mair FS. Associations between multimorbidity and adverse health outcomes in UK Biobank and the SAIL Databank: a comparison of longitudinal cohort studies. PLoS Med. 2022;19:e1003931.

    听 听 听 听

  14. Kabir A, Tran A, Ansari S, Conway DP, Barr M. Impact of multimorbidity and complex multimorbidity on mortality among older australians aged 45 years and over: a large population-based record linkage study. BMJ Open. 2022;12:e060001.

    听 听 听 听

  15. Fan J, Sun Z, Yu C, Guo Y, Pei P, Yang L, et al. Multimorbidity patterns and association with mortality in 0.5 million Chinese adults. Chin Med J (Engl). 2022;135:648鈥�57.

    听 听 听

  16. Zou S, Wang Z, Bhura M, Tang K. Association of multimorbidity of non-communicable diseases with mortality: a 10-year prospective study of 0.5 million Chinese adults. Public Health. 2022;205:63鈥�71.

    听 CAS听 听 听

  17. Read JR, Sharpe L, Modini M, Dear BF. Multimorbidity and depression: a systematic review and meta-analysis. J Affect Disord. 2017;221:36鈥�46.

    听 听 听

  18. Jing Z, Li J, Fu PP, Wang Y, Yuan Y, Zhao D, et al. Physical multimorbidity and lifetime suicidal ideation and plans among rural older adults: the mediating role of psychological distress. 樱花视频 Psychiatry. 2021;21:78.

    听 听 听 听

  19. Stewart Williams J, Kowal P, Hestekin H, O鈥橠riscoll T, Peltzer K, Yawson A, et al. Prevalence, risk factors and disability associated with fall-related injury in older adults in low- and middle-incomecountries: results from the WHO Study on global AGEing and adult health (SAGE). 樱花视频 Med. 2015;13:147.

    听 听 听 听

  20. Reyes-Ortiz CA, Al Snih S, Loera J, Ray LA, Markides K. Risk factors for falling in older Mexican americans. Ethn Dis. 2004;14:417鈥�22.

    听 听

  21. Gale CR, Westbury LD, Cooper C, Dennison EM. Risk factors for incident falls in older men and women: the English longitudinal study of ageing. 樱花视频 Geriatr. 2018;18:117.

    听 听 听 听

  22. Su Z, Huang L, Zhu J, Cui S. Effects of multimorbidity coexistence on the risk of mortality in the older adult population in China. Front Public Health. 2023;11:1110876.

    听 听 听 听

  23. Zhang D, Tang X, Shen P, Si Y, Liu X, Xu Z, et al. Multimorbidity of cardiometabolic diseases: prevalence and risk for mortality from one million Chinese adults in a longitudinal cohort study. BMJ Open. 2019;9:e024476.

    听 听 听 听

  24. Kato D, Kawachi I, Saito J, Kondo N. Complex multimorbidity and mortality in Japan: a prospective propensity-matched cohort study. BMJ Open. 2021;11:e046749.

    听 听 听 听

  25. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19路2 million participants. Lancet. 2016;387:1377鈥�96.

    听 听

  26. Boutari C, Mantzoros CS. A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. Metabolism. 2022;133:155217.

    听 CAS听 听 听 听

  27. Abe SK, Ihira H, Minami T, Imatoh T, Inoue Y, Tsutsumimoto K, et al. Prevalence of family history of cancer in the NC-CCAPH consortium of Japan. Sci Rep. 2023;13:3128.

    听 CAS听 听 听 听

  28. Tsugane S, Sawada N. The JPHC Study: design and some findings on the typical Japanese Diet. Jpn J Clin Oncol. 2014;44:777鈥�82.

    听 听 听

  29. Islam Z, Akter S, Inoue Y, Hu H, Kuwahara K, Nakagawa T, et al. Prediabetes, Diabetes, and the risk of all-cause and cause-specific mortality in a Japanese Working Population: Japan Epidemiology collaboration on Occupational Health Study. Diabetes Care. 2021;44:757鈥�64.

    听 听 听 听

  30. Inoue Y, Nomura S, Nishiura C, Hori A, Yamamoto K, Nakagawa T, et al. Loss of Working Life Years due to mortality, sickness absence, or ill-health Retirement: a Comprehensive Approach to estimating Disease Burden in the Workplace. J Epidemiol. 2021;31:403鈥�9.

    听 听 听 听

  31. Tsugane S, Sobue T. Baseline survey of JPHC Study Design and Participation Rate. J Epidemiol. 2001;11:24鈥�9.

    听 听

  32. Akter S, Nakagawa T, Honda T, Yamamoto S, Kuwahara K, Okazaki H, et al. Smoking, Smoking Cessation, and risk of Mortality in a Japanese Working Population 鈥� Japan Epidemiology collaboration on Occupational Health Study 鈥�. Circ J. 2018;82:3005鈥�12.

    听 听 听

  33. Jain P, Binder A, Chen B, Parada H, Gallo LC, Alcaraz J, et al. The Association of Epigenetic Age Acceleration and Multimorbidity at Age 90 in the women鈥檚 Health Initiative. J Gerontol Biol Sci Med Sci. 2023;78:2274鈥�81.

    听 CAS听 听

  34. Powell M. Making sense of the evidence: Multiple long-term conditions (multimorbidity). NIHR Evidence. 2021. . Accessed 4 Oct 2023.

  35. Tran KB, Lang JJ, Compton K, Xu R, Acheson AR, Henrikson HJ, et al. The global burden of cancer attributable to risk factors, 2010鈥�19: a systematic analysis for the global burden of Disease Study 2019. Lancet. 2022;400:563鈥�91.

    听 听

  36. Liu EE, Suthahar N, Paniagua SM, Wang D, Lau ES, Li SX, et al. Association of Cardiometabolic Disease with Cancer in the community. JACC CardioOncol. 2022;4:69鈥�81.

    听 听 听 听

  37. Michels N, van Aart C, Morisse J, Mullee A, Huybrechts I. Chronic inflammation towards cancer incidence: a systematic review and meta-analysis of epidemiological studies. Crit Rev Oncol Hematol. 2021;157:103177.

    听 听 听

  38. Vaduganathan M, Mensah GA, Turco JV, Fuster V, Roth GA. The Global Burden of Cardiovascular diseases and Risk. J Am Coll Cardiol. 2022;80:2361鈥�71.

    听 听 听

  39. Lin EHB, Katon W, Von Korff M, Rutter C, Simon GE, Oliver M, et al. Relationship of Depression and Diabetes Self-Care, Medication Adherence, and Preventive Care. Diabetes Care. 2004;27:2154鈥�60.

    听 听 听

  40. Polsky D, Doshi JA, Marcus S, Oslin D, Rothbard A, Thomas N, et al. Long-term risk for depressive symptoms after a medical diagnosis. Arch Intern Med. 2005;165:1260鈥�6.

    听 听 听

  41. Wang J, Williams J, Lavorato D, Schmitz N, Dewa C, Patten SB. The incidence of major depression in Canada: the National Population Health Survey. J Affect Disord. 2010;123:158鈥�63.

    听 听 听

  42. Barik M, Panda SN, Tripathy SS, Sinha A, Ghosal S, Acharya AS, et al. Is multimorbidity associated with higher risk of falls among older adults in India? 樱花视频 Geriatr. 2022;22:486.

    听 听 听 听

  43. You L, Guo L, Li N, Zhong J, Er Y, Zhao M. Association between multimorbidity and falls and fear of falling among older adults in eastern China: a cross-sectional study. Front Public Health. 2023;11:1146899.

    听 听 听 听

  44. Yang Y, Hu X, Zhang Q, Zou R. Diabetes mellitus and risk of falls in older adults: a systematic review and meta-analysis. Age Ageing. 2016;45:761鈥�7.

    听 听 听

  45. Yang K, Zheng Y, Peng J, Chen J, Feng H, Yu K, et al. Incidence of Death from Unintentional Injury among patients with Cancer in the United States. JAMA Netw Open. 2020;3:e1921647.

    听 听 听 听

  46. Srivastava S, Muhammad T. Prevalence and risk factors of fall-related injury among older adults in India: evidence from a cross-sectional observational study. 樱花视频. 2022;22:550.

    听 听 听 听

  47. Rebholz CM, Gu D, Yang W, Chen J, Wu X, Huang J, et al. Mortality from suicide and other external cause injuries in China: a prospective cohort study. 樱花视频. 2011;11:56.

    听 听 听 听

  48. Yang K, Yang S, Chen Y, Cao G, Xu R, Jia X, et al. Multimorbidity patterns and associations with Gait, Balance and Lower Extremity muscle function in the Elderly: a cross-sectional study in Northwest China. Int J Gen Med. 2023;16:3179鈥�92.

    听 听 听 听

  49. Yao S-S, Meng X, Cao G-Y, Huang Z-T, Chen Z-S, Han L, et al. Associations between Multimorbidity and physical performance in older Chinese adults. Int J Environ Res Public Health. 2020;17:4546.

    听 听 听 听

  50. Hara M, Sasaki S, Sobue T, Yamamoto S, Tsugane S. Comparison of cause-specific mortality between respondents and nonrespondents in a population-based prospective study: ten-year follow-up of JPHC Study Cohort I. Japan Public Health Center. J Clin Epidemiol. 2002;55:150鈥�6.

    听 听 听

  51. Iwasaki M, Yamamoto S, Otani T, Inoue M, Hanaoka T, Sobue T, et al. Generalizability of relative risk estimates from a well-defined Population to a General Population. Eur J Epidemiol. 2006;21:253鈥�62.

    听 听 听

Acknowledgements

We would like to thank the participants in the JPHC and J-ECOH studies. We are also grateful to the members of the Secretariat Office of the NC-CCPAH for their active support.

Funding

This study was financially supported by the Japan Health Research Promotion Bureau.

360 (JH) (2019-(1)-1; 2024-B-05). The Japan Public Health Center Study (JPHC) was supported by the National Cancer Center Research and Development Fund (since 2011) and a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (from 1989 to 2010). The Japan Epidemiology Collaboration on Occupational Health (J-ECOH) was financially supported by the Industrial Health Foundation of Japan, Ministry of Health, Labour and Welfare of Japan (140202-01, 150903-01, 170301-01), Japan Society for the Promotion of Science (JSPS KAKENHI JP25293146, JP25702006, JP16H05251, JP20H03952), and National Center for Global Health and Medicine (28-Shi-1206, 30-Shi-2003; 19A1006, 21A1020, 22A1008). The funders had no role in the study design, data collection, analysis, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan

    Yosuke Inoue听&听Tetsuya Mizoue

  2. Division of Cohort Research, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan

    Seitaro Suzuki,听Norie Sawada听&听Motoki Iwasaki

  3. Department of Social Medicine, Research Institute, National Center for Child Health and Development, Tokyo, Japan

    Naho Morisaki

  4. Department of Behavioral Medicine, National Institute of Mental Health, National Center for Neurology and Psychiatry, Tokyo, Japan

    Zui Narita

  5. Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan

    Taiki Yamaji听&听Motoki Iwasaki

  6. Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan

    Yoshihiro Kokubo

  7. Department of Preventive Gerontology, Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Aichi, Japan

    Takehiko Doi

  8. Department of Epidemiology of Aging, Center for Gerontology and Social Science, National Center for Geriatrics and Gerontology, Aichi, Japan

    Yukiko Nishita

  9. Division of Prevention, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan

    Manami Inoue

Authors
  1. Yosuke Inoue

    You can also search for this author in 听

  2. Seitaro Suzuki

    You can also search for this author in 听

  3. Norie Sawada

    You can also search for this author in 听

  4. Naho Morisaki

    You can also search for this author in 听

  5. Zui Narita

    You can also search for this author in 听

  6. Taiki Yamaji

    You can also search for this author in 听

  7. Yoshihiro Kokubo

    You can also search for this author in 听

  8. Takehiko Doi

    You can also search for this author in 听

  9. Yukiko Nishita

    You can also search for this author in 听

  10. Motoki Iwasaki

    You can also search for this author in 听

  11. Manami Inoue

    You can also search for this author in 听

  12. Tetsuya Mizoue

    You can also search for this author in 听

Contributions

Conceptualization: YI, TM; Data Curation: YI, SS, NS; Formal Analysis: YI, SS, NS; Funding Acquisition: NS, MaI, TM; Methodology: YI, NS, ZN, TY; Project Administration: NS, MoI, MaI, TM; Resources: NS, MoI, MaI, TM; Supervision: NM, ZN, YK, TD, YN, MI, TM; Writing 鈥� Original Draft: YI, SS, NS, ZN, TY; Writing 鈥� Review & Editing: NH, YK, TD, YN, MoI, MaI, TM.

Corresponding author

Correspondence to Yosuke Inoue.

Ethics declarations

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Institutional Review Board of the National Cancer Center (NCC), Japan (approval number 2018鈥�194), with specific approval obtained at NCC (2001-021) and National Center for Global Health and Medicine (NCGM-S-001140). Informed consent was assumed on the voluntary response to the JPHC questionnaire and if the participants did not opt out of the in-company bulletin board for the J-ECOH. Participants were informed that they could withdraw their participation at any time.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher鈥檚 note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article鈥檚 Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article鈥檚 Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit .

About this article

Cite this article

Inoue, Y., Suzuki, S., Sawada, N. et al. Association between physical multimorbidity in middle adulthood and mortality: findings from two large cohort studies in Japan. 樱花视频 25, 92 (2025). https://doi.org/10.1186/s12889-024-21166-5

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12889-024-21166-5

Keywords

樱花视频

ISSN: 1471-2458

Contact us