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Background Serum growth differentiation factor 15 (GDF15) is associated with age-related adverse outcomes. However, renal function has not been thoroughly evaluated in studies addressing the association between GDF15 and mortality. We aimed to clarify whether GDF15 is associated with total mortality after carefully controlling renal function markers. Methods We divided 1 801 community-dwelling Japanese older adults into quartiles according to their serum GDF15 concentrations. The correlation of GDF15 with renal function and inflammation markers was assessed by calculating Spearman correlation coefficients. Cumulative survival rates of the quartiles were estimated. In a Cox regression analysis adjusted for confounders, the association between GDF15 and mortality was evaluated. The discriminative capacity of GDF15 for the prediction of mortality was assessed with receiver-operating characteristic analysis. Results GDF15 was correlated with cystatin C (r = 0.394), β2-microglobulin (r = 0.382), C-reactive protein (r = 0.124), and interleukin-6 (r = 0.166). The highest GDF15 quartile showed poor survival compared to the others. Older adults with higher GDF15 were associated with an increased mortality risk, independent of demographics and clinically relevant variables (hazard ratio [95% confidence interval]: 1.98 [1.09–3.59]). This significant association disappeared when additionally adjusted for cystatin C (1.65 [0.89–3.05]) or β2-microglobulin (1.69 [0.91–3.12]). The ability to predict mortality was approximately comparable between GDF15 (area under the curve: 0.667), cystatin C (0.691), and β2-microglobulin (0.715). Conclusions Serum GDF15 is associated with total mortality in older Japanese after adjustment for major confounders. The increased mortality risk in older adults with higher GDF15 may be partly attributed to decreased renal function.

It is well known that social contribution such as working maintains the functional health and prevents frailty of older adults. However, the effect of employment in old age with frailty on health outcomes is not well-established.This 3.6-year prospective study examined the influence of working on all-cause mortality in urban community-dwelling Japanese older adults. Participants were 10,591 initially non-disabled residents (5,180 men; 5,411 women) aged 65–84 years of Ota City, Tokyo, Japan. We applied the Cox proportional hazard model by gender and with/without frailty, controlling for age, years of education, equivalent income, number of chronic diseases, body mass index, instrumental activities of daily living (IADLs), smoking and drinking status, exercise habits, social activities, and social interaction for evaluating the predictive value of working status (full-time worker, part time worker, occasional worker and non-worker) at baseline for all-cause mortality.During a follow-up of 3.6 years, 328 (3.1%) individuals died. Compared with non-workers, independent multivariate-hazard ratios (95% confidence intervals) of part-time workers for all-cause mortality in men with/without frailty were 0.35 (0.13–0.97) and 0.54 (0.28–1.01), respectively. Corresponding female multivariate-adjusted HRs with/without frailty were 1.21 (0.34–4.34) and 0.23 (0.05–0.99). Also, for both genders, full-time workers and occasional workers did not have significantly lower adjusted hazard ratios of all-cause mortality, compared to non-workers, regardless of frailty. In conclusion, moderate employment resulted in lower risk of all-cause mortality, even in frail older men.

Background We examined whether dietary variety (DV) might alleviate poor mental health (MH) of living-alone (LA) older adults. Methods Cross-sensational data from 15073 (7566 men; 7507 women) residents aged 65-84 years were assessed using the WHO-Five Well-being Index to determine poor MH (defined by a score ≤ 12) and DV (low and high DV defined by a score ≤ 3 and ≥ 4, respectively). Participants were divided into living together with high DV (G1), living together with low DV (G2), LA with high DV (G3), and LA with low DV (G4). Logistic regression analyses stratified by gender were performed to examine the association of poor MH with LA and DV. Results Prevalence of LA, low DV, and poor MH were 13.6%, 63.3%, and 26.1%, respectively, in men, and 21.2%, 54.6%, and 24.8%, respectively, in women. Compared with the G1, the multivariate-adjusted odds ratios (ORs) (95% confidence intervals) for worse MH were 1.69 (1.49-1.93) for G2, 2.04 (1.50-2.78) for G3, and 3.34 (2.70-4.11) for G4 in men. Corresponding ORs were 1.73 (1.52-1.96), 1.02 (0.83-1.26), and 1.66 (1.36-2.01) in women. Conclusions The association of poor MH with LA was more apparent in older adults with low DV than in those with high DV; however, this association differed with gender. Key message Eating a variety of food may help alleviate the negative effects of living alone on mental health in older adults.

Background Folate regulates homocysteine metabolism and high blood homocysteine level has been associated with risk of dementia. Accordingly, serum folate is hypothesized to decrease the risk of dementia but epidemiological evidence, especially for Japanese, is scant. The aim of this study was to examine associations between serum folate and risk of disabling dementia within a Japanese cohort over 20 years of follow-up. Methods We performed an intracohort case-control study nested in a community-based cohort, the Circulatory Risk in Communities Study (CIRCS), involving 13934 Japanese individuals aged 40-84 years at the baseline period of 1984-2005. Serum folate was measured in 511 cases of incident disabling dementia, and in 1022 controls whose age (±1 years), sex, area, and baseline year were matched with the cases. The diagnosis of disabling dementia was performed by attending physicians under the National Long-Term Care Insurance System in Japan. Conditional odds ratios of disabling dementia according to quintiles of serum folate were calculated using conditional logistic regression models. Results Serum folate was inversely associated with risk of disabling dementia. The multivariate odds ratios (95% confidence intervals) were 0.62(0.43-0.88), 0.71(0.49-1.00), 0.63(0.43-0.91), and 0.51(0.34-0.76) for persons with the second, third, fourth, and highest quintiles of serum folate, respectively, compared with the lowest quintiles (P for trend = 0.19). Conclusions Low serum folate level was associated with increased risk of disabling dementia among Japanese. Key messages e Low folate intake may have an adverse effect on developing dementia.

Background Although consuming a variety of foods is an internationally accepted recommendation for a healthy diet, little is known about the association between dietary variety and incident dementia. This study aimed to examine the association between dietary variety and incident disabling dementia in community-dwelling elderly Japanese adults. Methods We conducted a prospective study of 721 participants (age range: 65–97 years) of the 2012–2013 Kusatsu Longitudinal Study. Dietary variety was assessed based on a food frequency questionnaire that encompassed the 10 main food components of Japanese meals: meat, fish/shellfish, eggs, milk, soybean products, green/yellow vegetables, potatoes, fruit, seaweed, and fats/oils). Participants were then categorized into low (0–2 points), middle (3–5 points), and high (6–10 points) groups based on the scores. Data regarding incident disabling dementia were retrieved from the public Long-term Care Insurance database. The Cox proportional hazards model was used to estimate the hazard ratios (HRs) with 95% confidence intervals (CIs). Results During the median follow-up of 6.5 years, the incidence of disabling dementia was 9.3%. After adjusting for confounders, the multivariate HR for incident disabling dementia was 0.52 (95% CI, 0.27–1.00) for participants in the highest category of the dietary variety score compared to that for those in the lowest category. Conclusions Greater dietary variety is associated with a reduced risk of incident disabling dementia in elderly Japanese adults. Key messages Consuming a variety of foods may be necessary for dementia prevention.

Background: Subjective age (SA) has been found to be a biopsychosocial marker of aging, yet little is known about factors that influence SA development. This study examined factors influencing SA using longitudinal data of community-dwelling older Japanese. Methods: Data drawn from the Kusatsu Longitudinal Study were collected during annual health check-ups in 2017 and 2018 from participants (aged 65-95) who completed all the measurement items used for this analysis (N=981). SA was indexed by asking participants to specify in years how old they felt. Proportional discrepancy scores ((subjective age - chronological age)/chronological age ×100) were calculated to indicate younger or older SAs and used as a dependent variable. As influencing factors of SA, chronological age, sex, years of schooling, history of smoking, cognitive function (using MMSE scores, range 14-30 at baseline), depressive symptoms, physical function (gait speed), and social function (employment status) were examined. Analyses were performed with random-effects GLS regression models. Results: Significant partial regression coefficients were found for cognitive function (0.48%, CI: 0.18, 0.79), years of schooling (-0.42%, CI: -0.69, -0.15), depressive symptoms (0.32%, CI: 0.11, 0.53), and chronological age (-0.18%, CI: -0.30, -0.68). Implications: This study found that older age and longer years of schooling were associated with younger SA, while better cognition and depressive symptoms were linked to older SA. Better cognition being associated with older SA was inconsistent with existing studies. This may be due in part to the association of better cognition and the level of satisfaction influenced by awareness of age-related physical/social changes.

Regular physical activity, dietary variety, and active social participation are modifiable and influential factors of adverse health outcomes. However, the cumulative effects of these behaviors are unknown. We examined these cumulative associations with active life loss in older adults. We analyzed 3-year longitudinal data from 7246 initially non-disabled residents aged 65-84 years from 18 districts of Ota City, Tokyo. Sufficiency of moderate- to vigorous-intensity physical activity (MVPA) of ≥150 minutes/week, dietary variety score (DVS) of ≥3, and social participation of ≥1 time/month were assessed using self-administered questionnaires. We operationally defined active life loss for individuals as being newly certified for long-term care insurance or death without prior certification. Multilevel survival analyses were applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). During an average follow-up of 2.9 years, the cumulative incidence of active life loss was 11.3% (817 individuals: 650 new certifications and 167 deaths without prior certification). Multivariate-adjusted HRs (95% CIs) for active life loss were 0.73 (0.58-0.92) in only MVPA of ≥150 minutes/week, 0.88 (0.67-1.15) in only DVS of ≥3, 0.75 (0.51-1.09) in only social participation of ≥1 time/month, 0.56 (0.45-0.70) in the group satisfying any two, and 0.52 (0.40-0.67) in the group satisfying all three behaviors, compared with a reference group that did not satisfy any of the behaviors. Sensitivity analysis that excluded active life losses during the first year showed similar results. The combination of regular physical activity, dietary variety, and social participation further enhances the effects on active life expectancy than individual practices.

Background: Chronic kidney dysfunction is a well-known risk factor for cardiovascular disease and mortality. However, no study reported trajectory patterns of kidney function in later life. This prospective study aimed at examining age-associated changes in serum creatinine level (SCr) by sex, classifying trajectory patterns of SCr, and identifying associated factors. Methods: We collected data from annual geriatric health checkups (GHC) conducted during 2002 through 2017 in Kusatsu, Gunma prefecture, Japan. 1990 adults aged 65–90 years (mean age, 71.0 years; women, 57.0%) participated in the GHC at least once during the period and total observation number was 9291. To those data we applied the mixed-effects model, group-based semiparametric mixture model, and Chi-squared test and analysis of variance. Results: Men showed approximately 0.2mg/dL higher SCr than women. We identified three trajectory patterns of SCr and denoted as high, middle, and low trajectory groups. Proportions of each groups were 5.4%, 41.0% and 53.6% for men, and 5.4%, 33.5%, and 61.1% for women. Those in the high trajectory group tended to have history of lifestyle-related disease including hypertension (p

Objectives. Recent genome-wide association and functional studies have shown that the ABCG2 gene encodes for a urate transporter, and a common causal ABCG2 variant, rs2231142, leads to elevated uric acid levels and prevalent gout among Whites and Blacks. We examined whether this finding is observed in a Japanese population, since Asians have a high reported prevalence of the T-risk allele. Methods. A total of 3923 Japanese people from the Circulatory Risk in Communities Study aged 40–90 years were genotyped for rs2231142. Associations of the rs2231142 variant with serum uric acid levels and prevalence of gout and hyperuricaemia were examined. Results. The frequency of the T-risk allele was 31% in this Japanese sample. Multivariable adjusted mean uric acid levels were 7–9 μmol/l higher for TG and TT than GG carriers (P-additive = 0.0006). The multivariable-adjusted odds ratio (OR) of prevalent gout was 1.37 (95% CI 0.68, 2.76) for TG and 4.37 (95% CI 1.98, 9.62) for TT compared with the GG carriers (P-additive = 0.001). When evaluating the combined outcome of hyperuricaemia and gout, the respective ORs were 1.40 (95% CI 1.04, 1.87) for TG and 1.88 (95% CI 1.23, 2.89) for TT carriers. The population attributable risk was 29% for gout and 19% for gout and/or hyperuricaemia. Conclusions. The association of the causal ABCG2 rs2231142 variant with uric acid levels and gout was confirmed in a sample of Japanese ancestry. Our study emphasizes the importance of this common causal variant in a population with a high risk allele frequency, especially as more Japanese adopt a Western lifestyle with a concomitant increase in mean serum uric acid levels.

The authors examined the relation between low intakes of saturated fat and animal protein and risk of intraparenchymal hemorrhage in a 14-year prospective study (ending in 1997) of 4,775 Japanese aged 40-69 years who undertook a single 24-hour dietary recall. Compared with the highest quartile of energy-adjusted saturated fat intake (median, 17 g/day), multivariate relative risks, after adjustment for age, sex, community, total energy intake, and known cardiovascular risk factors, were 0.77 (95% confidence interval (CI): 0.42, 1.42) for the second quartile (12 g/day), 0.66 (95% CI: 0.34, 1.25) for the third quartile (8 g/day), and 0.30 (95% CI: 0.12, 0.71) for the lowest quartile (5 g/day); p for trend = 0.005. An inverse relation was observed among both hypertensives and nonhypertensives; the respective relative risks with a one standard deviation increase in saturated fat intake (15.4 g/day) were 0.72 (95% CI: 0.52, 1.00) and 0.36 (95% CI: 0.14, 0.95). Intake of animal protein tended to correlate inversely with risk; the relative risk with a one standard deviation increase in animal protein intake (17.6 g/day) was 0.79 (95% CI: 0.61, 1.02); p = 0.07. Results are similar to those recently reported for US women and together help to explain the high rate of this stroke subtype in Asian countries, where intakes of these nutrients are low.

This prospective study used repeated measures analysis to identify potential physical performance measures (PPM) trajectory patterns, and determine whether PPM trajectory patterns were associated with all-cause mortality in Kusatsu Longitudinal Study on Aging and Health. Among 1524 adults aged 65 years or older who participated in a baseline survey, 1048 adults (mean [SD] age, 71.6 [5.4] years; women, 57.0%) were followed-up at least once. The total number of observations was 4,747, and the average number of follow-up assessments was 4.5 during. The PPMs studied were hand-grip strength, usual gait speed, and one-leg standing time. We checked local registries to identify deaths from any cause; 89 (8.5%) participants died during follow-up. We identified 3 distinct trajectory patterns (high, middle, and low trajectory groups) for each PPM. After adjusting for important confounders, the trajectory groups for hand-grip strength and one-leg standing time were independent predictors of all-cause mortality.

This exploratory study aimed to identify clusters of declination trajectories in terms of longitudinal multi-domain measurements of cognitive function, which would be related to common or specific risk factors. We conducted annual health check-ups for aged residents in Kusatsu, Japan, in 2002–2014, which included the Mini-Mental State Examination (MMSE). This analysis utilized a part of the data composed of up to 10 observations for 887 participants who scored 25 or higher on the baseline MMSE. We applied the group-based multi-trajectory model to the repeated measurements of six sub scores of the MMSE to identify four typical trajectories, which were characterized by (1) intact cognitive function, (2) lower attention, (3) lower attention, early decline in recall and declining orientation, or (4) lower attention and declining recall, orientation, language and construction. The trajectories were taken by 49%, 39%, 7%, and 4% of the subjects, respectively. The logistic regression analyses revealed that membership in each of the latter three trajectory groups was associated with (2) older age, lower education, diabetes mellitus, hypertension, and high white blood cell counts; (3) older age, low ankle-brachial blood pressure index, diabetes mellitus, and low hemoglobin levels; or (4) lower education, history of stroke, low hemoglobin levels, high white blood cell counts, tooth loss, and hypertension. There appeared two different trajectories of steep cognitive decline, one of which was related to diabetes mellitus and atherosclerosis; the other, to hypertension, inflammation, and stroke. In addition, tooth loss may be relevant to the latter, and anemia, to both.

This study used repeated measures analysis to identify potential Mini-Mental State Examination (MMSE) score trajectory and determine whether MMSE trajectory was associated with incident dementia among community-dwelling older Japanese. 1,724 older residents in Kusatsu participated in annual geriatric health assessments during 2002–14. The total number of observations was 6,755 and the average number of follow-up was 3.9. A review of municipal database in the Japanese public long-term care insurance system revealed that 205 (11.9%) participants developed dementia until the end of 2014. As a result, we identified 3 distinct MMSE score trajectory patterns (high, middle, and low). Participants with middle (42.8%) and low (5.1%) MMSE trajectories showed multi-variate adjusted hazard ratios of 2.46 (95% CI, 1.64–3.68) and 10.73 (95% CI, 4.91–23.45), respectively, for incident dementia, as compared with those in the high (52.1%) trajectory group. Present data help us to construct the strategy for prevention of dementia in the community.

To examine the relation of triglycerides with coronary heart disease among populations with low mean total cholesterol, the authors conducted a 15.5-year prospective study ending in 1997 of 11,068 Japanese aged 40-69 years (4,452 men and 6,616 women with mean total cholesterol = 4.73 mmol/liter and 5.03 mmol/liter, respectively), initially free of coronary heart disease or stroke. There were 236 coronary heart disease events comprising 133 myocardial infarctions, 68 angina pectoris events, and 44 sudden cardiac deaths. The coronary heart disease incidence was greater in a dose-response manner across increasing quartiles of nonfasting triglycerides for both sexes. The multivariate relative risk of coronary heart disease adjusting for coronary risk factors and time since last meal associated with a 1-mmol/liter increase in triglycerides was 1.29 (95% confidence interval (CI): 1.09, 1.53; p = 0.004) for men and 1.42 (95% CI: 1.15, 1.75; p = 0.001) for women. The trend was similar for myocardial infarction, angina pectoris, and sudden cardiac death. The relation of triglycerides with coronary heart disease was not influenced materially by total cholesterol levels or, in a subsample analysis (51% of total sample), by high density lipoprotein cholesterol levels. Nonfasting serum triglycerides predict the incidence of coronary heart disease among Japanese men and women who possess low mean values of total cholesterol. Further adjustment for high density lipoprotein cholesterol suggests an independent role of triglycerides on the coronary heart disease risk.

The relation of body fat distribution and body mass with haemoglobin A1c, blood pressure and blood lipids were examined in 874 men aged 40 to 59 not taking medication for diabetes mellitus and who worked for an urban company in Japan. Body fat distribution was measured by the waist hip circumference ratio. Body mass was estimated by Quetelet index. Haemoglobin A1c was measured from casual venous blood samples by high-pressure liquid chromatography. Measurement of haemoglobin A1c was validated by a 75 g oral glucose tolerance test conducted in a 7% sample. There was a dose-response relation between waist-hip ratio and haemoglobin A1c concentration while the relation between body mass index and haemoglobin A1c was not evident. Using linear regression to control for age, serum total cholesterol, usual alcohol consumption, cigarette smoking and body mass index, the positive association between waist-hip ratio and haemoglobin A1c remained significant (p = 0.02). This was not true for the positive association between body mass index and haemoglobin A1c (p = 0.32). Both waist-hip ratio and body mass index were positively associated with blood pressure and serum total cholesterol, and inversely associated with HDL-cholesterol. The associations of waist-hip ratio with blood pressure and blood lipids were significant after controlling for body mass index. Therefore, the waist-hip ratio is a correlate of both glucose abnormalities and known coronary risk factors in urban Japanese men even when body mass is controlled for.