KORA-Age Study Research Articles

Derivation and validation of an epigenetic frailty risk score in population-based cohorts of older adults

DNA methylation (DNAm) patterns in peripheral blood have been shown to be associated with aging related health outcomes. We perform an epigenome-wide screening to identify CpGs related to frailty, defined by a frailty index (FI), in a large population-based cohort of older adults from Germany, the ESTHER study. Sixty-five CpGs are identified as frailty related methylation loci. Using LASSO regression, 20 CpGs are selected to derive a DNAm based algorithm for predicting frailty, the epigenetic frailty risk score (eFRS). The eFRS exhibits strong associations with frailty at baseline and after up to five-years of follow-up independently of established frailty risk factors. These associations are confirmed in another independent population-based cohort study, the KORA-Age study, conducted in older adults. In conclusion, we identify 65 CpGs as frailty-related loci, of which 20 CpGs are used to calculate the eFRS with predictive performance for frailty over long-term follow-up.

Impact of prenatal and childhood adversity\xa0effects around World War II on multimorbidity: results from the KORA-Age study

BackgroundWhile risk factors for age-related diseases may increase multimorbidity (MM), early life deprivation may also accelerate the development of chronic diseases and MM.MethodsThis study explores the prevalence and pattern of MM in 65–71 year-old individuals born before, during, and after World War II in Southern Germany based on two large cross-sectional KORA (Cooperative Health Research in the Region of Augsburg) -Age studies in 2008/9 and 2016. MM was defined as having at least two chronic diseases, and birth periods were classified into five phases: pre-war, early war, late war, famine, and after the famine period. Logistic regression models were used to analyze the effect of the birth phases on MM with adjustment for sociodemographic and lifestyle risk factors. Furthermore, we used agglomerative hierarchical clustering to investigate the co-occurrence of diseases.ResultsParticipants born during the late war phase had the highest prevalence of MM (62.2%) and single chronic diseases compared to participants born during the other phases. Being born in the late war phase was significantly associated with a higher odds of MM (OR = 1.83, 95% CI: 1.15–2.91) after adjustment for sociodemographic and lifestyle factors. In women, the prevalence of joint, gastrointestinal, eye diseases, and anxiety was higher, while heart disease, stroke, and diabetes were more common in men. Moreover, three main chronic disease clusters responsible for the observed associations were identified as: joint and psychosomatic, cardiometabolic and, other internal organ diseases.ConclusionsOur findings imply that adverse early-life exposure may increase the risk of MM in adults aged 65–71 years. Moreover, identified disease clusters are not coincidental and require more investigation.

Chronic Inflammation Mediates the Association between Cortisol and Hyperglycemia: Findings from the Cross-Sectional Population-Based KORA Age Study.

(1) Background: The study aimed to investigate the role of subclinical inflammation on the association between diurnal cortisol patterns and glycaemia in an aged population. (2) Methods: Salivary cortisol, interleukin-6 (IL-6) and glycated haemoglobin (HbA1c) were analysed in a sample of 394 men and 364 women (mean age = 5 ± 6.3, 65–90 years). The ratio of morning after awakening and late-night cortisol was calculated as an indication of diurnal cortisol slope (DCS). Multivariable regression models were run to examine whether IL-6 mediates the relationship between the DCS and glycaemia. The Sobel test and bootstrapping methods were used to quantify the mediation analyses. (3) Results: In comparison to normoglycaemic counterparts (n = 676, 89.2%), an increase in IL-6 concentrations, in individuals with hyperglycaemia (HbA1c ≥ 6.5%) (n = 82, 10.8%) (p = 0.04), was significantly associated with a flatter DCS. The link between flatter DCS and elevated HbA1c level was significant mediated by a heightened IL-6 level. Our results do not suggest reverse-directionality, whereby cortisol did not mediate the association of IL-6 with HbA1c. (4) Conclusions: In our sample, the relation between flatter DCS and hyperglycaemia was partly explained by IL-6 levels. The paradigm of subclinical inflammation-mediated cortisol response on glucose metabolism could have widespread implications for improving our understanding of the pathophysiology of type 2 diabetes mellitus.

Association of generalized and central obesity with serum and salivary cortisol secretion patterns in the elderly: findings from the cross sectional KORA-Age study

The study aimed to examine the sex specific association of obesity with cortisol metabolism in a sample of older community dwelling people. The cross-sectional analysis included 394 men and 375 women (aged 65–90 years) of the population-based KORA-Age study. Multivariable regression analyses were employed to examine the association between cortisol samples (serum and salivary samples of morning after awakening (M1), 30 min later (M2) and at late night (LNSC)). Obesity was calculated as waist-to-hip ratio (WHR) and body mass index (BMI). Cortisol levels were not significantly different between obesity measures except for elevated serum cortisol (P = 0.02) levels in individuals with a low WHR. Higher M1 levels were especially apparent in women with normal BMI. Serum cortisol levels were inversely related to WHR (P = 0.004) and CARAUC was inversely associated with BMI (P = 0.007). Sex-stratified analytic models revealed that both obesity measures showed a non-linear association with cortisol diurnal pattern (M1/LNSC) in men. Impaired cortisol patterns emerged at both very ends of the body weight distribution. These findings do not support a cortisol driven obesity etiology in an older population and even point to an inverse association of body weight with cortisol levels. Differences of cortisol secretion patterns in generalized and abdominal fat distribution were marginal.

218 - Sex-specific association of melatonin levels and type 2 diabetes mellitus. Findings from the population-based KORA age study

218 - Sex-specific association of melatonin levels and type 2 diabetes mellitus. Findings from the population-based KORA age study

Chronic inflammation contributes to cortisol-induced hyperglycemia: Findings from the KORA Age study

Chronic inflammation contributes to cortisol-induced hyperglycemia: Findings from the KORA Age study

Higher oxytocin levels associated with a history of suicidal ideation in old age: Findings from the population based KORA Age Study

Higher oxytocin levels associated with a history of suicidal ideation in old age: Findings from the population based KORA Age Study

Vitamin D in Relation to Incident Sarcopenia and Changes in Muscle Parameters Among Older Adults: The KORA-Age Study.

Effects of low serum 25OHD on age-related changes in muscle mass and function remain unclear. Our aims were to explore associations of baseline 25OHD levels with prevalent and incident sarcopenia and changes in muscle parameters, and to examine the role of parathyroid hormone (PTH) therein. Cross-sectional (n = 975) and prospective analyses (n = 702) of older adults aged 65-93years participating in the KORA-Age study. Sarcopenia was defined using the 2010 European Working Group on Sarcopenia in Older People (EWGSOP) criteria as low muscle mass combined with low grip strength or low physical performance. Associations with baseline 25OHD were examined in multiple regression analyses. Low vitamin D status was linked to increased odds of prevalent sarcopenia. Over three years, low baseline 25OHD < 25 vs. ≥ 50nmol/L were associated with greater loss of muscle mass and increased time for the Timed Up and Go test. The risk for developing incident sarcopenia was not significantly elevated in individuals with low baseline 25OHD but when including death as combined outcome alongside incident sarcopenia, there was a strong positive association in multivariable analysis [OR (95% CI) 3.19 (1.54-6.57) for 25OHD < 25 vs. ≥ 50nmol/L]. There was no evidence for a PTH-mediating effect. Low baseline 25OHD levels were associated with unfavorable changes in muscle mass and physical performance, but not with incident sarcopenia. Future randomized trials are needed to assess causality and to address the issue of competing risks such as mortality in older cohorts.

Being born in the aftermath of World War II increases the risk for health deficit accumulation in older age: results from the KORA-Age study.

Morbidity trends may result from cohort experiences in critical developmental age. Our objective was to compare the health status of 65-71year-olds who were in critical developmental age before (1937-June 1945), during (June 1945-June 1948) and after (June 1948-1950) the early reconstruction and food crisis (ERFC) period in Germany following World War II. Data originate from the KORA (Cooperative Health Research in the Region of Augsburg)-Age study in Southern Germany. We used the 2008 baseline sample born 1937-1943 and the 2015 enrichment sample born 1944-1950. Health status was assessed as the number of accumulated health deficits using a Frailty Index (FI). Cohorts were defined based on co-occurrence of critical developmental age (gestation and the first 2years of life) and the ERFC period. Cohort, age and sex effects on older-age health status were analyzed using generalized linear models. We included 590 (53% male) pre-war and war (PWW), 475 (51% male) ERFC and 171 post-currency reform (PCR) cohort participants (46% male). Adjusted for covariates, FI levels were significantly higher for the ERFC (Ratio 1.14, CL [1.06, 1.23]) but not for the PCR (Ratio 1.06, CL [0.94, 1.20]) as compared to the PWW cohort. Being in critical developmental age during the ERFC period increased FI levels in adults aged 65-71years. Covariates did not explain these effects, suggesting a direct detrimental effect from being in critical developmental age during the ERFC period on older-age health. This expansion of morbidity in Germany was not detected in the PCR cohort.

Prevalence and predictors of subclinical micronutrient deficiency in German older adults: Results from the population-based KORA-Age study

Introduction Subclinical micronutrient deficiency in older adults is associated with chronic age-related diseases and adverse functional outcomes. In Germany, the older population is at-risk of insufficient micronutrient intake, but representative studies on micronutrient status in old and very old adults are scarce. This study's objectives were to estimate the prevalence of subclinical vitamin D, folate, vitamin B12 and iron deficiencies among older adults, aged 65 to 93, from the KORA-Age study in Augsburg, Germany (n = 1079), and to examine associated predictors. Methods Serum concentrations of 25-hydroxyvitamin D (25OHD), folate, vitamin B12, and iron were analyzed and compared to selected cut-offs for subclinical micronutrient deficiency. Associated predictors were investigated using multiple logistic regression analysis. Results The prevalence of subclinical vitamin D and vitamin B12 deficiencies were high, with 52.0% and 27.3% of individuals having low 25OHD ( Conclusion Subclinical micronutrient deficiency is a public health concern among KORA-Age participants, especially for vitamins D and B12. The predictors identified provide further rationale for screening high-risk subgroups and developing targeted public health interventions to tackle prevailing micronutrient inadequacies among older adults.

Do birth cohorts make a difference for deficit accumulation trajectories in older age? First results from the KORA-Age study

Introduction Higher age is related to higher numbers of accumulated health deficits. However, to date it remains unclear how much of this association is due to age effects, how much is contributed by birth cohort effects and if a general trend of compression or expansion of morbidity can be assumed. The objective of this study was to investigate the role of cohort effects with regard to health deficit accumulation (DA) trajectories in people aged 65 and older. Methods Data originates from the baseline assessment of participants aged 65–71 years in 2008 (i.e. born 1937 to 1943) from the KORA (Cooperative Health Research in the Region of Augsburg)-Age study in Southern Germany as well as from an independent assessment in 2015 consisting of a younger birth cohort (aged 65–71 years in 2015, i.e. born 1944 to 1950). All participants were former participants of the population representative MONICA/KORA surveys conducted between 1984 and 2001. DA was measured with a Frailty Index (FI). This KORA-Age FI includes in total 33 items, covering 10 diseases, 13 measures of functioning and 10 signs and symptoms. All deficit items were coded as values between 0 (deficit absent) and 1 (deficit fully present). The FI for a person results as the number of the person-specific deficits divided by the total number of listed deficits. Thus, FI scores range from 0 (= no deficits present) to 1 (= all deficits present). If a participant scored missing on one or more of the deficit items, the denominator of the FI was reduced accordingly. Age-specific mean FI scores were graphically presented separately for the younger (born 1944 to 1950) and the older birth cohort (born 1937 to 1943), stratified by sex. The effects of birth cohort, age and sex (all coded as factor variables) on FI levels were analyzed using a generalized linear model (GLM) with the number of present health deficits as negative binomially distributed outcome and the number of possible health deficits as offset term. Significance level was set to 0.05. Results FI values were available for 1919 participants aged 65–71 years in 2008 (51% female) and for 1456 participants aged 65–71 years in 2015 (53% female). Participants from the younger birth cohort aged 65–71 years in 2015 had average FI values (FI = 0.141) comparable to participants from the older birth cohort aged 65–71 years in 2008 (FI = 0.136, P = 0.1071). Plotting birth cohort and sex-specific FI averages by age revealed that both birth cohorts started at the same FI levels, but thereafter, age-specific FI values were higher for the younger birth cohort and for women, specifically for those born in 1944 and 1945. These results were partly confirmed by the GLM. Higher age, especially for those aged 70 (RR: 1.23, KI [1.13; 1.34]) and those aged 71 years (RR: 1.23, KI [1.14; 1.34]) as compared to those aged 65 years, was associated with higher FI values. Also female sex (RR: 1.14, KI [1.09; 1.19]) was independently, significantly and positively associated with higher FI values. Having been born 1944–50 (RR: 1.04, KI [1.00; 1.09]) was positively associated with higher FI values, but the effect was not significant (P = 0.059926). Conclusion Based on our comparison of adults of the same age from different birth cohorts, an expansion of morbidity cannot fully be excluded. This seems to be largely due to the comparatively high levels of deficit accumulation for women born in 1944 and 1945, which coincides with the last years of World War II. Further research is warranted to investigate how specific life course experiences including deprivation in critical developmental periods for these cohorts may have contributed to these effects.

The association between midlife type 2 diabetes and late-life cognitive status: Findings from KORA-Age study

Systems of care have been established to ensure patients with ST-elevation myocardial infarction (STEMI) get timely access to primary percutaneous coronary intervention (PPCI). In this study, we evaluated whether patients undergoing PPCI both in-hours and out-of-hours experience similar care and clinical outcomes.Of 9,865 patients who underwent PCI for STEMI from 2005 to 2016 and were enrolled in the multi-centre Melbourne Interventional Group registry, patients who had initially presented to a non-PCI capable hospital, received thrombolysis or presented >12 hours post-symptom onset were excluded. Our final study cohort of 4,590 patients were dichotomised by whether PPCI was performed in-hours or out-of-hours, and compared. The primary outcome was 30-day mortality.The in-hours group included 1,865 patients (40.6%) while 2,725 patients (59.4%) had out-of-hours PPCI. Patients presenting out-of-hours had longer median door-to-balloon time (DTBT; 83 [IQR 61–109] vs. 60 [IQR 41–88] mins, p < 0.01) and were more likely to receive a drug-eluting stent (p = 0.001). Procedural characteristics were otherwise similar although rates of radial access were low overall (18.4%). No differences in in-hospital, 30-day or 12-month mortality were observed between the groups (p = NS). On Cox proportional hazards modelling, out-of-hours presentation was not an independent predictor of 30-day mortality (HR 0.94, 95% CI 0.71–1.22). A landmark analysis of data from 2012 did not change the primary outcome.Despite a slightly longer DTBT, patients undergoing PPCI out-of-hours experienced similar care and clinical outcomes to the in-hours group. Given the majority of patients with STEMI present out-of-hours, these data have implications for STEMI systems of care.

Late night salivary cortisol, stress-resilience and Type 2 diabetes mellitus. Findings from population-based KORA Age study

The main limitation to successful transplantation is the antigraft response developed by the recipient immune system, and the adverse side effects of immunosuppressive agents which are associated with significant toxicity and counter indications such as infection and cancer. Furthermore, immunosuppressants do little to prevent ischemia-reperfusion injury during the transplantation procedure itself hence there is a growing need to develop novel immunosuppressive drugs specifically aimed at prolonging graft survival. Linear tetrapyrroles derived from the breakdown of mammalian heme have been shown in numerous studies to play a protective role in allograft transplantation and ischemia-reperfusion injury; however, commercial sources of these products have not been approved for use in humans. Plants and algae produce equivalent linear tetrapyrroles called bilins that serve as chromophores in light-sensing. One such marine-derived tetrapyrrole, phycocyanobilin (PCB), shows significant structural similarity to mammalian biliverdin (BV) and may prove to be a safer alternative for use in the clinic if it can exert direct effects on human immune cells. Using a mixed lymphocyte reaction, we quantified the allogeneic responses of recipient cells to donor cells and found that PCB, like BV, effectively suppressed proliferation and proinflammatory cytokine production. In addition, we found that BV and PCB can directly downregulate the proinflammatory responses of both innate dendritic cells and adaptive T cells. We therefore propose that PCB may be an effective therapeutic drug in the clinical setting of transplantation and may also have wider applications in regulating inappropriate inflammation.

Muscular Strength is Independently Associated with Cystatin C: The KORA-Age Study.

The purpose of this study was to investigate if there is a link between muscular strength (MS) and markers of chronic kidney disease (CKD) among older adults. The cross-sectional analysis based on 1041 men and women, aged 65-94 years, who participated in the KORA-Age study. Participants underwent an interview and extensive examinations including anthropometric measurements, diseases and drug intake registration, determination of health-related behaviors, collection of blood samples for measurements of cystatin C and maximal muscle strength evaluation. One-Way ANOVA revealed significant differences in both mean cystatin C (1.16±0.37 vs. 1.03±0.29 vs. 0.93±0.24 mg/L, p<0.001) and mean eGFRcysC (63.61±18.61 vs. 72.14±18.92 vs. 79.87±18.19 ml/min/1.73 m2, p<0.05) across thirds of maximal muscular strength (from lowest to highest). MS in the lowest third was significantly associated with increased odds of having elevated cystatin C (OR: 1.70, 95% CI: 1.01-2.85, p=0.043) after controlling for age, gender, fat mass, fat-free mass, alcohol intake, smoking status, number of regularly used medications, multimorbidity status, hs-CRP, telomere length and levels of physical activity. Lower levels of MS are independently associated with higher concentrations of cystatin C and lower eGFRcysC in older individuals. Increasing the levels of muscular strength may be useful to prevent the age-related CKD disease of older adults.

Mediator Effect of Balance Problems on Association Between Grip Strength and Falls in Older Adults: Results From the KORA-Age Study

Objective: To examine the association between grip strength and history of falls among older individuals, and to assess the possible mediating effect of balance problems on this relationship. Method: Data originate from KORA (Cooperative Health Research in the Region of Augsburg)-Age Study of 808 individuals (65 years and above). Follow-up assessment occurred 3 years later. Results: The risk of falls within the last 12 months was reduced on average by 3% (odds ratio [OR] 95% confidence interval [95% CI] = 0.97 [0.94, 0.99]; p value = .026) per 1-kg increase in maximum grip strength after adjusting for age and gender. There was a trend toward an indirect effect of grip strength through the mediator variable balance problems (p value = .043). Discussion: Increased muscular strength is associated with a reduced risk of falls in older age after adjustment for age and gender. The association is partially mediated by balance problems. Thus, in older adults, muscle-strengthening exercises may decrease the risk of falling.

The association between anemia and falls in community-living women and men aged 65 years and older from the fifth Troms\xf8 Study 2001-02: a replication study

BackgroundFalls are common among elderly people, and the risk increase with age. Falls are associated with both health and social consequences for the patient, and major societal costs. Identification of risk factors should be investigated to prevent falls. Previous studies have shown anemia to be associated with increased risk of falling, but the results are inconsistent. The aim of this study was to investigate the association between anemia and self-reported falls among community-living elderly people. The study is a replication of the study by Thaler-Kall and colleagues from 2014, who studied the association between anemia and self-reported falls among 967 women and men 65 years and older in the KORA-Age study from 2009.MethodsWe included 2441 participants (54% women) 65 years and older from the population-based Tromsø 5 Study 2001-2002. Logistic regression models were used to investigate the association between anemia (hemoglobin <12 g/dL in women and <13 g/dL in men) or hemoglobin level and self-reported falls last year, adjusted for sex, age, medication use and disability. Further, associations between combinations of anemia and frailty or disability, and falls, were investigated.ResultsNo statistical significant associations were found between anemia and falls (OR 95% CI: 0.83, 0.50-1.37) or hemoglobin level and falls (OR, 95% CI: 0.94, 0.81-1.09), or with combinations of anemia and frailty or disability, and falls (OR, 95%: CI: 0.94, 0.40-2.22 and 0.78, 0.34-1.81, respectively).ConclusionsIn this replication analysis, in accordance with the results from the original study, no statistically significant association between anemia or hemoglobin and falls was found among community-living women and men aged 65 years or older.

The impact of inflammation-mediated stress reactivity in type 2 diabetes patients. Findings from the population-based KORA age study

The impact of inflammation-mediated stress reactivity in type 2 diabetes patients. Findings from the population-based KORA age study

Physical activity, muscular strength, and polypharmacy among older multimorbid persons: Results from the KORA-Age study.

The purpose of this study was to examine whether physical activity (PA) and muscular strength (MS) are related to polypharmacy. Our cross-sectional analysis was based on 711 patients with multimorbidity (MMB), aged 65-94years, who participated in the KORA-Age study. Participants underwent a face-to-face interview and extensive physical examinations including anthropometric measurements, registration of chronic diseases, determination of health-related behaviors (smoking, alcohol intake, physical activity, etc.), collection of blood samples and measurement of hand-grip strength. PPha was defined as the use of >4 drugs and MMB as having ≥2 of 13 chronic diseases. Prevalence of PPha was 44.6% (n=317), and a significant difference was found in the number of drugs used between participants with and without PPha (7.2±2.1 vs 2.5±1.2, P<.001). Patients in the lower compared to the upper tertile of physical activity had a significantly increased odds to be on PPha (OR: 1.64, 95% CI: 1.05-2.56, P=.031) after controlling for age, gender, BMI, family status, education, alcohol intake, smoking habits, number of diseases, hs-CRP, and telomere length. On the contrary, no significant association between muscular strength and PPha was found (OR: 1.04, 95% CI: 0.66-1.63, P=.873) after multivariable adjustment. Among older persons with MMB, lower levels of physical activity, but not low muscular strength, are associated with higher odds of PPha. Increasing the levels of physical activity appears to be highly recommended in order to potentially reduce the risk of PPha among multimorbid persons aged 65 and older.

Sarcopenia is associated with disability status-results from the KORA-Age study.

The objectives of this study using data from a population-based cohort were to estimate the prevalence of sarcopenia in older people in Germany and to test the hypothesis that sarcopenia is associated with disability in older adults. Cross-sectional (n=927) and longitudinal analyses (n=859) of participants aged ≥65years at baseline from southern Germany enrolled in the Cooperative Health Research in the Region Augsburg (KORA)-Age study (2009-2012). Sarcopenia was defined based on the European Working Group on Sarcopenia in Older People (EWGSOP) algorithm which includes the presence of both low muscle mass and low muscle function (strength or performance). Disability status was measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI). The presence of disability was defined as HAQ-DI >0. Directed acyclic graphs (DAGs) were constructed to identify potential confounders. The effect of sarcopenia on disability was analyzed using linear mixed effect models with disability values as a continuous outcome. The overall prevalence of sarcopenia was 5.7% (men 4.0%, women 7.5%) and increased with age. The 3-year incidence of disability was 32.7%. After adjustment for potential confounders, presence of sarcopenia was significantly associated with higher disability scores (0.142 [confidence interval 0.029-0.254]). The prevalence of sarcopenia is consistent with estimates from other European studies using this algorithm. Our results suggest that sarcopenia can contribute to higher disability scores in older adults. However, our study was not able to show any influence of sarcopenia on the rate of functional decline using the EWGSOP diagnostic algorithm for sarcopenia. This directs attention to an accurate diagnosis of sarcopenia as the onset may be influenced, but its rate may not.

Relationship between sleep disturbances and multimorbidity among community-dwelling men and women aged 65–93 years: results from the KORA Age Study

Background/ObjectiveAlthough the association of disturbed sleep with specific chronic conditions is well known, the relationship between sleep disturbances and multiple diseases is less clear. Therefore, the objectives of this study were to examine the independent relationships of various sleep disturbances with 1) multimorbidity (≥2 chronic conditions) and 2) commonly co-occurring pairs of chronic conditions. MethodsAnalyses were based on data from 4127 individuals aged ≥65 years participating in the population-based cross-sectional Cooperative Health Research in the Region of Augsburg (KORA) Age Study conducted from 2008 to 2009 in Germany. Sex-specific odds ratios (OR) and 95% confidence intervals (CI) were calculated from sequential logistic regression models. ResultsNeither short nor long daily sleep duration was significantly associated with multimorbidity among men; a significant positive relationship was identified regarding short sleep duration among women (OR 2.16, 95% CI: 1.42–3.30). While insomnia and all unique symptoms of insomnia were connected to multimorbidity among women in the multivariable models, the relationship concerning trouble falling asleep no longer remained significant after adjustment for all covariables among men. Regarding commonly co-occurring pairs of conditions, the clearest associations were observed between insomnia and daytime tiredness with joint diseases/eye diseases in men and joint diseases/heart diseases in women. ConclusionsThere seems to be sex-specific particularities in the relationship between sleep disturbances and sleep duration with multimorbidity and commonly co-occurring pairs of chronic conditions in older adults from the general population.