Cohort profile: follow-up of a Berlin Aging Study II (BASE-II) subsample as part of the GendAge study

Demuth, Ilja et al. Article — Published Version Cohort profile: follow-up of a Berlin Aging Study II (BASEII) subsample as part of the GendAge study BMJ Open Provided in Cooperation with: German Institute for Economic Research (DIW Berlin) Suggested Citation: Demuth, Ilja et al. (2021) : Cohort profile: follow-up of a Berlin Aging Study II (BASE-II) subsample as part of the GendAge study, BMJ Open, ISSN 2044-6055, British Medical Journal Publishing Group, London, Vol. 11, Iss. 6, https://doi.org/10.1136/bmjopen-2020-045576 This Version is available at: https://hdl.handle.net/10419/238208 Standard-Nutzungsbedingungen: Die Dokumente auf EconStor dürfen zu eigenen wissenschaftlichen Zwecken und zum Privatgebrauch gespeichert und kopiert werden. Sie dürfen die Dokumente nicht für öffentliche oder kommerzielle Zwecke vervielfältigen, öffentlich ausstellen, öffentlich zugänglich machen, vertreiben oder anderweitig nutzen. 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BMJ Open 2021;11:e045576. doi:10.1136/bmjopen-2020-045576 Open access Cohort profile: followup of a Berlin Aging Study II (BASEII) subsample as part of the GendAge study Ilja Demuth ,1,2 Verena Banszerus,1 Johanna Drewelies,3 Sandra Düzel,4 Ute Seeland,5,6 Dominik Spira,1 Esther Tse,7 Julian Braun,8,9 Elisabeth SteinhagenThiessen,1 Lars Bertram,10,11 Andreas Thiel,8,9 Ulman Lindenberger,4,12 Vera RegitzZagrosek,6,7,13 Denis Gerstorf,3 Additional BASEII/GendAge investigators To cite: DemuthI, BanszerusV, DreweliesJ, etal. Cohort profile: followup of a Berlin Aging Study II (BASEII) subsample as part of the GendAge study. BMJ Open 2021;11:e045576. doi:10.1136/ bmjopen-2020-045576 ►Prepublication history for this paper is available online. To view these files, please visit the journal online (http:// dx. doi. org/ 10. 1136/ bmjopen2020045576). Received 05 October 2020 Accepted 20 May 2021 For numbered affiliations see end of article. Correspondence to Professor Ilja Demuth; ilja. demuth@ charite. de Cohort profile © Author(s) (or their employer(s)) 2021. Reuse permitted under CC BYNC. No commercial reuse. See rights and permissions. Published by BMJ. ABSTRACT Purpose The study ‘Sexand gendersensitive prevention of cardiovascular and metabolic disease in older adults in Germany’, the GendAge study, focuses on major risk factors for cardiovascular and metabolic diseases and on the development of major outcomes from intermediate phenotypes in the context of sex and gender differences. It is based on a followup examination of a subsample (older group) of the Berlin Aging Study II (BASEII). Participants The GendAge study assessments took place between 22 June 2018 and 10 March 2020. A total of 1100 participants (older BASEII subsample, aged ≥65 years) with baseline data assessed at least by one of the BASEII partner sites were investigated in the followup. These participants had a mean age of 75.6 years (SD ±3.8), with a mean followup at 7.4 years (SD ±1.5). Findings to date Data from different domains such as internal medicine, geriatrics, immunology and psychology were collected, with a focus on cardiometabolic diseases and in the context of sex and gender differences. Diabetes mellitus type 2 was reported by 15.6% and 8.6% of men and women, respectively. In contrast, this disease was diagnosed in 20.7% of men and 13.3% of women, indicating that a substantial proportion of almost 30% was unaware of the disease. Echocardiography revealed that left ventricular ejection fraction was higher in women than in men, in agreement with previous reports. Future plans A gender questionnaire assessing sociocultural aspects implemented as part of the followup described here will allow to calculate a gender score and its evaluation based on the newly collected data. At the same time, the other BASEII research foci established over the past 10 years will be continued and strengthened by the BASEII transition into a longitudinal study with followup data on the older subsample. Trial registration number DRKS00016157. INTRODUCTION The original BASE-II cohort The Berlin Aging Study II (BASEII) was launched as a multidisciplinary study aimed at better understanding the multitude of different ways in which age and ageing evolve and identifying the underlying mechanisms and contributing factors. Baseline recruitment of 2200 adult volunteers from the Berlin metropolitan area and baseline assessments were completed in 2014.1 The ascertainment protocol included the collection of data from different domains for each of the 2200 participants (about 75% aged 60 years and above, the older group of BASEII participants), namely, geriatrics and internal medicine, immunology, genetics, psychology, sociology and economics.1 2 BASEII baseline data were used in a multitude of analysis projects focusing on key questions revolving around age and ageing. Research topics of the ongoing study include, but are not limited to, cognitive ageing,3–5 cardiovascular and metabolic health,6–8 sarcopenia and frailty,9 10 psychosocial factors of Strengths and limitations of this study ►The GendAge study focuses on major risk factors for cardiovascular and metabolic diseases and on the development of major outcomes from intermediate phenotypes in the context of sex and gender differences. ►The Berlin Aging Study II (BASEII) followup as part of the GendAge study assessments covered most of the medical, psychosocial and cognitive domains and variables assessed at baseline. ►Comprehensive and longitudinal study data offer the potential to answer a number of questions that are of crucial relevance for the health of old women and men. ►The possibility of a selection bias in the followup study population is a limitation, which we have made various efforts to accommodate. ►We are able to systematically quantify the sampling bias and even account for it when it comes to the question of generalisability of study results to a population as a whole. on August 31, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2020-045576 on 23 June 2021. Downloaded from 2DemuthI, etal. BMJ Open 2021;11:e045576. doi:10.1136/bmjopen-2020-045576 Open access ageing,11 12 genetic risk factors of ageing and disease,13–15 the impact of characteristics of the neighbourhood people are living in,16 as well as indicators of biological age17 18 and immune biomarkers.19 For an overview of the BASEII research foci and publications, refer to a previous work20 and the BASEII website (https://www. base2. mpg. de/ en/ projectinformation/ publications). Contact procedure: follow-up assessments Of the original BASEII sample consisting of 2200 participants, 1671 aged 60 years and above (=older group) were assessed medically at baseline between 2009 and 2014. The followup assessments within the GendAge study took place between 22 June 2018 and 10 March 2020 at the Charité Universitaetsmedizin Berlin. During the recruitment of the followup cohort, we approached all BASEII participants of the remaining pool of 1428 subjects out of the originally 1671 subjects who completed the baseline medical assessments at an age of 60 years and older (older BASEII group, see figure 1). Between 7 February 2020 and 13 March 2020, we additionally performed followup assessments in a total of 64 participants of the younger BASEII group aged 20–35 years at baseline until these assessments were suspended because of the SARSCoV-2 pandemic. Potential followup participants were contacted via telephone and an invitation letter that contained a comprehensive participant’s information sheet. Letters of consent were sent at least 5 days before the scheduled first of two assessment days to all subjects who agreed to participate. As a result of a 4week pilot phase, we reduced the maximum number of participants examined on each of the first two study days from 6 to 4, with an interval of usually 7 days between study visit 1 and 2. Largely because of this early adjustment, followup examinations lasted 21 months instead of the 15 months originally planned. Moreover, another wave of cognitive assessments carried out by the Max Planck Institute for Human Development (MPIB) has been tightly linked to the GendAge assessment of BASEII participants. The cognitive session (=third study visit) followed about 7 days after the second medical examination. What is the reason for the new data collection? The study ‘Sexand gendersensitive prevention of cardiovascular and metabolic disease in older adults in Germany’, the GendAge study, focuses on major risk factors for cardiovascular and metabolic diseases and on the development of major outcomes from intermediate phenotypes in the context of biological sex and gender differences. Major outcomes include, but are not limited to, myocardial infarction (MI), heart failure and diabetes mellitus type 2 (T2D), as well as mortality and quality of life. Gender was quantitated in two ways: by a retrospective approach, based on available data at study entry (2009– 2014) and already published (GenderScoreI, GSI)21 as well as by a comprehensive gender questionnaire covering a range of sociocultural gender characteristics as a central instrument (GenderScoreII, GSII). This questionnaire contains an adapted version of the gender questionnaire developed by Pelletier and colleagues covering most of the four gender aspects described by the Women Health Research Network of the Canadian Institute of Health Research (gender roles, gender identity, gender relations and institutionalised gender).22 23 The variables finally constituting the GSI were chronic stress, marital status, risktaking behaviour, personality attributes: agreeableness, neuroticism, extraversion, loneliness, conscientiousness and level of education.21 What will be the new areas of research? There is new knowledge showing that sex differences play a role in all major diseases, their prevention and treatment.24 Other studies showed that gender as the sociocultural dimension of being a woman or a man affects disease and treatment outcomes and also wellbeing.22 25 The new areas of research cover the systemic inclusion of sexspecific analysis and the inclusion of gender. Ageing interacts with sex and gender differences in health, but it is not clear, which mechanisms are most important. GendAge aims to better understand, which mechanisms affect cardiometabolic morbidity, mortality and quality of life among older adults in a sexsensitive and gendersensitive manner. While on different occasions followup data were ascertained for questionnaire and cognitive data,5 26–30 as being part of the GendAge study, this cohort profile update describes the first comprehensive followup assessments in a BASEII subsample (older group) that also includes Figure 1 Flowchart explaining the final Berlin Aging Study II (BASEII) sample with followup assessments completed in GendAge. A total of 17 of the 1,100 participants examined atfollowup were not medically examined at baseline but were examined at least atone of the other BASEII study sites. on August 31, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2020-045576 on 23 June 2021. Downloaded from 3 DemuthI, etal. BMJ Open 2021;11:e045576. doi:10.1136/bmjopen-2020-045576 Open access a reassessment of central variables in the areas of internal medicine and geriatrics. COHORT DESCRIPTION As presented in the flowchart (figure 1), following the contact procedure until the participant pool was exhausted resulted in a total of 1100 participants of the older BASEII group investigated in the followup. These participants had a mean age of 75.6 years (SD ±3.8, range 64.9–94.1 years), with up to 10.4 years of followup (mean followup at 7.4 years, SD ±1.5). At followup, almost all of the older participants were retired (97.3%) as compared with 86% at the time of baseline assessment. At baseline, BASEII participants were characterised by higher education and better selfreported health status than the general population of Berlin and Germany.1 At followup, this selection seems to have increased, with 68.8% of the participants reported to have a high school degree (51% at baseline) and about 61% rated their health as very good or good (40% at baseline). The rate of divorce had been above average at baseline with 29% and had dropped to 21.7% at followup, which is still significantly above the German and Berlin average (ie, 12.0% and 17.4%, respectively),31 while the proportion of widowed participants increased from 5% at baseline to 10.5% in the followup dataset of older BASEII participants. As shown in table 1, differences between men and women are evident with respect to the sociodemographic status and psychosocial functioning in the followup cohort: Men reported significantly higher school degrees and higher satisfaction with life in general than women. Interestingly, selfrated health did not differ between men and women, which matches to the overall morbidity estimated by an adapted version of the Charlson morbidity index,17 32 which also did not differ between men and woman (p=0.98, table 1). This morbidity index, however, increased between baseline and followup (p<0.001, Wilcoxon signedrank test and data not shown). Differences between men and women exist in the followup dataset with respect to the prevalence of some, but not all cardiovascular risk factors and diseases (table 1). Men, for example, had a higher BMI and a higher proportion of men reported to have T2D and MI than women. No significant differences between men and women were evident in the reporting of hypertension, peripheral artery disease and stroke. With the aim of investigating human ageing processes in BASEII under consideration of different disciplines and longitudinally, the baseline investigation aimed at the most comprehensive data collection possible. At followup, most of these data in the field of geriatrics, internal medicine and psychology were again part of the study protocol (for a select overview, see table 2). Findings to date With a focus on cardiometabolic diseases in GendAge, we extended the broad range of data assessed in this area at baseline by echocardiography. Data on right and left ventricular and atrial morphology and systolic and diastolic function and vascular stiffness were obtained. Left ventricular ejection fraction was higher in women than in men, in agreement with previous reports.33 34 Furthermore, increased LV mass and volumes in men before and after indexing to body surface area were confirmed, underscoring major sex differences in cardiovascular pathophysiology.35 With the aim of achieving a particularly highquality standard in the assessment of participant’s medical history at baseline and followup, including past and current diseases, the information given by the participants was recorded from study physicians as part of a structured onetoone interview, allowing to consider its plausibility. This, however, does not cover the gap between reported (anamnestic) diseases and the diseases diagnosed in the course of the study. This is exemplified by T2D, which was reported by 15.6% and 8.6% of men and women, respectively. In contrast, this disease was diagnosed in 20.7% of men and 13.3% of women based on the American Diabetes Association guidelines 2019,36 indicating that a substantial proportion of almost 30% was unaware of the disease (table 1). As part of our endeavours, we have developed a retrospective gender score taking BASEII baseline data reflecting sociocultural aspects (eg, level of education, marital status and chronic stress) into account. This retrospective gender score (GSI) was associated with a number of clinical and psychosocial variables and performed better in predicting differences in a subset of variables (eg, depression and life satisfaction) compared with biological sex.21 In addition, we have implemented a comprehensive gender questionnaire as part of the followup assessments described here, to calculate a prospective gender score as proposed by Pelletier and colleagues.22 Peripheral blood mononuclear cells were prepared from 903 participants at followup, of which 845 were fully analysable (58 were dropouts) and frequencies as well as absolute counts of recent thymic emigrants (RTEs), TEMRA effector T cell subsets (TEMRA) and cytotoxic CD4+ T cells were directly assessed. While RTEs are known to decrease with ageing,37 alterations in TEMRA and specialised cytotoxic CD4+ T cell compartments can be indicative of agerelated perturbations of systemic T cell immunity.38 The immunological screening has so far revealed significantly higher frequencies of RTEs in women as compared with men, indicating a higher thymic T cell production even at the advanced ages of the GendAge participants. In men, more CD45RA+ reexpressing TEMRAs were detected than in women (table 1). These cells are associated with chronic viral infections (eg, CMV) and can serve as a signature of immunesenescence.39 We found no significant difference in the frequencies of cytotoxic CD4+ T cells. Together, these preliminary findings confirm the better immune status of aged women as compared with men. A detailed analysis of the datasets will identify additional correlates of sex and gender, ageing and the immune system. on August 31, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2020-045576 on 23 June 2021. Downloaded from 4DemuthI, etal. BMJ Open 2021;11:e045576. doi:10.1136/bmjopen-2020-045576 Open access Table 1 Selection of BASEII followup characteristics as assessed of theGendAge study Total number of observations Women* (N=573, 52.1%) Men* (N=527, 47.9%) P value† Age (years) 1100 75.7 (±3.5) 75.5 (±4.0) 0.276 Highest school degree Elementary school 1095 35 (6.1%) 18 (3.4%) <0.001 Intermediate school 183 (32.0%) 104 (19.9%) High school 354 (61.9%) 401 (76.7%) Family status Married 1098 218 (38.0%) 386 (73.5%) <0.001 Not married, in partnership 12 (2.1%) 19 (3.6%) Single 60 (10.5%) 33 (6.3%) Divorced 187 (32.6) 51 (9.7%) Widowed 89 (15.5%) 26 (5.0%) Other 7 (1.2%) 10 (1.9) Employment status Retired 1055 540 (97.6) 486 (96.8) 0.689 Selfrated health Very good 1096 56 (9.8%) 65 (12.4%) 0.499 Good 284 (49.7%) 262 (50.0%) Fair 166 (29.0%) 143 (27.3%) Poor or very poor 66 (11.5%) 54 (10.3%) Satisfaction with life in general 1097 7.9 (±1.6) 8.1 (±1.4) <0.05 Digit Symbol Substitution Test‡ 1095 41.37 (±8.48) 39.21 (±9.67) <0.001 Verbal learning test 925 41.6 (±12.3) 44.0 (±12.8) <0.01 Depression (ever diagnosed) 1095 122 (21.3%) 63 (12.0%) <0.001 BMI 1098 26.6 (±4.7) 27.4 (±3.7) <0.01 Physical inactive§ 1096 67 (11.7%) 65 (12.4%) 0.781 Diabetes mellitus type II (selfreported) 1097 49 (8.6%) 82 (15.6%) <0.001 Diabetes mellitus type II (diagnosed/ American Diabetes Association guidelines 2019) 1097 76 (13.3%) 109 (20.7%) <0.01 Metabolic syndrome (diagnosed, American Heart Association/ International Diabetes Federation/ National Heart, Lung,and Blood Institute criteria 2009) 1074 252 (45.5%) 327 (62.9%) <0.001 Hypertension 1097 296 (51.7%) 311 (59.2%) <0.05 Myocardial infarction 1097 11 (1.9%) 24 (4.6%) <0.05 Stroke 1096 13 (2.3%) 20 (3.8%) 0.158 Peripheral artery disease 1094 8 (1.4%) 15 (2.9%) 0.138 Morbidity index 955 1.0 (IQR 2.0) 1.0 (IQR 2.0) 0.981 Pulse wave velocity (m/s) 932 11.21 (±0.92) 11.04 (±0.91) <0.01 Left ventricular ejection fraction (%) 773 64.12 (±6.24) 62.92 (±5.76) <0.01 Left ventricular mass (g) 691 135.24 (±31.87) 179.76 (±38.96) <0.001 Left ventricular mass index (g)¶ 690 78.55 (±16.83) 91.22 (±17.96) <0.001 Left ventricular enddiastolic volume (mL)¶ 773 54.10 (±12.24) 63.67 (±13.58) <0.001 Frailty (Fried) Not frail 1087 260 (45.4%) 251 (47.6%) 0.542 Prefrail 280 (48.9%) 248 (47.1%) Frail 28 (4.9%) 20 (3.8%) Maximal hand grip strength (kg) 1098 20.5 (±4.4) 35.1 (±6.8) <0.001 Continued on August 31, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2020-045576 on 23 June 2021. Downloaded from 5 DemuthI, etal. BMJ Open 2021;11:e045576. doi:10.1136/bmjopen-2020-045576 Open access The gender questionnaire implemented as part of the followup assessments described here will allow to calculate a gender score and its evaluation based on the newly collected clinical and psychosocial followup data. At the same time, the other BASEII research foci established over the past 10 years will be continued and strengthened with the transition of BASEII into a longitudinal study with followup data on the older subsample. Other measurements Similar to baseline, we determined numerous routine laboratory parameters from blood and urine (table 2), and also stored blood plasma/serum and urine samples for future analyses. Genomic DNA was already extracted from EDTAblood and buccal swab samples from GendAge participants, which will be used, for example, for the profiling of genomewide DNA methylation signatures and new genomewide single nucleotide polymorphism genotyping experiments (table 2). In between the two assessment days at the Charité, participants were asked to fill out a comprehensive psychosocial takehome questionnaire and return this at their second Charité visit. At baseline, the BASEII included a group of 600 younger subjects aged 20–35 years serving as a reference population,1 of which 500 completed baseline medical assessments. Between 7 February 2020 and 13 March 2020, we performed followup assessments in a total of 64 participants of this younger group until these assessments were suspended because of the SARSCoV-2 pandemic. These younger participants had a mean age of 36.8 years (SD ±3.5, range 29.3–44.1 years), with up to 10.7 years of followup (minimum 6.1 years, mean followup at 8.2 years, SD ±1.6). Followup for these younger BASEII participants essentially followed the protocol used for the 1100 older BASEII participants. Because this younger group is not primarily part of the analyses planned in GendAge, further details about this group will be described elsewhere. The cognitive session carried out by the MPIB lasted about 4.5–5 hours (third study visit). Subjects were tested in groups of 4–6 individuals. The cognitive battery included 17 measures of learning and memory performance, attention/processing speed, working memory, executive functioning and perceptual speed (see table 2). Within the week between study visit 2 (Charité) and 3 (MPIB), accelerometers (ActiGraph wGT3XBT) have been used to track participants’ physical activity and sleep in a subset of our participants (n=750). After the cognitive session, participants were invited to take part in a onetoone interview on a different day. This additional individual assessment took up to 60 min and serves as a cohort comparison between the BASE and BASEII study populations. This additional data collection will also contribute to the BASEII cognitive waves, allowing us to further investigate individual differences in ageing trajectories (for an overview, refer to previous work20). Furthermore, and as part of a collaboration with the Lifebrain study, a consortium of European studies funded by the EU Horizon 2020 Framework Programme,40 we collected blood samples using dried blood cards, in order to determine laboratory parameters with identical methods used for all Lifebrain participating sites. Lifebrain aims at identifying determinants of healthy lifespan development by integrating and harmonising data and results from 11 large and predominantly longitudinal European samples from seven countries. This has yielded a database of finegrained measures focusing on brain and cognition from more than 7000 individual participants. The GendAge study was approved by the Ethics Committee of the Charité–Universitätsmedizin Berlin (approval number EA2/144/16) and all participants gave written informed consent. GendAge is registered in the German Clinical Trials Register (StudyID: DRKS00016157). The cognitive battery was approved by the Ethics Committee of the MaxPlanckInstitute and the genomics experiments were approved by the Ethics Committees of the Charité (approval number EA2/144/16) and the University of Lübeck (approval numbers AZ19390A and 19391A). Total number of observations Women* (N=573, 52.1%) Men* (N=527, 47.9%) P value† Recent thymic emigrants (naïve CD4+ T cells) 395** 64.69 (±16.34) 51.03 (±13.69) <0.001 TEMRA (effector memory T cells reexpressing CD45RA) 395** 32.82 (±19.96) 34.94 (±21.29) 0.309 Cytotoxic SLAMF7+CD4+ T cells 181†† 6.02 (±5.98) 6.05 (±6.60) 0.974 *Data are presented as N (%), mean±SD or median (IQR). †Differences between women and men were assessed using the parametric ttest, the nonparametric MannWhitney U test or the χ2 where appropriate. ‡Assessed at study visit 1. §Assessed with the question, ‘Are you seldom or never physically active?’. ¶Adjusted for body surface area. **845 expected to be available after completion of the analyses. ††629 expected to be available after completion of the analyses. BMI, body mass index. Table 1 Continued on August 31, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2020-045576 on 23 June 2021. Downloaded from 6DemuthI, etal. BMJ Open 2021;11:e045576. doi:10.1136/bmjopen-2020-045576 Open access Strengths and limitations The BASEII followup assessments covered most of the medical, psychosocial and cognitive domains, and variables assessed at baseline, and thereby taking the BASEII characteristic of an exceptionally broad and indepth data collection to a next, longitudinal level. In addition, and in the context of the GendAge focus on cardiometabolic disease, we extended the assessments in this area, for example, by including highquality echocardiography resulting in a unique data collection. This strength with respect to comprehensive and longitudinal data offers the potential to answer a number of questions that are of Table 2 BASEII followup assessments during the two GendAge study visits and the cognitive sessions (third study visit) Type of assessment/domain Example assessments/tests Physical examination and medical history Medical history structured by organ systems, medication, body weight, height, lifestyle (including smoking status, alcohol consumption, physical activity) Physical status and functional tests Tinetti Mobility Test, Timed up & Go Test, Barthel Index (ADL), Lawton Instrumental Activities of Daily Living Scale (IADL), hand grip strength, anthropometric parameters, pulse wave velocity/ arterial stiffness (MobiloGraph), echocardiography, ECG, spirometry, motion monitoring (Actigraph), dualenergy Xray absorptiometry (DXA) Psychological screening tests Mini Mental State Examination (MMSE), Digit Symbol Substitution Test (DSST)*, Center for Epidemiologic Studies Depression Scale (CESD) Questionnaires EPIC (FoodFrequency Questionnaire), Gender Questionnaire, Pittsburgh Sleep Quality Index, Rapid Assessment of Physical Activity, SARCF, SF-36 Laboratory values† Blood, serum or plasma: 25hydroxyvitamin D, apolipoprotein A1, apolipoprotein B, basophiles, calcium, cortisol, creatinine, creatine kinase, Creactive protein, cystatin C, dehydroepiandrosterone, eosinophils, erythrocytes, ferritin, folic acid, gammaglutamyltransferase, glucose 1, glucose 2‡, glutamate, oxalacetate transaminase, glutamatepyruvate transaminase, HbA1c, highdensitylipoprotein cholesterol, hematocrit, haemoglobin, homocysteine, international normalised ratio, iron, lowdensitylipoprotein cholesterol, leucocytes, lipoprotein (a), lymphocytes, magnesium, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, monocytes, neutrophils, oestradiol, osteocalcin, partial thromboplastin time, RDW, sex hormonebinding globulin, testosterone, thrombocytes, thyroidstimulating hormone, thyroxine, total cholesterol, triglycerides, triiodothyronine, urea, uric acid, vitamin B12, zinc. Urine: albumin, creatinine, desoxypyridinoline, test strip: bilirubin, blood (erythrocytes), glucose, ketones, leucocytes, nitrite, pH value, protein, specific weight, urobilinogen Dried blood cards: arsenic, brain derived neurotropicfactor, cadmium, chromium, fatty acids (C12:0, C14:0, C15:0, C16:0, C16:1n7, C17:0, C18:0, C18:1,t6-11, C18:1,c9, C18:1,c11, C18:2,n-6, C20:0, C18:3,n-6, C18:3,n-3, C20:1,n-9, C20:2,n-6, C22:0/C20:3,n-6, C20:4,n-6, C20:5,n-3, C24:0, C22:5,n-3, C22:6,n-3, unknown), HbA1c, hsCRP, lead, mercury, nickel, total cholesterol Genomics Genomewide single nucleotide polymorphism genotyping using the ‘Global Screening Array’ (Illumina); genomewide DNA methylation profiling using the ‘Infinium MethylationEPIC’ array (Illumina) Psychosocial questionnaire Wellbeing, positive affect and negative affect, emotion regulation, stress, personality, control beliefs, domainspecific control, time perception, embitterment, loneliness, solitude, social activities, network structure, sexuality, risk behaviour, etc Biobanking Blood plasma and serum, urine, DNA extracted from EDTAblood and buccal swaps Cognitive tests (third study visit) Episodic memory (PictureWordTask, FaceProfessionTask, Object Location Task, SceneEncoding, Verbal learning and memory test), Working memory (Letter Updating, Spatial Updating, NumberNBack), Executive functioning/processing speed (MultiSourceInterference Task, Digit Symbol Substitutions Test*), Fluid intelligence (Letter series, Number series, Practical Problems), Subjective Health Horizon Questionnaire (SHHQ) Immunological assessment Cryopreservation of whole blood (SmartTube system) or isolated peripheral blood mononuclearcells, and serum samples. Direct ex vivo staining of recent thymic emigrants (RTE, CD31+CD45RA+CD4+T cells), TEMRA (CD45RA+CD8+T cells), Tregs (CD25bright CD127CD4+T cells), cytotoxic CD4+Tcells, among others using four different panels: (1) ImmunoCount Panel (CD45, CD3, CD56, CD19, CD16, CD14, CD123, CD1c); (2) RTE panel (CD3, CD4, CD8, CD45RA, CCR7, CD31, CD95, CD11a); (3) TREG panel (CD3, CD4, CD8, CD25, CD127); (4) Effector T cell panel (CD3, CD4, CD8, CD45RA, CCR7, SLAMF7, IL6R, CD57, PD-1). Panels were measured on MacsQuant 10 (Miltenyi), MacsQuant 16 (Miltenyi) or LSR II (BD) *Assessed at study visit 1 and visit 3. †Blood samples were drawn after a fasting period of at least 8 hours (if not otherwise indicated). ‡Postload (75 g glucose, 2 hours), not assessed in participants with known diabetes. BASEII, Berlin Aging Study II. on August 31, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2020-045576 on 23 June 2021. Downloaded from 7 DemuthI, etal. BMJ Open 2021;11:e045576. doi:10.1136/bmjopen-2020-045576 Open access crucial relevance for the health of old women and men. Thus, GendAge will make important contributions for improvements in understanding the health and wellbeing of older adults in both genders. BASEII was initiated as a multidisciplinary study with expertise in a broad range of fields relevant for ageing research (eg, internal medicine and geriatrics, biology, psychology, genetics, immunology, socioeconomics and now in GendAge further extended by sociocultural aspects of gender). The past 10 years of BASEII research have shown that multidisciplinary collaboration is not only a statement of intent, but a fruitbearing working posture and a clear strength of BASEII. Sampling bias is a challenge which cohort studies have to deal with, and this is especially an issue in the followup of older study populations such as the older group of BASEII participants. To address this, we have made a considerable effort (eg, offering a taxi service for participants not able to travel independently) to include as many participants in the followup as possible. Additionally, and similar to baseline, we are able to systematically quantify the sampling bias and even account for it when it comes to the question of generalisability of study results to a population as a whole (eg, Berlin or Germany), due to the evaluation of selectivity and representativeness via the German SocioEconomic Panel Study (SOEP).1 Despite these possibilities, we cannot rule out the possibility of a selection bias completely, which certainly is a weakness of this study, a weakness that applies to all cohort studies relying on voluntary participants who have been nonrandomly recruited. With our direct comparability to the national representative SOEP study, we are in a position though to quantify the amount of selectivity and, if need, take measures to correct and adjust our results. Author affiliations 1Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and HumboldtUniversität zu Berlin, and Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany 2BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany 3Department of Psychology, Humboldt University of Berlin, Berlin, Berlin, Germany 4Center for Lifespan Psychology, MaxPlanckInstitute for Human Development, Berlin, Germany 5Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, HumboldtUniversität zu Berlin, and Berlin Institute of Health; Institute of Social Medicine, Epidemiology and Health Economics, Berlin, Germany 6DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Berlin, Germany 7Berlin Institute for Gender in Medicine, Charite Universitatsmedizin Berlin, Berlin, Germany 8SiM / “Der Simulierte Mensch” a science framework of Technische, Universitat Berlin andCharité - Universitatsmedizin Berlin, Berlin, Germany 9Regenerative Immunology and Aging, BIH Center for Regenerative Therapies, Charité Universitatsmedizin Berlin, Berlin, Germany 10Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany 11Center for Lifespan Changes in Brain and Cognition (LCBC), Dept of Psychology, University of Oslo, Oslo, Norway 12Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin, Germany 13Department of Cardiology, University Hospital Zürich, University of Zürich, Zürich, Switzerland Acknowledgements We are deeply indebted to all individuals of the BASEII cohort who have agreed to participate in the followup assessments. We would further like to thank all staff members and students involved in the medical examinations of participants and documentation, especially Nora Berger, Janina Dombrowski, Mergim Domuzeti, Elisa Dreißig, Ilona Enarovic, Anthony Ganswindt, Thomas Grenkowitz, Anna Hunold, Ilias Katsianas, YooRi Kim, Jörn Kiselev, Paula Krull, Christine Kytmannow, Elisa Lemke, Julia Mätzkow, Charlotte Mentzel, Nadja Mielke, Narantuya Mishig, Angela Motz, Eduard Nitschke, Aabi Okute, Danai Pantelakis, Sophie Poser, Johanne Spieker and Taleka Vollmar (all Charité Universitaetsmedizin Berlin, Biology of Aging group); and Luisa Lüth, Mariebelle Kaus, Isabel Ganter, Marlene Rosendahl, Jasmin Boneberger, Antonia Sprenger, Hania ElKersh (all Humboldt University, Department of Psychology), and Kirsten Becker for the excellent daily organization of the running study within and between the research units, the Telefonstudio for their daily contact with the participants, Martin Becker for the continuous quality checks of our sample and Berndt Wischnewski for updating the database and cognitive battery (all Max Planck Institute for Human Development).We kindly acknowledge the excellent cooperation with the Central Biomaterial Bank, the joint core facility of the CharitéUniversitätsmedizin Berlin and the Berlin Institute for Health (BIH). Furthermore, we appreciate the great support by the BIHREDCap team and especially from Andreas Hetey. We would like to acknowledge the assistance of the Charité|BIH Cytometry Core. Collaborators Additional BASEII/GendAge investigators: Nikolaus Buchmanni, Peter Eibichii, Friederike Kendeliii, Maximilian Königiv, Christina M. Lillv, vi, Maike Mangoldvii, Ahmad Tauseef Naumaniii, Kristina Normanviii, ix, Graham Pawelecx, xi, Sarah Toepferiv, Valentin Max Vetteriv, Gert G. Wagnerxii, Ursula Wilkenshoffi, Kilian WistubaHamprechtxiiiiCharité; Department of Cardiology, Charité - University Medicine Berlin (Campus Benjamin Franklin), Berlin, Germany; iiMax Planck Institute for Demographic Research, Rostock, Germany; iiiBerlin Institute for Gender in Medicine, Charité – Universitätsmedizin Berlin; ivCharité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, HumboldtUniversität zu Berlin, and Berlin Institute of Health; Department of Endocrinology and Metabolism, Berlin, Germany; vSection for Translational Surgical Oncology and Biobanking, Department of Surgery, University of Lübeck and University Medical Center SchleswigHolstein, Campus Lübeck, 23552 Lübeck, Germany; viAgeing Epidemiology Research Unit, School of Public Health, Imperial College, London SW71, UK; viiRegenerative Immunology and Aging, BIH Center for Regenerative Therapies, Charité Universitatsmedizin Berlin, Berlin, Germany; viiiGerman Institute of Human Nutrition, Department of Nutrition and Gerontology, PotsdamRehbruecke (DIfE), Germany; ixCharité - Universitätsmedizin Berlin, Forschungsgruppe Geriatrie am EGZB, Berlin, Berlin, Germany; xDepartment of Immunology, University of Tübingen, Tübingen, Germany; xiHealth Sciences North Research Institute, Sudbury, ON, Canada; xiiGerman SocioEconomic Panel Study (SOEP); xiiiDivision of Dermatooncology Department of Dermatology, University of Tübingen, Tübingen, Germany. Contributors Conceived and designed the study: ID, VRZ, SD, UL and DG. Collected study specific data: ID, VB, JD, SD, US, DS, ET, JB, LB and AT. Providing BASEII baseline data: DG, EST, ID, JD, LB, SD and UL. Analysed the data: ID, ET and JB. Wrote the manuscript: ID. All authors revised and approved the manuscript. Funding The GendAge study research project (CoPIs are Ilja Demuth, Vera RegitzZagrosek, and Denis Gerstorf) is supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) grant numbers 01GL1716A (ID and VRZ) and 01GL1716B (DG). Genomics assessments are funded by the Cure Alzheimer’s Fund (as part of the “CIRCUITSAD” consortium project) and the European Research Council’s “Horizon2020” funding scheme (as part of the “Lifebrain” consortium project; both to LB). Additional contributions (e.g., equipment, logistics, personnel) are made from each of the participating sites. Competing interests None declared. Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research. Patient consent for publication Not required. Provenance and peer review Not commissioned; externally peer reviewed. Data availability statement Data are available on reasonable request. The GendAge study principal investigators welcome new collaborations with other investigators. Interested investigators are invited to contact the study coordinating on August 31, 2021 by guest. Protected by copyright.http://bmjopen.bmj.com/BMJ Open: first published as 10.1136/bmjopen-2020-045576 on 23 June 2021. Downloaded from 8DemuthI, etal. BMJ Open 2021;11:e045576. doi:10.1136/bmjopen-2020-045576 Open access PI Ilja Demuth at ilja. demuth@ charite. de to obtain additional information about the GendAge study and the datasharing application form. Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is noncommercial. See:http:// creativecommons. org/ licenses/ bync/ 4. 0/. ORCID iD IljaDemuth http:// orcid. org/ 0000000243402523 REFERENCES 1 Bertram L, Böckenhoff A, Demuth I, etal. Cohort profile: the Berlin aging study II (BASEII). Int J Epidemiol 2014;43:703–12. 2 Gerstorf D, Bertram L, Lindenberger U, etal. Editorial. Gerontology 2016;62:311–5. 3 Hensel C, Becker M, Düzel S, etal. Influence of nutritional tyrosine on cognition and functional connectivity in healthy old humans. Neuroimage 2019;193:139–45. 4 Bender AR, Brandmaier AM, Düzel S, etal. 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