Jungert et al. Nutrition Journal (2020) 19:64 https://doi.org/10.1186/s12937-020-00576-2 RESEARCH Open Access Dynamics and interactions of cobalamin and folate status during advanced aging – a longitudinal study in a community- dwelling cohort with multiple follow-ups Alexandra Jungert1,2 , Carola Zenke-Philippi3 and Monika Neuhäuser-Berthold1* Abstract Background: Older people are reported to be prone to imbalances between cobalamin and folate status with possible adverse effects on health. This longitudinal study investigates dynamics and interactions of cobalamin and folate status in a cohort of community-dwelling older adults by considering possible influencing factors. Methods: In total, 332 subjects ≥ 60 years were investigated over a mean observation period of 12 years. Data collection included serum cobalamin, folate and creatinine, dietary intakes of cobalamin, folate and alcohol, use of supplements, body composition, smoking behavior, and diseases. Linear mixed-effects models with repeated measurements were used to investigate the influence of variables on serum cobalamin and folate. Results: At baseline, median cobalamin intake exceeded the dietary reference value (DRV), while median folate intake was considerably below DRV. In most subjects, serum concentrations of both vitamins were within reference ranges. For serum cobalamin, apart from supplement use (Parameter estimate [95% confidence interval]: 130.17 [53.32, 207.01]), the main positive predictor was serum folate (4.63 [2.64, 6.62]). For serum folate, serum creatinine (10.85 [4.85, 16.86]), use of supplements (7.86 [5.05, 10.67]), serum cobalamin (0.01 [< 0.01, 0.01]), and dietary folate intake (0.02 [0.01, 0.03]) were positive predictors. No main effects of age, sex, body composition, alcohol intake or smoking were found after adjusting for simultaneous inference. Conclusions: Advancing age, per se, is no risk factor for a decline in serum concentrations of cobalamin or folate in subjects ≥ 60 years. Suboptimal folate intake may limit the function of folate regarding the supply of methyl groups for methylation of cobalamin and subsequent creatine biosynthesis. The positive association of serum creatinine with folate deserves further exploration with regard to its possible relevance for maintaining energy dependent functional integrity in the course of ageing. Keywords: Older adults, Folate, Cobalamin, Creatinine, Dietary intake, Longitudinal study * Correspondence: [email protected] 1Institute of Nutritional Science, Justus Liebig University, Goethestrasse 55, D-35390 Giessen, Germany Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Jungert et al. Nutrition Journal (2020) 19:64 Page 2 of 12 Highlights deterioration in either folate or cobalamin status under the condition of adequate intake and intact absorption Advancing age is per se no risk factor for a decline mechanisms. However, longitudinal studies are needed in serum cobalamin and folate to draw conclusions on age-related alterations in either Serum cobalamin and folate are positively folate or cobalamin status that are independent of other interlinked influencing factors. Against this background, the present Dietary cobalamin intake above reference value has study investigates dynamics and interactions of folate no impact on serum cobalamin and cobalamin status in a community-dwelling older co- Serum creatinine is independently associated with hort over a mean follow-up period of 12 years using serum folate multiple assessments. We also explore, whether folate and/or cobalamin status are possibly related to serum Background creatinine, which besides being used as a marker of kid- There is a continued increase in life expectancy, which, ney function serves as a proxy for total body pool of cre- however, is accompanied by an increased prevalence of atine [23]. age-related chronic diseases in the advanced ages. Sev- eral geriatric symptoms have been associated with low Subjects and methods cobalamin and/or low folate status, such as cognitive im- Study cohort pairment [1, 2], Parkinson’s disease [3], sarcopenia [4] The present investigation is based on the longitudinal and frailty [5]. However, the causal relevance of these as- study on nutrition and health status of senior citizens in sociations remains to be elucidated. An emerging focus Giessen (GISELA study), Germany, which is a prospect- is on the role of B-vitamins on epigenetic modification, ive cohort study initiated in 1994 and completed in such as DNA methylation, as an underlying mechanism 2014. Participants were recruited by physicians, notices, in the pathogenesis of age-related diseases, including senior citizens’ meetings, advertisements in local news- cancer, cardiovascular and neurological diseases [6–9]. papers and through individuals, who had already partici- DNA methylation requires the donation of methyl pated. Eligibility criteria were an age of at least 60 years, groups in which folate and cobalamin play a major role physical mobility and resident in Giessen or surrounding [9]. Folate and cobalamin interact with each other in the areas. The investigations took place at the Institute of methionine cycle via the remethylation of homocysteine Nutritional Science in Giessen from July to October at to methionine [10]. This process is important for folate annual intervals between 1994 and 1998 and since 1998 retention, DNA synthesis and subsequent production of at biannual intervals. Subjects joined the study until S-adenosyl-L-methionine (SAM) [10, 11]. The latter is 2006. required for the methylation of various substrates in cel- Overall, 587 subjects participated in the GISELA study. lular metabolism [11]. It has been estimated that about The assessed parameters varied among follow-ups and 40% of all SAM derived methyl groups are used for the not all subjects took part in each follow-up. For the synthesis of creatine, which plays a complex role in en- present analysis, data from the follow-ups in 1997, 1998, ergy metabolism [12, 13]. So far, human studies consid- 2002, 2006, 2010, 2012 and 2014 were analyzed because ering possible interrelations between cobalamin and duplicate measurements on both serum cobalamin and folate status in conjunction with creatine levels are folate were available. Records were in the first instance hardly available. excluded because of non-fasting state (n = 12) followed According to epidemiological studies, an imbalance of by the exclusion of records with missing data for serum folate and cobalamin status may negatively affect health cobalamin, serum folate, body composition, dietary in- status in older adults [14]. It is well known that cobalamin take and use of supplements, respectively (n = 285). Fi- deficiency can cause functional folate deficiency [10, 15]. nally, only subjects with at least three complete data However, it is not known which possible mechanisms records on relevant factors were considered, resulting in could explain the positive association between blood con- a study sample of 332 subjects with 1556 records, 233 centrations of both vitamins noted in some cross-sectional women and 99 men. A flow chart of the numbers and studies [16–20] and also found by our group [21]. reasons for excluding subjects is presented in the online Thus, more knowledge on the interdependency of fol- supporting material (Additional file 1: Figure S1). The ate and cobalamin status and possible influencing factors final number of subjects differed by follow-up year: 1997 is important for deriving conclusions on the impact of (n = 243), 1998 (n = 254), 2002 (n = 310), 2006 (n = 251), these two vitamins on age-related diseases and corre- 2010 (n = 185), 2012 (n = 176) and 2014 (n = 137). Of the sponding preventive measures. Although older individ- final cohort, 89, 73, 71, 51 and 48 subjects participated uals more often have an inferior cobalamin status [22], in 3, 4, 5, 6 and 7 follow-ups, respectively. The mean at present, there is little evidence for an age-related follow-up time was 12 years. Jungert et al. Nutrition Journal (2020) 19:64 Page 3 of 12 Anthropometric data and body composition because for 2008, no data on serum cobalamin and Body mass index (BMI) was calculated from measured serum folate were available. body height and body mass. Body composition was Serum cobalamin ≤ 148 pmol/L and serum folate < 7 assessed by bioelectrical impedance analysis (Akern-RJL nmol/L were