Metabolomics and aging

As life expectancy has risen steadily over the last years and diseasefree aging is more and more challenging, understanding the complexity of age and aging is of great importance. Metabolomics is one of the novel approaches in systems biology with high potential to deliver answers to these questions. However, only a few metabolic studies based on large samples are available so far. In this thesis, I present results from two population-based studies, the German KORA Follow-Up 4 (KORA F4) study as a discovery cohort with a sample of 1,038 female and 1,124 male healthy participants (32–81 years) and 724 healthy females from UK Adult Twin Registry (TwinsUK) as replication. Targeted metabolomics of fasting serum samples with flow injection analysis coupled with tandem mass spectrometry (FIA-MS/MS) positively quantified 131 metabolites after stringent quality control. Among these, 71 and 34 metabolites were significantly associated with age in females and males, respectively, after adjustment for body mass index (BMI), which is highly correlated (r=0.9) with age. These results indicate that metabolic profiles are age dependent and sex specific. Then, a set of the 12 most age-discriminative, independent metabolites was identified in women with an approach based on random forest and stepwise variable selection. This set showed highly significant differences between subjects aged 32–51 years and 52–77 (p-values range 1.3E-09 – 1.9E-46, significance threshold p=0.004). Ten out of these 12 metabolites replicated in unrelated females from the TwinsUK study, including five metabolites the concentrations of which increased with age (C12:1, C18:1, sphingomyelin (SM) C16:1, SM C18:1 and phosphatidylcholine (PC) aa C28:1), while histidine decreased gradually. Three glycerophospholipids (PC ae C42:4, PC ae C42:5, PC ae C44:4) showed declines around the age of 51 years. Meta-analysis of both studies gave virtually the same results as KORA alone. These observations might reflect many different processes of aging such as incomplete mitochondrial fatty acid oxidation, counteracting oxidative stress, and changes in vascular functions. The identification of these ten age-related metabolites should help better understand aging pathways and networks and with —more discoveries in the future— eventually help enhance healthy aging and longevity

Gene-Gene Interaction between APOA5 and USF1: Two Candidate Genes for the Metabolic Syndrome

Objective: The metabolic syndrome, a major cluster of risk factors for cardiovascular diseases, shows increasing prevalence worldwide. Several studies have established associations of both apolipoprotein A5 (APOA5) gene variants and upstream stimulatory factor 1 (USF1) gene variants with blood lipid levels and metabolic syndrome. USF1 is a transcription factor for APOA5. Methods: We investigated a possible interaction between these two genes on the risk for the metabolic syndrome, using data from the German population-based KORA survey 4 (1,622 men and women aged 55-74 years). Seven APOA5 single nucleotide polymorphisms (SNPs) were analyzed in combination with six USF1 SNPs, applying logistic regression in an additive model adjusting for age and sex and the definition for metabolic syndrome from the National Cholesterol Education Program's Adult Treatment Panel III (NCEP (AIII)) including medication. Results: The overall prevalence for metabolic syndrome was 41%. Two SNP combinations showed a nominal gene-gene interaction (p values 0.024 and 0.047). The effect of one SNP was modified by the other SNP, with a lower risk for the metabolic syndrome with odds ratios (ORs) between 0.33 (95% CI = 0.13-0.83) and 0.40 (95% CI = 0.15-1.12) when the other SNP was homozygous for the minor allele. Nevertheless, none of the associations remained significant after correction for multiple testing. Conclusion: Thus, there is an indication of an interaction between APOA5 and USF1 on the risk for metabolic syndrome

Human serum metabolic profiles are age dependent

Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age-related metabolite concentration changes in human homeostasis. We report results from two population-based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32–81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA-MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 × 10−04 to 7.8 × 10−42, αcorr = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging

Variants of the FADS1 FADS2 Gene Cluster, Blood Levels of Polyunsaturated Fatty Acids and Eczema in Children within the First 2 Years of Life

Association of genetic-variants in the FADS1-FADS2-gene-cluster with fatty-acid-composition in blood of adult-populations is well established. We analyze this genetic-association in two children-cohort-studies. In addition, the association between variants in the FADS-gene-cluster and blood-fatty-acid-composition with eczema was studied. Data of two population-based-birth-cohorts in The Netherlands and Germany (KOALA, LISA) were pooled (n = 879) and analyzed by (logistic) regression regarding the mutual influence of single-nucleotide-polymorphisms (SNPs) in the FADS-gene-cluster (rs174545, rs174546, rs174556, rs174561, rs3834458), on polyunsaturated fatty acids (PUFA) in blood and parent-reported eczema until the age of 2 years. All SNPs were highly significantly associated with all PUFAs except for alpha-linolenic-acid and eicosapentaenoic-acid, also after correction for multiple-testing. All tested SNPs showed associations with eczema in the LISA-study, but not in the KOALA-study. None of the PUFAs was significantly associated with eczema neither in the pooled nor in the analyses stratified by study-cohort. PUFA-composition in young children's blood is under strong control of the FADS-gene-cluster. Inconsistent results were found for a link between these genetic-variants with eczema. PUFA in blood was not associated with eczema. Thus the hypothesis of an inflammatory-link between PUFA and eczema by the metabolic-pathway of LC-PUFAs as precursors for inflammatory prostaglandins and leukotrienes could not be confirmed by these data

The transcriptional landscape of age in human peripheral blood

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.Peer reviewe

Metabolomics reveals determinants of weight loss during lifestyle intervention in obese children

Wahl S, Holzapfel C, Yu Z, et al. Metabolomics reveals determinants of weight loss during lifestyle intervention in obese children. Metabolomics. 2013;9(6):1157-1167.The amount of weight loss in obese childrenduring lifestyle intervention differs strongly between indi-viduals. The metabolic processes underlying this variabilityare largely unknown. We hypothesize that metabolomicsanalyses of serum samples might help to identify metabolicpredictors of weight loss. In this study, we investigated 80obese children aged 6–15 years having completed the one-year lifestyle intervention program ‘Obeldicks’, 40 thatachieved a substantial reduction of their body mass indexstandard deviation score (BMI-SDS) during this interven-tion (defined as BMI-SDS reductionC0.5), and 40 thatdid not improve their overweight status (BMI-SDS reduc-tion\0.1). Anthropometric and clinical parameters weremeasured and baseline fasting serum samples of allchildren were analyzed with a mass spectrometry-basedmetabolomics approach targeting 163 metabolites. Bothunivariate regression models and a multivariate leastabsolute shrinkage and selection operator (LASSO)approach identified lower serum concentrations of long-chain unsaturated phosphatidylcholines as well as smallerwaist circumference as significant predictors of BMI-SDSreduction during intervention (p-values univariate models:5.3E-03 to 1.0E-04). A permutation test showed that theLASSO model explained a significant part of BMI-SDSchange (p=4.6E-03). Our results suggest a role ofphosphatidylcholine metabolism and abdominal obesity inbody weight regulation. These findings might lead to abetter understanding of the mechanisms behind the largeinter-individual variation in response to lifestyle interven-tions, which is a prerequisite for the development of indi-vidualized intervention programs

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups

MOESM6 of Characterization of whole-genome autosomal differences of DNA methylation between men and women

Additional file 6. Enrichment of SMAs for probes with high Cross-Hybridization value (CHV). CHV is the number of matching bases to XY chromosomes. CHV values greater than 46 tend to be enriched for SMAs (green line). To be conservative, we removed all SMAs, represented as correlation coefficients on the y-axis, with CHV > 40 (red line)