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Singmann, Paula (2015): Metabolomics and aging. Dissertation, LMU München: Faculty of Medicine



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.