Abstract
Ageing, one of the largest risk factors for many complex diseases, is highly interconnected to metabolic processes. Investigating the changes in metabolite concentration during ageing among healthy individuals offers us unique insights to healthy ageing. We aim to identify ageing-associated metabolites that are independent from chronological age to deepen our understanding of the long-term changes in metabolites upon ageing. Sex-stratified longitudinal analyses were performed using fasting serum samples of 590 healthy KORA individuals (317 women and 273 men) who participated in both baseline (KORA S4) and seven-year follow-up (KORA F4) studies. Replication was conducted using serum samples of 386 healthy CARLA participants (195 women and 191 men) in both baseline (CARLA-0) and four-year follow-up (CARLA-1) studies. Generalized estimation equation models were performed on each metabolite to identify ageing-associated metabolites after adjusting for baseline chronological age, body mass index, physical activity, smoking status, alcohol intake and systolic blood pressure. Literature researches were conducted to understand their biochemical relevance. Out of 122 metabolites analysed, we identified and replicated five (C18, arginine, ornithine, serine and tyrosine) and four (arginine, ornithine, PC aa C36:3 and PC ae C40:5) significant metabolites in women and men respectively. Arginine decreased, while ornithine increased in both sexes. These metabolites are involved in several ageing processes: apoptosis, mitochondrial dysfunction, inflammation, lipid metabolism, autophagy and oxidative stress resistance. The study reveals several significant ageing-associated metabolite changes with two-time-point measurements on healthy individuals. Larger studies are required to confirm our findings.
Highlights
Ageing, the deterioration of functional capacity and stress resistance over a lifetime [1,2], is a main driver of various complex pathologies [3,4]
KORA, aa total of healthy men were included for analysis
We found that all analysed lysoPCs and all sphingomyelins were negatively associated with ageing (Table S2)
Summary
The deterioration of functional capacity and stress resistance over a lifetime [1,2], is a main driver of various complex pathologies (e.g., cancer, cardiovascular diseases, metabolic diseases and neurodegeneration) [3,4]. Developing biomarkers that distinguish between normal and pathological biological ageing process helps us predict the long-term risks of morbidity and mortality [8] and explain individual variations in lifespan [9], which is crucial for achieving healthy ageing. Due to the high metabolic heterogeneity of individuals, the development of ageing biomarker remains a great challenge at technical level [1,10,11]. Several studies have shown that many proposed biological ageing pathways (e.g., oxidative stress, inflammatory responses and apoptosis) are intimately associated with metabolic processes. Metabolites have been proposed to be the ideal ageing biomarkers— are they the most proximal reporters of body alterations due to changes in biological processes [12] and satisfy all characteristics of an ideal ageing biomarker proposed by Sharman and Zhumadilov [13], they are: i. Metabolites have been proposed to be the ideal ageing biomarkers— are they the most proximal reporters of body alterations due to changes in biological processes [12] and satisfy all characteristics of an ideal ageing biomarker proposed by Sharman and Zhumadilov [13], they are: i. informative and reflective about the metabolic systems and functional conditions of the body [14]; ii. quantitatively correlated with age [11]; iii. of high reproducibility, sensitivity and specificity [15]; and iv. suitable for use in humans
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