Cardiorenal metabolic biomarkers link early life stress to risk of non-communicable diseases and adverse mental health outcomes

Stress is one of the most critical determinants of lifetime health and increases the risk of chronic non-communicable diseases. To gain insight into underlying environment-gene interactions, we analyzed the cardiorenal metabolome of adult mice exposed to multidimensional early-life transportation stress. Using proton nuclear magnetic resonance ((1)H NMR) spectroscopy, we show that early life stress permanently programs metabolic pathways in somatic organs linked to cardiorenal and mental health disorders in later life. Heart and kidneys of stressed mice revealed robust metabolic markers linked to abnormal energy metabolism, branched-chain amino acid biosynthesis and degradation, methylhistidine metabolism, arginine and proline metabolism, glycine and serine metabolism, and aminoacyl-tRNA biosynthesis. These markers were strongly associated with anxiety-like behaviours. Dysregulation of energy and protein metabolism suggests an increased risk of metabolic diseases like insulin resistance, cardiorenal syndrome, diabetes, and obesity. These findings provide novel insights into the direct effects of early life stress on cardiorenal metabolism and are consistent with prior observations of increased non-communicable disease risk in stressed populations. Thus, stress-associated metabolic signatures in somatic organs may provide early predictors of health risks in later life and reveal new candidates for peripheral biomarker detection with diagnostic value.