Regulation of the one carbon folate cycle as a shared metabolic signature of longevity

The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in heath and disease. Additionally, specific metabolites and metabolic signaling pathways have been shown to modulate animal ageing, but whether there are convergent mechanisms uniting these processes remains elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic profiles of canonical longevity pathways in C. elegans and identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle were pervasively regulated in common. We observed similar changes in long lived mouse models of reduced insulin/IGF signaling. Genetic manipulation of pathway enzymes and supplementation with one carbon metabolites reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection.