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Free keywords:
Animals
Caenorhabditis elegans
Carbon/*metabolism
Folic Acid/*metabolism
Insulin/metabolism
Longevity/genetics/*physiology
*Metabolic Networks and Pathways/genetics
Metabolome
Methionine/metabolism
Mice
Mitochondria/genetics/metabolism
Mutation
Peptides/metabolism
Signal Transduction
Tetrahydrofolate Dehydrogenase/genetics/metabolism
Tetrahydrofolates/metabolism
Thymidylate Synthase/genetics/metabolism
Abstract:
The metabolome represents a complex network of biological events that reflects the physiologic state of the organism in health 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 to identify metabolites regulating life span. By leveraging the metabolomic profiles across pathways, we found that one carbon metabolism and the folate cycle are 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 in C. elegans reveal that regulation of the folate cycle represents a shared causal mechanism of longevity and proteoprotection. Such interventions impact the methionine cycle, and reveal methionine restriction as an underlying mechanism. This comparative approach reveals key metabolic nodes to enhance healthy ageing.
