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

Nat Commun. 2021 Jun 9;12(1):3486. doi: 10.1038/s41467-021-23856-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans
  • Carbon / metabolism*
  • Folic Acid / metabolism*
  • Insulin / metabolism
  • Longevity / genetics
  • Longevity / physiology*
  • Metabolic Networks and Pathways* / genetics
  • Metabolome
  • Methionine / metabolism
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mutation
  • Peptides / metabolism
  • Signal Transduction
  • Tetrahydrofolate Dehydrogenase / genetics
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Tetrahydrofolates / metabolism
  • Thymidylate Synthase / genetics
  • Thymidylate Synthase / metabolism


  • Insulin
  • Peptides
  • Tetrahydrofolates
  • polyglutamine
  • Carbon
  • Folic Acid
  • Methionine
  • Tetrahydrofolate Dehydrogenase
  • Thymidylate Synthase
  • 5-methyltetrahydrofolate