Title : Regulation of the one carbon folate cycle as a shared metabolic signature of 1 longevity 2 3

12 13 The metabolome represents a complex network of biological events that reflects the 14 physiologic state of the organism in heath and disease. Additionally, specific 15 metabolites and metabolic signaling pathways have been shown to modulate animal 16 ageing, but whether there are convergent mechanisms uniting these processes remains 17 elusive. Here, we used high resolution mass spectrometry to obtain the metabolomic 18 profiles of canonical longevity pathways in C. elegans and identify metabolites 19 regulating life span. By leveraging the metabolomic profiles across pathways, we found 20 that one carbon metabolism and the folate cycle were pervasively regulated in common. 21 We observed similar changes in long lived mouse models of reduced insulin/IGF 22 signaling. Genetic manipulation of pathway enzymes and supplementation with one 23 carbon metabolites reveal that regulation of the folate cycle represents a shared causal 24 mechanism of longevity and proteoprotection. 25 was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which this version posted July 8, 2020. ; https://doi.org/10.1101/2020.07.07.191544 doi: bioRxiv preprint