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

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.

Metabolomic Investigation of Synergistic Mechanism for Fangfeng Extract Preventing LPS Induced Neuroinflammation in BV-2 Microglia Cells

“…The impaired one-carbon metabolism and lower folate levels tightly correlated with elevated tau phosphorylation levels in neurodegenerative diseases and disturbed neuronal homeostasis [31]. However, recent research on the genetic and supplementation-manipulated C. elegans indicated that specific folate and one carbon metabolism reduction could be beneficial for longevity and proteoprotection [32]. These disparate observations probably reflect multi-layering of FFE effects on LPS-induced BV-2 cells since it could effectively decrease pro-inflammatory factor expression and downregulate folate metabolisms.…”

One-Carbon Metabolism: Pulling the Strings behind Aging and Neurodegeneration

“…Interestingly, transcriptional activation of glycine metabolism and folate-dependent OCM is a prominent trait of longevity shared between seemingly different longevity paradigms [ 65 ]. Recently, it was reported that folate intermediates undergo extensive quantitative changes that are often common among long-lived nematode mutants [ 63 ]. Folate, THF, and 5,10-methylene-THF are increased while 5-methyl-THF, 10-formyl-THF, and 5,10 methenyl-THF are robustly and reproducibly decreased.…”

“…Similar data were obtained when the DHFR enzyme was genetically suppressed in nematodes, also leading to lifespan extension. Notably, supplementation with 5-methyl-THF reversed longevity of long-lived mutants, of reduced insulin signaling (rIIS), inherently caloric restricted, and mitochondrial mutants, while folic acid supplementation did not alter lifespan of wt nematodes [ 63 ]. Conclusively, increasing reports suggest that altered OCM may be a shared metabolic trait of longevity.…”

Meeting Report: Aging Research and Drug Discovery

“…Adam Antebi, Max Planck Institute for Biology of Ageing, Germany, presented their latest study in which they used metabolic profiling of longlived C. elegans strains and identified the folate/ methionine cycle as a convergence point of aging pathways. This elucidates how single genes or metabolites can regulate lifespan through multiple pathways [16].…”