Research Paper Volume 11, Issue 12 pp 3993—4010
Intermediate metabolites of the pyrimidine metabolism pathway extend the lifespan of C. elegans through regulating reproductive signals
- 1 The Center for Precision Medicine of First Affiliated Hospital, Biomedical Translational Research Institute, Jinan University, Guangzhou 510632, China
Received: January 20, 2019 Accepted: June 13, 2019 Published: June 21, 2019
https://doi.org/10.18632/aging.102033How to Cite
Copyright: Wan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The pyrimidine metabolism pathway has important biological functions; it not only maintains appropriate pyrimidine pools but also produces bioactive intermediate metabolites. In a previous study, we identified that the pyrimidine metabolism pathway is associated with aging regulation. However, the molecular mechanism by which the pyrimidine metabolism pathway regulates aging remains unclear. Here, we investigated the longevity effect of pyrimidine intermediates on Caenorhabditis elegans (C. elegans). Our results demonstrated that the supplementation of some pyrimidine intermediates could extend the lifespan of C. elegans. In addition, the RNAi knockdown of essential enzymes involved in pyrimidine metabolism could also significantly affect lifespan. We further investigated the molecular mechanism by which a representative intermediate metabolite, thymine, extends the lifespan of worms and found that thymine-induced longevity required the nuclear receptors DAF-12 and NHR-49, and the transcription factor DAF-16/FOXO. Further pathway analysis revealed that the longevity effect of thymine depended on the inhibition of reproductive signals. Additionally, we found that other pyrimidine intermediates functioned in a manner similar to thymine to prolong lifespan in C. elegans. Taken together, our results revealed that pyrimidine intermediates increased lifespan by inhibiting reproductive signals and subsequently inducing the function of DAF-12, NHR-49 and DAF-16 in C. elegans.