A genetic model of methionine restriction extends health- and lifespan. Author Andrey Parkhitko, Lin Wang, Elizabeth Filine, Patrick Jouandin, Dmitry Leshchiner, Richard Binari, John Asara, Joshua Rabinowitz, Norbert Perrimon Publication Year 2021 Type Journal Article Abstract Loss of metabolic homeostasis is a hallmark of aging and is characterized by dramatic metabolic reprogramming. To analyze how the fate of labeled methionine is altered during aging, we applied C5-Methionine labeling to and demonstrated significant changes in the activity of different branches of the methionine metabolism as flies age. We further tested whether targeted degradation of methionine metabolism components would "reset" methionine metabolism flux and extend the fly lifespan. Specifically, we created transgenic flies with inducible expression of , a bacterial enzyme capable of degrading methionine and revealed methionine requirements for normal maintenance of lifespan. We also demonstrated that microbiota-derived methionine is an alternative and important source in addition to food-derived methionine. In this genetic model of methionine restriction (MetR), we also demonstrate that either whole-body or tissue-specific expression can dramatically extend health- and lifespan and exerts physiological effects associated with MetR. Interestingly, while previous dietary MetR extended lifespan in flies only in low amino acid conditions, MetR from expression extends lifespan independently of amino acid levels in the food. Finally, because impairment of the methionine metabolism has been previously associated with the development of Alzheimer's disease, we compared methionine metabolism reprogramming between aging flies and a model relevant to Alzheimer's disease, and found that overexpression of human Tau caused methionine metabolism flux reprogramming similar to the changes found in aged flies. Altogether, our study highlights Methioninase as a potential agent for health- and lifespan extension. Keywords Animals, Drosophila, Humans, Carbon-Sulfur Lyases, Models, Genetic, Animals, Genetically Modified, Aging, Alzheimer Disease, Longevity, Methionine, Amino Acids, Food Journal Proc Natl Acad Sci U S A Volume 118 Issue 40 Date Published 2021 Oct 05 ISSN Number 1091-6490 DOI 10.1073/pnas.2110387118 Alternate Journal Proc Natl Acad Sci U S A PMCID PMC8501845 PMID 34588310 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML