Uncoupling of lifespan and reproductive tradeoffs by dietary methionine and one-carbon metabolism

Abstract

Abstract Aging has been proposed to be a consequence of reproductive ability and longevity thus occurs as a tradeoff with organismal reproduction1, 2. Lifespan extending interventions generally at the expense of fertility3. How this principle extends to nutrition and metabolism is not understood. We considered dietary methionine restriction (MR) that is linked to one carbon metabolism as well as to Mediterranean or plant-based diets4 ,5 and known to influence cancer6, metabolic health7, and longevity3, 8. Using a chemically defined diet (CDD) we developed for Drosophila melanogaster, we found that MR-mediated lifespan extension indeed occurs at the expense of reproduction. A survey of the nutritional landscape in the background of MR revealed that folic acid, a vitamin linked to one carbon metabolism, surprisingly was the lone nutrient that restored reproductive defects without compromising lifespan extension. In vivo isotope tracing, metabolomics and flux analysis identified the Tricarboxylic (TCA) cycle and redox coupling as the primary determinants of MR benefits. Interestingly, the fecundity defect occurred through altered sperm function and its restoration by folic acid supplementation also restored sperm mitochondrial metabolism. Together these findings suggest that dietary interventions connected to specific changes in metabolism can separate adverse effects that may occur by enhancing longevity.