A Feedforward Loop Governs The Relationship Between Lipid Metabolism And Longevity

Abstract

The relationship between lipid metabolism and longevity remains unclear. In particular although fat oxidation is essential for weight loss, whether it is remains beneficial when sustained for long periods, and the extent to which it may alter lifespan remains an important unanswered question. Here we develop an experimental handle in the C. elegans model system, that uncovers the mechanisms that connect long-term fat oxidation with longevity. We find that sustained {square}-oxidation, via activation of the conserved triglyceride lipase ATGL-1, triggers a feedforward transcriptional loop that involves the mito-nuclear transcription factor ATFS-1, and a previously unknown and highly conserved repressor of ATGL-1 called HLH-11/AP4. This feedforward loop orchestrates the dual control of fat oxidation and lifespan protection, shielding the organism from life-shortening mitochondrial stress in the face of continuous fat oxidation. Thus, we uncover one mechanism by which fat oxidation can be sustained for long periods without deleterious effects on longevity.