Long-lived yeast-derived lipids promote longevity via regional and systemic metabolic remodeling

Abstract

Aging is marked by a progressive breakdown of intestinal integrity and metabolic homeostasis, which together drive systemic decline in physiology and reduced lifespan. Here, we demonstrate that dietary lipids extracted from a genetically engineered long-lived yeast strain robustly extend lifespan in Drosophila by preserving gut function and modulating the gut brain axis. Using deuterium oxide probed stimulated Raman scattering microscopy, we show that these yeast-derived lipids restore age-related declines in gut lipid droplet abundance, enhance membrane lipid incorporation, and increase de novo lipid synthesis, thereby improving epithelial structure and barrier function. Single nucleus RNA sequencing reveals transcriptional remodeling in metabolically active enterocytes, including upregulation of autophagy and protein turnover genes, alongside reduction of unsaturated fatty acid biosynthesis. Complementary Raman spectroscopy and lipidomics demonstrate that the yeast lipids are enriched in shorter, more saturated fatty acids and phospholipids, contributing to increased membrane order and reduced lipid storage. Functionally, targeted dietary supplementation with these lipid components synergistically prolongs fly lifespan. In the brain, dietary lipids orchestrate a dual metabolic strategy, promoting energy conservation and enhanced signaling across most neuronal and glial populations, while selectively boosting mitochondrial function in memory-critical Kenyon cells. We also identify strengthened gut-to-glia communication, particularly through EGFR and FGFR pathways. Finally, a newly developed computational tool, FLY-MAP, reveals that yeast lipids restructure gut metabolic modules to coordinate energy production, redox balance, and nutrient flexibility. Our study uncovers a cross-kingdom mechanism of metabolic longevity regulation, paving the way for leveraging yeast-derived nutritional components to support tissue homeostasis and promote healthy aging.