Regional and Systemic Metabolic Remodeling Promotes Longevity by Bioengineered Yeast-Derived Lipids

Aging is marked by a progressive breakdown of intestinal integrity and metabolic homeostasis, which together drives systemic decline in physiology and reduces lifespan. Here, we found that dietary lipids extracted from a genetically engineered long-lived yeast strain robustly extend lifespan in Drosophila and further uncovered the mechanisms using deuterium oxide-probed stimulated Raman scattering microscopy to image metabolic dynamics and single nucleus RNA sequencing (scRNA-seq) to unveil the underlying pathways. These yeast lipids are enriched in shorter, more saturated fatty acids and phospholipids as revealed by Raman spectroscopy and lipidomics, contributing to increased membrane order and reduced lipid storage. Functionally, targeted dietary supplementation with these lipid components synergistically prolongs fly lifespan. We show that these lipids reverse age-related declines in gut lipid droplet abundance, enhance membrane lipid incorporation, and increase de novo lipid synthesis, thereby improving epithelial structural integrity and barrier function. snRNA-seq identifies transcriptional remodeling in metabolically active enterocytes, including upregulation of autophagy and protein turnover genes, alongside reduction of unsaturated fatty acid biosynthesis. 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. All these leads to the enhancement of gut-to-glia communication, particularly through EGFR and FGFR pathways. Finally, analysis of our data with the Fly Metabolic Analysis Pipeline (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.