Mice deficient for growth hormone receptor (ghrKO) have a dramatic lifespan extension, through an unknown mechanism. Compared to normal littermates,ghrKO mice have elevated levels of hepatic chaperone-mediated autophagy (CMA). Using quantitative proteomics to identify protein changes in purified liver lysosomes and whole liver lysates, we provide evidence that elevated CMA in ghrKO mice specifically downregulates proteins involved in ribosomal structure, translation initiation and elongation, and nucleocytosolic acetyl-coA production. Using a combination of cell culture and mouse models, we show that CMA is both necessary and sufficient to regulate the abundance of ACLY and ACSS2, the two enzymes that produce nucleocytosolic (but not mitochondrial) acetyl-coA. Degradation of ACLY and ACSS2 by CMA prevents aberrant accumulation of lipid droplets in NIH3T3 cells. Nucleocytosolic acetyl-coA has been implicated in longevity. Elevated CMA in ghrKO mice might contribute to their long lifespan by diminishing nucleocytoplasmic acetyl-coA availability.