Drosophila in the midlife crisis: Aging in all living organisms is characterized by diminished metabolic activity and increased errors in gene regulation as they reach old age. This favors the emergence of diseases. Using the Drosophila fruit fly, we find that age-related changes in metabolic activity and protein acetylation are already seen in middle age. By lowering the production of a key metabolite, acetyl-CoA, or by reducing the activity of a key acetyltransferase enzyme, we find that we can obtain flies that are much fitter at midlife and live longer. Our study reveals new avenues for promoting longevity by reducing metabolic activity and protein acetylation.