Salicylate, the active derivative of
aspirin (acetylsalicylate), recapitulates the mode of action of
caloric restriction inasmuch as it stimulates autophagy through the inhibition of the
acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of
aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome.
Aspirin caused a transient reduction of general
protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global
protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-
proteome from
salicylate-treated EP300-deficient cells.
Aspirin reduced high-fat diet-induced
obesity, diabetes, and hepatosteatosis. These
aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b-/- or Bcln1+/-) autophagy-deficiency.
Aspirin also improved
tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in
cancer cells. Hence, the health-improving effects of
aspirin depend on autophagy.