Autophagy-mediated metabolic effects of aspirin

Francesca Castoldi,Elisa Elena Baracco,Sylvère Durand,Lucillia Bezu,Juliette Humeau,Sylvie Lachkar,Fanny Aprahamian,Paule Opolon,Yohann Demont,Maria Chiara Maiuri,Valentina Sica,Guido Kroemer,Norma Bloy,Michaela Semeraro,Nicolas Signolle,Allan Sauvat,Florent Dingli,Sophie Lévesque ,Alexis Chery,Damarys Loew,Isabelle Martins,Noëlie Bossut ,David Enot,Jonathan Pol ,Erika Vacchelli,Federico Pietrocola

doi:10.1038/s41420-020-00365-0

Abstract

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.

Highlights

Aspirin is one of the oldest molecules to be used as a chemically defined entity for the treatment of human disease
Comparison of aspirin vs fasting effects in mice The biochemical features of starvation can be partially recapitulated by so-called caloric restriction mimetics (CRMs), which are non-toxic synthetic molecules or natural compounds endowed with the capacity to reduce cellular protein acetylation, thereby igniting the autophagic reaction[34]
These results suggest that aspirin can induce changes similar to fasting in the extracellular compartment in vivo, while it displays an organspecific pattern of metabolic effects at the intracellular level

Summary

Introduction

Aspirin is one of the oldest molecules to be used as a chemically defined entity for the treatment of human disease. We investigated the metabolic effects of aspirin on the extracellular (plasma) and intracellular metabolome in mice by comparing them with those elicited by fasting, which is known to reduce protein acetylation and ignite autophagy in several tissues[20,21,22].

Results

Conclusion