The capacity of cells and organisms to sustain, and to eventually adapt to, environmental and genetic insults declines with age. Because macroautophagy/autophagy is regarded as one of the major determinants of cellular fitness in vitro and in vivo, maneuvers that aim at promoting autophagy may slow down aging and promote health span. Caloric restriction (CR), a reduction in caloric intake without malnutrition, efficiently counteracts aging-associated features, yet is difficult to be applied to humans. Caloric-restriction mimetics (CRMs) are pharmacological agents that recapitulate the main biochemical properties of CR, namely a global reduction of protein acetylation and the induction of autophagy. We found that the ancient drug aspirin and its active metabolite salicylate stimulate autophagic flux by virtue of their inhibitory action on acetyltransferase EP300. The inhibition of EP300 results from a direct competition between salicylate and acetyl coenzyme A for binding to the catalytic domain of the enzyme. This mode of action appears to be conserved across evolution as it accounts for the induction of autophagy by aspirin in various mouse models and in the nematode Caenorhabditis elegans. In sum, aspirin acts as a CRM.
Keywords: AMPK; Acetylation; aging; autophagy; fasting; inflammation; longevity; mitophagy; salicylate.
- Aspirin Recapitulates Features of Caloric Restriction.Cell Rep. 2018 Feb 27;22(9):2395-2407. doi: 10.1016/j.celrep.2018.02.024.PMID:29490275Free PMC article.
- Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers.Autophagy. 2014;10(11):1879-82. doi: 10.4161/auto.36413.PMID:25484097Free PMC article.
- A discovery platform for the identification of caloric restriction mimetics with broad health-improving effects.Autophagy. 2020 Jan;16(1):188-189. doi: 10.1080/15548627.2019.1688984. Epub 2019 Nov 7.PMID:31690168Free PMC article.
- Caloric restriction mimetics: towards a molecular definition.Nat Rev Drug Discov. 2014 Oct;13(10):727-40. doi: 10.1038/nrd4391. Epub 2014 Sep 12.PMID:25212602Review.
- Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential.Cell Metab. 2019 Mar 5;29(3):592-610. doi: 10.1016/j.cmet.2019.01.018.PMID:30840912Review.
Aspirin looks like a good for longevity anti-aging purposes!