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Aspirin Recapitulates Features of Caloric Restriction.

ABSTRACT: The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.

SUBMITTER: Pietrocola F

PROVIDER: S-EPMC5848858 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Aspirin Recapitulates Features of Caloric Restriction.

Pietrocola Federico F Castoldi Francesca F Markaki Maria M Lachkar Sylvie S Chen Guo G Enot David P DP Durand Sylvere S Bossut Noelie N Tong Mingming M Malik Shoaib A SA Loos Friedemann F Dupont Nicolas N Mariño Guillermo G Abdelkader Nejma N Madeo Frank F Maiuri Maria Chiara MC Kroemer Romano R Codogno Patrice P Sadoshima Junichi J Tavernarakis Nektarios N Kroemer Guido G

Cell reports 20180201 9

The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate in ...[more]

PMID: 29490275

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Project description:ObjectivesCaloric restriction (CR) has been shown to slow the aging processes in a number of preclinical studies and reduces expression of aging-associated biomarkers in human trials. We hypothesized that CR would lead to increased incidence of ketosis and that ketosis in CR individuals would alter the aging-protective effects of CR or biomarkers thereof.Design/setting/participantsWe analyzed data from the "Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE, Phase 2)" Public Use Database available at calerie.duke.edu. In this study, non-obese adults between the ages of 21 and 50 were randomized to 25% CR or control (ad lib) diet groups and extensively monitored for two years. Given our focus on the effect of caloric restriction on ketosis, individuals with detectible ketones during the baseline visit (pre-randomization) and those with missing data for ketone testing were excluded from the analysis, leaving 71 control and 117 CR participants.MeasurementsWe analyzed the incidence of ketosis as well as ketosis free survival in control and CR participants and assessed the effect of ketosis on a number of clinical lab values, functional assessments, and participant survey data related to aging biology.ResultsWe report that CR was associated with modestly increased incidence of ketosis (4.4% in CR vs 1.9% in control), though CR-associated changes in T3, VO2, SUMPT-WT (weight normalized composite strength score - peak torque), physical functioning, and general health did not appear to be altered by the presence or absence of ketosis. Additional observations of interest include: 1) striking patterns of biomarker expression changes (MCP-1, TNFα, TGF-β1, GH) in both the control and CR participants between the baseline visit and the 24-month post-randomization visit and 2) pro-growth/anti-inflammatory baseline (pre-randomization) biomarker expression profile in CR individuals that later test ketone positive relative to other CR individuals.ConclusionsCR modestly increases the incidence of ketosis in healthy adults, yet the increase in ketosis in CR patients did not significantly affect the aging-protective effects of CR. However, given the relatively small number of participants who were ketone positive, further investigation in larger study cohorts is still required for definitive conclusions.

Dataset Information

Aspirin Recapitulates Features of Caloric Restriction.

Publications

Aspirin Recapitulates Features of Caloric Restriction.

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