Nucleocytosolic Depletion of the Energy Metabolite Acetyl-Coenzyme A Stimulates Autophagy and Prolongs Lifespan

Abstract

SummaryHealthy aging depends on removal of damaged cellular material that is in part mediated by autophagy. The nutritional status of cells affects both aging and autophagy through as-yet-elusive metabolic circuitries. Here, we show that nucleocytosolic acetyl-coenzyme A (AcCoA) production is a metabolic repressor of autophagy during aging in yeast. Blocking the mitochondrial route to AcCoA by deletion of the CoA-transferase ACH1 caused cytosolic accumulation of the AcCoA precursor acetate. This led to hyperactivation of nucleocytosolic AcCoA-synthetase Acs2p, triggering histone acetylation, repression of autophagy genes, and an age-dependent defect in autophagic flux, culminating in a reduced lifespan. Inhibition of nutrient signaling failed to restore, while simultaneous knockdown of ACS2 reinstated, autophagy and survival of ach1 mutant. Brain-specific knockdown of Drosophila AcCoA synthetase was sufficient to enhance autophagic protein clearance and prolong lifespan. Since AcCoA integrates various nutrition pathways, our findings may explain diet-dependent lifespan and autophagy regulation.

Targeting chromatin aging - The epigenetic impact of longevity-associated interventions

“…Inhibition of lysine acetyl transferases and acetyl-CoA synthases resulted in H3 and H4 hypoacetylation and increased lifespan (Eisenberg et al, 2014). These observations open up the possibility that by ameliorating global age-related histone hyperacetylation using small molecule and dietary intervention, we may be able to enhance health and longevity.…”

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

“…Compared with BMI-matched individuals, obese patients with NAFLD exhibit increased hepatic glucose production and TCA cycle flux without augmented ketogenesis (28). DNA methylation, nuclear receptor-mediated transcriptional activation, and reversible succinylation, acetylation, acetylation (45,46), autophagy (47,48), and histone acetylation and subsequent transcriptional changes (49,50). Future experiments will explore the scope of signaling consequences of insufficient ketogenesis, how altered acetyl-CoA metabolism may mediate those effects, and how discrete acetyl-CoA pools target distinct fates based on the original source of acetyl-CoA.…”

Programmed cell death 50 (and beyond)

“…Electron micrographs from the study by Lockshin and Williams; 14 graph from the study by Lockshin and Williams 12 cells -their current metabolic reserves, their antecedent history, or distance from mitosis, the proximity of other cells that can support or undermine them, or many other factorsmakes it possible for cells to respond differently to the same stress. 5,[68][69][70][71][72][73][74] When we attempt to change their fate, it is not sufficient to consider that we can block or induce apoptosis. Cells have far more options than apoptosis, especially when we consider their behavior in an organism rather than in a Petri dish.…”