Is Gcn4-induced autophagy the ultimate downstream mechanism by which hormesis extends yeast replicative lifespan?

Abstract

The number of times a cell divides before irreversibly arresting is termed replicative lifespan. Despite discovery of many chemical, dietary and genetic interventions that extend replicative lifespan, usually first discovered in budding yeast and subsequently shown to apply to metazoans, there is still little understanding of the underlying molecular mechanisms involved. One unifying theme is that most, if not all, interventions that extend replicative lifespan induce "hormesis", where a little inflicted damage makes cells more able to resist similar challenges in the future. One of the many cellular changes that occur during hormesis is a global reduction in protein synthesis, which has been linked to enhanced longevity in many organisms. Our recent study in budding yeast found that it was not the reduction in protein synthesis per se, but rather the subsequent induction of the conserved Gcn4 transcriptional regulator and its ability to induce autophagy that was responsible for extending replicative lifespan. We propose that Gcn4-dependent induction of autophagy occurring downstream of reduced global protein synthesis may be a unifying molecular mechanism for many interventions that extend replicative lifespan.

Keywords: Aging; Autophagy; Gcn4; Hormesis; Yeast.

Figure 1.

Left side: in normal growth conditions, yeast Gcn4 is not efficiently synthesized due to engagement of the ribosome with the inhibitory upstream open reading frames (uORFs), leading to ribosome dissociation by the time they reach the Gcn4 protein coding ORF. Upon deletion of the GCN4 uORFs (bottom), the ribosomes efficiently scan to the Gcn4 protein coding ORF, inducing Gcn4 production. Gcn4 induces transcription of genes important for key stress responses, some of which are indicated. Induction of Gcn4 in this way extended yeast replicative lifespan in a manner that was totally dependent on autophagy, but independent of Tor1 inhibition and independent of noticable effects on global protein synthesis. Right side: nutrient depletion or other stresses (indicated in red) that induce hormesis and extend replicative lifespan reduce global Cap-dependent protein synthesis, leading to less efficient translation machinery which promotes leaky scanning of the ribosomes along the mRNA to translate Gcn4. Whether autophagy is involved in the replicative lifespan extension that is stimulated by hormesis is unknown (hence the “?”).