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Review
. 2017 Oct 24;4(11):368-375.
doi: 10.15698/mic2017.11.597.

The integrated stress response in budding yeast lifespan extension

Affiliations
Review

The integrated stress response in budding yeast lifespan extension

Spike D L Postnikoff et al. Microb Cell. .

Abstract

Aging is a complex, multi-factorial biological process shared by all living organisms. It is manifested by a gradual accumulation of molecular alterations that lead to the decline of normal physiological functions in a time-dependent fashion. The ultimate goal of aging research is to develop therapeutic means to extend human lifespan, while reducing susceptibility to many age-related diseases including cancer, as well as metabolic, cardiovascular and neurodegenerative disorders. However, this first requires elucidation of the causes of aging, which has been greatly facilitated by the use of model organisms. In particular, the budding yeast Saccharomyces cerevisiae has been invaluable in the identification of conserved molecular and cellular determinants of aging and for the development of approaches to manipulate these aging determinants to extend lifespan. Strikingly, where examined, virtually all means to experimentally extend lifespan result in the induction of cellular stress responses. This review describes growing evidence in yeast that activation of the integrated stress response contributes significantly to lifespan extension. These findings demonstrate that yeast remains a powerful model system for elucidating conserved mechanisms to achieve lifespan extension that are likely to drive therapeutic approaches to extend human lifespan and healthspan.

Keywords: autophagy; budding yeast; chronological lifespan; integrated stress response; replicative lifespan.

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Conflict of interest statement

Conflict of interest: The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. FIGURE 1: Overview of the yeast integrated stress response and how it is influenced by lifespan extending interventions.
During growth in nutrient rich conditions, the ternary complex is formed from eIF2, methionine bound to tRNAiMet, and GTP, which then delivers Met-tRNAiMet to the 40S ribosome to make the 43S complex, which is a key rate-limiting step in translational initiation. Under rich growth conditions, efficient translation of the inhibitory upstream ORFs (uORFs) of the GCN4 mRNA causes dissociation of the ribosome, preventing it scanning along the mRNA to the protein coding ORF (blue). The regimens indicated in pink, which all extend RLS, either result in increased abundance of uncharged tRNAs that activate Gcn2 to phosphorylate eIF2α to prevent formation of functional eIF2-GTP, or they activate Gcn4 in a Gcn2-independent manner, in conditions that reduce formation of the ternary complex directly (reduced amounts of processed tRNAs in the cytoplasm, reduced amino acids) or via reduced amounts of ribosomal subunits. In either case, the end result is inefficient 80S ribosome formation, which promotes leaky scanning along the mRNA to the protein coding ORF of GCN4. The resulting Gcn4 protein induces transcription of genes required for the indicated stress response pathways.

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