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.
Highlights
TO YEAST AGING The intent of lifespan-extending regimens is to prevent and treat the major diseases of society
In this review we provide an overview of emerging evidence indicating the importance of the Integrated Stress Response (ISR) as a parallel, yet opposing, nutrient-signaling mechanism to target of rapamycin (TOR) signaling
We highlight findings suggesting a fundamental role of the ISR as a target effector of nutrient signaling on yeast lifespan
Summary
TO YEAST AGING The intent of lifespan-extending regimens is to prevent and treat the major diseases of society. Amino acid depletion is a clear mechanism to extend both RLS and CLS, while reduced abundance of ribosomal subunits or deletion of the LOS1 gene required for tRNA export extend RLS in a manner dependent on Gcn4 but not Gcn2 [22,23,24]. We are still at an early stage in trying to understand which of the downstream stress response pathways induced by Gcn4 are key to the lifespan extension mediated by the ISR (Fig. 1).
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