The integrated stress response in budding yeast lifespan extension

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.

Identifying Longevity Associated Genes by Integrating Gene Expression and Curated Annotations

“…Telomeres are known to be important in yeast longevity (Austriaco & Guarente, 1997;Liu, Wang, Wang, & Liu, 2019), so a large coefficient for telomere maintenance makes sense. Longevity effects of cellular response to oxidative stress are corroborated in the literature (Postnikoff, Johnson, & Tyler, 2017). Finally, a negative coefficient for zinc ion binding is consistent with experimental evidence that zinc limitation extends chronological lifespan (Shimasaki et al, 2017).…”

Guidelines and recommendations on yeast cell death nomenclature

“…In fact, ROS play a crucial role in intracellular signaling 129 130 131 132 , functioning, for instance, as direct and indirect regulators of diverse physiologically relevant targets 133 134 135 . In addition, limited ROS generation might be beneficial under certain conditions, since the resulting adaptive responses can promote stress resistance as a form of preconditioning (hormesis) 131 136 137 138 139 . Thus, an increase in ROS should be regarded as a cell death-correlated phenotype only in connection with assays that directly determine increased plasma membrane disintegration and loss of clonogenicity (see above).…”

The role of autophagy in the regulation of yeast life span

“…However, another possibility is that elevated levels of tRNAs might extend life span cooperatively through activation of both retrograde signaling and the integrated stress response. 73 In either case, a putative role for tRNAs in yeast life span regulation is notable given a recent report describing how abrogation of MAFR-1 (a repressor of RNA polymerase III) in Caenorhabditis elegans alleviates the inhibition of tRNA synthesis that normally accompanies CR, thereby upregulating various stress responses, activating autophagy, and extending life span. 74 These findings thus provide a tantalizing suggestion that tRNA-related mechanisms that regulate longevity in response to dietary interventions may be conserved from yeast to more complex organisms.…”

“…One output of the integrated stress response is autophagy induction. The role of the integrated stress response in RLS extension has been reviewed elsewhere recently 73 and will not be discussed further here.…”