Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation

Abstract

Protein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging. The integrated stress response (ISR) is a conserved stress-signaling pathway that tunes mRNA translation via phosphorylation of the translation initiation factor eIF2. ISR activation and translation initiation are finely balanced by eIF2 kinases and by the eIF2 guanine nucleotide exchange factor eIF2B. However, the role of the ISR during aging remains poorly understood. Using a genomic mutagenesis screen for longevity in Caenorhabditis elegans, we define a role of eIF2 modulation in aging. By inhibiting the ISR, dominant mutations in eIF2B enhance protein homeostasis and increase lifespan. Consistently, full ISR inhibition using phosphorylation-defective eIF2α or pharmacological ISR inhibition prolong lifespan. Lifespan extension through impeding the ISR occurs without a reduction in overall protein synthesis. Instead, we observe changes in the translational efficiency of a subset of mRNAs, of which the putative kinase kin-35 is required for lifespan extension. Evidently, lifespan is limited by the ISR and its inhibition may provide an intervention in aging.

ATF-4 and hydrogen sulfide signalling mediate longevity from inhibition of translation or mTORC1

“…Although inhibition of mTORC1 has received widespread enthusiasm as an anti-ageing strategy, mTORC1 maintains fundamental processes that include protein synthesis, mRNA splicing, and metabolic pathways 2,3,[48][49][50] , suggesting that not all effects of mTORC1 suppression are necessarily beneficial. Similarly, although conditions that suppress ISR signalling can promote longevity through effects on selective translation 15 , ISR signalling through eIF2 contributes to lifespan extension from reduced insulin/IGF-1 signalling 24 , and our results demonstrate that the downstream ISR effector ATF-4 is a potent pro-longevity factor. Furthermore, while pharmacological ISR inhibition preserves cognitive functions during ageing by maintaining protein synthesis 14,16 , our findings suggest that ISR suppression could reduce levels of H2S, which has been shown to prevent neurodegeneration 51,52 .…”

“…Puromycin incorporation and detection assays were adapted from previous studies 15,59 . Approximately 500 L4 animals were resuspended in M9 and transferred to NGM plates containing 50 µM FUdR seeded with RNAi bacteria clones.…”

“…This suppression of translation leads in turn to preferential translation of the activating transcription factor ATF4, which mobilizes stress defense mechanisms to reestablish homeostasis 13,14  Although the ISR has important protective functions, its effects on longevity and health are complex. In C. elegans, genetic or pharmacological interventions that impair the ISR extend lifespan by inducing preferential translation of selective mRNAs 15 . In older mice, pharmacological ISR inhibition enhances memory and cognition by allowing protein synthesis to be maintained 14,16 .…”

Roles of interacting stress related genes in lifespan regulation: insights for translating experimental findings to humans

“…Cellular stressors may be intrinsic (e.g., misfolded proteins, genetic polymorphisms [53] ) or external (e.g., nutrient deprivation, viral infection, hypoxia, UVirradiation, and others [54][55][56] ). Experimental and clinical studies provide evidence about involvement of ISR in lifespan regulation [57,58] , as well as in the development of agingrelated diseases including cognitive and neurodegenerative disorders [49,55] , cancer [59][60][61] , pulmonary disease [62] , atherosclerosis [63,64] , diabetes [65] and other metabolic disorders [66] .…”

“…Experimental studies provide evidence about both positive and negative influence of the ISR initiation on health and survival traits [57,58,62] . The improvement in survival is likely to be related with the reduction of the metabolic rate in the cells at the time of cellular stress response, which is in concert with the Max Rubner's "rate of living theory of aging" [161] .…”