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Modulating the integrated stress response to slow aging and ameliorate age-related pathology

Abstract

Healthy aging requires the coordination of numerous stress signaling pathways that converge on the protein homeostasis network. The integrated stress response (ISR) is activated by diverse stimuli, leading to phosphorylation of the eukaryotic translation initiation factor eIF2 in its α-subunit. Under replete conditions, eIF2 orchestrates 5′ cap–dependent mRNA translation and is thus responsible for general protein synthesis. eIF2α phosphorylation, the key event of the ISR, reduces global mRNA translation while enhancing the expression of a signature set of stress response genes. Despite the critical role of protein quality control in healthy aging and in numerous longevity pathways, the role of the ISR in longevity remains largely unexplored. ISR activity increases with age, suggesting a potential link with the aging process. Although decreased protein biosynthesis, which occurs during ISR activation, has been linked to lifespan extension, recent data show that lifespan is limited by the ISR as its inhibition extends survival in nematodes and enhances cognitive function in aged mice. Here we survey how aging affects the ISR, the role of the ISR in modulating aging, and pharmacological interventions to tune the ISR. Finally, we will explore the ISR as a plausible target for clinical interventions in aging and age-related disease.

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Fig. 1: The ISR signaling pathway.

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Acknowledgements

We thank all Denzel laboratory members for helpful discussions about this manuscript. We further thank P. Walter, M. Costa-Mattioli and A. Bertolotti for valuable comments on the manuscript. Figure 1 was created with BioRender.com. This work was supported by the European Commission (ERC-2014-StG-640254-MetAGEn) and by the Max Planck Society.

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M.J.D., M.D.H. and M.S.D. wrote and edited the manuscript.

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Correspondence to Martin S. Denzel.

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M.S.D. is cofounder of Acus Laboratories GmbH and scientific advisor to JLP Health GmbH. All other authors declare no competing interests.

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Derisbourg, M.J., Hartman, M.D. & Denzel, M.S. Modulating the integrated stress response to slow aging and ameliorate age-related pathology. Nat Aging 1, 760–768 (2021). https://doi.org/10.1038/s43587-021-00112-9

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