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

Nature Aging volume 1, pages 760–768 (2021)Cite this article

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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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References

  1. The Lancet Diabetes & Endocrinology. Opening the door to treating ageing as a disease. Lancet Diabetes Endocrinol. 6, 587 (2018).

  2. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  3. Kourtis, N. & Tavernarakis, N. Cellular stress response pathways and ageing: intricate molecular relationships. EMBO J. 30, 2520–2531 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kyriakakis, E., Princz, A. & Tavernarakis, N. Stress responses during ageing: molecular pathways regulating protein homeostasis. Methods Mol. Biol. 1292, 215–234 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Klaips, C. L., Jayaraj, G. G. & Hartl, F. U. Pathways of cellular proteostasis in aging and disease. J. Cell Biol. 217, 51–63 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dever, T. E. et al. Phosphorylation of initiation factor 2α by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell 68, 585–596 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Brostrom, C. O., Prostko, C. R., Kaufman, R. J. & Brostrom, M. A. Inhibition of translational initiation by activators of the glucose-regulated stress protein and heat shock protein stress response systems. Role of the interferon-inducible double-stranded RNA-activated eukaryotic initiation factor 2α kinase. J. Biol. Chem. 271, 24995–25002 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).

    Article  CAS  PubMed  Google Scholar 

  9. Merrick, W. C. & Pavitt, G. D. Protein synthesis initiation in eukaryotic cells. Cold Spring Harb. Perspect. Biol. 10, a033092 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lomakin, I. B. & Steitz, T. A. The initiation of mammalian protein synthesis and mRNA scanning mechanism. Nature 500, 307–311 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pavitt, G. D., Ramaiah, K. V., Kimball, S. R. & Hinnebusch, A. G. eIF2 independently binds two distinct eIF2B subcomplexes that catalyze and regulate guanine-nucleotide exchange. Genes Dev. 12, 514–526 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Han, A.-P. et al. Heme-regulated eIF2α kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency. EMBO J. 20, 6909–6918 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kumar, K. U., Srivastava, S. P. & Kaufman, R. J. Double-stranded RNA-activated protein kinase (PKR) is negatively regulated by 60S ribosomal subunit protein L18. Mol. Cell. Biol. 19, 1116–1125 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Shi, Y. et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 α-subunit kinase, PEK, involved in translational control. Mol. Cell. Biol. 18, 7499–7509 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Guo, X. et al. Mitochondrial stress is relayed to the cytosol by an OMA1–DELE1–HRI pathway. Nature 579, 427–432 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fessler, E. et al. A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579, 433–437 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Taniuchi, S., Miyake, M., Tsugawa, K., Oyadomari, M. & Oyadomari, S. Integrated stress response of vertebrates is regulated by four eIF2α kinases. Sci. Rep. 6, 32886 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kimball, S. R., Fabian, J. R., Pavitt, G. D., Hinnebusch, A. G. & Jefferson, L. S. Regulation of guanine nucleotide exchange through phosphorylation of eukaryotic initiation factor eIF2α. Role of the α- and δ-subunits of eiF2b. J. Biol. Chem. 273, 12841–12845 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Adomavicius, T. et al. The structural basis of translational control by eIF2 phosphorylation. Nat. Commun. 10, 2136 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Gordiyenko, Y., Llácer, J. L. & Ramakrishnan, V. Structural basis for the inhibition of translation through eIF2α phosphorylation. Nat. Commun. 10, 2640 (2019).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Vattem, K. M. & Wek, R. C. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc. Natl Acad. Sci. USA 101, 11269–11274 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sidrauski, C., McGeachy, A. M., Ingolia, N. T. & Walter, P. The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife 4, e05033 (2015).

    Article  CAS  PubMed Central  Google Scholar 

  23. Lee, Y.-Y., Cevallos, R. C. & Jan, E. An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2α phosphorylation. J. Biol. Chem. 284, 6661–6673 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jousse, C. et al. Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5′UTR. Nucl. Acids Res. 29, 4341–4351 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jousse, C. et al. Inhibition of a constitutive translation initiation factor 2α phosphatase, CReP, promotes survival of stressed cells. J. Cell Biol. 163, 767–775 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Novoa, I., Zeng, H., Harding, H. P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J. Cell Biol. 153, 1011–1022 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rutkowski, D. T. et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol. 4, e374 (2006).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Marciniak, S. J. et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18, 3066–3077 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Frakes, A. E. & Dillin, A. The UPRER: sensor and coordinator of organismal homeostasis. Mol. Cell 66, 761–771 (2017).

    Article  CAS  PubMed  Google Scholar 

  31. Cullinan, S. B. et al. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol. Cell. Biol. 23, 7198–7209 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728–733 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Torrence, M. E. et al. The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals. Elife 10, (2021).

  34. McConkey, D. J. The integrated stress response and proteotoxicity in cancer therapy. Biochem. Biophys. Res. Commun. 482, 450–453 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Moortgat, S. et al. Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy. Am. J. Med. Genet. A 170, 2927–2933 (2016).

    Article  CAS  PubMed  Google Scholar 

  36. Skopkova, M. et al. EIF2S3 mutations associated with severe X-linked intellectual disability syndrome MEHMO. Hum. Mutat. 38, 409–425 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nguyen, H. G. et al. Development of a stress response therapy targeting aggressive prostate cancer. Sci. Transl. Med. 10, eaar2036 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. Tameire, F. et al. ATF4 couples MYC-dependent translational activity to bioenergetic demands during tumour progression. Nat. Cell Biol. 21, 889–899 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chou, A. et al. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proc. Natl Acad. Sci. USA 114, E6420–E6426 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhu, P. J. et al. Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome. Science 366, 843–849 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bugallo, R. et al. Fine tuning of the unfolded protein response by ISRIB improves neuronal survival in a model of amyotrophic lateral sclerosis. Cell Death Dis. 11, 397 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Oliveira, M. M. et al. Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease. Sci. Signal. 14, eabc5429 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Colla, E. et al. Accumulation of toxic α-synuclein oligomer within endoplasmic reticulum occurs in α-synucleinopathy in vivo. J. Neurosci. 32, 3301–3305 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jiang, H.-Q. et al. Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. Neuroscience 277, 132–138 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Özcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    Article  PubMed  CAS  Google Scholar 

  46. Scali, O., Di Perri, C. & Federico, A. The spectrum of mutations for the diagnosis of vanishing white matter disease. Neurol. Sci. 27, 271–277 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Hanefeld, F. et al. Diffuse white matter disease in three children: an encephalopathy with unique features on magnetic resonance imaging and proton magnetic resonance spectroscopy. Neuropediatrics 24, 244–248 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Schiffmann, R. et al. Childhood ataxia with diffuse central nervous system hypomyelination. Ann. Neurol. 35, 331–340 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Mao, D. et al. De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation. Am. J. Hum. Genet. 106, 570–583 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. DeLozier-Blanchet, C. D., Haenggeli, C. A. & Bottani, A. MEHMO, a novel syndrome: assignment of disease locus to Xp21.1-p22.13. Mental retardation, epileptic seizures, hypogonadism and genitalism, microcephaly, obesity. Eur. J. Hum. Genet. 7, 621–622 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Hunter, J. M. et al. Review of X-linked syndromes with arthrogryposis or early contractures—aid to diagnosis and pathway identification. Am. J. Med. Genet. A 167A, 931–973 (2015).

    Article  PubMed  Google Scholar 

  52. Gregory, L. C. et al. Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation. EBioMedicine 42, 470–480 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Abdulkarim, B. et al. A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature, and microcephaly. Diabetes 64, 3951–3962 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kernohan, K. D. et al. Homozygous mutation in the eukaryotic translation initiation factor 2α phosphatase gene, PPP1R15B, is associated with severe microcephaly, short stature and intellectual disability. Hum. Mol. Genet. 24, 6293–6300 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wolcott, C. D. & Rallison, M. L. Infancy-onset diabetes mellitus and multiple epiphyseal dysplasia. J. Pediatr. 80, 292–297 (1972).

    Article  CAS  PubMed  Google Scholar 

  56. Julier, C. & Nicolino, M. Wolcott-Rallison syndrome. Orphanet J. Rare Dis. 5, 29–13 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Eyries, M. et al. EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension. Nat. Genet. 46, 65–69 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Naidoo, N. et al. Aging and sleep deprivation induce the unfolded protein response in the pancreas: implications for metabolism. Aging Cell 13, 131–141 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Ladiges, W., Morton, J., Blakely, C. & Gale, M. Tissue specific expression of PKR protein kinase in aging B6D2F1 mice. Mech. Ageing Dev. 114, 123–132 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Ubaida-Mohien, C. et al. Discovery proteomics in aging human skeletal muscle finds change in spliceosome, immunity, proteostasis and mitochondria. Elife 8, 852 (2019).

    Article  Google Scholar 

  61. Krukowski, K. et al. Small molecule cognitive enhancer reverses age-related memory decline in mice. Elife 9, 1671 (2020).

    Article  Google Scholar 

  62. Chalil, S. et al. Aging related ER stress is not responsible for anabolic resistance in mouse skeletal muscle. Biochem. Biophys. Res. Commun. 468, 702–707 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. Segev, Y., Michaelson, D. M. & Rosenblum, K. ApoE ε4 is associated with eIF2α phosphorylation and impaired learning in young mice. Neurobiol. Aging 34, 863–872 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Brown, M. K. et al. Aging induced endoplasmic reticulum stress alters sleep and sleep homeostasis. Neurobiol. Aging 35, 1431–1441 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Derisbourg, M. J., Wester, L. E., Baddi, R. & Denzel, M. S. Mutagenesis screen uncovers lifespan extension through integrated stress response inhibition without reduced mRNA translation. Nat. Commun. 12, 1678 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Salganik, M. et al. The loss of glucose-regulated protein 78 (GRP78) during normal aging or from siRNA knockdown augments human alpha-synuclein (α-syn) toxicity to rat nigral neurons. Neurobiol. Aging 36, 2213–2223 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Li, W., Li, X. & Miller, R. A. ATF4 activity: a common feature shared by many kinds of slow-aging mice. Aging Cell 13, 1012–1018 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Li, W. & Miller, R. A. Elevated ATF4 function in fibroblasts and liver of slow-aging mutant mice. J. Gerontol. A Biol. Sci. Med. Sci. 70, 263–272 (2015).

    Article  CAS  PubMed  Google Scholar 

  69. Makrides, S. C. Protein synthesis and degradation during aging and senescence. Biol. Rev. 58, 343–422 (1983).

    Article  CAS  PubMed  Google Scholar 

  70. Johnson, T. E. & McCaffrey, G. Programmed aging or error catastrophe? An examination by two-dimensional polyacrylamide gel electrophoresis. Mech. Ageing Dev. 30, 285–297 (1985).

    Article  CAS  PubMed  Google Scholar 

  71. Rattan, S. I. & Clark, B. F. Intracellular protein synthesis, modifications and aging. Biochem. Soc. Trans. 24, 1043–1049 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Tavernarakis, N. Ageing and the regulation of protein synthesis: a balancing act? Trends Cell Biol. 18, 228–235 (2008).

    Article  CAS  PubMed  Google Scholar 

  73. Iwawaki, T. et al. Transgenic mouse model for imaging of ATF4 translational activation-related cellular stress responses in vivo. Sci. Rep. 7, 46230–46239 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Helseth, A. R. et al. Cholinergic neurons constitutively engage the ISR for dopamine modulation and skill learning in mice. Science https://doi.org/10.1126/science.abe1931 (2021).

  75. Wu, C. C.-C., Peterson, A., Zinshteyn, B., Regot, S. & Green, R. Ribosome collisions trigger general stress responses to regulate cell fate. Cell 182, 404–416 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Peidis, P., Papadakis, A. I., Muaddi, H., Richard, S. & Koromilas, A. E. Doxorubicin bypasses the cytoprotective effects of eIF2α phosphorylation and promotes PKR-mediated cell death. Cell Death Differ. 18, 145–154 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Hao, S. et al. Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307, 1776–1778 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Seo, J. et al. Atf4 regulates obesity, glucose homeostasis, and energy expenditure. Diabetes 58, 2565–2573 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ye, J. et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation. EMBO J. 29, 2082–2096 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rozpedek, W. et al. The role of the PERK/eIF2α/ATF4/CHOP signaling pathway in tumor progression during endoplasmic reticulum stress. Curr. Mol. Med. 16, 533–544 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hu, Z. et al. Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan. Elife 7, 4443 (2018).

    Google Scholar 

  82. Postnikoff, S. D. L., Johnson, J. E. & Tyler, J. K. The integrated stress response in budding yeast lifespan extension. Microb. Cell 4, 368–375 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Richardson, C. E., Kinkel, S. & Kim, D. H. Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity. PLoS Genet. 7, e1002391 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Horsman, J. W. & Miller, D. L. Mitochondrial sulfide quinone oxidoreductase prevents activation of the unfolded protein response in hydrogen sulfide. J. Biol. Chem. 291, 5320–5325 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Tohyama, D., Yamaguchi, A. & Yamashita, T. Inhibition of a eukaryotic initiation factor (eIF2Bδ/F11A3.2) during adulthood extends lifespan in Caenorhabditis elegans. FASEB J. 22, 4327–4337 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Horn, M. et al. Hexosamine pathway activation improves protein homeostasis through the integrated stress response. iScience 23, 100887 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rousakis, A. et al. The general control nonderepressible-2 kinase mediates stress response and longevity induced by target of rapamycin inactivation in Caenorhabditis elegans. Aging Cell 12, 742–751 (2013).

    Article  CAS  PubMed  Google Scholar 

  88. Shen, X. et al. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 107, 893–903 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Cassada, R. C. & Russell, R. L. The dauerlarva, a post-embryonic developmental variant of the nematode Caenorhabditis elegans. Dev. Biol. 46, 326–342 (1975).

    Article  CAS  PubMed  Google Scholar 

  90. Kulalert, W. & Kim, D. H. The unfolded protein response in a pair of sensory neurons promotes entry of C. elegans into dauer diapause. Curr. Biol. 23, 2540–2545 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Kulalert, W., Sadeeshkumar, H., Zhang, Y. K., Schroeder, F. C. & Kim, D. H. Molecular determinants of the regulation of development and metabolism by neuronal eIF2α phosphorylation in Caenorhabditis elegans. Genetics 206, 251–263 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Baker, B. M., Nargund, A. M., Sun, T. & Haynes, C. M. Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2. PLoS Genet. 8, e1002760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Lee, E. C.-H. & Strange, K. GCN-2 dependent inhibition of protein synthesis activates osmosensitive gene transcription via WNK and Ste20 kinase signaling. Am. J. Physiol. Cell Physiol. 303, C1269–C1277 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim, H. & Strange, K. Changes in translation rate modulate stress-induced damage of diverse proteins. Am. J. Physiol. Cell Physiol. 305, C1257–C1264 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Garcia-Barrio, M., Dong, J., Ufano, S. & Hinnebusch, A. G. Association of GCN1-GCN20 regulatory complex with the N-terminus of eIF2α kinase GCN2 is required for GCN2 activation. EMBO J. 19, 1887–1899 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Pereira, C. M. et al. IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation. J. Biol. Chem. 280, 28316–28323 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Ferraz, R. C. et al. IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans. BMC Biol. 14, 87 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  98. Santoyo, J., Alcalde, J., Méndez, R., Pulido, D. & de Haro, C. Cloning and characterization of a cDNA encoding a protein synthesis initiation factor-2α (eIF-2α) kinase from Drosophila melanogaster homology to yeast GCN2 protein kinase. J. Biol. Chem. 272, 12544–12550 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Olsen, D. S., Jordan, B., Chen, D., Wek, R. C. & Cavener, D. R. Isolation of the gene encoding the Drosophila melanogaster homolog of the Saccharomyces cerevisiae GCN2 eIF-2α kinase. Genetics 149, 1495–1509 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Pomar, N. et al. Functional characterization of Drosophila melanogaster PERK eukaryotic initiation factor 2α (eIF2α) kinase. Eur. J. Biochem. 270, 293–306 (2003).

    Article  CAS  PubMed  Google Scholar 

  101. Malzer, E. et al. Coordinate regulation of eIF2α phosphorylation by PPP1R15 and GCN2 is required during Drosophila development. J. Cell Sci. 126, 1406–1415 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Malzer, E. et al. Impaired tissue growth is mediated by checkpoint kinase 1 (CHK1) in the integrated stress response. J. Cell Sci. 123, 2892–2900 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang, L., Ryoo, H. D., Qi, Y. & Jasper, H. PERK limits Drosophila lifespan by promoting intestinal stem cell proliferation in response to ER stress. PLoS Genet. 11, e1005220 (2015).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  104. Kang, M.-J. et al. 4E-BP is a target of the GCN2-ATF4 pathway during Drosophila development and aging. J. Cell Biol. 216, 115–129 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165–1176 (2001).

    Article  CAS  PubMed  Google Scholar 

  106. Zhang, P. et al. The PERK eukaryotic initiation factor 2 α kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol. Cell. Biol. 22, 3864–3874 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Harding, H. P. et al. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 α (eIF2α) dephosphorylation in mammalian development. Proc. Natl Acad. Sci. USA 106, 1832–1837 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Krzyzosiak, A. et al. Target-based discovery of an inhibitor of the regulatory phosphatase PPP1R15B. Cell 174, 1216–1228 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Das, I. et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348, 239–242 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang, L., Popko, B., Tixier, E. & Roos, R. P. Guanabenz, which enhances the unfolded protein response, ameliorates mutant SOD1-induced amyotrophic lateral sclerosis. Neurobiol. Dis. 71, 317–324 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Way, S. W. et al. Pharmaceutical integrated stress response enhancement protects oligodendrocytes and provides a potential multiple sclerosis therapeutic. Nat. Commun. 6, 6532 (2015).

    Article  CAS  PubMed  Google Scholar 

  112. Chen, T. et al. Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase. J. Med. Chem. 56, 9457–9470 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Boyce, M. et al. A selective inhibitor of eIF2α dephosphorylation protects cells from ER stress. Science 307, 935–939 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Costa-Mattioli, M. et al. eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129, 195–206 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tsaytler, P., Harding, H. P., Ron, D. & Bertolotti, A. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 332, 91–94 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Carrara, M., Sigurdardottir, A. & Bertolotti, A. Decoding the selectivity of eIF2α holophosphatases and PPP1R15A inhibitors. Nat. Struct. Mol. Biol. 24, 708–716 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Dedigama-Arachchige, P. M., Acharige, N. P. N. & Pflum, M. K. H. Identification of PP1-Gadd34 substrates involved in the unfolded protein response using K-BIPS, a method for phosphatase substrate identification. Mol. Omics 14, 121–133 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Crespillo-Casado, A., Chambers, J. E., Fischer, P. M., Marciniak, S. J. & Ron, D. PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz. Elife 6, 209 (2017).

    Article  Google Scholar 

  119. Crespillo-Casado, A. et al. A Sephin1-insensitive tripartite holophosphatase dephosphorylates translation initiation factor 2α. J. Biol. Chem. 293, 7766–7776 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dash, P. K. et al. Inhibition of eukaryotic initiation factor 2 α phosphatase reduces tissue damage and improves learning and memory after experimental traumatic brain injury. J. Neurotrauma 32, 1608–1620 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Dooves, S. et al. Bergmann glia translocation: a new disease marker for vanishing white matter identifies therapeutic effects of Guanabenz treatment. Neuropathol. Appl. Neurobiol. 44, 391–403 (2018).

    Article  CAS  PubMed  Google Scholar 

  122. Chen, Y. et al. Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis. Brain 142, 344–361 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Bella, E. D. et al. The unfolded protein response in amyotrophic later sclerosis: results of a phase 2 trial. Brain https://doi.org/10.1093/brain/awab167 (2021).

  124. Axten, J. M. et al. Discovery of 7-methyl-5-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J. Med. Chem. 55, 7193–7207 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Rozpędek, W. et al. Inhibition of PERK-dependent pro-adaptive signaling pathway as a promising approach for cancer treatment. Pol. Przegl. Chir. 89, 7–10 (2017).

    Article  PubMed  Google Scholar 

  126. Halliday, M. et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis. 6, e1672 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Moreno, J. A. et al. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci. Transl. Med. 5, 206ra138 (2013).

    Article  PubMed  CAS  Google Scholar 

  128. Sidrauski, C. et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. Elife 2, e00498 (2013).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  129. Sekine, Y. et al. Mutations in a translation initiation factor identify the target of a memory-enhancing compound. Science 348, 1027–1030 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Tsai, J. C. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science 359, eaaq0939 (2018).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  131. Schoof, M. et al. eIF2B conformation and assembly state regulate the integrated stress response. Elife 10, (2021).

  132. Zyryanova, A. F. et al. ISRIB blunts the integrated stress response by allosterically antagonising the inhibitory effect of phosphorylated eIF2 on eIF2B. Mol. Cell 81, 88–103 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wong, Y. L. et al. eIF2B activator prevents neurological defects caused by a chronic integrated stress response. Elife 8, 1867 (2019).

    Google Scholar 

  134. Halliday, M. et al. Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice. Brain 140, 1768–1783 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Radford, H., Moreno, J. A., Verity, N., Halliday, M. & Mallucci, G. R. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol. 130, 633–642 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Briggs, D. I. et al. Role of endoplasmic reticulum stress in learning and memory impairment and Alzheimer’s disease-like neuropathology in the PS19 and APPSwe mouse models of tauopathy and amyloidosis. eNeuro 4, ENEURO.0025-17.2017 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Johnson, E. C. B. & Kang, J. A small molecule targeting protein translation does not rescue spatial learning and memory deficits in the hAPP-J20 mouse model of Alzheimer’s disease. PeerJ 4, e2565 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Luh, L. M. & Bertolotti, A. Potential benefit of manipulating protein quality control systems in neurodegenerative diseases. Curr. Opin. Neurobiol. 61, 125–132 (2020).

    Article  CAS  PubMed  Google Scholar 

  139. Anand, A. A. & Walter, P. Structural insights into ISRIB, a memory-enhancing inhibitor of the integrated stress response. FEBS J. 287, 239–245 (2020).

    Article  CAS  PubMed  Google Scholar 

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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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  1. These authors contributed equally: Maxime J. Derisbourg, Matías D. Hartman.

Authors and Affiliations

  1. Max Planck Institute for Biology of Ageing, Cologne, Germany

    Maxime J. Derisbourg, Matías D. Hartman & Martin S. Denzel

  2. CECAD - Cluster of Excellence, University of Cologne, Cologne, Germany

    Martin S. Denzel

  3. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

    Martin S. Denzel

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  1. Maxime J. Derisbourg
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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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