Is Gcn4-induced autophagy the ultimate downstream mechanism by which hormesis extends yeast replicative lifespan?

  • Zih-Jie Shen
  • Spike Postnikoff
  • Jessica K. TylerEmail author


The number of times a cell divides before irreversibly arresting is termed replicative lifespan. Despite discovery of many chemical, dietary and genetic interventions that extend replicative lifespan, usually first discovered in budding yeast and subsequently shown to apply to metazoans, there is still little understanding of the underlying molecular mechanisms involved. One unifying theme is that most, if not all, interventions that extend replicative lifespan induce “hormesis”, where a little inflicted damage makes cells more able to resist similar challenges in the future. One of the many cellular changes that occur during hormesis is a global reduction in protein synthesis, which has been linked to enhanced longevity in many organisms. Our recent study in budding yeast found that it was not the reduction in protein synthesis per se, but rather the subsequent induction of the conserved Gcn4 transcriptional regulator and its ability to induce autophagy that was responsible for extending replicative lifespan. We propose that Gcn4-dependent induction of autophagy occurring downstream of reduced global protein synthesis may be a unifying molecular mechanism for many interventions that extend replicative lifespan.


Aging Yeast Autophagy Hormesis Gcn4 



  1. Ables GP, Johnson JE (2017) Pleiotropic responses to methionine restriction. Exp Gerontol 94:83–88CrossRefGoogle Scholar
  2. Castilho BA, Shanmugam R, Silva RC, Ramesh R, Himme BM, Sattlegger E (2014) Keeping the eIF2 alpha kinase Gcn2 in check. Biochim Biophys Acta 1843:1948–1968CrossRefGoogle Scholar
  3. Delaney JR, Ahmed U, Chou A, Sim S, Carr D, Murakami CJ, Schleit J, Sutphin GL, An EH, Castanza A et al (2013) Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging. Aging Cell 12:156–166CrossRefGoogle Scholar
  4. Deloche O, de la Cruz J, Kressler D, Doere M, Linder P (2004) A membrane transport defect leads to a rapid attenuation of translation initiation in Saccharomyces cerevisiae. Mol Cell 13:357–366CrossRefGoogle Scholar
  5. Ghavidel A, Baxi K, Ignatchenko V, Prusinkiewicz M, Arnason TG, Kislinger T, Carvalho CE, Harkness TA (2015) A genome scale screen for mutants with delayed exit from mitosis: ire1-independent induction of autophagy integrates ER homeostasis into mitotic lifespan. PLoS Genet 11:e1005429CrossRefGoogle Scholar
  6. Gonskikh Y, Polacek N (2017) Alterations of the translation apparatus during aging and stress response. Mech Ageing Dev 168:30–36CrossRefGoogle Scholar
  7. Hansen M, Taubert S, Crawford D, Libina N, Lee SJ, Kenyon C (2007) Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6:95–110CrossRefGoogle Scholar
  8. Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59:407–450CrossRefGoogle Scholar
  9. Hu Z, Xia B, Postnikoff SD, Shen ZJ, Tomoiaga AS, Harkness TA, Seol JH, Li W, Chen K, Tyler JK (2018) Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan. eLife. Google Scholar
  10. Kubota H, Obata T, Ota K, Sasaki T, Ito T (2003) Rapamycin-induced translational derepression of GCN4 mRNA involves a novel mechanism for activation of the eIF2 alpha kinase GCN2. J Biol Chem 278:20457–20460CrossRefGoogle Scholar
  11. Lord CL, Timney BL, Rout MP, Wente SR (2015) Altering nuclear pore complex function impacts longevity and mitochondrial function in S. cerevisiae. J Cell Biol 208:729–744CrossRefGoogle Scholar
  12. Lord CL, Ospovat O, Wente SR (2017) Nup100 regulates Saccharomyces cerevisiae replicative life span by mediating the nuclear export of specific tRNAs. RNA 23:365–377CrossRefGoogle Scholar
  13. McCormick MA, Delaney JR, Tsuchiya M, Tsuchiyama S, Shemorry A, Sim S, Chou AC, Ahmed U, Carr D, Murakami CJ et al (2015) A comprehensive analysis of replicative lifespan in 4698 single-gene deletion strains uncovers conserved mechanisms of aging. Cell Metab 22:895–906CrossRefGoogle Scholar
  14. Mehta R, Chandler-Brown D, Ramos FJ, Shamieh LS, Kaeberlein M (2010) Regulation of mRNA translation as a conserved mechanism of longevity control. Adv Exp Med Biol 694:14–29CrossRefGoogle Scholar
  15. Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, Madeo F, Kroemer G (2009) Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging 1:961–970CrossRefGoogle Scholar
  16. Nakamura S, Yoshimori T (2018) Autophagy and longevity. Mol Cells 41:65–72Google Scholar
  17. Palikaras K, Lionaki E, Tavernarakis N (2015) Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis. Cell Death Differ 22:1399–1401CrossRefGoogle Scholar
  18. Postnikoff SDL, Johnson JE, Tyler JK (2017) The integrated stress response in budding yeast lifespan extension. Microb Cell 4:368–375CrossRefGoogle Scholar
  19. Steffen KK, MacKay VL, Kerr EO, Tsuchiya M, Hu D, Fox LA, Dang N, Johnston ED, Oakes JA, Tchao BN et al (2008) Yeast life span extension by depletion of 60 s ribosomal subunits is mediated by Gcn4. Cell 133:292–302CrossRefGoogle Scholar
  20. Tang F, Watkins JW, Bermudez M, Gray R, Gaban A, Portie K, Grace S, Kleve M, Craciun G (2008) A life-span extending form of autophagy employs the vacuole–vacuole fusion machinery. Autophagy 4:874–886CrossRefGoogle Scholar
  21. Tyler JK, Johnson JE (2018) The role of autophagy in the regulation of yeast life span. Ann N Y Acad Sci 1418:31–43CrossRefGoogle Scholar
  22. Yang R, Wek SA, Wek RC (2000) Glucose limitation induces GCN4 translation by activation of Gcn2 protein kinase. Mol Cell Biol 20:2706–2717CrossRefGoogle Scholar
  23. Yu L, Chen Y, Tooze SA (2018) Autophagy pathway: Cellular and molecular mechanisms. Autophagy 14:207–215CrossRefGoogle Scholar
  24. Zou K, Ouyang Q, Li H, Zheng J (2017) A global characterization of the translational and transcriptional programs induced by methionine restriction through ribosome profiling and RNA-sEq. BMC Genom 18:189CrossRefGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineWeill Cornell MedicineNew YorkUSA

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