Skip to main content
SpringerLink
Log in

Protein Synthesis and the Antagonistic Pleiotropy Hypothesis of Aging

  • Chapter
Protein Metabolism and Homeostasis in Aging

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 694))

Abstract

Growth and somatic maintenance are thought to be antagonistic pleiotropic traits, but the molecular basis for this tradeoff is poorly understood. Here it is proposed that changes in protein synthesis mediate the tradeoffs that take place upon genetic and environmental manipulation in various model systems including yeast, worms, flies and mice. This hypothesis is supported by evidence that inhibition of the TOR (target of rapamycin) pathway and various translation factors that inhibit protein synthesis lead to slowing of growth and development but extend lifespan. Furthermore, dietary restriction (DR) that leads to antagonistic changes in growth and lifespan, also mediates this change by inhibiting protein synthesis. Direct screens to identify genes that extend lifespan from a subset of genes that are essential for growth and development have also uncovered a number of genes involved in protein synthesis. Given the conserved mechanisms of protein synthesis across species, I discuss potential mechanisms that mediate the lifespan extension by inhibition of protein synthesis that are likely to be important for aging and age-related disorders in humans.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Medawar PB. An Unsolved Problem of Biology. London: H.K. Lewis. 1952. 2._Williams GC. Pleiotropy, natural selection and evolution of senescence. Evolution 1957; 11:398–411.

    Article  Google Scholar 

  2. Martin GM, Austad SN, Johnson TE. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet 1996; 13(1):25–34.

    Article  CAS  PubMed  Google Scholar 

  3. Britton JS, Lockwood WK, Li L et al. Drosophila’s insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev Cell 2002; 2(2):239–49.

    Article  CAS  PubMed  Google Scholar 

  4. Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science 2003; 299(5611):1346–51.

    Article  CAS  PubMed  Google Scholar 

  5. Partridge L, Gems D. Mechanisms of ageing: public or private? Nat Rev Genet 2002; 3(3):165–75.

    Article  CAS  PubMed  Google Scholar 

  6. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature 2000; 408(6809):255–62.

    Article  CAS  PubMed  Google Scholar 

  7. Bohni R, Riesgo-Escovar J, Oldham S et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1–4. Cell 1999; 97(7):865–75.

    Article  CAS  PubMed  Google Scholar 

  8. Tatar M, Kopelman A, Epstein D et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 2001; 292(5514):107–10.

    Article  CAS  PubMed  Google Scholar 

  9. Clancy DJ, Gems D, Harshman LG et al. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 2001; 292(5514):104–6.

    Article  CAS  PubMed  Google Scholar 

  10. Riddle DL, Swanson MM, Albert PS. Interacting genes in nematode dauer larva formation. Nature 1981; 290(5808):668–71.

    Article  CAS  PubMed  Google Scholar 

  11. Klass M, Hirsh D. Non-ageing developmental variant of Caenorhabditis elegans. Nature 1976; 260(5551):523–5.

    Article  CAS  PubMed  Google Scholar 

  12. Kenyon C, Chang J, Gensch E et al. A C. elegans mutant that lives twice as long as wild type. Nature 1993; 366(6454):461–4.

    Article  CAS  PubMed  Google Scholar 

  13. Johnson TE. Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science 1990; 249(4971):908–12.

    Article  CAS  PubMed  Google Scholar 

  14. Vowels JJ, Thomas JH. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics 1992; 130(1):105–23.

    CAS  PubMed  Google Scholar 

  15. Ogg S, Paradis S, Gottlieb S et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 1997; 389(6654):994–9.

    Article  CAS  PubMed  Google Scholar 

  16. Murphy CT, McCarroll SA, Bargmann CI et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 2003; 424(6946):277–83.

    Article  CAS  PubMed  Google Scholar 

  17. McElwee J, Bubb K, Thomas JH. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2003; 2(2):111–21.

    Article  CAS  PubMed  Google Scholar 

  18. Walker DW, McColl G, Jenkins NL et al. Evolution of lifespan in C. elegans. Nature 2000; 405(6784):296–7.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang H, Stallock JP, Ng JC et al. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev 2000; 14(21):2712–24.

    Article  CAS  PubMed  Google Scholar 

  20. Kapahi P, Zid BM, Harper T et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 2004; 14(10):885–90.

    Article  CAS  PubMed  Google Scholar 

  21. Long X, Spycher C, Han ZS et al. TOR deficiency in C. elegans causes developmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr Biol 2002; 12(17):1448–61.

    Article  CAS  PubMed  Google Scholar 

  22. Jia K, Chen D, Riddle DL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 2004; 131(16):3897–906.

    Article  CAS  PubMed  Google Scholar 

  23. Syntichaki P, Troulinaki K, Tavernarakis N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 2007; 445(7130):922–6.

    Article  CAS  PubMed  Google Scholar 

  24. Hansen M, Taubert S, Crawford D et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 2007; 6(1):95–110.

    Article  CAS  PubMed  Google Scholar 

  25. Pan KZ, Palter JE, Rogers AN et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 2007; 6(1):111–9.

    Article  CAS  PubMed  Google Scholar 

  26. Vellai T, Takacs-Vellai K, Zhang Y et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426(6967):620.

    Article  CAS  PubMed  Google Scholar 

  27. Henderson ST, Bonafe M, Johnson TE. daf-16 protects the nematode Caenorhabditis elegans during food deprivation. J Gerontol A Biol Sci Med Sci 2006; 61(5):444–60.

    PubMed  Google Scholar 

  28. Kapahi P, Zid B. TOR pathway: linking nutrient sensing to life span. Sci Aging Knowledge Environ 2004; 2004(36):PE34.

    Article  PubMed  Google Scholar 

  29. Shamji AF, Nghiem P, Schreiber SL. Integration of growth factor and nutrient signaling: implications for cancer biology. Mol Cell 2003; 12(2):271–80.

    Article  CAS  PubMed  Google Scholar 

  30. Harris TE, Lawrence JC Jr. TOR signaling. Sci STKE 2003; 2003(212):re15.

    Article  Google Scholar 

  31. Sonenberg N, Hershey JWB, Mathews BM. Translational Control of Gene Expression. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 2000.

    Google Scholar 

  32. Steffen KK, MacKay VL, Kerr EO et al. Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4. Cell 2008; 133(2):292–302.

    Article  CAS  PubMed  Google Scholar 

  33. Miller RA, Buehner G, Chang Y et al. Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels and increases hepatocyte MIF levels and stress resistance. Aging Cell 2005; 4(3):119–25.

    Article  CAS  PubMed  Google Scholar 

  34. Richie JP Jr, Leutzinger Y, Parthasarathy S et al. Methionine restriction increases blood glutathione and longevity in F344 rats. FASEB J 1994; 8(15):1302–7.

    CAS  PubMed  Google Scholar 

  35. Orentreich N, Matias JR, DeFelice A et al. Low methionine ingestion by rats extends life span. J Nutr 1993; 123(2):269–74.

    CAS  PubMed  Google Scholar 

  36. Curran SP, Ruvkun G. Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet 2007; 3(4):e56.

    Article  Google Scholar 

  37. Hershey JWB, Merrick WC. The pathway and mechanism of initiation of protein synthesis. In Translational Control of Gene Expression (eds Sonenberg et al). 2000:33–8.

    Google Scholar 

  38. Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5′ cap. Nature 1990; 345(6275):544–7.

    Article  CAS  PubMed  Google Scholar 

  39. Lachance PE, Miron M, Raught B et al. Phosphorylation of eukaryotic translation initiation factor 4E is critical for growth. Mol Cell Biol 2002; 22(6):1656–63.

    Article  CAS  PubMed  Google Scholar 

  40. Ruggero D, Montanaro L, Ma L et al. The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis. Nat Med 2004; 10(5):484–6.

    Article  CAS  PubMed  Google Scholar 

  41. Hamilton B, Dong Y, Shindo M et al. A systematic RNAi screen for longevity genes in C. elegans. Genes Dev 2005; 19(13):1544–55.

    Article  CAS  PubMed  Google Scholar 

  42. Hansen M, Hsu AL, Dillin A. New genes tied to endocrine, metabolic and dietary regulation of lifespan from a Caenorhabditis elegans genomic RNAi screen. PLoS Genet 2005; 1(1):119–28.

    Article  CAS  PubMed  Google Scholar 

  43. Chen D, Pan KZ, Palter JE et al. Longevity determined by developmental arrest genes in Caenorhabditis elegans. Aging Cell 2007.

    Google Scholar 

  44. Kamath RS, Fraser AG, Dong Y et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 2003; 421(6920):231–7.

    Article  CAS  PubMed  Google Scholar 

  45. Lee SS, Lee RY, Fraser AG et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 2002.

    Google Scholar 

  46. Finch CE. Longevity, Senescence and the Genome. Chicago: University of Chicago Press; 1990.

    Google Scholar 

  47. Munro HN. Evolution of protein metabolism in mammals. In: Munro HN, Allison JB, eds. Mammalian Protein Metabolism, vol. 3. Academic Press Inc, 1969:133–82.

    Google Scholar 

  48. Holliday R. Food, reproduction and longevity: is the extended lifespan of calorie-restricted animals an evolutionary adaptation? Bioessays 1989; 10(4):125–7.

    Article  CAS  PubMed  Google Scholar 

  49. Zimmerman JA, Malloy V, Krajcik R et al. Nutritional control of aging. Exp Gerontol 2003; 38(1–2):47–52.

    Article  CAS  PubMed  Google Scholar 

  50. Clancy DJ, Gems D, Hafen E et al. Dietary restriction in long-lived dwarf flies. Science 2002; 296(5566):319.

    Article  CAS  PubMed  Google Scholar 

  51. Rogina B, Helfand SL, Frankel S. Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction. Science 2002; 298(5599):1745.

    Article  CAS  PubMed  Google Scholar 

  52. Mair W, Goymer P, Pletcher SD et al. Demography of dietary restriction and death in Drosophila. Science 2003; 301(5640):1731–3.

    Article  CAS  PubMed  Google Scholar 

  53. Chippindale AK, Leroi AM, Kim SB et al. Phenotypic plasticity and selection in Drosophila life-history evolution. I. Nutrition and the cost of reproduction. J Evol Biology 1993; 6:171–93.

    Article  Google Scholar 

  54. Nusbaum J, Rose MR. The effects of nutritional manipulation and laboratory selection on lifespan in Drosophila melanogaster. Journal of Gerontology: Biological Sciences 1999; 54A:B192–B8.

    CAS  Google Scholar 

  55. Good TP, Tatar M. Age-specific mortality and reproduction respond to adult dietary restriction in Drosophila melanogaster. J Insect Physiol 2001; 47(12):1467–73.

    Article  CAS  PubMed  Google Scholar 

  56. Mair W, Piper MD, Partridge L. Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol 2005; 3(7):e223.

    Article  Google Scholar 

  57. Kaeberlein M, Powers RW 3rd, Steffen KK et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 2005; 310(5751):1193–6.

    Article  CAS  PubMed  Google Scholar 

  58. Chen D, Thomas EL, Kapahi P. HIF-1 modulates dietary restriction-mediated lifespan extension via IRE-1 in Caenorhabditis elegans. PLoS Genet 2009; 5(5):e1000486.

    Article  Google Scholar 

  59. Hansen M, Chandra A, Mitic LL et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 2008;4(2):e24.

    Article  Google Scholar 

  60. Zid BM, Rogers A, Katewa SD et al. 4E-BP modulates lifespan and mitochondrial translation upon dietary restriction in Drosophila. Cell 2009; Manuscript accepted.

    Google Scholar 

  61. Hipkiss AR. On why decreasing protein synthesis can increase lifespan. Mech Ageing Dev 2007.

    Google Scholar 

  62. Kaeberlein M, Kennedy BK. Protein translation, 2007. Aging Cell 2007; 6(6):731–4.

    Article  CAS  PubMed  Google Scholar 

  63. Sonenberg N, Hinnebusch AG. New modes of translational control in development, behavior and disease. Mol Cell 2007; 28(5):721–9.

    Article  CAS  PubMed  Google Scholar 

  64. Zong Q, Schummer M, Hood L et al. Messenger RNA translation state: the second dimension of high-throughput expression screening. Proc Natl Acad Sci USA 1999; 96(19):10632–6.

    Article  CAS  PubMed  Google Scholar 

  65. Rajasekhar VK, Viale A, Socci ND et al. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol Cell 2003; 12(4):889–901.

    Article  CAS  PubMed  Google Scholar 

  66. Joshi-Barve S, De Benedetti A, Rhoads RE. Preferential translation of heat shock mRNAs in HeLa cells deficient in protein synthesis initiation factors eIF-4E and eIF-4 gamma. J Biol Chem 1992; 267(29):21038–43.

    CAS  PubMed  Google Scholar 

  67. Tzamarias D, Roussou I, Thireos G. Coupling of GCN4 mRNA translational activation with decreased rates of polypeptide chain initiation. Cell 1989; 57(6):947–54.

    Article  CAS  PubMed  Google Scholar 

  68. Hinnebusch AG. Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 2005; 59:407–50.

    Article  CAS  PubMed  Google Scholar 

  69. Serikawa KA, Xu XL, MacKay VL et al. The Transcriptome and Its Translation during Recovery from Cell Cycle Arrest in Saccharomyces cerevisiae. Mol Cell Proteomics 2003; 2(3):191–204.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Buck Institute for Age Research, 8001 Redwood Blvd., Novato, California, 94945, USA

    Pankaj Kapahi

Authors
  1. Pankaj Kapahi
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology Hellas (FORTH), Heraklion, Crete, Greece

    Nektarios Tavernarakis PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Kapahi, P. (2010). Protein Synthesis and the Antagonistic Pleiotropy Hypothesis of Aging. In: Tavernarakis, N. (eds) Protein Metabolism and Homeostasis in Aging. Advances in Experimental Medicine and Biology, vol 694. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-7002-2_3

Download citation

Publish with us

Policies and ethics

Search

Navigation