Protein Synthesis and the Antagonistic Pleiotropy Hypothesis of Aging

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


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.


Dietary Restriction mRNA Translation Lifespan Extension Developmental Arrest Antagonistic Pleiotropy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 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.CrossRefGoogle Scholar
  2. 3.
    Martin GM, Austad SN, Johnson TE. Genetic analysis of ageing: role of oxidative damage and environmental stresses. Nat Genet 1996; 13(1):25–34.CrossRefPubMedGoogle Scholar
  3. 4.
    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.CrossRefPubMedGoogle Scholar
  4. 5.
    Tatar M, Bartke A, Antebi A. The endocrine regulation of aging by insulin-like signals. Science 2003; 299(5611):1346–51.CrossRefPubMedGoogle Scholar
  5. 6.
    Partridge L, Gems D. Mechanisms of ageing: public or private? Nat Rev Genet 2002; 3(3):165–75.CrossRefPubMedGoogle Scholar
  6. 7.
    Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature 2000; 408(6809):255–62.CrossRefPubMedGoogle Scholar
  7. 8.
    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.CrossRefPubMedGoogle Scholar
  8. 9.
    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.CrossRefPubMedGoogle Scholar
  9. 10.
    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.CrossRefPubMedGoogle Scholar
  10. 11.
    Riddle DL, Swanson MM, Albert PS. Interacting genes in nematode dauer larva formation. Nature 1981; 290(5808):668–71.CrossRefPubMedGoogle Scholar
  11. 12.
    Klass M, Hirsh D. Non-ageing developmental variant of Caenorhabditis elegans. Nature 1976; 260(5551):523–5.CrossRefPubMedGoogle Scholar
  12. 13.
    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.CrossRefPubMedGoogle Scholar
  13. 14.
    Johnson TE. Increased life-span of age-1 mutants in Caenorhabditis elegans and lower Gompertz rate of aging. Science 1990; 249(4971):908–12.CrossRefPubMedGoogle Scholar
  14. 15.
    Vowels JJ, Thomas JH. Genetic analysis of chemosensory control of dauer formation in Caenorhabditis elegans. Genetics 1992; 130(1):105–23.PubMedGoogle Scholar
  15. 16.
    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.CrossRefPubMedGoogle Scholar
  16. 17.
    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.CrossRefPubMedGoogle Scholar
  17. 18.
    McElwee J, Bubb K, Thomas JH. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2003; 2(2):111–21.CrossRefPubMedGoogle Scholar
  18. 19.
    Walker DW, McColl G, Jenkins NL et al. Evolution of lifespan in C. elegans. Nature 2000; 405(6784):296–7.CrossRefPubMedGoogle Scholar
  19. 20.
    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.CrossRefPubMedGoogle Scholar
  20. 21.
    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.CrossRefPubMedGoogle Scholar
  21. 22.
    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.CrossRefPubMedGoogle Scholar
  22. 23.
    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.CrossRefPubMedGoogle Scholar
  23. 24.
    Syntichaki P, Troulinaki K, Tavernarakis N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 2007; 445(7130):922–6.CrossRefPubMedGoogle Scholar
  24. 25.
    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.CrossRefPubMedGoogle Scholar
  25. 26.
    Pan KZ, Palter JE, Rogers AN et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 2007; 6(1):111–9.CrossRefPubMedGoogle Scholar
  26. 27.
    Vellai T, Takacs-Vellai K, Zhang Y et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426(6967):620.CrossRefPubMedGoogle Scholar
  27. 28.
    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.PubMedGoogle Scholar
  28. 29.
    Kapahi P, Zid B. TOR pathway: linking nutrient sensing to life span. Sci Aging Knowledge Environ 2004; 2004(36):PE34.CrossRefPubMedGoogle Scholar
  29. 30.
    Shamji AF, Nghiem P, Schreiber SL. Integration of growth factor and nutrient signaling: implications for cancer biology. Mol Cell 2003; 12(2):271–80.CrossRefPubMedGoogle Scholar
  30. 31.
    Harris TE, Lawrence JC Jr. TOR signaling. Sci STKE 2003; 2003(212):re15.CrossRefGoogle Scholar
  31. 32.
    Sonenberg N, Hershey JWB, Mathews BM. Translational Control of Gene Expression. Cold Spring Harbor: Cold Spring Harbor Laboratory Press, 2000.Google Scholar
  32. 33.
    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.CrossRefPubMedGoogle Scholar
  33. 34.
    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.CrossRefPubMedGoogle Scholar
  34. 35.
    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.PubMedGoogle Scholar
  35. 36.
    Orentreich N, Matias JR, DeFelice A et al. Low methionine ingestion by rats extends life span. J Nutr 1993; 123(2):269–74.PubMedGoogle Scholar
  36. 37.
    Curran SP, Ruvkun G. Lifespan regulation by evolutionarily conserved genes essential for viability. PLoS Genet 2007; 3(4):e56.CrossRefGoogle Scholar
  37. 38.
    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. 39.
    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.CrossRefPubMedGoogle Scholar
  39. 40.
    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.CrossRefPubMedGoogle Scholar
  40. 41.
    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.CrossRefPubMedGoogle Scholar
  41. 42.
    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.CrossRefPubMedGoogle Scholar
  42. 43.
    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.CrossRefPubMedGoogle Scholar
  43. 44.
    Chen D, Pan KZ, Palter JE et al. Longevity determined by developmental arrest genes in Caenorhabditis elegans. Aging Cell 2007.Google Scholar
  44. 45.
    Kamath RS, Fraser AG, Dong Y et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 2003; 421(6920):231–7.CrossRefPubMedGoogle Scholar
  45. 46.
    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. 47.
    Finch CE. Longevity, Senescence and the Genome. Chicago: University of Chicago Press; 1990.Google Scholar
  47. 48.
    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. 49.
    Holliday R. Food, reproduction and longevity: is the extended lifespan of calorie-restricted animals an evolutionary adaptation? Bioessays 1989; 10(4):125–7.CrossRefPubMedGoogle Scholar
  49. 50.
    Zimmerman JA, Malloy V, Krajcik R et al. Nutritional control of aging. Exp Gerontol 2003; 38(1–2):47–52.CrossRefPubMedGoogle Scholar
  50. 51.
    Clancy DJ, Gems D, Hafen E et al. Dietary restriction in long-lived dwarf flies. Science 2002; 296(5566):319.CrossRefPubMedGoogle Scholar
  51. 52.
    Rogina B, Helfand SL, Frankel S. Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction. Science 2002; 298(5599):1745.CrossRefPubMedGoogle Scholar
  52. 53.
    Mair W, Goymer P, Pletcher SD et al. Demography of dietary restriction and death in Drosophila. Science 2003; 301(5640):1731–3.CrossRefPubMedGoogle Scholar
  53. 54.
    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.CrossRefGoogle Scholar
  54. 55.
    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.Google Scholar
  55. 56.
    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.CrossRefPubMedGoogle Scholar
  56. 57.
    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.CrossRefGoogle Scholar
  57. 58.
    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.CrossRefPubMedGoogle Scholar
  58. 59.
    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.CrossRefGoogle Scholar
  59. 60.
    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.CrossRefGoogle Scholar
  60. 61.
    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. 62.
    Hipkiss AR. On why decreasing protein synthesis can increase lifespan. Mech Ageing Dev 2007.Google Scholar
  62. 63.
    Kaeberlein M, Kennedy BK. Protein translation, 2007. Aging Cell 2007; 6(6):731–4.CrossRefPubMedGoogle Scholar
  63. 64.
    Sonenberg N, Hinnebusch AG. New modes of translational control in development, behavior and disease. Mol Cell 2007; 28(5):721–9.CrossRefPubMedGoogle Scholar
  64. 65.
    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.CrossRefPubMedGoogle Scholar
  65. 66.
    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.CrossRefPubMedGoogle Scholar
  66. 67.
    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.PubMedGoogle Scholar
  67. 68.
    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.CrossRefPubMedGoogle Scholar
  68. 69.
    Hinnebusch AG. Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 2005; 59:407–50.CrossRefPubMedGoogle Scholar
  69. 70.
    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.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Pankaj Kapahi
    • 1
  1. 1.Buck Institute for Age ResearchNovatoCaliforniaUSA

Personalised recommendations