Abstract
Cellular homeostasis, which is needed for the cells to survive, requires a well-controlled balance in protein turnover. Both protein synthesis and degradation are influenced by distinct genetic pathways that control aging in divergent eukaryotic species. These conserved mechanisms involve the insulin/IGF-1 (Insulin-like Growth Factor-1), TGF-β (Transforming Growth Factor-β), JNK (c-Jun terminal kinase), RTK/Ras/MAPK (Receptor Tyrosine Kinase/ Ras/Mitogen-Activated Protein Kinase) and TOR (kinase Target Of Rapamycin) signaling cascades and the mitochondrial respiratory system—each of them promotes protein synthesis; as well as the intracellular protein degradation machineries, including the ubiquitin-proteasome system and lysosome-mediated autophagy. In addition to providing building blocks for generation of new proteins and fuelling the cell with energy under starvation, the protein degradation processes eliminate damaged, nonfunctional proteins, the accumulation of which serves as the primary contributory factor to aging. Interestingly, a complex, intimate regulatory relationship exists between mechanisms promoting protein synthesis and those mediating protein degradation: under certain circumstances the former downregulate the latter. Thus, conditions that favor protein synthesis can enhance the rate at which damaged proteins accumulate. This may explain why genetic interventions and environmental factors (e.g., dietary restriction) that reduce protein synthesis, at least to tolerable levels, extend lifespan and increase resistance to cellular stress in various experimental model organisms of aging. In this chapter, the molecular mechanisms by which protein synthesis-promoting longevity pathways and protein degradation pathways interact with each other are discussed.
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References
Tavernarakis N. Ageing and the regulation of protein synthesis: a balancing act? Trends Cell Biol 2008; 18:228–35.
Syntichaki P, Troulinaki K, Tavernarakis N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans. Nature 2007; 445:922–6.
Hansen M, Taubert S, Crawford D et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 2007; 6:95–110.
Pan KZ, Palter JE, Rogers AN et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 2007; 6:111–9.
Hekimi S, Guarente L. Genetics and the specificity of the aging process. Science 2003; 299:1351–4.
Kirkwood TBL. A systematic look at an old problem. Nature 2008; 451:644–7.
Vellai T, Takács-Vellai K, Sass M et al. The regulation of aging—does autophagy underlie longevity? Trends Cell Biol 2009; in press.
Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006; 443:780–6.
Hirsch C, Gauss R, Horn SC et al. The ubiquitylation machinery of the endoplasmic reticulum. Nature 2009; 485:453–60.
Soti C, Sreedhar AS, Csermely P. Apoptosis, necrosis and cellular senescence: chaperone occupancy as a potential switch. Aging Cell 2003; 2:39–45.
Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008; 132:27–42.
Mizushima M, Levine B, Cuervo AM et al. Autophagy fights disease through cellular selfdigestion. Nature 2008; 451:1069–75.
Cuervo AM. Autophagy and aging: keeping that old broom working. Trends Genet 2008; 24:604–12.
Kimura KD, Tissenbaum HA, Liu Y et al. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997; 277:942–6.
Morris JZ, Tissenbaum HA, Ruvkun G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature. 1996; 382:536–9.
Kenyon C, Chang J, Gensch E et al. A C. elegans mutant that lives twice as long as wild type. Nature 1993; 366:461–4.
Dorman JB, Albinder B, Shroyer T et al. The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 1995; 141:1399–406.
Tatar M, Kopelman A, Epstein D et al. A mutant Drososphila insulin receptor homolog that extends lifespan and impairs neuroendocrine functions. Science 2001; 292:107–10.
Holzenberger M, Dupont J, Ducos B et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 2003; 421:125–6.
Lakowski B, Hekimi S. The genetics of caloric restriction in Caenorhabditis elegans. Proc Natl Acad Sci USA 1998; 95:13091–6.
Miyadera H, Amino H, Hiraishi A et al. Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans. J Biol Chem 2001; 276:7713–6.
Oldham S, Hafen E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol 2003; 13:79–85.
Vellai T. Autophagy genes and ageing. Cell Death Differ 2009; 16:94–102.
Lin K, Dorman JB, Rodan A et al. daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 1997; 278:1319–22.
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; 389:994–9.
Hwangbo DS, Gersham B, Tu M-P et al. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 2004; 429:562–6.
Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001; 414:799–806.
Jünger MA, Rintelen F, Stocker H et al. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J Biol 2003; 2:20.
Williams DD, Pavitt GD, Proud CG. Characterization of the initiation factor eIF2B and its regulation in Drosophila melanogaster. 2J Biol Chem 2003; 76:3733–3742.
Pan D, Dong J, Zhang Y et al. Tuberous sclerosis complex: from Drosophila to human disease. Trends Cell Biol 2004; 14:78–85.
Apfeld J, O’Connor G, McDonagh T et al. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 2004; 18:3004–9.
Vellai T, Takács-Vellai K, Zhang Y et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426:620.
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; 131:3897–906.
Kim DH, Sarbassov DD, Ali S et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163–75.
Hara K, Maruki Y, Long X et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177–89.
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; 14:885–90.
Kaeberlein M, Powers III WR, Steffen KK et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 2005; 310:1193–96.
Harrison DE, Strong R, Sharp ZD et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009; 460:392–5.
Fafournoux P, Bruhat A, Jousse C. Amino acid regulation of gene expression. Biochem J 2000; 351:1–12.
Gingras AC, Raught B, Sonenberg N. eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 1999; 68:913–63.
Wei M, Fabrizio P, Hu J et al. Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor and Sch9. PLoS Genet 2008; 4:e13.
Skolnik EY, Lee CH, Batzer A et al. The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J 1993; 12:1929–36.
Fabrizio P, Pletcher SD, Minois N et al. Chronological aging-independent replicative life span regulation by Msn2/Msn4 and Sod2 in Saccharomyces cerevisiae. FEBS Lett 2004; 557:136–42.
Budovskaya YV, Stephan JS, Reggiori F et al. The Ras/cAMP-dependent protein kinase signaling pathway regulates an early step of the autophagy process in Saccharomyces cerevisiae. J Biol Chem 2004; 279:20663–71.
Yan L, Vatner DE, O’Connor JP et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 2007; 130:247–58.
Pyronnet S, Dostie J, Sonenberg N. Suppression of cap-dependent translation in mitosis. Genes Dev 2001; 15:2083–93.
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-b family signalling. Nature 2003; 425:577–84.
Shaw WM, Luo S, Landis J et al. The C. elegans TGF-β dauer pathway regulates longevity via insulin signalling. Curr Biol 2007; 17:1635–45.
Krishna S, Maduzia LL, Padgett RV. Specificity of TGFb signaling is conferred by distinct type I receptors and their associated SMAD proteins in Caenorhabditis elegans. Development 1999; 126:251–60.
Vellai T, Bicsák B, Tóth ML et al. Regulation of cell growth by autophagy. Autophagy 2008; 4:507–9.
Petritsch C, Beug H, Balmain A et al. TGF-b inhibits p70 S6 kinase via protein phosphatase 2A to induce G1 arrest. Genes Dev 2000; 14:3093–101.
Wang MC, Bohmann D, Jasper H. JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 2005; 121:115–25.
Oh SW, Mukhopadhyay A, Svrzikapa N et al. JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor DAF-16. Proc Natl Acad Sci USA 2005; 102:4494–9.
Buttgereit F, Brand MD. A hierarchy of ATP-consuming processes in mammalian cells. Biochem J 1995; 312:163–7.
Cunningham JT, Rodgers JT, Arlow DH et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 2007; 450:736–40.
Dillin A, Hsu AL, Arantes-Oliveira N et al. Rates of behavior and aging specified by mitochondrial function during development. Science 2002; 298:2398–401.
Lee SS, Lee RY, Fraser AG et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat Genet 2003; 33:40–8.
Zhao J, Brault JJ, Schild A et al. FoxO3 co-ordinately activates protein degradation by the autophagic/ lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 2007; 6:472–83.
Meléndez A, Tallóczy Z, Seaman M et al. Autophagy genes are essential for dauer development and life span extension in C. elegans. Science 2003; 301:1387–91.
Tóth ML, Sigmond T, Borsos É et al. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 2008; 4:330–8.
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:e24.
Ghazi A, Henis-Korenblit S, Kenyon C. Regulation of Caenorhabditis elegans life span by a proteasomal E3 ligase complex. Proc Natl Acad Sci USA 2007; 104:5947–52.
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Vellai, T., Takács-Vellai, K. (2010). Regulation of Protein Turnover by Longevity Pathways. 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_7
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DOI: https://doi.org/10.1007/978-1-4419-7002-2_7
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