The insulin paradox: aging, proteotoxicity and neurodegeneration (original) (raw)

• Reichel, W. The biology of aging. J. Am. Geriatr. Soc. 14, 431–436 (1966).
  CAS PubMed Google Scholar
• Bishop, N. A. & Guarente, L. Genetic links between diet and lifespan: shared mechanisms from yeast to humans. Nature Rev. Genet. 8, 835–844 (2007).
  Article CAS PubMed Google Scholar
• Mair, W. & Dillin, A. Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727–754 (2008).
  CAS PubMed Google Scholar
• Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).
  CAS PubMed Google Scholar
• Giannakou, M. E. & Partridge, L. Role of insulin-like signalling in Drosophila lifespan. Trends Biochem. Sci. 32, 180–188 (2007).
  CAS PubMed Google Scholar
• Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107–110 (2001).
  CAS PubMed Google Scholar
• Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003). This study established that the longevity and stress-resistance effects of reduced IIS are conserved from invertebrates to mammals.
  CAS PubMed Google Scholar
• Russell, S. J. & Kahn, C. R. Endocrine regulation of ageing. Nature Rev. Mol. Cell Biol. 8, 681–691 (2007).
  CAS Google Scholar
• Taguchi, A., Wartschow, L. M. & White, M. F. Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317, 369–372 (2007).
  CAS PubMed Google Scholar
• Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002).
  CAS PubMed Google Scholar
• Lee, S. S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nature Genet. 33, 40–48 (2003).
  CAS PubMed Google Scholar
• Taguchi, A. & White, M. F. Insulin-like signaling, nutrient homeostasis, and life span. Annu. Rev. Physiol. 70, 191–212 (2008).
  CAS PubMed Google Scholar
• Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).
  CAS PubMed Google Scholar
• Aguilaniu, H., Gustafsson, L., Rigoulet, M. & Nystrom, T. Asymmetric inheritance of oxidatively damaged proteins during cytokinesis. Science 299, 1751–1753 (2003).
  CAS PubMed Google Scholar
• Hebert, D. N. & Molinari, M. In and out of the ER: protein folding, quality control, degradation, and related human diseases. Physiol. Rev. 87, 1377–1408 (2007).
  CAS PubMed Google Scholar
• Gidalevitz, T., Ben-Zvi, A., Ho, K. H., Brignull, H. R. & Morimoto, R. I. Progressive disruption of cellular protein folding in models of polyglutamine diseases. Science 311, 1471–1474 (2006). In this article the authors reported that the expression of one aggregation-prone polyQ protein can destabilize the genome and lead to the aggregation of other proteins.
  CAS PubMed Google Scholar
• Kopito, R. R. & Ron, D. Conformational disease. Nature Cell Biol. 2, E207–E209 (2000).
  CAS PubMed Google Scholar
• Selkoe, D. J. Folding proteins in fatal ways. Nature 426, 900–904 (2003).
  CAS PubMed Google Scholar
• Bates, G. Huntingtin aggregation and toxicity in Huntington's disease. Lancet 361, 1642–1644 (2003).
  CAS PubMed Google Scholar
• Caughey, B. & Lansbury, P. T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267–298 (2003).
  CAS PubMed Google Scholar
• Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid b-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007).
  CAS Google Scholar
• Forloni, G. Neurotoxicity of beta-amyloid and prion peptides. Curr. Opin. Neurol. 9, 492–500 (1996).
  CAS PubMed Google Scholar
• Kim, S. J. & Linden, D. J. Ubiquitous plasticity and memory storage. Neuron 56, 582–592 (2007).
  CAS PubMed Google Scholar
• Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nature Med. 22 Jun 2008 (doi:10.1038/nm1782).
  CAS PubMed PubMed Central Google Scholar
• Townsend, M., Shankar, G. M., Mehta, T., Walsh, D. M. & Selkoe, D. J. Effects of secreted oligomers of amyloid β-protein on hippocampal synaptic plasticity: a potent role for trimers. J. Physiol. 572, 477–492 (2006).
  CAS PubMed PubMed Central Google Scholar
• Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. & Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810 (2004).
  CAS PubMed Google Scholar
• Behrends, C. et al. Chaperonin TRiC promotes the assembly of polyQ expansion proteins into nontoxic oligomers. Mol. Cell 23, 887–897 (2006). Along with reference 28, this work indicated that chaperones, which are known to disrupt protein aggregates, switch to actively create aggregates of high molecular mass when the concentration of the aggregating protein is high. These papers thus established the idea that active aggregation can be protective.
  CAS PubMed Google Scholar
• Shorter, J. & Lindquist, S. Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304, 1793–1797 (2004).
  CAS PubMed Google Scholar
• Amaducci, L. & Tesco, G. Aging as a major risk for degenerative diseases of the central nervous system. Curr. Opin. Neurol. 7, 283–286 (1994).
  CAS PubMed Google Scholar
• Brignull, H. R., Morley, J. F. & Morimoto, R. I. The stress of misfolded proteins: C. elegans models for neurodegenerative disease and aging. Adv. Exp. Med. Biol. 594, 167–189 (2007).
  PubMed Google Scholar
• Jankowsky, J. L. et al. Transgenic mouse models of neurodegenerative disease: opportunities for therapeutic development. Curr. Neurol. Neurosci. Rep. 2, 457–464 (2002).
  PubMed Google Scholar
• Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006).
  CAS PubMed Google Scholar
• Hsu, A. L., Murphy, C. T. & Kenyon, C. Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300, 1142–1145 (2003). This paper showed that HSF-1 is crucial for enabling reduced IIS to extend lifespan.
  CAS PubMed Google Scholar
• Morley, J. F., Brignull, H. R., Weyers, J. J. & Morimoto, R. I. The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 99, 10417–10422 (2002). This seminal study indicated that the minimal number of polyQ repeats that is needed to enable aggregation declines with age. It also showed that a reduction in IIS protects worms from polyQ aggregation.
  PubMed PubMed Central Google Scholar
• Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997).
  CAS PubMed Google Scholar
• Morris, J. Z., Tissenbaum, H. A. & Ruvkun, G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382, 536–539 (1996).
  CAS PubMed Google Scholar
• Kops, G. J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630–634 (1999).
  CAS PubMed Google Scholar
• Paradis, S. & Ruvkun, G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 12, 2488–2498 (1998).
  CAS PubMed PubMed Central Google Scholar
• Ogg, S. & Ruvkun, G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol. Cell 2, 887–893 (1998).
  CAS PubMed Google Scholar
• Henderson, S. T. & Johnson, T. E. daf-16 integrates developmental and environmental inputs to mediate aging in the nematode Caenorhabditis elegans. Curr. Biol. 11, 1975–1980 (2001).
  CAS PubMed Google Scholar
• Lee, R. Y., Hench, J. & Ruvkun, G. Regulation of C. elegans DAF-16 and its human ortholog FKHRL1 by the daf-2 insulin-like signaling pathway. Curr. Biol. 11, 1950–1957 (2001).
  CAS PubMed Google Scholar
• Murphy, C. T. et al. Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. Nature 424, 277–283 (2003).
  CAS PubMed Google Scholar
• Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005).
  CAS PubMed Google Scholar
• Bluher, M., Kahn, B. B. & Kahn, C. R. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003).
  PubMed Google Scholar
• Suh, Y. et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl Acad. Sci. USA 105, 3438–3442 (2008). This report indicated that reduced IGF signalling is typical in the offspring of centenarians and suggested that the regulation of lifespan by IGF signalling is conserved in humans. It also showed that high IGF plasma levels can lead to reduced IGF signalling, supporting the idea that feedback loops regulate the IIS pathway.
  CAS PubMed PubMed Central Google Scholar
• Morley, J. F. & Morimoto, R. I. Regulation of longevity in Caenorhabditis elegans by heat shock factor and molecular chaperones. Mol. Biol. Cell 15, 657–664 (2004).
  CAS PubMed PubMed Central Google Scholar
• Liu, X. D., Liu, P. C., Santoro, N. & Thiele, D. J. Conservation of a stress response: human heat shock transcription factors functionally substitute for yeast HSF. EMBO J. 16, 6466–6477 (1997).
  CAS PubMed PubMed Central Google Scholar
• Rabindran, S. K., Haroun, R. I., Clos, J., Wisniewski, J. & Wu, C. Regulation of heat shock factor trimer formation: role of a conserved leucine zipper. Science 259, 230–234 (1993).
  CAS PubMed Google Scholar
• Walker, G. A., Thompson, F. J., Brawley, A., Scanlon, T. & Devaney, E. Heat shock factor functions at the convergence of the stress response and developmental pathways in Caenorhabditis elegans. FASEB J. 17, 1960–1962 (2003).
  CAS PubMed Google Scholar
• Sarge, K. D., Murphy, S. P. & Morimoto, R. I. Activation of heat shock gene transcription by heat shock factor 1 involves oligomerization, acquisition of DNA-binding activity, and nuclear localization and can occur in the absence of stress. Mol. Cell. Biol. 13, 1392–1407 (1993).
  CAS PubMed PubMed Central Google Scholar
• Baird, N. A., Turnbull, D. W. & Johnson, E. A. Induction of the heat shock pathway during hypoxia requires regulation of heat shock factor by hypoxia-inducible factor-1. J. Biol. Chem. 281, 38675–38681 (2006).
  CAS PubMed Google Scholar
• Reinke, H. et al. Differential display of DNA-binding proteins reveals heat-shock factor 1 as a circadian transcription factor. Genes Dev. 22, 331–345 (2008).
  CAS PubMed PubMed Central Google Scholar
• Singh, V. & Aballay, A. Heat-shock transcription factor (HSF)-1 pathway required for Caenorhabditis elegans immunity. Proc. Natl Acad. Sci. USA 103, 13092–13097 (2006).
  CAS PubMed PubMed Central Google Scholar
• Bishop, N. A. & Guarente, L. Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature 447, 545–549 (2007).
  CAS PubMed Google Scholar
• Tullet, J. M. et al. Direct inhibition of the longevity-promoting factor SKN-1 by insulin-like signaling in C. elegans. Cell 132, 1025–1038 (2008).
  CAS PubMed PubMed Central Google Scholar
• McElwee, J., Bubb, K. & Thomas, J. H. Transcriptional outputs of the Caenorhabditis elegans forkhead protein DAF-16. Aging Cell 2, 111–121 (2003).
  CAS PubMed Google Scholar
• Halaschek-Wiener, J. et al. Analysis of long-lived C. elegans daf-2 mutants using serial analysis of gene expression. Genome Res. 15, 603–615 (2005).
  CAS PubMed PubMed Central Google Scholar
• Oh, S. W. et al. Identification of direct DAF-16 targets controlling longevity, metabolism and diapause by chromatin immunoprecipitation. Nature Genet. 38, 251–257 (2006).
  PubMed Google Scholar
• Dong, M. Q. et al. Quantitative mass spectrometry identifies insulin signaling targets in C. elegans. Science 317, 660–663 (2007).
  CAS PubMed Google Scholar
• Tonkiss, J. & Calderwood, S. K. Regulation of heat shock gene transcription in neuronal cells. Int. J. Hyperthermia 21, 433–444 (2005).
  CAS PubMed Google Scholar
• Hartl, F. U. & Hayer-Hartl, M. Molecular chaperones in the cytosol: from nascent chain to folded protein. Science 295, 1852–1858 (2002).
  CAS PubMed Google Scholar
• Barral, J. M., Broadley, S. A., Schaffar, G. & Hartl, F. U. Roles of molecular chaperones in protein misfolding diseases. Semin. Cell Dev. Biol. 15, 17–29 (2004).
  CAS PubMed Google Scholar
• Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).
  CAS PubMed Google Scholar
• Wood, J. G. et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686–689 (2004).
  CAS PubMed Google Scholar
• Valenzano, D. R. et al. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr. Biol. 16, 296–300 (2006).
  CAS PubMed Google Scholar
• Parker, J. A. et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nature Genet. 37, 349–350 (2005). This study showed that altering aging with the drug Resveratrol protects PolyQ-expressing neurons from protein aggregation. It thus linked the aging process and protein-aggregation neurotoxicity.
  CAS PubMed Google Scholar
• Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001).
  CAS PubMed Google Scholar
• Link, C. Expression of human β-amyloid peptide in transgenic Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 92, 9368–9372 (1995).
  CAS PubMed PubMed Central Google Scholar
• Humbert, S. et al. The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev. Cell 2, 831–837 (2002).
  CAS PubMed Google Scholar
• Yamamoto, A., Cremona, M. L. & Rothman, J. E. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172, 719–731 (2006).
  CAS PubMed PubMed Central Google Scholar
• Carro, E., Trejo, J. L., Gomez-Isla, T., LeRoith, D. & Torres-Aleman, I. Serum insulin-like growth factor I regulates brain amyloid-β levels. Nature Med. 8, 1390–1397 (2002).
  CAS PubMed Google Scholar
• Carro, E. et al. Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis. Neurobiol. Aging 27, 1250–1257 (2006).
  CAS PubMed Google Scholar
• Gasparini, L. & Xu, H. Potential roles of insulin and IGF-1 in Alzheimer's disease. Trends Neurosci. 26, 404–406 (2003).
  CAS PubMed Google Scholar
• Bonkowski, M. S., Rocha, J. S., Masternak, M. M., Al Regaiey, K. A. & Bartke, A. Targeted disruption of growth hormone receptor interferes with the beneficial actions of calorie restriction. Proc. Natl Acad. Sci. USA 103, 7901–7905 (2006).
  CAS PubMed PubMed Central Google Scholar
• Tomlinson, D. R. & Gardiner, N. J. Glucose neurotoxicity. Nature Rev. Neurosci. 9, 36–45 (2008).
  CAS Google Scholar
• Zick, Y. Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci. STKE pe4 (2005).
  Google Scholar
• George, S. et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304, 1325–1328 (2004).
  CAS PubMed PubMed Central Google Scholar
• Biddinger, S. B. et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell. Metab. 7, 125–134 (2008).
  CAS PubMed PubMed Central Google Scholar
• Brown, M. S. & Goldstein, J. L. Selective versus total insulin resistance: a pathogenic paradox. Cell. Metab. 7, 95–96 (2008).
  CAS PubMed Google Scholar
• Michael, M. D. et al. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol. Cell 6, 87–97 (2000).
  CAS PubMed Google Scholar
• Craft, S. et al. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 50, 164–168 (1998). This study indicated that insulin levels can vary in the plasma and in the CSF, and it correlated these levels with severity of dementia in Alzheimer's disease.
  Google Scholar
• Teede, H. J., Hutchison, S., Zoungas, S. & Meyer, C. Insulin resistance, the metabolic syndrome, diabetes, and cardiovascular disease risk in women with PCOS. Endocrine 30, 45–53 (2006).
  CAS PubMed Google Scholar
• Walker, D. W., McColl, G., Jenkins, N. L., Harris, J. & Lithgow, G. J. Evolution of lifespan in C. elegans. Nature 405, 296–297 (2000).
  CAS PubMed Google Scholar
• Golden, J. W. & Riddle, D. L. The Caenorhabditis elegans dauer larva: developmental effects of pheromone, food and temperature. Dev. Biol. 102, 368–378 (1984).
  CAS PubMed Google Scholar
• Holzenberger, M. et al. Experimental IGF-I receptor deficiency generates a sexually dimorphic pattern of organ-specific growth deficits in mice, affecting fat tissue in particular. Endocrinology 142, 4469–4478 (2001).
  CAS PubMed Google Scholar
• Patel, D. S. et al. Clustering of genetically defined allele classes in the Caenorhabditis elegans DAF-2 insulin/IGF-1 receptor. Genetics 178, 931–946 (2008).
  CAS PubMed PubMed Central Google Scholar
• Leibson, C. L. et al. The risk of dementia among persons with diabetes mellitus: a population-based cohort study. Ann. NY Acad. Sci. 826, 422–427 (1997).
  CAS PubMed Google Scholar
• Ott, A. et al. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 1937–1942 (1999).
  CAS PubMed Google Scholar
• Dillin, A., Crawford, D. K. & Kenyon, C. Timing requirements for insulin/IGF-1 signaling in C. elegans. Science 298, 830–834 (2002).
  CAS PubMed Google Scholar
• McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life span and upon the ultimate body size. 1935. Nutrition 5, 155–171; discussion 172 (1989).
  CAS PubMed Google Scholar
• Lin, S. J. et al. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Nature 418, 344–348 (2002).
  CAS PubMed Google Scholar
• Klass, M. R. Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech. Ageing Dev. 6, 413–429 (1977).
  CAS PubMed Google Scholar
• Partridge, L., Piper, M. D. & Mair, W. Dietary restriction in Drosophila. Mech. Ageing Dev. 126, 938–950 (2005).
  CAS PubMed Google Scholar
• Mair, W., Piper, M. D. & Partridge, L. Calories do not explain extension of life span by dietary restriction in Drosophila. PLoS Biol. 3, e223 (2005).
  PubMed PubMed Central Google Scholar
• Panowski, S. H., Wolff, S., Aguilaniu, H., Durieux, J. & Dillin, A. PHA-4/Foxa mediates diet-restriction-induced longevity of C. elegans. Nature 447, 550–555 (2007).
  CAS PubMed Google Scholar
• Larsen, P. L., Albert, P. S. & Riddle, D. L. Genes that regulate both development and longevity in Caenorhabditis elegans. Genetics 139, 1567–1583 (1995).
  CAS PubMed PubMed Central Google Scholar
• Honda, Y. & Honda, S. The daf-2 gene network for longevity regulates oxidative stress resistance and Mn-superoxide dismutase gene expression in Caenorhabditis elegans. FASEB J. 13, 1385–1393 (1999).
  CAS PubMed Google Scholar
• Lithgow, G. J., White, T. M., Melov, S. & Johnson, T. E. Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress. Proc. Natl Acad. Sci. USA 92, 7540–7544 (1995).
  CAS PubMed PubMed Central Google Scholar
• Pinkston, J. M., Garigan, D., Hansen, M. & Kenyon, C. Mutations that increase the life span of C. elegans inhibit tumor growth. Science 313, 971–975 (2006).
  CAS PubMed Google Scholar
• Pinkston-Gosse, J. & Kenyon, C. DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans. Nature Genet. 39, 1403–1409 (2007).
  CAS PubMed Google Scholar
• Hightower, L. E. Heat shock, stress proteins, chaperones, and proteotoxicity. Cell 66, 191–197 (1991).
  CAS PubMed Google Scholar
• Outeiro, T. F. et al. Sirtuin 2 inhibitors rescue α-synuclein-mediated toxicity in models of Parkinson's disease. Science 317, 516–519 (2007).
  CAS PubMed Google Scholar
• Bossy-Wetzel, E., Schwarzenbacher, R. & Lipton, S. A. Molecular pathways to neurodegeneration. Nature Med. 10 (Suppl.), S2–S9 (2004).
  PubMed Google Scholar
• Muchowski, P. J. & Wacker, J. L. Modulation of neurodegeneration by molecular chaperones. Nature Rev. Neurosci. 6, 11–22 (2005).
  CAS Google Scholar