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Progeria syndromes and ageing: what is the connection?

Key Points

  • Despite decades of research, the extent to which human progerias resemble accelerated ageing is still unclear and highly debated. To understand this connection, an ongoing characterization of genetic pathways that influence the ageing process in model systems and investigations into molecular pathways that define the pathogenesis of human progerias are required.

  • Ageing research has focused on lifespan-extending pathways in model organisms. This has led to the identification of several pathways that impinge on the ageing process, fortifying a multifactorial hypothesis to explain the underlying causes of organismal ageing.

  • Hutchinson–Gilford progeria syndrome (HGPS) and other human progerias allow researchers a unique glimpse at the molecular pathways that accelerate age-associated phenotypes. These insights can be translated back to model systems to identify the molecular events underlying pathology.

  • HGPS cells show defects in cellular proliferation and premature senescence, suggesting that advanced ageing of tissues may be the result of impaired growth or decreased replicative potential at the cellular level.

  • Multiple progeria models are associated with enhanced DNA damage, implicating this form of cellular damage as a cause of these diseases.

  • Disease-causing mutations in lamin A/C (LMNA) impair the ability of mesenchymal stem cells to differentiate down specific lineages. These results suggest that the loss of tissue homeostasis plays an important part in multicellular ageing.

  • A comprehensive understanding of the molecular basis of ageing will benefit from a fusion of studies in long-lived models and models resembling accelerated ageing.

Abstract

One of the many debated topics in ageing research is whether progeroid syndromes are really accelerated forms of human ageing. The answer requires a better understanding of the normal ageing process and the molecular pathology underlying these rare diseases. Exciting recent findings regarding a severe human progeria, Hutchinson–Gilford progeria syndrome, have implicated molecular changes that are also linked to normal ageing, such as genome instability, telomere attrition, premature senescence and defective stem cell homeostasis in disease development. These observations, coupled with genetic studies of longevity, lead to a hypothesis whereby progeria syndromes accelerate a subset of the pathological changes that together drive the normal ageing process.

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Figure 1: Genetic models for progerias and enhanced longevity.
Figure 2: Crosstalk between insulin or IGF1 signalling and the nutrient-sensing TOR kinase pathway.
Figure 3: Pathways shared between ageing in invertebrate model organisms, mammals and human progerias.

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References

  1. Kennedy, B. K., Steffen, K. K. & Kaeberlein, M. Ruminations on dietary restriction and aging. Cell. Mol. Life Sci. 64, 1323–1328 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Anderson, R. M., Shanmuganayagam, D. & Weindruch, R. Caloric restriction and aging: studies in mice and monkeys. Toxicol. Pathol. 37, 47–51 (2009).

    Article  PubMed  Google Scholar 

  3. Lin, S. J., Defossez, P. A. & Guarente, L. Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126–2128 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Jiang, J. C., Jaruga, E., Repnevskaya, M. V. & Jazwinski, S. M. An intervention resembling caloric restriction prolongs life span and retards aging in yeast. FASEB J. 14, 2135–2137 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Fabrizio, P. et al. Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae. J. Cell Biol. 166, 1055–1067 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 95, 13091–13096 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chapman, T. & Partridge, L. Female fitness in Drosophila melanogaster: an interaction between the effect of nutrition and of encounter rate with males. Proc. Biol. Sci. 263, 755–759 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. Good, T. P. & Tatar, M. Age-specific mortality and reproduction respond to adult dietary restriction in Drosophila melanogaster. J. Insect Physiol. 47, 1467–1473 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. McCay, C. M., Crowell, M. F. & Maynard, L. A. The effect of retarded growth upon the length of life and upon ultimate size. J. Nutr. 10, 63–79 (1935).

    Article  CAS  Google Scholar 

  10. Colman, R. J. et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009). Documents the response to caloric restriction in rhesus monkeys and an associated improvement in lifespan.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Smith, E. D. et al. Quantitative evidence for conserved longevity pathways between divergent eukaryotic species. Genome Res. 18, 564–570 (2008). A statistical analysis showing that yeast homologues of longevity genes identified in C. elegans screens are conserved modifiers of replicative lifespan in yeast.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Steinkraus, K. A. et al. Dietary restriction suppresses proteotoxicity and enhances longevity by an hsf-1-dependent mechanism in Caenorhabditis elegans. Aging Cell 7, 394–404 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Joseph, J., Cole, G., Head, E. & Ingram, D. Nutrition, brain aging, and neurodegeneration. J. Neurosci. 29, 12795–12801 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Fontana, L. Calorie restriction and cardiometabolic health. Eur. J. Cardiovasc. Prev. Rehabil 15, 3–9 (2008).

    Article  PubMed  Google Scholar 

  15. Hursting, S. D., Smith, S. M., Lashinger, L. M., Harvey, A. E. & Perkins, S. N. Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis 31, 83–89 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Gerstbrein, B., Stamatas, G., Kollias, N. & Driscoll, M. In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans. Aging Cell 4, 127–137 (2005).

    Article  CAS  PubMed  Google Scholar 

  17. Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol 11, 298–300 (1956).

    Article  CAS  PubMed  Google Scholar 

  18. Valko, M. et al. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39, 44–84 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Lapointe, J. & Hekimi, S. When a theory of aging ages badly. Cell. Mol. Life Sci. 67, 1–8 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schriner, S. E. et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 308, 1909–1911 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Landis, G. N. & Tower, J. Superoxide dismutase evolution and life span regulation. Mech. Ageing Dev. 126, 365–379 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Van Raamsdonk, J. M. & Hekimi, S. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet. 5, e1000361 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Perez, V. I. et al. Is the oxidative stress theory of aging dead? Biochim. Biophys. Acta 1790, 1005–1014 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gems, D. & Doonan, R. Antioxidant defense and aging in C. elegans: is the oxidative damage theory of aging wrong? Cell Cycle 8, 1681–1687 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. De la Fuente, M. & Miquel, J. An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Curr. Pharm. Des 15, 3003–3026 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Morimoto, R. I. & Cuervo, A. M. Protein homeostasis and aging: taking care of proteins from the cradle to the grave. J. Gerontol. A. Biol. Sci. Med. Sci. 64, 167–170 (2009).

    Article  PubMed  CAS  Google Scholar 

  27. Cohen, E. et al. Reduced IGF-1 signaling delays age-associated proteotoxicity in mice. Cell 139, 1157–1169 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Florez-McClure, M. L., Hohsfield, L. A., Fonte, G., Bealor, M. T. & Link, C. D. Decreased insulin-receptor signaling promotes the autophagic degradation of β-amyloid peptide in C. elegans. Autophagy 3, 569–580 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. 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).

    Article  CAS  PubMed  Google Scholar 

  32. Blasco, M. A. Telomere length, stem cells and aging. Nature Chem. Biol. 3, 640–649 (2007).

    Article  CAS  Google Scholar 

  33. Kennedy, B. K. The genetics of ageing: insight from genome-wide approaches in invertebrate model organisms. J. Intern. Med. 263, 142–152 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Lee, S. S. Whole genome RNAi screens for increased longevity: important new insights but not the whole story. Exp. Gerontol. 41, 968–973 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Smith, E. D., Kennedy, B. K. & Kaeberlein, M. Genome-wide identification of conserved longevity genes in yeast and worms. Mech. Ageing Dev. 128, 106–111 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Powers, R. W. 3rd, Kaeberlein, M., Caldwell, S. D., Kennedy, B. K. & Fields, S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev. 20, 174–184 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kaeberlein, M. et al. Regulation of yeast replicative life-span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Steffen, K. K. et al. Yeast lifespan extension by depletion of 60S ribosomal subunits is mediated by Gcn4. Cell 133, 292–302 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Klass, M. R. A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results. Mech. Ageing Dev. 22, 279–286 (1983).

    Article  CAS  PubMed  Google Scholar 

  40. Friedman, D. B. & Johnson, T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. Panowski, S. H. & Dillin, A. Signals of youth: endocrine regulation of aging in Caenorhabditis elegans. Trends Endocrinol. Metab. 20, 259–264 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Kleemann, G. A. & Murphy, C. T. The endocrine regulation of aging in Caenorhabditis elegans. Mol. Cell Endocrinol. 299, 51–57 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Avruch, J. et al. Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 25, 6361–6372 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Broughton, S. & Partridge, L. Insulin/IGF-like signalling, the central nervous system and aging. Biochem. J. 418, 1–12 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Stanfel, M. N., Shamieh, L. S., Kaeberlein, M. & Kennedy, B. K. The TOR pathway comes of age. Biochim. Biophys. Acta 1790, 1067–1074 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Polak, P. & Hall, M. N. mTOR and the control of whole body metabolism. Curr. Opin. Cell Biol. 21, 209–218 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Helliwell, S. B., Howald, I., Barbet, N. & Hall, M. N. TOR2 is part of two related signaling pathways coordinating cell growth in Saccharomyces cerevisiae. Genetics 148, 99–112 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Loewith, R. et al. Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457–468 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Soukas, A. A., Kane, E. A., Carr, C. E., Melo, J. A. & Ruvkun, G. Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23, 496–511 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kennedy, B. K. & Kaeberlein, M. Hot topics in aging research: protein translation, 2009. Aging Cell 8, 617–623 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Canto, C. & Auwerx, J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol. Metab. 20, 325–331 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sinclair, D. A. & Guarente, L. Extrachromosomal rDNA circles — a cause of aging in yeast. Cell 91, 1033–1042 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227–230 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Partridge, L., Piper, M. D. & Mair, W. Dietary restriction in Drosophila. Mech. Ageing Dev. 126, 938–950 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Liang, H. et al. Genetic mouse models of extended lifespan. Exp. Gerontol 38, 1353–1364 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Kappeler, L. et al. Brain IGF-1 receptors control mammalian growth and lifespan through a neuroendocrine mechanism. PLoS Biol. 6, e254 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Bluher, M., Kahn, B. B. & Kahn, R. C. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572–574 (2003).

    Article  PubMed  CAS  Google Scholar 

  59. Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Inoki, K., Li, Y., Xu, T. & Guan, K. L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829–1834 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648–657 (2002).

    Article  CAS  PubMed  Google Scholar 

  63. Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/Akt pathway. Mol. Cell 10, 151–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Bolster, D. R., Crozier, S. J., Kimball, S. R. & Jefferson, L. S. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J. Biol. Chem. 277, 23977–23980 (2002).

    Article  CAS  PubMed  Google Scholar 

  65. Krause, U., Bertrand, L. & Hue, L. Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes. Eur. J. Biochem. 269, 3751–3759 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Kimura, N. et al. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 8, 65–79 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Sarbassov, D. D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nature Cell Biol. 6, 1122–1128 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Jacinto, E. et al. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127, 125–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Harrington, L. S. et al. The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213–223 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Shah, O. J., Wang, Z. & Hunter, T. Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Curr. Biol. 14, 1650–1656 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Shah, O. J. & Hunter, T. Turnover of the active fraction of IRS1 involves raptor-mTOR- and S6K1-dependent serine phosphorylation in cell culture models of tuberous sclerosis. Mol. Cell. Biol. 26, 6425–6434 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Trinei, M. et al. P66Shc signals to age. Aging (Albany NY) 1, 503–510 (2009).

    Article  CAS  Google Scholar 

  74. Enns, L. C. et al. Disruption of protein kinase A in mice enhances healthy aging. PLoS One 4, e5963 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Matheu, A. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Martin, G. M., Bergman, A. & Barzilai, N. Genetic determinants of human health span and life span: progress and new opportunities. PLoS Genet. 3, e125 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Melzer, D. Genetic polymorphisms and human aging: association studies deliver. Rejuvenation Res. 11, 523–526 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Bonafe, M. & Olivieri, F. Genetic polymorphism in long-lived people: cues for the presence of an insulin/IGF-pathway-dependent network affecting human longevity. Mol. Cell. Endocrinol. 299, 118–123 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Campisi, J. & d'Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nature Rev. Mol. Cell Biol. 8, 729–740 (2007).

    Article  CAS  Google Scholar 

  82. Adams, P. D. Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol. Cell 36, 2–14 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Martin, G. M. & Oshima, J. Lessons from human progeroid syndromes. Nature 408, 263–266 (2000).

    Article  CAS  PubMed  Google Scholar 

  84. Stewart, C. L., Kozlov, S., Fong, L. G. & Young, S. G. Mouse models of the laminopathies. Exp. Cell Res. 313, 2144–2156 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Stuurman, N., Heins, S. & Aebi, U. Nuclear lamins: their structure, assembly, and interactions. J. Struct. Biol. 122, 42–66 (1998).

    Article  CAS  PubMed  Google Scholar 

  86. Mounkes, L., Kozlov, S., Burke, B. & Stewart, C. L. The laminopathies: nuclear structure meets disease. Curr. Opin. Genet. Dev. 13, 223–230 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Rober, R. A., Weber, K. & Osborn, M. Differential timing of nuclear lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study. Development 105, 365–378 (1989).

    Article  CAS  PubMed  Google Scholar 

  88. Sullivan, T. et al. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy. J. Cell Biol. 147, 913–920 (1999). Generation and characterization of the Lmna−/− mouse strain, which shows symptoms of muscular dystrophy and loss of emerin at the nuclear periphery.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kudlow, B. A., Kennedy, B. K. & Monnat, R. J. Jr. Werner and Hutchinson–Gilford progeria syndromes: mechanistic basis of human progeroid diseases. Nature Rev. Mol. Cell Biol. 8, 394–404 (2007).

    Article  CAS  Google Scholar 

  90. Rusinol, A. E. & Sinensky, M. S. Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors. J. Cell Sci. 119, 3265–3272 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Liu, B. & Zhou, Z. Lamin A/C, laminopathies and premature ageing. Histol. Histopathol. 23, 747–763 (2008).

    CAS  PubMed  Google Scholar 

  92. Pollex, R. L. & Hegele, R. A. Hutchinson-Gilford progeria syndrome. Clin. Genet. 66, 375–381 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. De Sandre-Giovannoli, A. et al. Lamin A truncation in Hutchinson-Gilford progeria. Science 300, 2055 (2003). Identification of the main disease-causing mutation in HGPS.

    Article  CAS  PubMed  Google Scholar 

  94. Moulson, C. L. et al. Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. Hum. Mutat. 28, 882–889 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Andres, V. & Gonzalez, J. M. Role of A-type lamins in signaling, transcription, and chromatin organization. J. Cell Biol. 187, 945–957 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Frock, R. L. et al. Lamin A/C and emerin are critical for skeletal muscle satellite cell differentiation. Genes Dev. 20, 486–500 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Ivorra, C. et al. A mechanism of AP-1 suppression through interaction of c-Fos with lamin A/C. Genes Dev. 20, 307–320 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Muchir, A. et al. Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophy. J. Clin. Invest. 117, 1282–1293 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Markiewicz, E. et al. The inner nuclear membrane protein emerin regulates β-catenin activity by restricting its accumulation in the nucleus. EMBO J. 25, 3275–3285 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Scaffidi, P. & Misteli, T. Lamin A-dependent misregulation of adult stem cells associated with accelerated ageing. Nature Cell Biol. 10, 452–459 (2008). Expression of the HGPS disease-causing protein in mesenchymal stem cells results in abnormalities in lineage differentiation.

    Article  CAS  PubMed  Google Scholar 

  101. Shumaker, D. K. et al. Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc. Natl Acad. Sci. USA 103, 8703–8708 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Columbaro, M. et al. Rescue of heterochromatin organization in Hutchinson-Gilford progeria by drug treatment. Cell. Mol. Life Sci. 62, 2669–2678 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gonzalez-Suarez, I. et al. Novel roles for A-type lamins in telomere biology and the DNA damage response pathway. EMBO J. 28, 2414–2427 (2009). Lamin A has a role in the compartmentalization of telomeres in the nucleus, and loss of lamin A results in telomere shortening and affects the epigenetic status of constitutive heterochromatin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Scaffidi, P. & Misteli, T. Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nature Med. 11, 440–445 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Viteri, G., Chung, Y. W. & Stadtman, E. R. Effect of progerin on the accumulation of oxidized proteins in fibroblasts from Hutchinson Gilford progeria patients. Mech. Ageing Dev. 131, 2–8 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Huang, S. et al. Correction of cellular phenotypes of Hutchinson-Gilford progeria cells by RNA interference. Hum. Genet. 118, 444–450 (2005).

    Article  CAS  PubMed  Google Scholar 

  107. Gonzalez-Suarez, I., Redwood, A. B. & Gonzalo, S. Loss of A-type lamins and genomic instability. Cell Cycle 8, 3860–3865 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Liu, Y., Rusinol, A., Sinensky, M., Wang, Y. & Zou, Y. DNA damage responses in progeroid syndromes arise from defective maturation of prelamin, A. J. Cell Sci. 119, 4644–4649 (2006). Describes the activation of ATM and ATR in HGPS cells and establishes this checkpoint pathway in HGPS replication arrest.

    Article  CAS  PubMed  Google Scholar 

  109. Liu, Y. et al. Involvement of xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin, A. FASEB J. 22, 603–611 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Liu, B. et al. Genomic instability in laminopathy-based premature aging. Nature Med. 11, 780–785 (2005). Accumulation of prelamin A was shown to delay the recruitment of RAD51 and 53BP1 to sites of DNA lesions.

    Article  CAS  PubMed  Google Scholar 

  111. Pendas, A. M. et al. Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase-deficient mice. Nature Genet. 31, 94–99 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Varela, I. et al. Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation. Nature 437, 564–568 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Kudlow, B. A., Stanfel, M. N., Burtner, C. R., Johnston, E. D. & Kennedy, B. K. Suppression of proliferative defects associated with processing-defective lamin A mutants by hTERT or inactivation of p53. Mol. Biol. Cell 19, 5238–5248 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Huang, S., Risques, R. A., Martin, G. M., Rabinovitch, P. S. & Oshima, J. Accelerated telomere shortening and replicative senescence in human fibroblasts overexpressing mutant and wild-type lamin A. Exp. Cell Res. 314, 82–91 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Candelario, J., Sudhakar, S., Navarro, S., Reddy, S. & Comai, L. Perturbation of wild-type lamin A metabolism results in a progeroid phenotype. Aging Cell 7, 355–367 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Scaffidi, P. & Misteli, T. Lamin A-dependent nuclear defects in human aging. Science 312, 1059–1063 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cao, K., Capell, B. C., Erdos, M. R., Djabali, K. & Collins, F. S. A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells. Proc. Natl Acad. Sci. USA 104, 4949–4954 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. McClintock, D. et al. The mutant form of lamin A that causes Hutchinson-Gilford progeria is a biomarker of cellular aging in human skin. PLoS ONE 2, e1269 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Hennekam, R. C. Hutchinson-Gilford progeria syndrome: review of the phenotype. Am. J. Med. Genet. A 140, 2603–2624 (2006).

    Article  PubMed  CAS  Google Scholar 

  120. King, C. R., Lemmer, J., Campbell, J. R. & Atkins, A. R. Osteosarcoma in a patient with Hutchinson-Gilford progeria. J. Med. Genet. 15, 481–484 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Shalev, S. A., De Sandre-Giovannoli, A., Shani, A. A. & Levy, N. An association of Hutchinson-Gilford progeria and malignancy. Am. J. Med. Genet. A 143, 1821–1826 (2007).

    Article  CAS  Google Scholar 

  122. Fukuchi, K. et al. LMNA mutation in a 45 year old Japanese subject with Hutchinson-Gilford progeria syndrome. J. Med. Genet. 41, e67 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wadayama, B. et al. Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res. 54, 3042–3048 (1994).

    CAS  PubMed  Google Scholar 

  124. Mancini, M. A., Shan, B., Nickerson, J. A., Penman, S. & Lee, W. H. The retinoblastoma gene product is a cell cycle-dependent, nuclear matrix-associated protein. Proc. Natl Acad. Sci. USA 91, 418–422 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Mittnacht, S. & Weinberg, R. A. G1/S phosphorylation of the retinoblastoma protein is associated with an altered affinity for the nuclear compartment. Cell 65, 381–393 (1991).

    Article  CAS  PubMed  Google Scholar 

  126. Ozaki, T. et al. Complex formation between lamin A and the retinoblastoma gene product: identification of the domain on lamin A required for its interaction. Oncogene 9, 2649–2653 (1994).

    CAS  PubMed  Google Scholar 

  127. Markiewicz, E., Dechat, T., Foisner, R., Quinlan, R. A. & Hutchison, C. J. Lamin A/C binding protein LAP2α is required for nuclear anchorage of retinoblastoma protein. Mol. Biol. Cell 13, 4401–4413 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Johnson, B. R. et al. A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation. Proc. Natl Acad. Sci. USA 101, 9677–9682 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Nitta, R. T., Jameson, S. A., Kudlow, B. A., Conlan, L. A. & Kennedy, B. K. Stabilization of the retinoblastoma protein by A-type nuclear lamins is required for INK4A-mediated cell cycle arrest. Mol. Cell. Biol. 26, 5360–5372 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Broers, J. L. et al. Nuclear A-type lamins are differentially expressed in human lung cancer subtypes. Am. J. Pathol. 143, 211–220 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Kaufmann, S. H., Mabry, M., Jasti, R. & Shaper, J. H. Differential expression of nuclear envelope lamins A and C in human lung cancer cell lines. Cancer Res. 51, 581–586 (1991).

    CAS  PubMed  Google Scholar 

  132. Moss, S. F. et al. Decreased and aberrant nuclear lamin expression in gastrointestinal tract neoplasms. Gut 45, 723–729 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Han, X. et al. Tethering by lamin A stabilizes and targets the ING1 tumour suppressor. Nature Cell Biol. 10, 1333–1340 (2008).

    Article  CAS  PubMed  Google Scholar 

  134. Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990).

    Article  CAS  PubMed  Google Scholar 

  135. d'Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). Telomere-initiated senescence results in increased expression of markers for DNA damage and induces a DNA damage-like checkpoint response in fibroblasts.

    Article  CAS  PubMed  Google Scholar 

  136. Sedelnikova, O. A. et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nature Cell Biol. 6, 168–170 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114–10118 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Decker, M. L., Chavez, E., Vulto, I. & Lansdorp, P. M. Telomere length in Hutchinson-Gilford progeria syndrome. Mech. Ageing Dev. 130, 377–383 (2009).

    Article  CAS  PubMed  Google Scholar 

  139. Raz, V. et al. Changes in lamina structure are followed by spatial reorganization of heterochromatic regions in caspase-8-activated human mesenchymal stem cells. J. Cell Sci. 119, 4247–4256 (2006).

    Article  CAS  PubMed  Google Scholar 

  140. Raz, V. et al. The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells. J. Cell Sci. 121, 4018–4028 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Gotzmann, J. & Foisner, R. A-type lamin complexes and regenerative potential: a step towards understanding laminopathic diseases? Histochem. Cell Biol. 125, 33–41 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Kudlow, B. A., Jameson, S. A. & Kennedy, B. K. HIV protease inhibitors block adipocyte differentiation independently of lamin A/C. AIDS 19, 1565–1573 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Constantinescu, D., Gray, H. L., Sammak, P. J., Schatten, G. P. & Csoka, A. B. Lamin A/C expression is a marker of mouse and human embryonic stem cell differentiation. Stem Cells 24, 177–185 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Espada, J. et al. Nuclear envelope defects cause stem cell dysfunction in premature-aging mice. J. Cell Biol. 181, 27–35 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Burtner, C. R., Murakami, C. J., Kennedy, B. K. & Kaeberlein, M. A molecular mechanism of chronological aging in yeast. Cell Cycle 8, 1256–1270 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Kirwan, M. & Dokal, I. Dyskeratosis congenita, stem cells and telomeres. Biochim. Biophys. Acta 1792, 371–379 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Medawar, P. An Unsolved Problem in Biology (H. K. Lewis, London, 1952).

    Google Scholar 

  148. Williams, G. C. Pleiotropy, natural selection and the evolution of senescence. Evolution 11, 398–411 (1957).

    Article  Google Scholar 

  149. Kirkwood, T. B. Evolution of ageing. Nature 270, 301–304 (1977).

    Article  CAS  PubMed  Google Scholar 

  150. Kirkwood, T. B. & Holliday, R. The evolution of ageing and longevity. Proc. R. Soc. Lond. B Biol. Sci. 205, 531–546 (1979).

    Article  CAS  PubMed  Google Scholar 

  151. Epstein, C. J., Martin, G. M., Schultz, A. L. & Motulsky, A. G. Werner's syndrome a review of its symptomatology, natural history, pathologic features, genetics and relationship to the natural aging process. Medicine (Baltimore) 45, 177–221 (1966).

    Article  CAS  Google Scholar 

  152. Ozgenc, A. & Loeb, L. A. Werner Syndrome, aging and cancer. Genome Dyn. 1, 206–217 (2006).

    Article  CAS  PubMed  Google Scholar 

  153. Bohr, V. A. Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance. Trends Biochem. Sci. 33, 609–620 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Garinis, G. A., van der Horst, G. T., Vijg, J. & Hoeijmakers, J. H. DNA damage and ageing: new-age ideas for an age-old problem. Nature Cell Biol. 10, 1241–1247 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Cleaver, J. E., Lam, E. T. & Revet, I. Disorders of nucleotide excision repair: the genetic and molecular basis of heterogeneity. Nature Rev. Genet. 10, 756–768 (2009).

    Article  CAS  PubMed  Google Scholar 

  156. van der Pluijm, I. et al. Impaired genome maintenance suppresses the growth hormone–insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biol. 5, e2 (2007).

    Article  PubMed  CAS  Google Scholar 

  157. Schumacher, B. et al. Delayed and accelerated aging share common longevity assurance mechanisms. PLoS Genet. 4, e1000161 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Young, S. G., Meta, M., Yang, S. H. & Fong, L. G. Prelamin A farnesylation and progeroid syndromes. J. Biol. Chem. 281, 39741–39745 (2006).

    Article  CAS  PubMed  Google Scholar 

  159. Yang, S. H., Qiao, X., Fong, L. G. & Young, S. G. Treatment with a farnesyltransferase inhibitor improves survival in mice with a Hutchinson-Gilford progeria syndrome mutation. Biochim. Biophys. Acta 1781, 36–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  160. Delbarre, E. et al. The truncated prelamin A in Hutchinson-Gilford progeria syndrome alters segregation of A-type and B-type lamin homopolymers. Hum. Mol. Genet. 15, 1113–1122 (2006).

    Article  CAS  PubMed  Google Scholar 

  161. Varela, I. et al. Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging. Nature Med. 14, 767–772 (2008).

    Article  CAS  PubMed  Google Scholar 

  162. Yang, S. H., Andres, D. A., Spielmann, H. P., Young, S. G. & Fong, L. G. Progerin elicits disease phenotypes of progeria in mice whether or not it is farnesylated. J. Clin. Invest. 118, 3291–3300 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors apologize to researchers whose data we did not have space to incorporate into this Review. Given reference limits and the scope of the material to be covered, reviews were referenced whenever possible to direct readers to sources of more detailed information. Ageing research in the University of Washington laboratory of B.K.K. is supported by funding from the National Institute of Aging and by a Julie Martin Mid-Career Award in Aging Research. C.R.B. was supported in part by a grant to the University of Washington from the Howard Hughes Medical Institute through the Med into Grad Initiative, and by the National Institutes of Health Training Grant T32 AG00057.

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DATABASES

OMIM

Charcot–Marie–Tooth neuropathy

Cockayne syndrome

Emery–Dreifuss muscular dystrophy

familial partial lipodystrophy

HGPS

limb girdle muscular dystrophy

mandibuloacral dysplasia

trichothiodystrophy

Werner syndrome

Glossary

Proteotoxicity model

A model in which the accumulation of aggregated or misfolded proteins causes cellular dysfunction that contributes partially to tissue damage and an ageing phenotype.

Forward genetic screen

A screening approach in which the phenotype is identified initially in a natural or mutagenized population, and the responsible gene is subsequently characterized.

Reverse genetics

A screening approach in which genotypic variation is identified initially in a natural or mutagenized population, and the phenotype or mutational effect is subsequently characterized.

Replicative lifespan

The lifespan of dividing cells, measured as the number of generations (or the number of daughter cells) produced by a single mother cell.

Hypomorphic mutation

A mutation that results in reduced, but not eliminated, function.

A-type lamin

A type V intermediate filament protein in the nucleus that is mutated in several human dystrophies and at least one severe progeria.

Cell senescence

The phenomenon in which replicatively dividing cells enter a non-dividing or quiescent phase that is accompanied by changes in gene transcription and metabolism.

Clavicular agenesis

The incomplete development of the clavicle.

Mesenchymal stem cell

A pluripotent progenitor cell of mesenchymal origin that gives rise to adult tissues such as bone, cartilage and adipose.

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Burtner, C., Kennedy, B. Progeria syndromes and ageing: what is the connection?. Nat Rev Mol Cell Biol 11, 567–578 (2010). https://doi.org/10.1038/nrm2944

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