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The genetics of ageing

An Erratum to this article was published on 29 September 2010

Abstract

The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions.

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Figure 1: Insulin/IGF-1 and FOXO signalling affects mouse and human lifespan.
Figure 2: The Caenorhabditis elegans transcription factor DAF-16/FOXO promotes longevity in response to many inputs.
Figure 3: Pathways that influence lifespan extension in response to chronic dietary restriction.
Figure 4: Different Caenorhabditis elegans nutrient sensors (red) and transcription factors (blue) extend lifespan in response to different modes of dietary restriction.
Figure 5: Model for the regulation of lifespan by signals from the reproductive system.

References

  1. Colman, R. J. et al. Dietary restriction delays disease onset and mortality in rhesus monkeys. Science 325, 201–204 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mair, W., Goymer, P., Pletcher, S. D. & Partridge, L. Demography of dietary restriction and death in Drosophila . Science 301, 1731–1733 (2003).

    ADS  CAS  PubMed  Google Scholar 

  3. Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans . Aging Cell 6, 95–110 (2007).

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  5. Kapahi, P. et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885–890 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Greer, E. L. et al. An AMPK–FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans . Curr. Biol. 17, 1646–1656 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Rogina, B. & Helfand, S. L. Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl Acad. Sci. USA 101, 15998–16003 (2004).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 8, 38–48 (2008).

    PubMed  PubMed Central  Google Scholar 

  9. Honjoh, S., Yamamoto, T., Uno, M. & Nishida, E. Signalling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans . Nature 457, 726–730 (2009).

    ADS  CAS  PubMed  Google Scholar 

  10. Arum, O., Bonkowski, M. S., Rocha, J. S. & Bartke, A. The growth hormone receptor gene-disrupted (GHR-KO) mouse fails to respond to an intermittent fasting (IF) diet. Aging Cell 8, 756–760 (2009).

    CAS  PubMed  Google Scholar 

  11. Greer, E. L. & Brunet, A. Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans . Aging Cell 8, 113–127 (2009). This paper shows that different pathways extend lifespan in response to different methods of dietary restriction.

    CAS  PubMed  Google Scholar 

  12. Shama, S., Lai, C. Y., Antoniazzi, J. M., Jiang, J. C. & Jazwinski, S. M. Heat stress-induced life span extension in yeast. Exp. Cell Res. 245, 379–388 (1998).

    CAS  PubMed  Google Scholar 

  13. 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).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans . Genes Dev. 18, 3004–3009 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Heidlelr, T., Hartwig, K., Daniel, H. & Wenzel, U. Caenorhabditis elegans lifespan extension caused by treatment with an orally active ROS-generator is dependent on DAF-16 and SIR-2.1. Biogerontology doi:10.1007/s10522-009-9239-x (2009).

  16. Alcedo, J., Maier, W. & Ch'ng, Q. in Protein Metabolism and Homeostasis in Aging (ed. Tavernarakis, N.) (Landes Bioscience, 2010); available at <http://www.landesbioscience.com/curie/chapter/4546>.

    Google Scholar 

  17. Lee, S. J. & Kenyon, C. Regulation of the longevity response to temperature by thermosensory neurons in Caenorhabditis elegans . Curr. Biol. 19, 715–722 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Kenyon, C. A pathway that links reproductive status to lifespan in Caenorhabditis elegans . Ann. NY Acad. Sci. (in the press).

  19. Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005). Most of the pioneering studies in the field are cited in this review.

    CAS  PubMed  Google Scholar 

  20. Dell'agnello, C. et al. Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431–444 (2007).

    CAS  PubMed  Google Scholar 

  21. Copeland, J. M. et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19, 1591–1598 (2009).

    CAS  PubMed  Google Scholar 

  22. Pan, K. Z. et al. Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans . Aging Cell 6, 111–119 (2007).

    CAS  PubMed  Google Scholar 

  23. Hamilton, B. et al. A systematic RNAi screen for longevity genes in C. elegans . Genes Dev. 19, 1544–1555 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Syntichaki, P., Troulinaki, K. & Tavernarakis, N. eIF4E function in somatic cells modulates ageing in Caenorhabditis elegans . Nature 445, 922–926 (2007).

    ADS  CAS  PubMed  Google Scholar 

  25. Garigan, D. et al. Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation. Genetics 161, 1101–1112 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Herndon, L. A. et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans . Nature 419, 808–814 (2002). This paper lays out a clear case for stochastic determinants of ageing.

    ADS  CAS  PubMed  Google Scholar 

  27. 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 

  28. Wang, M. C., O' Rourke, E. J. & Ruvkun, G. Fat metabolism links germline stem cells and longevity in C. elegans . Science 322, 957–960 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Curran, S. P., Wu, X., Riedel, C. G. & Ruvkun, G. A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature 459, 1079–1084 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans . Science 301, 1387–1391 (2003). This study first linked autophagy to lifespan extension.

    ADS  CAS  PubMed  Google Scholar 

  31. Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans . PLoS Genet. 4, e24 (2008).

    PubMed  PubMed Central  Google Scholar 

  32. Murphy, C. T., Lee, S. J. & Kenyon, C. Tissue entrainment by feedback regulation of insulin gene expression in the endoderm of Caenorhabditis elegans . Proc. Natl Acad. Sci. USA 104, 19046–19050 (2007).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bishop, N. A. & Guarente, L. Two neurons mediate diet-restriction-induced longevity in C. elegans . Nature 447, 545–549 (2007).

    ADS  CAS  PubMed  Google Scholar 

  34. Bartke, A. Insulin and aging. Cell Cycle 7, 3338–3343 (2008).

    CAS  PubMed  Google Scholar 

  35. Yuan, R. et al. Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels. Aging Cell 8, 277–287 (2009).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  37. Selman, C. et al. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 22, 807–818 (2008).

    CAS  PubMed  Google Scholar 

  38. Suh, Y. et al. Functionally significant insulin-like growth factor I receptor mutations in centenarians. Proc. Natl Acad. Sci. USA 105, 3438–3442 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kojima, T. et al. Association analysis between longevity in the Japanese population and polymorphic variants of genes involved in insulin and insulin-like growth factor 1 signaling pathways. Exp. Gerontol. 39, 1595–1598 (2004).

    CAS  PubMed  Google Scholar 

  40. Pawlikowska, L. et al. Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8, 460–472 (2009).

    CAS  PubMed  Google Scholar 

  41. Willcox, B. J. et al. FOXO3A genotype is strongly associated with human longevity. Proc. Natl Acad. Sci. USA 105, 13987–13992 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. Anselmi, C. V. et al. Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuvenation Res. 12, 95–104 (2009).

    CAS  PubMed  Google Scholar 

  43. Flachsbart, F. et al. Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc. Natl Acad. Sci. USA 106, 2700–2705 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. Li, Y. et al. Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum. Mol. Genet. 18, 4897–4904 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Lunetta, K. L. et al. Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study. BMC Med. Genet. 8 (suppl. 1), S13 (2007).

    PubMed  PubMed Central  Google Scholar 

  46. 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).

    ADS  CAS  PubMed  Google Scholar 

  47. Clancy, D. J., Gems, D., Hafen, E., Leevers, S. J. & Partridge, L. Dietary restriction in long-lived dwarf flies. Science 296, 319 (2002).

    CAS  PubMed  Google Scholar 

  48. Grandison, R. C., Piper, M. D. & Partridge, L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila . Nature 462, 1061–1064 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kalaany, N. Y. & Sabatini, D. M. Tumors with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. Libert, S. et al. Regulation of Drosophila life span by olfaction and food-derived odors. Science 315, 1133–1137 (2007).

    ADS  CAS  PubMed  Google Scholar 

  51. Lee, S.-J., Murphy, C. & Kenyon, C. Glucose shortens the lifespan of C. elegans by down-regulating DAF-16/FOXO activity and aquaporin gene expression. Cell Metab. 10, 379–391 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Jia, K., Chen, D. & Riddle, D. L. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 131, 3897–3906 (2004).

    CAS  PubMed  Google Scholar 

  53. Vellai, T. et al. Genetics: influence of TOR kinase on lifespan in C. elegans . Nature 426, 620 (2003).

    ADS  CAS  PubMed  Google Scholar 

  54. Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). This is one of the most exciting demonstrations of lifespan extension by a drug that inhibits a genetically defined lifespan pathway.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sheaffer, K. L., Updike, D. L. & Mango, S. E. The target of rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr. Biol. 18, 1355–1364 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Medvedik, O., Lamming, D. W., Kim, K. D. & Sinclair, D. A. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae . PLoS Biol. 5, e261 (2007).

    PubMed  PubMed Central  Google Scholar 

  57. Zid, B. M. et al. 4E-BP extends lifespan upon dietary restriction by enhancing mitochondrial activity in Drosophila . Cell 139, 149–160 (2009). This study shows that selective translation of respiratory-chain components contributes to lifespan extension by TOR inhibition and dietary restriction.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  59. Steffen, K. K. et al. Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4. Cell 133, 292–302 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 43, 200–205 (2004).

    ADS  Google Scholar 

  61. Toth, M. L. et al. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4, 330–338 (2008).

    CAS  PubMed  Google Scholar 

  62. Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster . Cell Metab. 11, 35–46 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Anisimov, V. N. et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 7, 2769–2773 (2008).

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    ADS  CAS  PubMed  Google Scholar 

  66. Kaeberlein, M. & Powers, R. W. Sir2 and calorie restriction in yeast: a skeptical perspective. Ageing Res. Rev. 6, 128–140 (2007).

    CAS  PubMed  Google Scholar 

  67. Liu, B. et al. The polarisome is required for segregation and retrograde transport of protein aggregates. Cell 140, 257–267 (2010). This paper investigates the Sir2-dependent mechanism of polarized segregation of damaged macromolecules to yeast mother cells.

    CAS  PubMed  Google Scholar 

  68. Dang, W. et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature 459, 802–807 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  69. Berdichevsky, A., Viswanathan, M., Horvitz, H. R. & Guarente, L. C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span. Cell 125, 1165–1177 (2006).

    CAS  PubMed  Google Scholar 

  70. Hull- Thompson, J. et al. Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz. PLoS Genet. 4, e1000460 (2009).

    Google Scholar 

  71. Griswold, A., Chang, K. T., Runko, A. P., Knight, M. A. & Min, K. T. Sir2 mediates apoptosis through JNK-dependent pathways in Drosophila . Proc. Natl Acad. Sci. USA 105, 8673–8678 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pearson, K. J. et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab. 8, 157–168 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Beher, D. et al. Resveratrol is not a direct activator of SIRT1 enzyme activity. Chem. Biol. Drug Des. 74, 619–624 (2009).

    CAS  PubMed  Google Scholar 

  74. Viswanathan, M., Kim, S. K., Berdichevsky, A. & Guarente, L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev. Cell 9, 605–615 (2005). This is a powerful genetic demonstration that resveratrol does not behave as a simple sirtuin activator.

    CAS  PubMed  Google Scholar 

  75. Smith, D. L. Jr et al. Calorie restriction effects on silencing and recombination at the yeast rDNA. Aging Cell 8, 633–642 (2009).

    CAS  PubMed  Google Scholar 

  76. Riesen, M. & Morgan, A. Calorie restriction reduces rDNA recombination independently of rDNA silencing. Aging Cell 8, 624–632 (2009).

    CAS  PubMed  Google Scholar 

  77. Wang, Y. & Tissenbaum, H. A. Overlapping and distinct functions for Caenorhabditis elegans SIR2 and DAF-16/FOXO. Mech. Ageing Dev. 127, 48–56 (2006).

    CAS  PubMed  Google Scholar 

  78. Li, Y., Xu, W., McBurney, M. W. & Longo, V. D. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Cell Metab. 8, 38–48 (2008).

    PubMed  PubMed Central  Google Scholar 

  79. Kayser, E. B., Sedensky, M. M., Morgan, P. G. & Hoppel, C. L. Mitochondrial oxidative phosphorylation is defective in the long-lived mutant clk-1. J. Biol. Chem. 279, 54479–54486 (2004).

    CAS  PubMed  Google Scholar 

  80. Lapointe, J. & Hekimi, S. Early mitochondrial dysfunction in long-lived Mclk1+/− mice. J. Biol. Chem. 283, 26217–26227 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Rea, S. L., Ventura, N. & Johnson, T. E. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans . PLoS Biol. 5, e259 (2007).

    PubMed  PubMed Central  Google Scholar 

  82. Kirchman, P. A., Kim, S., Lai, C. Y. & Jazwinski, S. M. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae . Genetics 152, 179–190 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Cristina, D., Cary, M., Lunceford, A., Clarke, C. & Kenyon, C. A regulated response to impaired respiration slows behavioral rates and increases lifespan in Caenorhabditis elegans . PLoS Genet. 5, e1000450 (2009).

    PubMed  PubMed Central  Google Scholar 

  84. Hsin, H. & Kenyon, C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature 399, 362–366 (1999).

    ADS  CAS  PubMed  Google Scholar 

  85. Flatt, T. et al. Drosophila germ-line modulation of insulin signaling and lifespan. Proc. Natl Acad. Sci. USA 105, 6368–6373 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  86. Parker, W. H. et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses' health study. Obstet. Gynecol. 113, 1027–1037.

    Google Scholar 

  87. Tomas- Loba, A. et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609–622 (2008). This paper demonstrates a 'rate limiting' role for telomere length in mammalian longevity.

    Google Scholar 

  88. Pinkston, J. M., Garigan, D., Hansen, M. & Kenyon, C. Mutations that increase the lifespan of C. elegans inhibit tumor growth. Science 313, 971–975 (2006).

    ADS  CAS  PubMed  Google Scholar 

  89. Hernebring, M., Brolen, G., Aguilaniu, H., Semb, H. & Nystrom, T. Elimination of damaged proteins during differentiation of embryonic stem cells. Proc. Natl Acad. Sci. USA 103, 7700–7705 (2006).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  90. Fan, W. et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science 319, 958–962 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  91. Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008). References 90 and 91 demonstrate the existence of a quality-control mechanism for inheritance of mitochondrial DNA.

    PubMed  PubMed Central  Google Scholar 

  92. 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).

    CAS  PubMed  Google Scholar 

  93. Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007).

    CAS  PubMed  Google Scholar 

  94. Budovskaya, Y. V. et al. An elt-3/elt-5/elt-6 GATA transcription circuit guides aging in C. elegans . Cell 134, 291–303 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Boehm, M. & Slack, F. A developmental timing microRNA and its target regulate life span in C. elegans . Science 310, 1954–1957 (2005). This is the first demonstration that microRNAs affect ageing; interestingly, this microRNA also regulates the timing of developmental events.

    ADS  CAS  PubMed  Google Scholar 

  96. Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Brack, A. S. et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science 317, 807–810 (2007).

    ADS  CAS  PubMed  Google Scholar 

  98. Gachon, F., Olela, F. F., Schaad, O., Descombes, P. & Schibler, U. The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification. Cell Metab. 4, 25–36 (2006).

    CAS  PubMed  Google Scholar 

  99. Walker, R. F. et al. A case study of 'disorganized development' and its possible relevance to genetic determinants of aging. Mech. Ageing Dev. 130, 350–356 (2009).

    CAS  PubMed  Google Scholar 

  100. Hsu, A. L., Feng, Z., Hsieh, M. Y. & Xu, X. Z. Identification by machine vision of the rate of motor activity decline as a lifespan predictor in C. elegans . Neurobiol. Aging 30, 1498–1503 (2008).

    PubMed  PubMed Central  Google Scholar 

  101. Rea, S. L., Wu, D., Cypser, J. R., Vaupel, J. W. & Johnson, T. E. A stress-sensitive reporter predicts longevity in isogenic populations of Caenorhabditis elegans . Nature Genet. 37, 894–898 (2005).

    CAS  PubMed  Google Scholar 

  102. Ayyadevara, S. et al. C. elegans PI3K mutants reveal novel genes underlying exceptional stress resistance and lifespan. Aging Cell 8, 706–725 (2009).

    CAS  PubMed  Google Scholar 

  103. Davies, B. S., Fong, L. G., Yang, S. H., Coffinier, C. & Young, S. G. The posttranslational processing of prelamin A and disease. Annu. Rev. Genomics Hum. Genet. 10, 153–174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Barzilai, N. et al. Unique lipoprotein phenotype and genotype associated with exceptional longevity. J. Am. Med. Assoc. 290, 2030–2040 (2003).

    CAS  Google Scholar 

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Acknowledgements

I apologize to all those whose work was not cited because of space limitations. I thank the members of my lab, J. Rine, B. Meyer, R. Losick and the reviewers for comments on the manuscript.

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C.J.K. is a founder of Elixir Pharmaceuticals (Cambridge, Massachusetts).

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Reprints and permissions information is available at http://www.nature.com/reprints. Correspondence should be addressed to the author (cynthia.kenyon@ucsf.edu).

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Kenyon, C. The genetics of ageing. Nature 464, 504–512 (2010). https://doi.org/10.1038/nature08980

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