Linking functional decline of telomeres, mitochondria and stem cells during ageing (original) (raw)

• Kenyon, C. The plasticity of aging: insights from long-lived mutants. Cell 120, 449–460 (2005).
  CAS PubMed Google Scholar
• Guarente, L. Mitochondria — a nexus for aging, calorie restriction, and sirtuins? Cell 132, 171–176 (2008).
  CAS PubMed PubMed Central Google Scholar
• Finkel, T., Serrano, M. & Blasco, M. A. The common biology of cancer and ageing. Nature 448, 767–774 (2007).
  ADS CAS PubMed Google Scholar
• Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).
  CAS PubMed Google Scholar
• Kirkwood, T. B. Understanding the odd science of aging. Cell 120, 437–447 (2005).
  CAS PubMed Google Scholar
• Arrighi, H. M., McLaughlin, T. & Leibman, C. Prevalence and impact of dementia-related functional limitations in the United States, 2001 to 2005. Alzheimer Dis. Assoc. Disord. doi:10.1097/WAD.0b013e3181a1a87d (in the press).
• DePinho, R. A. The age of cancer. Nature 408, 248–254 (2000).
  ADS CAS PubMed Google Scholar
• Sharpless, N. E. & DePinho, R. A. How stem cells age and why this makes us grow old. Nature Rev. Mol. Cell Biol. 8, 703–713 (2007).
  CAS Google Scholar
• Rossi, D. J., Jamieson, C. H. & Weissman, I. L. Stems cells and the pathways to aging and cancer. Cell 132, 681–696 (2008).
  CAS PubMed Google Scholar
• Zhao, C., Deng, W. & Gage, F. H. Mechanisms and functional implications of adult neurogenesis. Cell 132, 645–660 (2008).
  CAS PubMed Google Scholar
• Linton, P. J. & Dorshkind, K. Age-related changes in lymphocyte development and function. Nature Immunol. 5, 133–139 (2004).
  CAS Google Scholar
• Kollman, C. et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 98, 2043–2051 (2001).
  CAS PubMed Google Scholar
• Gage, F. H. Mammalian neural stem cells. Science 287, 1433–1438 (2000).
  ADS CAS PubMed Google Scholar
• Maslov, A. Y., Barone, T. A., Plunkett, R. J. & Pruitt, S. C. Neural stem cell detection, characterization, and age-related changes in the subventricular zone of mice. J. Neurosci. 24, 1726–1733 (2004).
  CAS PubMed PubMed Central Google Scholar
• Molofsky, A. V. et al. Increasing p16 INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443, 448–452 (2006).
  ADS CAS PubMed PubMed Central Google Scholar
• Enwere, E. et al. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J. Neurosci. 24, 8354–8365 (2004).
  CAS PubMed PubMed Central Google Scholar
• Cerletti, M., Shadrach, J. L., Jurga, S., Sherwood, R. & Wagers, A. J. Regulation and function of skeletal muscle stem cells. Cold Spring Harb. Symp. Quant. Biol. 73, 317–322 (2008).
  CAS PubMed Google Scholar
• Di Iorio, A. et al. Sarcopenia: age-related skeletal muscle changes from determinants to physical disability. Int. J. Immunopathol. Pharmacol. 19, 703–719 (2006).
  PubMed Google Scholar
• Gopinath, S. D. & Rando, T. A. Aging of the skeletal muscle stem cell niche. Aging Cell 7, 590–598 (2008).
  CAS PubMed Google Scholar
• Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).
  ADS CAS PubMed Google Scholar
• Paik, J. H. et al. FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5, 540–553 (2009).
  CAS PubMed PubMed Central Google Scholar
• Tothova, Z. & Gilliland, D. G. FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 1, 140–152 (2007).
  CAS PubMed Google Scholar
• Gan, B. et al. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc. Natl Acad. Sci. USA 105, 19384–19389 (2008).
  ADS CAS PubMed PubMed Central Google Scholar
• Yilmaz, O. H. et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006).
  CAS Google Scholar
• 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
• Rudolph, K. L. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96, 701–712 (1999). This paper describes the effect of critically short telomeres on lifespan and stress response in telomerase knockout mice. Mice with short telomeres have a reduced lifespan and a diminished regenerative capacity when stressed, such as by wound healing or haematopoietic ablation.
  CAS PubMed Google Scholar
• Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999). This paper shows that p53 mediates the cellular response to telomere dysfunction in both normal and neoplastic cells and that p53 deficiency ameliorates degenerative phenotypes.
  CAS PubMed Google Scholar
• Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004).
  CAS PubMed PubMed Central Google Scholar
• Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002). References 28 and 29 describe the pro-ageing phenotype in mice with hyperactive p53.
  ADS CAS PubMed Google Scholar
• Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006).
  CAS PubMed Google Scholar
• Chen, M. L. et al. Erythroid dysplasia, megaloblastic anemia, and impaired lymphopoiesis arising from mitochondrial dysfunction. Blood 114, 4045–4053 (2009).
  CAS PubMed PubMed Central Google Scholar
• Liu, J. et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459, 387–392 (2009). This paper describes how in mice deficient in BMI1, mitochondrial dysfunction increases ROS levels and activates the DNA damage response, which can be partially rescued by antioxidant treatment.
  ADS CAS PubMed PubMed Central Google Scholar
• Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007).
  CAS PubMed Google Scholar
• Passos, J. F., Saretzki, G. & von Zglinicki, T. DNA damage in telomeres and mitochondria during cellular senescence: is there a connection? Nucleic Acids Res. 35, 7505–7513 (2007).
  CAS PubMed PubMed Central Google Scholar
• McClintock, B. The behavior in successive nuclear divisions of a chromosome broken at meiosis. Proc. Natl Acad. Sci. USA 25, 405–416 (1939).
  ADS CAS PubMed PubMed Central Google Scholar
• Szostak, J. W. & Blackburn, E. H. Cloning yeast telomeres on linear plasmid vectors. Cell 29, 245–255 (1982).
  CAS PubMed Google Scholar
• Shampay, J., Szostak, J. W. & Blackburn, E. H. DNA sequences of telomeres maintained in yeast. Nature 310, 154–157 (1984).
  ADS CAS PubMed Google Scholar
• Blackburn, E. H. Switching and signaling at the telomere. Cell 106, 661–673 (2001).
  CAS PubMed Google Scholar
• Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413 (1985). In this seminal paper, telomerase activity and its ability to lengthen a (TTGGGG) n oligonucleotide is identified in Tetrahymena cell extracts.
  CAS PubMed Google Scholar
• Greider, C. W. & Blackburn, E. H. The telomere terminal transferase of Tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity. Cell 51, 887–898 (1987).
  CAS PubMed Google Scholar
• Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).
  CAS PubMed Google Scholar
• Maser, R. S. & DePinho, R. A. Connecting chromosomes, crisis, and cancer. Science 297, 565–569 (2002).
  ADS CAS PubMed Google Scholar
• Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998). This seminal paper showed that reintroduction of telomerase into human retinal epithelial cells and fibroblasts prevents senescence and immortalizes human cells.
  ADS CAS PubMed Google Scholar
• Counter, C. M. et al. Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc. Natl Acad. Sci. USA 95, 14723–14728 (1998).
  ADS CAS PubMed PubMed Central Google Scholar
• Cawthon, R. M., Smith, K. R., O'Brien, E., Sivatchenko, A. & Kerber, R. A. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361, 393–395 (2003).
  CAS PubMed Google Scholar
• Njajou, O. T. et al. Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study. J. Gerontol. A 64, 860–864 (2009).
  Google Scholar
• Atzmon, G. et al. Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc. Natl Acad. Sci. USA 107 (suppl. 1), 1710–1717 (2010).
  ADS CAS PubMed Google Scholar
• Epel, E. S. et al. Accelerated telomere shortening in response to life stress. Proc. Natl Acad. Sci. USA 101, 17312–17315 (2004).
  ADS CAS PubMed PubMed Central Google Scholar
• Epel, E. S. et al. Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology 31, 277–287 (2006).
  CAS PubMed Google Scholar
• Simon, N. M. et al. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol. Psychiatry 60, 432–435 (2006).
  CAS PubMed Google Scholar
• Passos, J. F. & von Zglinicki, T. Mitochondria, telomeres and cell senescence. Exp. Gerontol. 40, 466–472 (2005).
  CAS PubMed Google Scholar
• Oexle, K. & Zwirner, A. Advanced telomere shortening in respiratory chain disorders. Hum. Mol. Genet. 6, 905–908 (1997).
  CAS PubMed Google Scholar
• Kirwan, M. & Dokal, I. Dyskeratosis congenita, stem cells and telomeres. Biochim. Biophys. Acta 1792, 371–379 (2009).
  CAS PubMed PubMed Central Google Scholar
• Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007).
  CAS PubMed Google Scholar
• Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005).
  CAS PubMed Google Scholar
• Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N. & DePinho, R. A. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 287, 1253–1258 (2000).
  ADS CAS PubMed Google Scholar
• Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997). This paper follows from the McClintock hypotheses, providing experimental proof that telomerase activity has an essential role in maintaining telomeres and preventing end-to-end recombination, using telomerase knockout mice.
  CAS PubMed Google Scholar
• Farazi, P. A., Glickman, J., Horner, J. & Depinho, R. A. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res. 66, 4766–4773 (2006).
  CAS PubMed Google Scholar
• Lee, H. W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998).
  ADS CAS PubMed Google Scholar
• Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003).
  CAS PubMed Google Scholar
• Hande, M. P., Samper, E., Lansdorp, P. & Blasco, M. A. Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J. Cell Biol. 144, 589–601 (1999).
  CAS PubMed PubMed Central Google Scholar
• Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nature Genet. 36, 877–882 (2004).
  CAS PubMed Google Scholar
• Wong, K. K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003). This paper demonstrates that ATM deficiency and telomere dysfunction act together to impair stem-cell and progenitor-cell reserves and negatively affect cellular and whole-organism viability.
  ADS CAS PubMed Google Scholar
• Rossi, D. J. et al. Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729 (2007). This paper shows that accumulated DNA damage in HSCs impairs their regenerative capacity, and it provides evidence that ageing-associated functional stem-cell decline is linked to DNA damage.
  ADS CAS PubMed Google Scholar
• Choudhury, A. R. et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genet. 39, 99–105 (2007).
  CAS PubMed Google Scholar
• Flores, I., Cayuela, M. L. & Blasco, M. A. Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309, 1253–1256 (2005).
  ADS CAS PubMed Google Scholar
• Ferron, S. et al. Telomere shortening and chromosomal instability abrogates proliferation of adult but not embryonic neural stem cells. Development 131, 4059–4070 (2004).
  CAS PubMed Google Scholar
• Sarin, K. Y. et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005).
  ADS CAS PubMed PubMed Central Google Scholar
• Maida, Y. et al. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 461, 230–235 (2009).
  ADS CAS PubMed PubMed Central Google Scholar
• Morales, M. et al. The Rad50 S allele promotes ATM-dependent DNA damage responses and suppresses ATM deficiency: implications for the Mre11 complex as a DNA damage sensor. Genes Dev. 19, 3043–3054 (2005).
  CAS PubMed PubMed Central Google Scholar
• Inomata, K. et al. Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137, 1088–1099 (2009).
  CAS PubMed Google Scholar
• Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006).
  CAS PubMed Google Scholar
• Michishita, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008).
  ADS CAS PubMed PubMed Central Google Scholar
• Vousden, K. H. & Lane, D. P. p53 in health and disease. Nature Rev. Mol. Cell Biol. 8, 275–283 (2007).
  CAS Google Scholar
• Flores, I. & Blasco, M. A. A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres. PLoS ONE 4, e4934 (2009).
  ADS PubMed PubMed Central Google Scholar
• Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).
  ADS CAS PubMed Google Scholar
• Khoo, C. M., Carrasco, D. R., Bosenberg, M. W., Paik, J. H. & Depinho, R. A. Ink4a/Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse. Proc. Natl Acad. Sci. USA 104, 3931–3936 (2007).
  ADS CAS PubMed PubMed Central Google Scholar
• Chambers, S. M. et al. Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation. PLoS Biol. 5, e201 (2007).
  PubMed PubMed Central Google Scholar
• Donehower, L. A. & Lozano, G. 20 years studying p53 functions in genetically engineered mice. Nature Rev. Cancer 9, 831–841 (2009).
  CAS Google Scholar
• Matheu, A., Maraver, A. & Serrano, M. The Arf/p53 pathway in cancer and aging. Cancer Res. 68, 6031–6034 (2008).
  CAS PubMed Google Scholar
• Matheu, A. et al. Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448, 375–379 (2007).
  ADS CAS PubMed Google Scholar
• Mendrysa, S. M. et al. Tumor suppression and normal aging in mice with constitutively high p53 activity. Genes Dev. 20, 16–21 (2006).
  CAS PubMed PubMed Central Google Scholar
• Serrano, M. & Blasco, M. A. Cancer and ageing: convergent and divergent mechanisms. Nature Rev. Mol. Cell Biol. 8, 715–722 (2007).
  CAS Google Scholar
• Begus-Nahrmann, Y. et al. p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice. Nature Genet. 41, 1138–1143 (2009).
  CAS PubMed Google Scholar
• Leri, A. et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 22, 131–139 (2003).
  CAS PubMed PubMed Central Google Scholar
• Sablina, A. A. et al. The antioxidant function of the p53 tumor suppressor. Nature Med. 11, 1306–1313 (2005).
  CAS PubMed Google Scholar
• Finkel, T., Deng, C. X. & Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 460, 587–591 (2009).
  ADS CAS PubMed PubMed Central Google Scholar
• Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).
  ADS CAS PubMed Google Scholar
• St- Pierre, J. et al. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell 127, 397–408 (2006). In this paper, the authors demonstrate that PGC-1 α is a strong positive regulator of the ROS defence system and that PGC-1 α deficiency leads to ROS-induced neurodegeneration.
  Google Scholar
• Vianna, C. R. et al. Hypomorphic mutation of PGC-1β causes mitochondrial dysfunction and liver insulin resistance. Cell Metab. 4, 453–464 (2006).
  CAS PubMed PubMed Central Google Scholar
• Vijg, J. Aging of the Genome: The Dual Role of DNA in Life and Death (Oxford Univ. Press, 2007).
  Google Scholar
• Ruzankina, Y. et al. Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell 1, 113–126 (2007).
  CAS PubMed PubMed Central Google Scholar
• Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004).
  ADS CAS PubMed Google Scholar
• Tomas- Loba, A. et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell 135, 609–622 (2008).
  Google Scholar
• Coviello- McLaughlin, G. M. & Prowse, K. R. Telomere length regulation during postnatal development and ageing in Mus spretus. Nucleic Acids Res. 25, 3051–3058 (1997).
  Google Scholar
• Flores, I. et al. The longest telomeres: a general signature of adult stem cell compartments. Genes Dev. 22, 654–667 (2008).
  CAS PubMed PubMed Central Google Scholar
• Armanios, M. et al. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am. J. Hum. Genet. 85, 823–832 (2009).
  CAS PubMed PubMed Central Google Scholar
• Hao, L. Y. et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123, 1121–1131 (2005).
  CAS PubMed Google Scholar
• Martin, G. M. Genetic modulation of senescent phenotypes in Homo sapiens. Cell 120, 523–532 (2005).
  CAS PubMed Google Scholar