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• W2124013587 abstract "Telomerase function is critical for telomere maintenance. Mutations in telomerase components lead to telomere shortening and progressive bone marrow failure in the premature aging syndrome dyskeratosis congenita. Short telomeres are also acquired with aging, yet the role that they play in mediating age-related disease is not fully known. We generated wild-type mice that have short telomeres. In these mice, we identified hematopoietic and immune defects that resembled those present in dyskeratosis congenita patients. When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wild-type mice with short telomeres still displayed degenerative defects. Our findings implicate telomere length as a unique heritable trait that, when short, is sufficient to mediate the degenerative defects of aging, even when telomerase is wild-type. Telomerase function is critical for telomere maintenance. Mutations in telomerase components lead to telomere shortening and progressive bone marrow failure in the premature aging syndrome dyskeratosis congenita. Short telomeres are also acquired with aging, yet the role that they play in mediating age-related disease is not fully known. We generated wild-type mice that have short telomeres. In these mice, we identified hematopoietic and immune defects that resembled those present in dyskeratosis congenita patients. When mice with short telomeres were interbred, telomere length was only incrementally restored, and even several generations later, wild-type mice with short telomeres still displayed degenerative defects. Our findings implicate telomere length as a unique heritable trait that, when short, is sufficient to mediate the degenerative defects of aging, even when telomerase is wild-type. Telomeres are DNA-protein structures that protect chromosome ends. With cell replication, telomeres shorten successively and ultimately lead to apoptosis or permanent cell-cycle arrest. Telomeres have thus been long appreciated as a determinant of replicative senescence in cells.1Harley C.B. Futcher A.B. Greider C.W. Telomeres shorten during ageing of human fibroblasts.Nature. 1990; 345: 458-460Crossref PubMed Scopus (4665) Google Scholar With aging, telomeres also shorten in humans, yet their role in mediating age-related disease is not fully known. In the presence of mutant telomerase components, short telomeres cause a premature aging syndrome. In telomere-mediated syndromes, short telomeres clinically manifest as aplastic anemia in the bone marrow and progressive fibrosis in the lung and liver.2Armanios M. Syndromes of telomere shortening.Annu. Rev. Genomics Hum. Genet. 2009; 10: 45-61Crossref PubMed Scopus (262) Google Scholar Disease-associated mutations in telomerase components were initially identified in the context of dyskeratosis congenita (DKCX [MIM 305000]), a disorder characterized by early mortality due to bone marrow failure.3Heiss N.S. Knight S.W. Vulliamy T.J. Klauck S.M. Wiemann S. Mason P.J. Poustka A. Dokal I. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions.Nat. Genet. 1998; 19: 32-38Crossref PubMed Scopus (753) Google Scholar, 4Mitchell J.R. Wood E. Collins K. A telomerase component is defective in the human disease dyskeratosis congenita.Nature. 1999; 402: 551-555Crossref PubMed Scopus (911) Google Scholar Loss-of-function mutations in the essential components of telomerase, hTR, the telomerase RNA (MIM 602322), and hTERT, the catalytic reverse transcriptase (MIM 187270), lead to telomerase haploinsufficiency and autosomal-dominant inheritance of dyskeratosis congenita (DKCA [MIM 127550]).5Armanios M. Chen J.L. Chang Y.P. Brodsky R.A. Hawkins A. Griffin C.A. Eshleman J.R. Cohen A.R. Chakravarti A. Hamosh A. et al.Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita.Proc. Natl. Acad. Sci. USA. 2005; 102: 15960-15964Crossref PubMed Scopus (372) Google Scholar, 6Vulliamy T. Marrone A. Goldman F. Dearlove A. Bessler M. Mason P.J. Dokal I. The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita.Nature. 2001; 413: 432-435Crossref PubMed Scopus (772) Google Scholar In families, the organ failure displays anticipation, an earlier and more severe onset with each generation, which is associated with progressive telomere shortening.5Armanios M. Chen J.L. Chang Y.P. Brodsky R.A. Hawkins A. Griffin C.A. Eshleman J.R. Cohen A.R. Chakravarti A. Hamosh A. et al.Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita.Proc. Natl. Acad. Sci. USA. 2005; 102: 15960-15964Crossref PubMed Scopus (372) Google Scholar, 7Vulliamy T. Marrone A. Szydlo R. Walne A. Mason P.J. Dokal I. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC.Nat. Genet. 2004; 36: 447-449Crossref PubMed Scopus (369) Google Scholar These observations have implicated telomere length as an important modifier of disease penetrance in families that carry mutant telomerase genes. However, whether short telomeres alone, in the absence of telomerase mutations, can mediate disease with aging is not known. Telomerase function is critical for organ homeostasis. Hematopoietic stem cells and lymphocytes are enriched for telomerase activity, suggesting that their self-renewal potential may depend on the presence of telomerase.8Morrison S.J. Prowse K.R. Ho P. Weissman I.L. Telomerase activity in hematopoietic cells is associated with self-renewal potential.Immunity. 1996; 5: 207-216Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 9Chiu C.P. Dragowska W. Kim N.W. Vaziri H. Yui J. Thomas T.E. Harley C.B. Lansdorp P.M. Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow.Stem Cells. 1996; 14: 239-248Crossref PubMed Scopus (356) Google Scholar This observation would imply that telomerase may protect against degenerative defects in these compartments by preventing telomere shortening. In approaching these questions, the study of telomerase function in mammalian models has relied on laboratory mouse strains that possess long, heterogeneous telomere lengths that do not mimic human telomere dynamics.10Blasco M.A. Lee H.W. Hande M.P. Samper E. Lansdorp P.M. DePinho R.A. Greider C.W. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.Cell. 1997; 91: 25-34Abstract Full Text Full Text PDF PubMed Scopus (1807) Google Scholar, 11Lee H.W. Blasco M.A. Gottlieb G.J. Horner 2nd, J.W. Greider C.W. DePinho R.A. Essential role of mouse telomerase in highly proliferative organs.Nature. 1998; 392: 569-574Crossref PubMed Scopus (1098) Google Scholar, 12Rudolph K.L. Chang S. Lee H.W. Blasco M. Gottlieb G.J. Greider C. DePinho R.A. Longevity, stress response, and cancer in aging telomerase-deficient mice.Cell. 1999; 96: 701-712Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar, 13Herrera E. Samper E. Martin-Caballero J. Flores J.M. Lee H.W. Blasco M.A. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres.EMBO J. 1999; 18: 2950-2960Crossref PubMed Scopus (392) Google Scholar In most laboratory strains, the average telomere length is ∼50–70 kb, compared with the average human telomere length of ∼10 kb.14Kipling D. Cooke H.J. Hypervariable ultra-long telomeres in mice.Nature. 1990; 347: 400-402Crossref PubMed Scopus (517) Google Scholar Therefore, on these strains, end organ dysfunction is present only when telomerase is null and after several generations of breeding when telomeres are short. Late-generation mTR−/− mice have organ dysfunction that manifests as a stem cell failure disorder and prominently affects tissues of high turnover: the hematopoietic system, the gastrointestinal tract, and male germ cells.10Blasco M.A. Lee H.W. Hande M.P. Samper E. Lansdorp P.M. DePinho R.A. Greider C.W. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA.Cell. 1997; 91: 25-34Abstract Full Text Full Text PDF PubMed Scopus (1807) Google Scholar, 11Lee H.W. Blasco M.A. Gottlieb G.J. Horner 2nd, J.W. Greider C.W. DePinho R.A. Essential role of mouse telomerase in highly proliferative organs.Nature. 1998; 392: 569-574Crossref PubMed Scopus (1098) Google Scholar, 12Rudolph K.L. Chang S. Lee H.W. Blasco M. Gottlieb G.J. Greider C. DePinho R.A. Longevity, stress response, and cancer in aging telomerase-deficient mice.Cell. 1999; 96: 701-712Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar, 13Herrera E. Samper E. Martin-Caballero J. Flores J.M. Lee H.W. Blasco M.A. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres.EMBO J. 1999; 18: 2950-2960Crossref PubMed Scopus (392) Google Scholar, 15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar Distinct from other laboratory strains, CAST/EiJ mice have telomere length and distribution that mimic those of humans (average telomere length ∼15 kb).16Hemann M.T. Greider C.W. Wild-derived inbred mouse strains have short telomeres.Nucleic Acids Res. 2000; 28: 4474-4478Crossref PubMed Scopus (182) Google Scholar We have previously shown that, similar to dyskeratosis congenita patients, CAST/EiJ mTR+/− mice are haploinsufficient for telomerase and develop end organ defects when telomeres are short.15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 17Hathcock K.S. Hemann M.T. Opperman K.K. Strong M.A. Greider C.W. Hodes R.J. Haploinsufficiency of mTR results in defects in telomere elongation.Proc. Natl. Acad. Sci. USA. 2002; 99: 3591-3596Crossref PubMed Scopus (93) Google Scholar Wild-type littermates of late-generation heterozygous mice also inherit short telomeres.15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar However, whether these short telomeres can cause clinically relevant phenotypes that resemble those of aging is not known. Here, we show that mice that are otherwise wild-type at the telomerase locus but have short telomeres develop degenerative defects in both hematopoietic and immune systems. These defects mimic the hematopoietic and immunosenescence phenotypes present in dyskeratosis congenita patients. Our findings suggest that the short-telomere genotype (telotype)18Makovets S. Williams T.L. Blackburn E.H. The telotype defines the telomere state in Saccharomyces cerevisiae and is inherited as a dominant non-Mendelian characteristic in cells lacking telomerase.Genetics. 2008; 178: 245-257Crossref PubMed Scopus (13) Google Scholar is a unique heritable trait, sufficient to mediate degenerative disease even when telomerase is wild-type. Mice were housed on the Johns Hopkins University School of Medicine campus, and all procedures were approved by its Institutional Animal Care and Use Committee. Blood counts and differentials were performed in a clinical lab with the use of standard antibodies: anti-Annexin V, B220, CD3, CD4, CD8, CD48, CD150, and c-kit (Becton Dickinson). Flow cytometry was performed on a FACS Calibur with the use of standard antibodies (Becton Dickinson). Quantitative fluorescence in situ hybridization (qFISH) and 5-fluorouracil studies were performed as described previously.19Morra M. Barrington R.A. Abadia-Molina A.C. Okamoto S. Julien A. Gullo C. Kalsy A. Edwards M.J. Chen G. Spolski R. et al.Defective B cell responses in the absence of SH2D1A.Proc. Natl. Acad. Sci. USA. 2005; 102: 4819-4823Crossref PubMed Scopus (65) Google Scholar IgM quantitation was performed via standard ELISA (Bethyl Laboratories). Mice were immunized with TNP-Ficoll (10 μg, Biosearch Technologies) and Imject Alum (Pierce) similarly to the methods described in Morra et al.19Morra M. Barrington R.A. Abadia-Molina A.C. Okamoto S. Julien A. Gullo C. Kalsy A. Edwards M.J. Chen G. Spolski R. et al.Defective B cell responses in the absence of SH2D1A.Proc. Natl. Acad. Sci. USA. 2005; 102: 4819-4823Crossref PubMed Scopus (65) Google Scholar We quantitated antigen-specific IgM 3 days prior to immunization and on day 7 after using ELISA (TNP-OVA, Biosearch Technologies) as described previously.19Morra M. Barrington R.A. Abadia-Molina A.C. Okamoto S. Julien A. Gullo C. Kalsy A. Edwards M.J. Chen G. Spolski R. et al.Defective B cell responses in the absence of SH2D1A.Proc. Natl. Acad. Sci. USA. 2005; 102: 4819-4823Crossref PubMed Scopus (65) Google Scholar T cell isolation was performed with EasySep (StemCell Technologies). T cells were stimulated with CD3 5 μg/mL (platebound) and CD28 10 ng/mL (eBioscience). Cells were plated at 1.5 × 106 per mL. MTT assay was performed in accordance with the manufacturer's instructions (Roche). EdU detection was performed 16 hr after incubation (Invitrogen). Tissues were prepared and fixed as described previously,15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar and all pathologic analyses were performed blinded to genotype. Statistical analyses were performed with Prism software for Windows. Means were compared with Student's t test, and all p values shown are two-sided. To examine the consequences of short telomeres when telomerase is wild-type, we bred CAST/EiJ mTR+/− mice successively.15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar We bred mTR+/− mice to each other and assigned the generation number. For example, first-heterozygous-generation mTR+/− mice were termed HG1, second heterozygous generation as HG2, etc. To distinguish wild-type progeny from these crosses, we termed them wt∗ and indicated the generation number. For example, wild-type mice born of mTR+/− HG7 were named wt8∗1 (Figure 1A). As previously shown,15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar wt∗ mice inherit the short telomeres and thus have a shorter telotype than wild-types (Figure 1B). With these short telomeres, wt∗ mice provide an opportunity to understand the contribution of short telomeres to human aging. Haploinsufficiency for telomerase components leads to aplastic anemia, and mTR+/− mice with short telomeres have low blood counts.15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar Hematopoietic function also declines with age and manifests as progressive cytopenias, a decrease in hematopoietic organ cellularity, and a decreasing tolerance to cumulative doses of chemotherapy.20Segal J.B. Moliterno A.R. Platelet counts differ by sex, ethnicity, and age in the United States.Ann. Epidemiol. 2006; 16: 123-130Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 21Hartsock R.J. Smith E.B. Petty C.S. Normal Variations With Aging Of The Amount Of Hematopoietic Tissue In Bone Marrow From The Anterior Iliac Crest. A Study Made From 177 Cases Of Sudden Death Examined By Necropsy.Am. J. Clin. Pathol. 1965; 43: 326-331Crossref PubMed Scopus (232) Google Scholar, 22Smith T.J. Khatcheressian J. Lyman G.H. Ozer H. Armitage J.O. Balducci L. Bennett C.L. Cantor S.B. Crawford J. Cross S.J. et al.2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline.J. Clin. Oncol. 2006; 24: 3187-3205Crossref PubMed Scopus (1464) Google Scholar To determine whether short telomeres are sufficient to mediate these defects, we examined blood counts. wt∗ mice developed low absolute neutrophil and platelet counts (Figures 1C and 1D). These cytopenias were associated with a decrease in bone marrow and spleen cellularity, consistent with a defect in bone marrow production (Figures 1E and 1F). When we challenged wt∗ mice with 5-fluorouracil, they had a more profound nadir and lower leukocyte counts at the time of expected recovery, though these defects were more profound in mTR+/− littermates (Figure 1G). The delay in recovery of white cell count after chemotherapy is consistent with a defect in bone marrow progenitor pools. Thus, even when telomerase is wild-type, the short telotype leads to a degenerative bone marrow failure syndrome. Although stem cell function declines with age, in certain mouse strains the frequency of hematopoietic stem cells increases with age.23Schlessinger D. Van Zant G. Does functional depletion of stem cells drive aging?.Mech. Ageing Dev. 2001; 122: 1537-1553Crossref PubMed Scopus (51) Google Scholar To examine whether wt∗ mice have an increase in stem cell number, we assayed the frequency of SLAM cells.24Kiel M.J. Yilmaz O.H. Iwashita T. Terhorst C. Morrison S.J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells.Cell. 2005; 121: 1109-1121Abstract Full Text Full Text PDF PubMed Scopus (2442) Google Scholar, 25Yilmaz O.H. Kiel M.J. Morrison S.J. SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity.Blood. 2006; 107: 924-930Crossref PubMed Scopus (202) Google Scholar Consistent with their progenitor phenotype, SLAM cells in CAST/EiJ mice express the c-kit antigen and are enriched by depleting committed lineages (Figure S1).24Kiel M.J. Yilmaz O.H. Iwashita T. Terhorst C. Morrison S.J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells.Cell. 2005; 121: 1109-1121Abstract Full Text Full Text PDF PubMed Scopus (2442) Google Scholar We also found that the frequency of SLAM cells increased in aging CAST/EiJ mice, similar to what has been described for other strains (Figure 1H).23Schlessinger D. Van Zant G. Does functional depletion of stem cells drive aging?.Mech. Ageing Dev. 2001; 122: 1537-1553Crossref PubMed Scopus (51) Google Scholar To examine whether young wt∗ mice develop an age-related phenotype in the hematopoietic stem cell compartment, we quantitated the frequency of CD150+CD48−c-kit+ cells and found that they had a nearly 2-fold increase in comparison to age-matched wild-types (Figure 1H). Therefore, although hematopoiesis is impaired in wt∗ mice, the pool of hematopoietic stem cells increases, suggesting that these cells may have defects in proliferative expansion. Lymphocyte function declines with age in humans, and cells rely on self-renewal and proliferative potential to maintain antigen specificity throughout adult life. To test whether short telomeres can mediate immunosenescence, we examined lymphocyte compartments. wt∗ mice had a profound peripheral B cell lymphopenia that led to a significant decrease in IgM production (Figures 2A and 2B). When challenged with immunization, wt∗ mice failed to mount a robust immune response after antigen exposure (Figure 2C). mTR+/− mice with short telomeres also developed similar defects, consistent with observations in dyskeratosis congenita patients who have defects in antibody production and humoral immunity (Figures 2A–2C).26Knudson M. Kulkarni S. Ballas Z.K. Bessler M. Goldman F. Association of immune abnormalities with telomere shortening in autosomal-dominant dyskeratosis congenita.Blood. 2005; 105: 682-688Crossref PubMed Scopus (67) Google Scholar T cell function also declines with age, and CD4 lymphopenia in the presence of an intact CD8 count is characteristic of immunosenescence.27Weng N.P. Aging of the immune system: how much can the adaptive immune system adapt?.Immunity. 2006; 24: 495-499Abstract Full Text Full Text PDF PubMed Scopus (352) Google Scholar We therefore examined T cell numbers in wt∗ mice and found that short telomeres led to a general T cell lymphopenia (Figure 2D). Specifically, wt∗ mice developed an asymmetric lymphopenia with a more severe deficit in CD4 cells in comparison to CD8 cells (Figure 2E). mTR+/− mice with short telomeres developed similar patterns of preferential CD4 lymphopenia. This is noteworthy given the predilection of dyskeratosis congenita patients to an opportunistic infection spectrum similar to that of patients with the acquired immunodeficiency syndrome (e.g., Pneumocystis carinii).28Rose C. Kern W.V. Another case of Pneumocystis carinii pneumonia in a patient with dyskeratosis congenita (Zinsser-Cole-Engman syndrome).Clin. Infect. Dis. 1992; 15: 1056-1057Crossref PubMed Scopus (11) Google Scholar, 29Lee B.W. Yap H.K. Quah T.C. Chong A. Seah C.C. T cell immunodeficiency in dyskeratosis congenita.Arch. Dis. Child. 1992; 67: 524-526Crossref PubMed Scopus (25) Google Scholar Therefore, short telomeres in wt∗ mice are sufficient to cause features of the combined immunodeficiency associated with aging. These findings are particularly significant given the association of short telomeres with an increased mortality due to infection in elderly individuals,30Cawthon 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. 2003; 361: 393-395Abstract Full Text Full Text PDF PubMed Scopus (1378) Google Scholar and they suggest that short telomeres can directly mediate an immunodeficient state. To determine whether short telomeres can cause qualitative T cell defects when telomerase is wild-type, we isolated and stimulated T cells. T cell activation and proliferation are known to be associated with a burst in telomerase activity that sustains clonal expansion after antigen stimulation.11Lee H.W. Blasco M.A. Gottlieb G.J. Horner 2nd, J.W. Greider C.W. DePinho R.A. Essential role of mouse telomerase in highly proliferative organs.Nature. 1998; 392: 569-574Crossref PubMed Scopus (1098) Google Scholar, 31Weng N.P. Levine B.L. June C.H. Hodes R.J. Regulated expression of telomerase activity in human T lymphocyte development and activation.J. Exp. Med. 1996; 183: 2471-2479Crossref PubMed Scopus (368) Google Scholar, 32Buchkovich K.J. Greider C.W. Telomerase regulation during entry into the cell cycle in normal human T cells.Mol. Biol. Cell. 1996; 7: 1443-1454Crossref PubMed Scopus (203) Google Scholar We therefore reasoned that wild-type telomerase may sustain the proliferative capacity of T cells even when telomeres are short. When we stimulated wt∗ T cells in vitro, they failed to expand in comparison to cells from true wild-types, and in fact responded similarly to those of mTR+/− mice (Figure 2F). To examine the underlying mechanism, we assayed for apoptosis, and we found that although there were no baseline differences (not shown), wt∗ T cells had an increase in the apoptotic fraction after stimulation in comparison to wild-type cells (Figures 2G and 2H). Because short telomeres also impair cell-cycle progression,33d'Adda di Fagagna F. Reaper P.M. Clay-Farrace L. Fiegler H. Carr P. Von Zglinicki T. Saretzki G. Carter N.P. Jackson S.P. A DNA damage checkpoint response in telomere-initiated senescence.Nature. 2003; 426: 194-198Crossref PubMed Scopus (2079) Google Scholar we examined cell-cycle profiles. We found that wt∗ T cells had fewer cells in S-phase in comparison to wild-type cells (Figures 2I and 2J). This was associated with an accumulation at G2-M, a checkpoint that is well characterized in response to telomere shortening.33d'Adda di Fagagna F. Reaper P.M. Clay-Farrace L. Fiegler H. Carr P. Von Zglinicki T. Saretzki G. Carter N.P. Jackson S.P. A DNA damage checkpoint response in telomere-initiated senescence.Nature. 2003; 426: 194-198Crossref PubMed Scopus (2079) Google Scholar, 34Enomoto S. Glowczewski L. Berman J. MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae.Mol. Biol. Cell. 2002; 13: 2626-2638Crossref PubMed Scopus (105) Google Scholar, 35IJpma A.S. Greider C.W. Short telomeres induce a DNA damage response in Saccharomyces cerevisiae.Mol. Biol. Cell. 2003; 14: 987-1001Crossref PubMed Scopus (147) Google Scholar These defects were all more prominent in mTR+/− mice. Thus, when telomeres are short, T cell proliferation cannot be sustained and short telomeres cause qualitative defects by inducing both apoptosis and impaired cell-cycle progression, even when telomerase is wild-type. To examine the clinical consequences of short telomeres, we examined survival. mTR−/− mice showed progressive worsening of a survival defect with each generation, similar to what was previously shown (Figure 3A).15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar In fact, the generation number, a surrogate for telomere length, could precisely predict the median survival of mTR−/− mice (R2 = 0.95, p < 0.0001) (Figure 3B). Late generation mTR+/−mice also had an increased incidence of premature death. In these mice, similar to mTR−/− mice, the survival defect displayed genetic anticipation (Figure 3C). Consistent with a pattern of anticipation, the Mendelian ratio of mTR−/− pups from late-generation mTR+/− parents decreased successively. By the tenth generation of heterozygous breeding, only 9% of pups had the mTR−/− genotype, compared with an expected 25% (p = 0.004, chi-square test). We also examined whether wt∗ mice had a survival defect and were able to document several premature deaths in the first 6 mo of life. However, these trends have not reached statistical significance and need to be verified in ongoing long-term prospective studies. Together our data indicate that, at least when mice are null or haploinsufficient for telomerase, short telomeres can predict the onset of a fatal illness. Short telomeres have been implicated in genomic instability and in promoting tumorigenesis.12Rudolph K.L. Chang S. Lee H.W. Blasco M. Gottlieb G.J. Greider C. DePinho R.A. Longevity, stress response, and cancer in aging telomerase-deficient mice.Cell. 1999; 96: 701-712Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar, 36Artandi S.E. Chang S. Lee S.L. Alson S. Gottlieb G.J. Chin L. DePinho R.A. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.Nature. 2000; 406: 641-645Crossref PubMed Scopus (936) Google Scholar To examine whether mice with short telomeres on the CAST/EiJ background have an increased incidence of tumors, we performed careful necropsies. As previously shown,15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar mTR−/− mice had microadenomas in the lower gastrointestinal tract. However, these small lesions were localized to the mucosa and did not invade the basement membrane. Microadenomas were notably absent in wt∗ and mTR+/− mice up to the tenth generation. Furthermore, we did not detect any evidence of gross or microscopic malignancy in early- or late-generation mTR−/−, mTR+/−, and wt∗ mice that we examined (50 mice per group). To determine whether short telomeres cause genomic instability, we examined metaphases prepared from primary cells from CAST/EiJ mice with short telomeres. We also did not detect spontaneous chromosome fusions in any of the three groups of mice (n = 20 mice per group, 20 metaphases per mouse). Together, these data indicate that in the presence of an intact DNA damage response, and in the CAST/EiJ strain that possesses a human telomere length and distribution, the most prominent clinical consequences of short telomeres manifest as degenerative disease. Humans with short telomeres have an 8-fold increased risk of mortality due to infection, and wt∗ mice share with mTR+/− and mTR−/− mice all of the hematopoietic and immune defects, albeit less severely. To examine the cause of death in these mice, we performed careful histopathology. Two features consistently distinguished mTR−/− and mTR+/− mice from wild-type mice. Mice with short telomeres had evidence of severe extramedulllary hematopoiesis (0 of 9 wild-type, 5 of 5 mTR−/−, and 4 of 5 mTR+/− mice; p = 0.01 and p = 0.02, respectively, as compared to wild-type; chi-square test) (Figure 4A). Extramedullary hematopoiesis is a compensatory response to bone marrow failure. Additionally, mTR−/− and mTR+/− mice had evidence of necrotizing typhlocolitis, an infection that is usually superimposed on areas of mucosal atrophy (Figure 4B). Typhlocolitis is a superinfection of the gastrointestinal tract that leads to microperforartion and death from bacteremia.37Davila M.L. Neutropenic enterocolitis.Curr. Treat. Options Gastroenterol. 2006; 9: 249-255Crossref PubMed Scopus (30) Google Scholar Typhlocolitis has been best described in the setting of bone marrow suppression and mucosal injury after chemotherapy, as well as in aplastic anemia.37Davila M.L. Neutropenic enterocolitis.Curr. Treat. Options Gastroenterol. 2006; 9: 249-255Crossref PubMed Scopus (30) Google Scholar mTR−/− and mTR+/− mice have known mucosal atrophy,15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar and wt∗ mice also had mucosal blunting and villous shortening (0 of 9 wild-types, 3 of 6 wt9∗1; p = 0.02; chi-square test) (Figure 4C). Wt∗ mice also had evidence of enteritis and extramedullary hematopoiesis, though these defects were less severe than those in null mice. Our analyses suggest that the primary cause of death in mice with short telomeres is opportunistic infection due to typhlocolitis, related to impaired bone marrow function and superimposed on mucosal defects in the gastrointestinal tract. The fact that first-generation wt∗ mice have short telomeres implies that when telomerase is haploinsufficient, telomere-length equilibrium cannot be established after one generation.15Hao L.Y. Armanios M. Strong M.A. Karim B. Feldser D.M. Huso D. Greider C.W. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity.Cell. 2005; 123: 1121-1131Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar To examine whether wild-type telomere length could be reestablished and to determine the rate of telomere elongation when telomerase is wild-type, we bred wt∗ mice to each other in two independent lines (Figure 5A and Figure S2A). Although telomerase elongated the shortest telomeres, it surprisingly did so only incrementally across each generation (Figure 5B and Figure S2B). In fact, telomere-length analysis showed that it took as many generations for telomeres to return to wild-type length as it took for them to shorten in heterozygous breeding. For example, wt5∗1 telomeres were approaching wild-type lengths after four generations of breeding (Figure 5B). Although the degenerative phenotype became less severe with successive generations of wt∗ breeding, in one line, even two generations later, there was evidence of organ dysfunction that was never seen in wild-type mice (Figures 5C and 5D and Figures S2C and S2D). These data indicate that although wild-type telomere lengths can eventually be reestablished, telomerase levels are tightly regulated in development and lead to incremental elongation across each generation. The phenotypes that we identify in wt∗ mice provide a model for understanding the role of short telomeres in human aging. In the hematopoietic and immune systems, short telomeres are sufficient to induce the age-associated degenerative changes that resemble those seen in dyskeratosis congenita. The presence of defects in tissues of high turnover indicates that short telomeres impair stem cell and lymphocyte proliferation even when the genes for telomerase are wild-type. Although telomerase activity is enriched in these compartments, this enrichment does not render to them an indefinite functional capacity. The clinical significance of the bone marrow defects that we identify is highlighted by the fact that short telomeres provoke a life-threatening illness in mTR+/− and mTR−/− mice and may also contribute to a survival defect in wt∗ mice. Short telomeres have been associated with premature death due to infection in elderly individuals,30Cawthon 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. 2003; 361: 393-395Abstract Full Text Full Text PDF PubMed Scopus (1378) Google Scholar and our data indicate that short telomeres alone are sufficient to mediate the immunodeficiency of aging and probably its consequent morbidities. We did not identify an increased incidence of tumors in CAST/EiJ mice with short telomeres. Aside from noninvasive microadenomas which were present in mTR−/− mice, we did not observe any evidence of a neoplastic process in mTR null, heterozygous, or wt∗ mice. Additionally, we did not observe any evidence of genomic instability. Our data are in contrast to prior studies in the C57BL/6 background, which noted an increase in spontaneous tumors in mTR−/− mice.12Rudolph K.L. Chang S. Lee H.W. Blasco M. Gottlieb G.J. Greider C. DePinho R.A. Longevity, stress response, and cancer in aging telomerase-deficient mice.Cell. 1999; 96: 701-712Abstract Full Text Full Text PDF PubMed Scopus (1134) Google Scholar, 36Artandi S.E. Chang S. Lee S.L. Alson S. Gottlieb G.J. Chin L. DePinho R.A. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.Nature. 2000; 406: 641-645Crossref PubMed Scopus (936) Google Scholar They indicate that, on the Castaneus genetic background, which possesses human telomere dynamics, and in the presence of an intact DNA damage response, short telomeres primarily mediate degenerative organ failure. Our observations are consistent with several studies in tumor-prone mouse models that have demonstrated that short telomeres are indeed protective and play a powerful tumor-suppressor role.38Greenberg R.A. Chin L. Femino A. Lee K.H. Gottlieb G.J. Singer R.H. Greider C.W. DePinho R.A. Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse.Cell. 1999; 97: 515-525Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, 39Rudolph K.L. Millard M. Bosenberg M.W. DePinho R.A. Telomere dysfunction and evolution of intestinal carcinoma in mice and humans.Nat. Genet. 2001; 28: 155-159Crossref PubMed Scopus (449) Google Scholar, 40Wong K.K. Maser R.S. Bachoo R.M. Menon J. Carrasco D.R. Gu Y. Alt F.W. DePinho R.A. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing.Nature. 2003; 421: 643-648Crossref PubMed Scopus (337) Google Scholar, 41Qi L. Strong M.A. Karim B.O. Armanios M. Huso D.L. Greider C.W. Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis.Cancer Res. 2003; 63: 8188-8196PubMed Google Scholar, 42Feldser D.M. Greider C.W. Short telomeres limit tumor progression in vivo by inducing senescence.Cancer Cell. 2007; 11: 461-469Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 43Guo X. Deng Y. Lin Y. Cosme-Blanco W. Chan S. He H. Yuan G. Brown E.J. Chang S. Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis.EMBO J. 2007; 26: 4709-4719Crossref PubMed Scopus (196) Google Scholar Also, in dyskeratosis congenita, the primary cause of mortality in more than 90% of cases is organ failure.44Dokal I. Vulliamy T. Dyskeratosis congenita: its link to telomerase and aplastic anaemia.Blood Rev. 2003; 17: 217-225Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Although dyskeratosis congenita patients do have an increased incidence of cancer,45Alter B.P. Giri N. Savage S.A. Rosenberg P.S. Cancer in dyskeratosis congenita.Blood. 2009; 113: 6549-6557Crossref PubMed Scopus (353) Google Scholar the predominant phenotype is degenerative, and cancer-related mortality is less common. Collectively, this evidence suggests that short telomeres have their most prominent clinical consequences in degenerative phenotypes that lead to organ failure. The molecular mechanisms by which short telomeres may, rarely, be associated with an increase in tumor incidence remain to be fully elucidated. Finally, our data indicate that telomere length is a unique heritable trait. Because telomerase levels are tightly regulated in development, parental telomere length partly determines telomere-length heterogeneity across populations.46Njajou O.T. Cawthon R.M. Damcott C.M. Wu S.H. Ott S. Garant M.J. Blackburn E.H. Mitchell B.D. Shuldiner A.R. Hsueh W.C. Telomere length is paternally inherited and is associated with parental lifespan.Proc. Natl. Acad. Sci. USA. 2007; 104: 12135-12139Crossref PubMed Scopus (298) Google Scholar Supporting these observations, in some human families that carry mutant telomerase genes, wild-type progeny also have short telomeres in comparison to those of age-matched controls.47Goldman F. Bouarich R. Kulkarni S. Freeman S. Du H.Y. Harrington L. Mason P.J. Londono-Vallejo A. Bessler M. The effect of TERC haploinsufficiency on the inheritance of telomere length.Proc. Natl. Acad. Sci. USA. 2005; 102: 17119-17124Crossref PubMed Scopus (90) Google Scholar The fact that telomerase dose is limiting across generations may have particular significance for attempts to use adult somatic cells, which may have short telomeres, in stem-cell-based applications. In this setting, short telomeres could theoretically limit the long-term viability of these cells, even when telomerase dose is restored. Given that the spectrum of telomere-mediated disease is broad and includes idiopathic pulmonary fibrosis as well as cryptogenic forms of liver cirrhosis,48Armanios M.Y. Chen J.J. Cogan J.D. Alder J.K. Ingersoll R.G. Markin C. Lawson W.E. Xie M. Vulto I. Phillips 3rd, J.A. et al.Telomerase mutations in families with idiopathic pulmonary fibrosis.N. Engl. J. Med. 2007; 356: 1317-1326Crossref PubMed Scopus (1037) Google Scholar, 49Tsakiri K.D. Cronkhite J.T. Kuan P.J. Xing C. Raghu G. Weissler J.C. Rosenblatt R.L. Shay J.W. Garcia C.K. Adult-onset pulmonary fibrosis caused by mutations in telomerase.Proc. Natl. Acad. Sci. USA. 2007; 104: 7552-7557Crossref PubMed Scopus (705) Google Scholar, 50Alder J.K. Chen J.J. Lancaster L. Danoff S. Su S.C. Cogan J.D. Vulto I. Xie M. Qi X. Tuder R.M. et al.Short telomeres are a risk factor for idiopathic pulmonary fibrosis.Proc. Natl. Acad. Sci. USA. 2008; 105: 13051-13056Crossref PubMed Scopus (575) Google Scholar our data implicate the short telotype as sufficient to induce features of dyskeratosis congenita in otherwise wild-type individuals. We are grateful to Curt Civin, Steve Desiderio, and Katie Whartenby, as well as lab members, for helpful discussions. We thank Ling-Yang Hao for setting up the wt∗ crosses and Brendan Cormack for critical comments on the manuscript. This work was supported by National Institutes of Health grants K08CA118416 (M.A.) and RO1AG27406 (C.W.G.), the Kimmel Foundation (M.A.), and a Maryland Stem Cell Research Fellowship (J.K.A.). E.M.P. received support from a Medical Scientist Training Program grant (T32GM007309). Download .pdf (.12 MB) Help with pdf files Document S1. Two Figures The URL for data presented herein is as follows:Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nih.gov/Omim" @default.
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