Short telomeres are sufficient to cause the degenerative defects associated with aging.

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.

[1]  S. Kulkarni,et al.  The effect of TERC haploinsufficiency on the inheritance of telomere length. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[2]  L. Chin,et al.  Short Dysfunctional Telomeres Impair Tumorigenesis in the INK4aΔ2/3 Cancer-Prone Mouse , 1999, Cell.

[3]  S. Morrison,et al.  Supplemental Experimental Procedures , 2022 .

[4]  N. Carter,et al.  A DNA damage checkpoint response in telomere-initiated senescence , 2003, Nature.

[5]  C. Rosé,et al.  Another case of Pneumocystis carinii pneumonia in a patient with dyskeratosis congenita (Zinsser-Cole-Engman syndrome) , 1992, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[6]  Thomas J. Smith,et al.  2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  Margaret A. Strong,et al.  Haploinsufficiency of mTR results in defects in telomere elongation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Robert M. Bachoo,et al.  Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing , 2003, Nature.

[9]  Chao Xing,et al.  Adult-onset pulmonary fibrosis caused by mutations in telomerase , 2007, Proceedings of the National Academy of Sciences.

[10]  S. Morrison,et al.  SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity. , 2006, Blood.

[11]  C. Greider,et al.  Telomerase regulation during entry into the cell cycle in normal human T cells. , 1996, Molecular biology of the cell.

[12]  D. Schlessinger,et al.  Does functional depletion of stem cells drive aging? , 2001, Mechanisms of Ageing and Development.

[13]  I. Weissman,et al.  Telomerase activity in hematopoietic cells is associated with self-renewal potential. , 1996, Immunity.

[14]  S. Kulkarni,et al.  Association of immune abnormalities with telomere shortening in autosomal-dominant dyskeratosis congenita. , 2005, Blood.

[15]  J. Segal,et al.  Platelet counts differ by sex, ethnicity, and age in the United States. , 2006, Annals of epidemiology.

[16]  Sandy Chang,et al.  Longevity, Stress Response, and Cancer in Aging Telomerase-Deficient Mice , 1999, Cell.

[17]  T. Vulliamy,et al.  Dyskeratosis congenita: its link to telomerase and aplastic anaemia. , 2003, Blood reviews.

[18]  M. Armanios.  Syndromes of telomere shortening. , 2009, Annual review of genomics and human genetics.

[19]  M. Hemann,et al.  Wild-derived inbred mouse strains have short telomeres. , 2000, Nucleic acids research.

[20]  J. Berman,et al.  MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae. , 2002, Molecular biology of the cell.

[21]  C. Harley,et al.  Differential Expression of Telomerase Activity in Hematopoietic Progenitors from Adult Human Bone Marrow , 1996, Stem cells.

[22]  P. Lansdorp,et al.  Telomerase mutations in families with idiopathic pulmonary fibrosis. , 2007, The New England journal of medicine.

[23]  W. Leonard,et al.  Defective B cell responses in the absence of SH2D1A. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[24]  Margaret A. Strong,et al.  Short Telomeres, even in the Presence of Telomerase, Limit Tissue Renewal Capacity , 2005, Cell.

[25]  C S PETTY,et al.  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. , 1965, American journal of clinical pathology.

[26]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.

[27]  P. Lansdorp,et al.  Short telomeres are a risk factor for idiopathic pulmonary fibrosis , 2008, Proceedings of the National Academy of Sciences.

[28]  R. DePinho,et al.  Essential role of mouse telomerase in highly proliferative organs , 1998, Nature.

[29]  N. Weng.  Aging of the immune system: how much can the adaptive immune system adapt? , 2006, Immunity.

[30]  Yen-Pei Christy Chang,et al.  Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Margaret A. Strong,et al.  Short telomeres and ataxia-telangiectasia mutated deficiency cooperatively increase telomere dysfunction and suppress tumorigenesis. , 2003, Cancer research.

[32]  T. Vulliamy,et al.  The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita , 2001, Nature.

[33]  M. Blasco,et al.  Disease states associated with telomerase deficiency appear earlier in mice with short telomeres , 1999, The EMBO journal.

[34]  Lynda Chin,et al.  Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice , 2000, Nature.

[35]  María A Blasco,et al.  Telomere Shortening and Tumor Formation by Mouse Cells Lacking Telomerase RNA , 1997, Cell.

[36]  B. Levine,et al.  Regulated expression of telomerase activity in human T lymphocyte development and activation , 1996, The Journal of experimental medicine.

[37]  A. Chong,et al.  T cell immunodeficiency in dyskeratosis congenita. , 1992, Archives of disease in childhood.

[38]  E. Blackburn,et al.  Telomere length is paternally inherited and is associated with parental lifespan , 2007, Proceedings of the National Academy of Sciences.

[39]  R. DePinho,et al.  Telomere dysfunction and evolution of intestinal carcinoma in mice and humans , 2001, Nature Genetics.

[40]  Sandy Chang,et al.  Dysfunctional telomeres activate an ATM‐ATR‐dependent DNA damage response to suppress tumorigenesis , 2007, The EMBO journal.

[41]  D. Feldser,et al.  Short telomeres limit tumor progression in vivo by inducing senescence. , 2007, Cancer cell.

[42]  P. Rosenberg,et al.  Cancer in dyskeratosis congenita. , 2009, Blood.

[43]  D. Kipling,et al.  Hypervariable ultra-long telomeres in mice , 1990, Nature.

[44]  T. Vulliamy,et al.  Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC , 2004, Nature Genetics.

[45]  K. Collins,et al.  A telomerase component is defective in the human disease dyskeratosis congenita , 1999, Nature.

[46]  E. Blackburn,et al.  The Telotype Defines the Telomere State in Saccharomyces cerevisiae and Is Inherited as a Dominant Non-Mendelian Characteristic in Cells Lacking Telomerase , 2008, Genetics.

[47]  R. Cawthon,et al.  Association between telomere length in blood and mortality in people aged 60 years or older , 2003, The Lancet.

[48]  C. Greider,et al.  Short telomeres induce a DNA damage response in Saccharomyces cerevisiae. , 2003, Molecular biology of the cell.