Elsevier

Ageing Research Reviews

Volume 33, January 2017, Pages 52-66
Ageing Research Reviews

Review
Telomere-associated aging disorders

https://doi.org/10.1016/j.arr.2016.05.009Get rights and content

Abstract

Telomeres are dynamic nucleoprotein-DNA structures that cap and protect linear chromosome ends. Several monogenic inherited diseases that display features of human premature aging correlate with shortened telomeres, and are referred to collectively as telomeropathies. These disorders have overlapping symptoms and a common underlying mechanism of telomere dysfunction, but also exhibit variable symptoms and age of onset, suggesting they fall along a spectrum of disorders. Primary telomeropathies are caused by defects in the telomere maintenance machinery, whereas secondary telomeropathies have some overlapping symptoms with primary telomeropathies, but are generally caused by mutations in DNA repair proteins that contribute to telomere preservation. Here we review both the primary and secondary telomeropathies, discuss potential mechanisms for tissue specificity and age of onset, and highlight outstanding questions in the field and future directions toward elucidating disease etiology and developing therapeutic strategies.

Introduction

The stability of the genome is critical for the survival and health of an organism. Telomeres, the ends of linear chromosomes, function in part to ensure the proper completion of replication of the genome after each cell cycle (see Box 1 for major historical milestones until the year 2000 in the telomere/telomerase biology field), and in combination with shelterin proteins, protect the ends from being recognized as DNA double-strand breaks (Palm and de Lange, 2008). It is well established that telomeres progressively shorten with advancing age in normal humans (Harley et al., 1990, Sanders and Newman, 2013). Critically short telomeres trigger what has been termed replicative senescence, which is believed to serve as a stress or DNA damage signaling mechanism to protect genome integrity and prevent further proliferation of cells that may harbor genetic alterations. In combination with oncogenic changes, genome stability may be altered as part of the normal aging process leading to an increased incidence of cancer. In addition, shortened telomeres have been associated with an increased risk of cardiovascular disease, liver cirrhosis, hypertension, atherosclerosis, and cancer (Haycock et al., 2014, Willeit et al., 2010a, Willeit et al., 2010b, Cawthon et al., 2003, Aubert and Lansdorp, 2008). While telomere lengths are partly genetically inherited (Slagboom et al., 1994, Wu et al., 2003, Rufer et al., 1999), accelerated telomeric loss can occur due to a variety of environmental factors and exposures including pollution, genotoxic stress and smoking (Zhang et al., 2013, Grahame and Schlesinger, 2012, Theall et al., 2013, Akiyama et al., 2015, Hoxha et al., 2009, Pavanello et al., 2010). It is believed that some of these environmental factors may contribute to age-associated diseases such as diabetes and neurodegenerative diseases (Uziel et al., 2007, Moverare-Skrtic et al., 2012, Hochstrasser et al., 2012).

In addition, numerous monogenic inherited diseases that display signatures of human premature aging are now recognized to correlate with much shorter telomeres compared to age-matched controls (Shay and Wright, 2004, Garcia et al., 2007, Armanios and Blackburn, 2012a, Vulliamy et al., 2001). The genetically inherited diseases have been termed telomere spectrum disorders or telomeropathies (Savage et al., 2009). The symptoms of these disorders and the age of onset are highly variable. However, the disorders share some similar underlying genetically inherited molecular mechanisms and have overlapping, incompletely penetrant phenotypes. In primary telomeropathies, the heritability of short telomere length can lead to genetic anticipation (e.g. decrease in the age of onset and increased severity of symptoms in later generations) (Shay and Wright, 2004, Armanios and Blackburn, 2012a). In addition to primary telomeropathies caused by defects in the telomere maintenance machinery, there are also secondary telomeropathies (such as RECQ helicase disorders, progeria and ataxia telangiectasia) that have some overlapping symptoms with monogenic primary telomeropathies but are not directly caused by mutations in the telomere maintenance machinery (Holohan et al., 2014). These secondary telomeropathies may involve environmental factors in addition to disease and tissue specific genetic alterations that lead to enhanced telomere damage and erosion. A better understanding of the unique vulnerabilities of telomeres to damage by environmental and endogenous genotoxic stressors (e.g. oxidative stress) may be useful for advancing therapies that reduce the rate of telomeric loss and thus, reduce the incidence and age of onset of disease in both primary and secondary telomeropathies. Conversely, in the case of cancer, accelerating the rate of telomeric attrition may lead to a more rapid arrest of proliferating cancer cells.

In this review we will cover both the primary and secondary telomeropathies, discuss potential mechanisms for tissue specificity and age of onset, and indicate outstanding questions and future directions for the field.

Section snippets

Telomeres: organization and function

Telomeres are specialized nucleoprotein structures consisting of DNA and shelterin protein complexes. Mammalian telomeric DNA contains a variable number of tandem repeats (10–15 kb long in human) of double-stranded DNA sequence 5′-(TTAGGG)n-3′, followed by a terminal 3′ G-rich single-stranded overhang (150–200 nucleotides long). The telomeres account for about 1/6000th of the genome and can be visualized in metaphase chromosome spreads or in interphase cells (Lansdorp et al., 1996), using a

Primary telomeropathies

Primary telomeropathies are also referred to as impaired telomere maintenance syndromes or simply telomere disorders. They are characterized by defects (mostly mutations) in core genes involved in telomere maintenance that result in a large overlapping spectrum of symptoms [reviewed in (Kirwan and Dokal, 2008, Tsangaris et al., 2008)] (Fig. 2 and Table 1). Not only are the symptoms extensive, but the age of onset is highly variable. Even so, the disorders almost universally share some similar

Secondary telomeropathies

Secondary telomeropathies refer to disorders in which the responsible gene mutation encodes a protein whose primary role is typically in DNA repair rather than in telomere maintenance (Table 2 and Fig. 2). Highly proliferative tissues that depend on telomerase, such as the bone marrow, are generally spared in these disorders. In addition, while patients typically exhibit shortened telomeres, they are normally not in the lower 1–10% percentiles as seen in primary telomeropathies. However, in

Conclusions

In this review we have given a brief overview of the causes and symptoms of the disorders linked to defects in telomere maintenance. In addition, we have reviewed a number of related syndromes that may be unrecognized telomeropathies (telomere spectrum disorders). The symptoms of these disorders are extensive and the age of onset is highly variable with genetic anticipation being involved. However, the disorders share a similar underlying molecular mechanism of premature telomere shortening,

Conflict of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

We apologize to those investigators whose reviews and primary research was not cited in the interest of preparing a concise review. Research in the Opresko lab is supported by the National Institute of Environmental Health (ES R01ES022944, R21/33ES025606), the National Institute of General Medicine (R43GM108187), and the National Institute on Aging (R21AG045545). Research in the Shay lab is supported by AG01228 from the National Institute on Aging and the Southland Financial Corporation

References (171)

  • L.B. Gordon et al.

    Progeria: a paradigm for translational medicine

    Cell

    (2014)
  • C.W. Greider et al.

    Identification of a specific telomere terminal transferase activity in Tetrahymena extracts

    Cell

    (1985)
  • J.D. Griffith et al.

    Mammalian telomeres end in a large duplex loop

    Cell

    (1999)
  • L. Hayflick et al.

    The serial cultivation of human diploid cell strains

    Exp. Cell Res.

    (1961)
  • B. Heidenreich et al.

    TERT promoter mutations in cancer development

    Curr. Opin. Genet. Dev.

    (2014)
  • M.T. Hemann et al.

    The shortest telomere not average telomere length, is critical for cell viability and chromosome stability

    Cell

    (2001)
  • T. Hochstrasser et al.

    Telomere length is age-dependent and reduced in monocytes of Alzheimer patients

    Exp. Gerontol.

    (2012)
  • P. Jia et al.

    DNA excision repair at telomeres

    DNA Repair (Amst.)

    (2015)
  • R. Kellermayer

    The versatile RECQL4

    Genet. Med.

    (2006)
  • S.S. Lee et al.

    ATM kinase is required for telomere elongation in mouse and human cells

    Cell Rep.

    (2015)
  • G.B. Morin

    The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats

    Cell

    (1989)
  • S. Moverare-Skrtic et al.

    Leukocyte telomere length (LTL) is reduced in stable mild cognitive impairment but low LTL is not associated with conversion to Alzheimer's disease: a pilot study

    Exp. Gerontol.

    (2012)
  • A.M. Olovnikov

    A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon

    J. Theor. Biol.

    (1973)
  • P.L. Opresko et al.

    Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases

    J. Biol. Chem.

    (2002)
  • P.L. Opresko et al.

    The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2

    Mol. Cell

    (2004)
  • C.M. Aalfs et al.

    The Hoyeraal-Hreidarsson syndrome: the fourth case of a separate entity with prenatal growth retardation, progressive pancytopenia and cerebellar hypoplasia

    Eur. J. Pediatr.

    (1995)
  • B.M. Akiyama et al.

    The telomerase essential N-terminal domain promotes DNA synthesis by stabilizing short RNA-DNA hybrids

    Nucleic Acids Res.

    (2015)
  • E. Albrecht et al.

    Telomere length in circulating leukocytes is associated with lung function and disease

    Eur. Respir. J.

    (2014)
  • B.H. Anderson et al.

    Mutations in CTC1 encoding conserved telomere maintenance component 1, cause coats plus

    Nat. Genet.

    (2012)
  • M. Armanios et al.

    The telomere syndromes

    Nat. Rev. Genet.

    (2012)
  • M. Armanios et al.

    The telomere syndromes

    Nat. Rev. Genet.

    (2012)
  • M. Armanios et al.

    Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita

    Proc. Natl. Acad. Sci. U. S. A.

    (2005)
  • M.Y. Armanios et al.

    Telomerase mutations in families with idiopathic pulmonary fibrosis

    N. Engl. J. Med.

    (2007)
  • M. Armanios

    Telomeres and age-related disease: how telomere biology informs clinical paradigms

    J. Clin. Invest.

    (2013)
  • G. Aubert et al.

    Telomeres and aging

    Physiol. Rev.

    (2008)
  • B.J. Ballew et al.

    Germline mutations of regulator of telomere elongation helicase 1 RTEL1, in dyskeratosis congenita

    Hum. Genet.

    (2013)
  • B.J. Ballew et al.

    A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome

    PLoS Genet.

    (2013)
  • J.A. Baur et al.

    Analysis of mammalian telomere position effect

    Methods Mol. Biol.

    (2004)
  • E.K. Benson et al.

    Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence

    J. Cell Sci.

    (2010)
  • K.B. Blagoev et al.

    Telomere sister chromatid exchange and the process of aging

    Aging (Albany, NY)

    (2010)
  • A.G. Bodnar et al.

    Extension of life-span by introduction of telomerase into normal human cells

    Science

    (1998)
  • S.E. Bojesen et al.

    Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

    Nat. Genet.

    (2013)
  • T.M. Bryan et al.

    G-quadruplexes: from guanine gels to chemotherapeutics

    Mol. Biotechnol.

    (2011)
  • A.M. Burris et al.

    Hoyeraal-Hreidarsson syndrome due to PARN mutations: fourteen years of follow-up

    Pediatr. Neurol.

    (2016)
  • R.T. Calado et al.

    A spectrum of severe familial liver disorders associate with telomerase mutations

    PLoS One

    (2009)
  • R.T. Calado et al.

    Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia

    Proc. Natl. Acad. Sci. U. S. A.

    (2009)
  • S. Canudas et al.

    Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2 respectively, in human cells

    J. Cell Biol.

    (2009)
  • C. Capp et al.

    RecQ4: the second replicative helicase?

    Crit. Rev. Biochem. Mol. Biol.

    (2010)
  • K.A. Carroll et al.

    Telomere dysfunction in human diseases: the long and short of it!

    Int. J. Clin. Exp. Pathol.

    (2009)
  • L. Carulli et al.

    Synchronous cryptogenic liver cirrhosis and idiopathic pulmonary fibrosis: a clue to telomere involvement

    Hepatology

    (2012)
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