ReviewTelomere-associated aging disorders
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)
Telomerase and idiopathic pulmonary fibrosis
Mutat. Res.
(2012)- et al.
A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena
J. Mol. Biol.
(1978) - et al.
Telomere shortening and tumor formation by mouse cells lacking telomerase RNA
Cell
(1997) - et al.
Cellular senescence: a link between cancer and age-related degenerative disease?
Semin. Cancer Biol.
(2011) - et al.
Association between telomere length in blood and mortality in people aged 60 years or older
Lancet
(2003) - et al.
Human telomeres are tethered to the nuclear envelope during postmitotic nuclear assembly
Cell Rep.
(2012) - et al.
Regulation of murine telomere length by Rtel: an essential gene encoding a helicase like protein
Cell
(2004) - et al.
Super-resolution fluorescence imaging of telomeres reveals TRF2-dependent T-loop formation
Cell
(2013) - et al.
Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA
Lancet
(2003) - et al.
RECQL4, the protein mutated in rothmund-Thomson syndrome functions in telomere maintenance
J. Biol. Chem.
(2012)
Progeria: a paradigm for translational medicine
Cell
Identification of a specific telomere terminal transferase activity in Tetrahymena extracts
Cell
Mammalian telomeres end in a large duplex loop
Cell
The serial cultivation of human diploid cell strains
Exp. Cell Res.
TERT promoter mutations in cancer development
Curr. Opin. Genet. Dev.
The shortest telomere not average telomere length, is critical for cell viability and chromosome stability
Cell
Telomere length is age-dependent and reduced in monocytes of Alzheimer patients
Exp. Gerontol.
DNA excision repair at telomeres
DNA Repair (Amst.)
The versatile RECQL4
Genet. Med.
ATM kinase is required for telomere elongation in mouse and human cells
Cell Rep.
The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats
Cell
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.
A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon
J. Theor. Biol.
Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases
J. Biol. Chem.
The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2
Mol. Cell
The Hoyeraal-Hreidarsson syndrome: the fourth case of a separate entity with prenatal growth retardation, progressive pancytopenia and cerebellar hypoplasia
Eur. J. Pediatr.
The telomerase essential N-terminal domain promotes DNA synthesis by stabilizing short RNA-DNA hybrids
Nucleic Acids Res.
Telomere length in circulating leukocytes is associated with lung function and disease
Eur. Respir. J.
Mutations in CTC1 encoding conserved telomere maintenance component 1, cause coats plus
Nat. Genet.
The telomere syndromes
Nat. Rev. Genet.
The telomere syndromes
Nat. Rev. Genet.
Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita
Proc. Natl. Acad. Sci. U. S. A.
Telomerase mutations in families with idiopathic pulmonary fibrosis
N. Engl. J. Med.
Telomeres and age-related disease: how telomere biology informs clinical paradigms
J. Clin. Invest.
Telomeres and aging
Physiol. Rev.
Germline mutations of regulator of telomere elongation helicase 1 RTEL1, in dyskeratosis congenita
Hum. Genet.
A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome
PLoS Genet.
Analysis of mammalian telomere position effect
Methods Mol. Biol.
Role of progerin-induced telomere dysfunction in HGPS premature cellular senescence
J. Cell Sci.
Telomere sister chromatid exchange and the process of aging
Aging (Albany, NY)
Extension of life-span by introduction of telomerase into normal human cells
Science
Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
Nat. Genet.
G-quadruplexes: from guanine gels to chemotherapeutics
Mol. Biotechnol.
Hoyeraal-Hreidarsson syndrome due to PARN mutations: fourteen years of follow-up
Pediatr. Neurol.
A spectrum of severe familial liver disorders associate with telomerase mutations
PLoS One
Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia
Proc. Natl. Acad. Sci. U. S. A.
Differential regulation of telomere and centromere cohesion by the Scc3 homologues SA1 and SA2 respectively, in human cells
J. Cell Biol.
RecQ4: the second replicative helicase?
Crit. Rev. Biochem. Mol. Biol.
Telomere dysfunction in human diseases: the long and short of it!
Int. J. Clin. Exp. Pathol.
Synchronous cryptogenic liver cirrhosis and idiopathic pulmonary fibrosis: a clue to telomere involvement
Hepatology
Cited by (108)
Links between telomere dysfunction and hallmarks of aging
2023, Mutation Research - Genetic Toxicology and Environmental MutagenesisOccupational exposure to pesticides and its association with telomere length - A systematic review and meta-analysis
2022, Science of the Total EnvironmentStem cells at odds with telomere maintenance and protection
2022, Trends in Cell BiologyCitation Excerpt :TERT silencing in somatic cells is thought to exert a tumor-suppressive effect by limiting the cellular lifespan of differentiated cells [49,51]. Instead, minimal telomerase activity in stem cells is necessary to counteract telomere erosion and maintain proper tissue function (reviewed in [52]). Mutations in telomerase pathways genes, including TERT and TERC, are associated with several short telomere syndromes, including dyskeratosis congenita (DC) and Hoyeraal–Hreidarsson syndrome, as well as lung fibrosis.
Telomerase activators from 20(27)-octanor-cycloastragenol via biotransformation by the fungal endophytes
2021, Bioorganic ChemistryCitation Excerpt :Telomere loss leads to critically shortened telomers that triggers replicative senescence, and it has been proposed as a major cause of aging and age-related diseases. In addition, mutations in the telomerase maintenance genes are associated with the development of certain diseases, including dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and liver fibrosis [6–8]. Thus, telomerase activators (TA) have been suggested as promising agents for healthy aging and in the treatment of telomere-driven diseases [9–11].