The role of telomeres in human health and disease is yet to be fully understood. The limitations of mouse models for the study of human telomere biology and difficulties in accurately measuring the ...length of telomere repeats in chromosomes and cells have diverted attention from many important and relevant observations. The goal of this perspective is to summarize some of these observations and to discuss the antagonistic role of telomere loss in aging and cancer in the context of developmental biology, cell turnover, and evolution. It is proposed that both damage to DNA and replicative loss of telomeric DNA contribute to aging in humans, with the differences in leukocyte telomere length between humans being linked to the risk of developing specific diseases. These ideas are captured in the Telomere Erosion in Disposable Soma theory of aging proposed herein.
Telomeres and Aging Aubert, Geraldine; Lansdorp, Peter M
Physiological reviews,
04/2008, Letnik:
88, Številka:
2
Journal Article
Recenzirano
Terry Fox Laboratory, British Columbia Cancer Agency, and Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
Telomeres play a central ...role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must "cap" each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or "uncapped" telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many "uncapped" telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.
1 Telomeric as well as centromeric sequences continue to be underrepresented in most of the genomes that have been "completely" sequenced.
Telomerase levels in most human cells are insufficient to prevent loss of telomeric DNA with each replication cycle. The resulting “Hayflick” limit may have allowed lifespan to increase by ...suppressing the development of tumors early in life be it at the expense of compromised cellular responses late in life. At any given age, the average telomere length in leukocytes shows considerably variation between individuals with females having, on average, longer telomeres than males. Sex differences in average telomere length are already present at birth and correspond to reported differences in the average life expectancy between the sexes. Levels of telomerase RNA and dyskerin, encoded by DKC1, are known to limit telomerase activity in embryonic stem cells. X‐linked DKC1 is expressed from both alleles in female embryo cells and higher levels of dyskerin and telomerase could elongate telomeres prior to embryo implantation. The hypothesis that embryonic telomerase levels set the stage for the sex differences in telomere length and lifespan deserves further study.
The telomere length in leukocytes declines with age. Short telomeres are a risk factor for cardiovascular and infectious diseases. Women have, on average, longer telomeres than males, a difference that is already present at birth. Here it is proposed that this difference originates during embryonic development as a result of bi‐allelic expression of X‐linked DKC1 encoding dyskerin, a major component of the telomerase enzyme.
Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear. Here, we test the consequence of centrosome amplification by ...creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects. We show that increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues. Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship among centrosome amplification, genomic instability, and tumor development.
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•Plk4 overexpression promotes persistent centrosome amplification in vivo•Centrosome amplification promotes aneuploidy in vivo•Extra centrosomes promote tumor initiation in a model of intestinal neoplasia•Centrosome amplification drives spontaneous tumorigenesis
Extra centrosomes are common in human cancers and are correlated with aneuploidy and poor patient prognosis. However, whether supernumerary centrosomes are a cause or consequence of tumorigenesis is still unclear. Levine et al. now demonstrate that centrosome amplification is sufficient to drive tumorigenesis in multiple tissues of mice.
Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in ...vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age.
Telomeres and telomerase play a crucial role in human aging and cancer. Three "drivers" of human aging can be identified. The developmental program encoded in DNA is the primary determinant of ...lifespan. Faithful execution of the developmental program requires stability of the (epi-)genome which is challenged throughout life by damage to DNA as well as epigenetic 'scars' from error-free DNA repair and stochastic errors made during the establishment and maintenance of the "epigenome". Over time (epi-)mutations accumulate, compromising cellular function and causing (pre-)malignant alterations. Damage to the genome and epigenome can be considered the second "driver" of aging. A third driver of the aging process, important to suppress tumors in long-lived animals, is caused by progressive loss of telomeric DNA. Telomere erosion protects against cancer early in life but limits cell renewal late in life, in agreement with the Antagonistic Pleiotropy theory on the evolutionary origin of aging. Malignant tumors arise when mutations and/or epimutations in cells (clock 2) corrupt the developmental program (clock 1) as well as tumor suppression by telomere erosion (clock 3). In cancer cells clock 3 is typically inactivated by loss of p53 as well as increased expression of telomerase. Taken together, aging in humans can be described by the ticking of three clocks: the clock that directs development, the accumulation of (epi-)mutations over time and the telomere clock that limits the number of cell divisions in normal stem and immune cells.
It has been proposed that guanine-rich DNA forms four-stranded structures in vivo called G-quadruplexes or G4 DNA. G4 DNA has been implicated in several biological processes, but tools to study G4 ...DNA structures in cells are limited. Here we report the development of novel murine monoclonal antibodies specific for different G4 DNA structures. We show that one of these antibodies designated 1H6 exhibits strong nuclear staining in most human and murine cells. Staining intensity increased on treatment of cells with agents that stabilize G4 DNA and, strikingly, cells deficient in FANCJ, a G4 DNA-specific helicase, showed stronger nuclear staining than controls. Our data strongly support the existence of G4 DNA structures in mammalian cells and indicate that the abundance of such structures is increased in the absence of FANCJ. We conclude that monoclonal antibody 1H6 is a valuable tool for further studies on the role of G4 DNA in cell and molecular biology.
The “immortal strand” hypothesis proposes that asymmetrically dividing stem cells selectively retain chromosomes containing “old” DNA to prevent accumulation of mutations. As I describe in this ...Essay, such a possibility seems unlikely. An alternative explanation is that asymmetric cell divisions and cell fate are codirected by epigenetic differences between sister chromatids.
Dyskeratosis congenita is a cancer-prone bone marrow failure syndrome caused by aberrations in telomere biology.
We studied 65 patients with dyskeratosis congenita and 127 unaffected relatives. ...Telomere length was measured by automated multicolor flow fluorescence in situ hybridization in peripheral blood leukocyte subsets. We age-adjusted telomere length using Z-scores (standard deviations from the mean for age).
We confirmed that telomere lengths below the first percentile for age are very sensitive and specific for the diagnosis of dyskeratosis congenita. We provide evidence that lymphocytes alone and not granulocytes may suffice for clinical screening, while lymphocyte subsets may be required for challenging cases, including identification of silent carriers. We show for the first time using flow fluorescence in situ hybridization that the shortest telomeres are associated with severe variants (Hoyeraal-Hreidarsson and Revesz syndromes), mutations in DKC1, TINF2, or unknown genes, and moderate or severe aplastic anemia. In the first longitudinal follow up of dyskeratosis congenita patients, we demonstrate that telomere lengths decline with age, in contrast to the apparent stable telomere length observed in cross-sectional data.
Telomere length by flow fluorescence in situ hybridization is an important diagnostic test for dyskeratosis congenita; age-adjusted values provide a quantitative measure of disease severity (clinical subset, mutated gene, and degree of bone marrow failure). Patients with dyskeratosis congenita have accelerated telomere shortening. This study is registered at www.clinicaltrials.gov (identifier: NCT00027274).
Telomeres and disease Lansdorp, Peter M
EMBO journal,
September 2, 2009, Letnik:
28, Številka:
17
Journal Article
Recenzirano
Odprti dostop
The telomeres of most eukaryotes are characterized by guanine‐rich repeats synthesized by the reverse transcriptase telomerase. Complete loss of telomerase is tolerated for several generations in ...most species, but modestly reduced telomerase levels in human beings are implicated in bone marrow failure, pulmonary fibrosis and a spectrum of other diseases including cancer. Differences in telomerase deficiency phenotypes between species most likely reflect a tumour suppressor function of telomeres in long‐lived mammals that does not exist as such in short‐lived organisms. Another puzzle provided by current observations is that family members with the same genetic defect, haplo‐insufficiency for one of the telomerase genes, can present with widely different diseases. Here, the crucial role of telomeres and telomerase in human (stem cell) biology is discussed from a Darwinian perspective. It is proposed that the variable phenotype and penetrance of heritable human telomerase deficiencies result from additional environmental, genetic and stochastic factors or combinations thereof.
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