Category — senescence

By John Gever, Senior Editor, MedPage Today
Published: September 21, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Shortened telomeres in peripheral blood leukocytes may predict relapse, malignant progression, and poorer survival in patients with severe aplastic anemia, researchers at the National Institutes of Health (NIH) reported.

An analysis of average pretreatment telomere length in almost 200 patients with severe aplastic anemia treated at the NIH, revealed that patients in the first quartile for telomere length — the shortest telomeres — had an overall six-year survival rate of 66% (95% CI 52.9% to 82.5%) compared with 83.8% (95% CI 77.3% to 90.0%) among those in the other three quartiles (P=0.008), according to the Sept. 22 issue of the Journal of the American Medical Association.

Having the shortest telomeres was also associated with greater risk of progression to malignancy (24.5% versus 8.4%, P=0.009) and with evolution to monosomy 7 or complex cytogenetics (18.8% versus 4.5%, P=0.002), wrote Phillip Scheinberg, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Md., and colleagues.

“Clonal evolution to myelodysplasia is a major adverse event in severe aplastic anemia; it cannot be routinely predicted and usually signals a poor prognosis,” Scheinberg and colleagues noted.

They suggested their findings point toward a practical method of identifying patients at heightened risk for progression who might receive more aggressive treatment.

“Higher-risk protocols such as stem cell transplants in older patients and alternative sources of stem cells might be considered earlier in younger patients,” the researchers wrote.

They also indicated that androgen treatment may lengthen telomeres, potentially altering patients’ risk profiles.

Telomeres are the protective end-caps on chromosomes. Portions are lopped off with each round of cell division, although they may be restored by the telomerase enzyme complex.

Cell senescence has been associated with critically short telomeres, but mutations in telomerase genes that result in extremely short telomeres have been found in some patients with severe aplastic anemia.

Scheinberg and colleagues measured telomere lengths in pretreatment peripheral blood samples from 183 patients treated for severe aplastic anemia at the NIH from 2000 to 2008.

They found no relationship between telomere length and initial treatment responses. Hematologic response rates were nearly identical in each quartile of telomere length, ranging from 54% to 60%.

But the subsequent course for patients in the first quartile — those with the shortest telomeres — differed significantly over as long as six years from patients in the second to fourth quartiles — those with longer telomeres.

By far the worst survival outcomes were in first-quartile patients who also had absolute reticulocyte counts below 25,000 per μL.

With four years of follow-up, just over 50% of these patients were still alive. The four-year survival rate among those in the first quartile but higher reticulocyte counts, and those with low counts but longer telomeres, was close to 80%.

Nearly all of those with longer telomeres and high reticulocyte counts survived at least four years. Few deaths occurred in study patients after year four irrespective of telomere or reticulocyte status.

For other outcomes — hematologic relapse, clonal evolution, progression to monosomy 7 or complex cytogenetics — differences according to telomere length were apparent in about two years.

Scheinberg and colleagues asserted that truncated telomeres are “not simply a biomarker,” but may play a direct role in the disease process.

“Ample in vitro and animal experimentation indicate that critical shortening of telomeres causes chromosome instability, tumor formation, and cancer progression,” they wrote.

Although short telomeres would ordinarily lead to senescence, the chromosomal damage that may result from defective end-caps may instead allow cells to turn malignant, especially if they also lack functional p53 or other tumor suppressor mechanisms, the researchers suggested.

Scheinberg and colleagues noted some limitations of their study. Its retrospective nature was one; another was the relatively small number of patients that precluded assembling a separate validation cohort. They also noted that the NIH patient pool may not be representative of patients elsewhere.

“Our results need to be replicated to validate the observed associations and to determine reliable telomere length thresholds that could be incorporated in treatment algorithms,” the researchers concluded.

The study was funded by the National Heart, Lung, and Blood Institute.

One author obtained salary support from a training program partially funded by Pfizer.

The authors declared they had no relevant financial interests.

Primary source: Journal of the American Medical Association
Source reference:
Scheinberg P, et al “Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia” JAMA 2010; 304: 1358-1364.

Christian Werner MD, Tobias Fürster MD, Thomas Widmann MD, Janine Pöss MD, Cristiana Roggia MD, Milad Hanhoun MD, Jürgen Scharhag MD, Nicole Büchner DBBSc, Tim Meyer MD, Wilfried Kindermann MD, Judith Haendeler PhD, Michael Böhm MD, and Ulrich Laufs MD

C57/Bl6 mice were randomized to voluntary running or no running wheel conditions for 3 weeks. Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle-checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls.

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Pauline Abdallah, Pierre Luciano, Kurt W. Runge, Michael Lisby, Vincent Géli, Eric Gilson and M. Teresa Teixeira

Telomeres protect chromosome ends from fusion and degradation. In the absence of a specific telomere elongation mechanism, their DNA shortens progressively with every round of replication, leading to replicative senescence. Here, we show that telomerase-deficient cells bearing a single, very short telomere senesce earlier, demonstrating that the length of the shortest telomere is a major determinant of the onset of senescence.

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Kajstura J, Rota M, Urbanek K, Hosoda T, Bearzi C, Anversa P, Bolli R, Leri A. Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA.

The preservation of myocyte number and cardiac mass throughout life is dependent on the balance between cell death and cell division. Rapidly emerging evidence indicates that new myocytes can be formed through the activation and differentiation of resident cardiac progenitor cells. The critical issue is the identification of mechanisms that define the aging of cardiac progenitor cells and, ultimately, their inability to replace dying myocytes. The most reliable marker of cellular senescence is the modification of the telomere-telomerase axis, together with the expression of the cell cycle inhibitors p16INK4a and p53. Cellular senescence is characterized by biochemical events that occur within the cell. In this regard, one of the most relevant processes is represented by repeated oxidative stress that may evolve into the activation of the cell death program or result in the development of a senescent phenotype. Thus, the modulation of telomerase activity and the control of telomeric length, together with the attenuation of the formation of reactive oxygen species, may represent important therapeutic tools in regenerative medicine and in prevention of aging and diabetic cardiomyopathies.

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Minamino T, Komuro I.:Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. Front. Biosci. 1;13:2971-9.

Telomeres are DNA regions composed of TTAGGG repeats that are located at the ends of chromosomes. Specific proteins associate with the telomeres and form non-nucleosomal DNA-protein complexes that serve as protective caps for the chromosome ends. There is accumulating evidence that progressive telomere shortening is closely related to cardiovascular disease. For example, vascular cell senescence has been reported to occur in human atherosclerotic lesions and this change is associated with telomere shortening. Impairment of telomere integrity causes vascular dysfunction, which is prevented by the activation of telomerase. Mice with short telomeres develop hypertension and exhibit impaired neovascularization. Short telomeres have also been reported in the leukocytes of patients with cardiovascular disease or various cardiovascular risk factors. Although it remains unclear whether short telomeres directly cause cardiovascular disease, manipulation of telomere function is potentially an attractive strategy for the treatment of vascular senescence.

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Joseph M. Raffaele MD gave a very well-received presentation November 11 2007 to the Age Management Medical Group (AMMG) Annual Meeting titled: “Report on Clinical Trials Involving Telomerase Activation, and the Impact on Aging.”. Topics covered include: h-tert, senescence, telomere length as biomarker for aging and survival, telomerase is not an oncogene.

Click below to view the presentation

Judith Campis and Fabrizio d’Adda di Fagagna; Nature Reviews | Molecular Cell Biology Volume 8 | 729

Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.

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Sheila A. Stewart – Departments of Cell Biology and Physiology and of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, and Robert A. Weinberg – Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142. Annu Rev Cell Dev Biol. 2006;22:531-57

The cell phenotypes of senescence and crisis operate to circumscribe the proliferative potential of mammalian cells, suggesting that both are capable of operating in vivo to suppress the formation of tumors. The key regulators of these phenotypes are the telomeres, which are located at the ends of chromosomes and operate to protect the chromosomes from end-to-end fusions. Telomere erosion below a certain length can trigger crisis. The relationship between senescence and telomere function is more complex, however: Cell-physiological stresses as well as dysfunction of the complex molecular structures at the ends of telomeric DNA can trigger senescence. Cells can escape senescence by inactivating the Rb and p53 tumor suppressor proteins and can surmount crisis by activating a telomere maintenance mechanism. The resulting cell immortalization is an essential component of the tumorigenic phenotype of human cancer cells. Here we discuss how telomeres are monitored and maintained and how loss of a functional telomere influences biological functions as diverse as aging and carcinogenesis.

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