Category — aging
Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long-term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes.
November 19, 2012 No Comments
A team of researchers from the Spanish National Cancer Research Centre (CNIO), headed by CNIO Director Mar-a Blasco, has demonstrated in a pioneering study on mammals that longevity is defined at a molecular level by the length of telomeres. The work-which is published today in the online edition of the journal Cell Reports-opens the door to further study of these cellular components in order to calculate the rate at which cells age and thus be able to determine life expectancy for a particular organism.
Chromosomes-the cellular containers holding the genetic information in living creatures-have repetitive sequences of DNA at their extremities called telomeres. These sequences act as hoods that protect the genetic material in the face of any external agent which might damage it and compromise the function of the cells.
October 3, 2012 No Comments
Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer
A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy.
May 18, 2012 No Comments
Mouse lifespan extended up to 24 percent with a single treatment.
A number of studies have shown that it is possible to lengthen the average life of individuals of many species, including mammals, by acting on specific genes. To date, however, this has meant altering the animals’ genes permanently from the embryonic stage – an approach impracticable in humans. Researchers at the Spanish National Cancer Research Centre (CNIO), led by its director María Blasco, have proved that mouse lifespan can be extended by the application in adult life of a single treatment acting directly on the animal’s genes. And they have done so using gene therapy, a strategy never before employed to combat ageing. The therapy has been found to be safe and effective in mice.
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May 15, 2012 No Comments
The load of short telomeres is increased and associated with lifetime number of depressive episodes in bipolar II disorder
It has recently been hypothesized that bipolar disorders are associated with accelerated aging. Telomere dysfunction, a biomarker of aging, is determined by the load of short telomeres, rather than by the mean telomere length. To our knowledge, the load of short telomeres has not been reported in any psychiatric disorder. The aims of the study were to examine the load of short telomeres and the mean telomere length and their relationships with illness duration and lifetime number of depressive episodes in bipolar II disorder (BD-II).
Twenty-eight patients (mean age = 34.8 ± 7.7) with a DSM-IV diagnosis of BD-II and 28 healthy control subjects (mean age = 34.8 ± 9.2) matched for age, sex, and education participated. The load of short telomeres (percentage of telomeres < 3 kilobases) and mean telomere length in peripheral blood mononuclear cells were measured using high-throughput quantitative fluorescence in situ hybridization.
The load of short telomeres was significantly increased in patients with BD-II relative to healthy controls and may represent 13 years of accelerated aging. The load of short telomeres and the mean telomere length were associated with lifetime number of depressive episodes, but not with illness duration.
Modest sample size and cross-sectional design.
Our results suggest that BD-II is associated with an increased load of short telomeres. Depressive episode-related stress may accelerate telomere shortening and aging. However, longitudinal studies are needed to fully clarify telomere shortening and its relationship with clinical variables in BD-II.
September 13, 2011 No Comments
In 1984, University of California, Berkeley biology professor Elizabeth Blackburn and then grad student Carol Greider made the discovery that a quarter century later would win them the Nobel Pnze: They identified telomerase as the enzyme that protects the DNA in our chromosomes, in effect keeping our cells-and, to some degree, us-young. But telomerase is naturally produced only minimally and intermittently in some of our cells-just enough to grt. disposable us a maximum life span of around 120 years. Unless, that is, someone figures out how to increase the telomerase inside our bodies. Such tinkering with the basic machinery of life has been a theoretical possibility since the 1990s, when scientists
at the Bay Area biotech firm Geron and elsewhere identified the human telomerase gene.
July 19, 2011 No Comments
Telomere dysfunction activates p53-mediated cellular growth arrest, senescence, and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart, and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1 and PGC-1 , also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1 expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1 and PGC-1 promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere–p53–PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
June 20, 2011 No Comments
Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study
1 Division of Cardiology, San Francisco General Hospital, San Francisco, California, United States of America, 2 Department of Medicine, University of California San Francisco, San Francisco, California, United States of America, 3 Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America, 4 Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America, 5 Veterans Affairs Medical Center, San Francisco, California, United States of America, 6 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America
Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality. However, the natural history of telomere length in patients with coronary artery disease has not been studied. We sought to investigate the longitudinal trajectory of telomere length, and to identify the independent predictors of telomere shortening, in persons with coronary artery disease.
In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001). Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6). Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1), male sex (OR = 2.4; 95% CI 1.3, 4.7), and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0).
Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening. The mechanisms and reversibility of telomeric aging in cardiovascular disease deserve further study.
June 1, 2011 No Comments
The rate of leukocyte telomere shortening predicts mortality from cardiovascular disease in elderly men
- ¹University of California, San Francisco, Department of Psychiatry, San Francisco, CA, 94143, USA
- ²University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA, 90095-1687, USA
- ³University of Utah, Human Genetics, Salt Lake City, UT 84112, USA
- 4University of California, San Francisco, Department of Biochemistry & Biophysics, San Francisco, CA, 94158, USA
- ⁵University of California, San Francisco, Department of Epidemiology & Biostatistics, San Francisco, CA, 94107, USA
- Running title:
- Telomere Shortening and Mortality
- Key words:
- aging, longevity, telomere length, cardiovascular disease, mortality
- 11/05/08; accepted: 12/01/08; published on line: 12/19/08
- Elissa S. Epel, PhD, University of California, San Francisco, Department of Psychiatry, 3333 California St, Ste. 465, San Francisco, CA, 94143, USA
- e-mail: EEpel@lppi.ucsf.edu
Telomere length (TL) has been proposed as a marker of mitotic cell age and as a general index of human organismic aging. Short absolute leukocyte telomere length has been linked to cardiovascular-related morbidity and mortality. Our aim was to test whether the rate of change in leukocyte TL is related to mortality in a healthy elderly cohort. We examined a subsample of 236 randomly selected Caucasian participants from the MacArthur Health Aging Study (aged 70 to 79 years). DNA samples from baseline and 2.5 years later were assayed for mean TL of leukocytes. Percent change in TL was calculated as a measure of TL change (TLC). Associations between TL and TLC with 12-year overall and cardiovascular mortality were assessed. Over the 2.5 year period, 46% of the study participants showed maintenance of mean bulk TL, whereas 30% showed telomere shortening, and, unexpectedly, 24% showed telomere lengthening. For women, short baseline TL was related to greater mortality from cardiovascular disease (OR = 2.3; 95% CI:1.0-5.3). For men, TLC (specifically shortening), but not baseline TL, was related to greater cardiovascular mortality, OR = 3.0 (95% CI: 1.1-8.2). This is the first demonstration that rate of telomere length change (TLC) predicts mortality and thus may be a useful prognostic factor for longevity.
June 1, 2011 No Comments
In the decade since the telomere hypothesis of cellular aging was proposed, the two essential genes for human telomerase were cloned and characterized, allowing experimental proof of the causal relationships between telomere loss and replicative senescence, and telomerase activation and immortalization. These relationships were established using a variety of cultured human cell types from both normal and tumor tissues, and were largely confirmed in the telomerase knockout mouse. Taken together, the data provide strong support for the potential utility of telomerase detection and inhibition for cancer, and telomerase activation for degenerative diseases. The specificity of the promoter for the telomerase catalytic gene and the antigenicity of the protein product, hTERT, provide additional strategies for killing telomerase-positive tumor cells. Unfortunately, the strong link between telomerase and cancer has led some to confuse telomerase activation with cancer, and others to overstate the cancer risk of telomerase activation therapies for degenerative diseases. This review clarifies the difference between telomerase, which does not cause growth deregulation, and oncogenes, which do. It also addresses the concept of telomerase repression as a tumor suppressor mechanism early in life, with detrimental tissue degeneration and tumor-promoting consequences late in life. This extended view of the telomere hypothesis helps explain how telomerase inhibition can be therapeutic in cancer patients, while controlled telomerase activation for degenerative diseases may actually reduce, rather than increase, the frequency of age-related tumorigenesis.
Oncogene (2002) 21, 494-502 DOI: 10.1038/sj/onc/1205076
June 1, 2011 No Comments