Category — aging

Received 14 October 2009; revised 26 January 2010; accepted 10 February 2010

Cataract formation represents a serious problem in the elderly and has a large impact on healthcare budget. Aging and cataract formation are relatively complex phenomena, both in vivo and in vitro. Telomeres are special structures at the end of chromosomes. They shorten during each round of replication, and this has been characterized as a mitotic counting mechanism. Our review analysis in this work shows that the rate of telomere shortening in human lens epithelial cells during aging and cataract formation is modulated by oxidative stress as well as by differences in antioxidative defense capacity of the normal and cataractous crystalline lenses. Presented in this review studies suggest that telomere shortening in human lens cells and increased oxidative stress are the result of the peroxidative damage to the lens cell membranes and biomolecules induced in the lack of reductive detoxification of phospholipid hydroperoxides as the triggering mechanism of cataractogenesis. Lipid peroxidation (LPO) is a causative factor of cataract. The increased concentrations of primary molecular LPO products (diene conjugates, lipid hydroperoxides) and end fluorescent LPO products were detected in the lipid moieties of the aqueous humor samples obtained from patients with senile and complicated cataracts when compared to normal donors. The progressive accumulation of oxidative damage may act as an important mechanism for organism aging and cataractogenesis. The oxidative stress form and intensity might determine the lens senescence rate and cataract type, making efforts in the cataract prevention challenge more complex. The analyzed challenge in this work is that the reduction in telomere shortening rate and damages in telomeric DNA make an important contribution to the anticataract and life-extension effect of carnosine administered systemically in the formulations stabilizing a dipeptide from the enzymatic hydrolysis with carnosinase, or topically administered to the eye with carnosine ophthalmic prodrug N-acetylcarnosine and lubricant formulations thereof including corneal absorption promoters. Telomere length in the human crystalline lens cells is a reflection of aging, cataractogenesis, and lifespan in biogerontological studies. ‘In the perspective of every person lies a lens through which we may better understand ourselves.’ Ellen J. Langer.

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Maria A Blasco, Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain. Published online 17 September 2007/ Nature Chemical Biology 2007.38

Telomere shortening occurs concomitant with organismal aging, and it is accelerated in the context of human diseases associated with mutations in telomerase, such as some cases of dyskeratosis congenita, idiopathic pulmonary fibrosis and aplastic anemia. People with these diseases, as well as Terc-deficient mice, show decreased lifespan coincidental with a premature loss of tissue renewal, which suggests that telomerase is rate-limiting for tissue homeostasis and organismal survival. These findings have gained special relevance as they suggest that telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice. Here, we will review the current evidence linking telomere shortening to aging and stem cell dysfunction.

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Inside chromosomes are telomeres that age as we age, and may serve as indicators of how long we’ll live.

L.A. Times |Cathryn Delude

Wrinkles may betray our age externally, but our cells divulge their age — and chronicle life’s toll — at the tips of our chromosomes. These tips, called telomeres, may also foretell our risk of early death.

Telomeres are the protective caps made of repetitive chunks of DNA that keep the rest of the gene-laden chromosome from disastrously unraveling. But they lose bits of themselves with each cell division, so over a lifetime, like a counter, telomeres shorten. Eventually, shortened telomeres send cells into senescence, a retirement-like state in which they no longer divide or remain active but do not die.

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NewScientist | Linda Geddes

COULD artificially raising levels of a key enzyme hold back the effects of ageing? It has long been a hope but now two lab experiments – one with human cells and one in animals – are providing the first evidence that this may actually be possible.

The enzyme in question is telomerase, which is present naturally in some mammalian cells. Its function is to maintain the protective caps called telomeres at the ends of our chromosomes, which unravel with each cell division as we get older. It has been suggested that this shortening triggers some of the negative effects of ageing at a cellular level. As a result, telomerase has been hailed by some as a potential elixir of life.

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Antonia Tomás-Loba1, Ignacio Flores1, Pablo J. Fernández-Marcos, María L. Cayuela1, Antonio Maraver, Agueda Tejera1, Consuelo Borrás, Ander Matheu, Peter Klatt1, Juana M. Flores, José Viña, Manuel Serrano and Maria A. Blasco1

Telomerase confers limitless proliferative potential to most human cells through its ability to elongate telomeres, the natural ends of chromosomes, which otherwise would undergo progressive attrition and eventually compromise cell viability. However, the role of telomerase in organismal aging has remained unaddressed, in part because of the cancer-promoting activity of telomerase. To circumvent this problem, we have constitutively expressed telomerase reverse transcriptase (TERT), one of the components of telomerase, in mice engineered to be cancer resistant by means of enhanced expression of the tumor suppressors p53, p16, and p19ARF. In this context, TERT overexpression improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span. These results demonstrate that constitutive expression of Tert provides antiaging activity in the context of a mammalian organism.

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SAUSALITO, Calif., Sept. 17 (UPI) — Shorter telomeres — DNA-protein complexes at the end of chromosomes — increase disease risk, but this may be reversed via lifestyle, a U.S. researcher says.

Dr. Dean Ornish of the Preventive Medicine Research Institute in Sausalito, Calif., and colleagues at the University of California, San Francisco, say telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression and premature mortality.

Severe stress such as caring for a spouse or parent with dementia has been shown to shorten telomeres of the caregiver, but Ornish says that telomere shortening
is counteracted by the cellular enzyme telomerase — via lifestyle changes.

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Prof Dean Ornish MD, Jue Lin PhD, Jennifer Daubenmier PhD, Gerdi Weidner PhD, Elissa Epel PhD, Colleen Kemp MSN, Mark Jesus M Magbanua PhD, Ruth Marlin MD, Loren Yglecias BA, Prof Peter R Carroll MD and Prof Elizabeth H Blackburn PhD

Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. Telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression, and premature mortality in many types of cancer, including breast, prostate, colorectal, bladder, head and neck, lung, and renal cell. Telomere shortening is counteracted by the cellular enzyme telomerase. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC).

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Masayuki Kimura, Jacob v. B. Hjelmborg, Jeffrey P. Gardner, Lise Bathum, Michael Brimacombe, Xiaobin Lu, Lene Christiansen, James W. Vaupel, Abraham Aviv, and Kaare Christensen; American Journal of Epidemiology Advance Access

Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality analysis in 548 same-sex Danish twins (274 pairs) aged 73-94 years, of whom 204 pairs experienced the death of one or both co-twins during 9-10 years of follow-up (1997-2007). From the terminal restriction fragment length (TRFL) distribution, the authors obtained the mean TRFL (mTRFL) and the mean values of the shorter 50% (mTRFL50) and shortest 25% (mTRFL25) of TRFLs in the distribution and computed the mode of TRFL (MTRFL). They analyzed the proportions of twin pairs in which the co-twin with the shorter telomeres died first. The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co-twin better than the mTRFL did (mTRFL: 0.56, 95% confidence interval (CI): 0.49, 0.63; mTRFL50: 0.59, 95% CI: 0.52, 0.66; mTRFL25: 0.59, 95% CI: 0.52, 0.66; MTRFL: 0.60, 95% CI: 0.53, 0.67). The telomere-mortality association was stronger in years 3-4 than in the rest of the follow-up period, and it grew stronger with increasing intrapair difference in all telomere parameters.

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Stephanie L. Bakaysa, Lorelei A. Mucci, P. Eline Slagboom, Dorret I. Boomsma, Gerald E. McClearn, Boo Johansson and Nancy L. Pedersen. Aging Cell, 2007.

Telomeres prevent the loss of coding genetic material during chromosomal replication. Previous research suggests that shorter telomere length may be associated with lower survival. Because genetic factors are important for individual differences in both telomere length and mortality, this association could reflect genetic or environmental pleiotropy rather than a direct biological effect of telomeres. We demonstrate through within-pair analyses of Swedish twins that telomere length at advanced age is a biomarker that predicts survival beyond the impact of early familial environment and genetic factors in common with telomere length and mortality. Twins with the shortest telomeres had a three times greater risk of death during the follow-up period than their co-twins with the longest telomere measurements [hazard ratio (RR) = 2.8, 95% confidence interval 1.1-7.3, P = 0.03].

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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