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Showing posts with label Telomerase. Show all posts
Showing posts with label Telomerase. Show all posts

Thursday, 27 January 2011

Stop, rewind: the scientists slowing the ageing process

reposted from: http://www.bbc.co.uk/news/science-environment-12207953
crabsallover highlights, key points, comments / links.

26 January 2011 Last updated at 09:46

Stop, rewind: the scientists slowing the ageing process

By Neil BowdlerScience reporter, BBC News
woman and childThe ageing process has been linked with many biological mechanisms

Related stories

Scientists are slowly unlocking the secrets of ageing, and some suggest treatments may soon be at hand to slow or even reverse the ageing process.
But what can science really achieve, and what are the dangers of meddling with our biological clocks?
Could such treatments induce cancers in humans, for example, and what about the world's burgeoning population and the West's "pension time bomb"?
Chromosome tips
The ageing process is a complex one, and for long remained an impenetrable mystery, but progress is now being made.
Late last year, a team at the Dana-Farber Cancer Institute in Boston published a Nature paper in which they detailed the reversing of the ageing process in mice.
They targeted the chromosomes that reside within the nuclei of all cells, and specifically telomeres, caps at the tips of chromosomes. The telomeres protect the chromosomes from damage, but also shorten with age, until the cells are no longer able to replicate.

“Start Quote

By understanding the ageing process, we can help combat arthritis, diabetes and heart disease”
Professor Tim SpectorKing's College London
Professor Ronald DePinho and colleagues manipulated the enzyme that regulates these tips - known as telomerase - and witnessed dramatic results. Boost the enzyme, and the mice appeared to rewind the clock.
Click to play
The BBC's Neil Bowdler reports on the science of ageing
"What we were expecting was a slowing or stabilisation of the ageing process," he told the BBC. "Instead we witnessed a dramatic reversal in the signs and symptoms of ageing."
"These animals had their brains increase in size, they improved their cognition, their coat-hair was restored to a healthy sheen and their fertility was also restored."
Of course, this was a story of mice, not men, and applying such principles to humans could be an altogether bigger challenge. Telomerase has been linked with cancer, and there are likely to be many other mechanisms involved in ageing.
Many believe mitochondria may play a bigger role - genetic material contained within the cell but outside the nucleus. Mitochondria are the "power houses" of cells, but have also been seen to generate harmful chemicals linked with aging.
Then there is the role played by free radicals, highly reactive atoms or molecules that attack our bodies. Stem cells, primitive cells which play a key role in renewing the human body, are also likely to be involved.
Anti-ageing drug
But even though a comprehensive picture of how we age is still to be constructed, there are scientists who are already testing anti-ageing treatments on humans.
Chromosome with telomeres at tipsTelomeres (in red) are found at the ends of each chromosome, and shorten with age
Professor David Sinclair also works in Boston at an ageing laboratory at Harvard Medical School. He and his colleagues have been working on synthetic drugs called "Sirtuin activating compounds" or STACs.
Animal studies have indicated STACs can restore the health and life prospects of obese mice and early-stage trials in humans are now underway.
The research follows earlier work on resveratrol, a naturally-occurring ingredient of red wine. Both resveratrol and STACs appear to mimic the effects of restricting calorie intake, which has been seen to slow ageing in animals.
"This isn't going to be an excuse to eat French fries all day and watch TV but is a way to augment your healthy lifestyle and give you the ultimate benefits of perfect health which your body is capable of," Professor Sinclair told the BBC.
"It doesn't change food intake - the mice eat just normally or they get fatter, but their body doesn't seem to know they're fat and their organs and even their longevity is as good as a really healthy mouse."
But should we be experimenting with something so fundamental as ageing in the first place? And what of the ethical issues?
Professor Tim Spector of King's College London, who also works on the ageing process, says the focus is not on extending life, but on extending good health.
"If it means by living a long time you're crippled by arthritis and can't get out of the house that's not much use to anyone."
"But by understanding the ageing process, we can help combat arthritis, diabetes, heart disease, all these things which are age-related."
Professor James Goodwin, head of research at Age UK, believes access will quickly emerge as a key issue, should effective anti-ageing medical treatments be developed.
"Will everybody be able to get this technology which will give them a longer healthier life, or will it be restricted to the rich and wealthy?" he asks.
"Or how will the poorer countries regard the richer countries of the world where everyone is living well and living longer?"


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Tuesday, 30 November 2010

Telomeres, Telomerase and Cancer

reposted from: http://www.scientificamerican.com/article.cfm?id=telomeres-telomerase-and



An unusual enzyme called telomerase acts on parts of chromosomes known as telomeres. The enzyme has recently been found in many human tumors and is being eyed as a new target for cancer therapy

By Carol W. Greider and Elizabeth H. Blackburn  October 5, 2009 5

telomeres appear as bright ends of chromosomesTELOMERES cap the ends of chromosomes.Image: WIKIMEDIA COMMONS/NATIONAL HUMAN GENOME RESEARCH (user GIAC38)
Editor's note: We are posting the main text of this article from the February 1996 issue of Scientific American for all our readers because the authors have won the 2009 Nobel Prize in Physiology or Medicine. Subscribers to the digital archive may obtain a full PDF version, complete with artwork and captions.
Often in nature things are not what they seem. A rock on the seafloor may be a poisonous fish; a beautiful flower in a garden may be a carnivorous insect lying in wait for prey. This misleading appearance extends to certain components of cells, including chromosomes—the strings of linear DNA that contain the genes. At one time, the DNA at the ends of chromosomes seemed to be static. Yet in most organisms that have been studied, the tips, called telomeres, are actually ever changing; they shorten and lengthen repeatedly.
During the past 15 years, investigation of this unexpected flux has produced a number of surprising discoveries. In particular, it has led to identification of an extraordinary enzyme named telomerase that acts on telomeres and is thought to be required for the maintenance of many human cancers. This last finding has sparked much speculation that drugs able to inhibit the enzyme might combat a wide array of malignancies. The research also opens the possibility that changes in telomere length over time may sometimes play a role in the aging of human cells.
Modern interest in telomeres and telomerase has its roots in experiments carried out in the 1930s by two remarkable geneticists: Barbara McClintock, then at the University of Missouri at Columbia, and Hermann J. Muller, then at the University of Edinburgh. Working separately and with different organisms, both investigators realized that chromosomes bore a special component at their ends that provided stability. Muller coined the term "telomere," from the Greek for "end" (telos ) and "part" ( meros ). McClintock noted that without these end caps, chromosomes stick to one another, undergo structural changes and misbehave in other ways. These activities threaten the survival and faithful replication of chromosomes and, consequently, of the cells housing them.
It was not until the 1970s, however, that the precise makeup of the telomere was determined. In 1978 one of us (Blackburn), then working with Joseph G. Gall of Yale University, found that the telomeres in Tetrahymena, a ciliated, single-cell pond dweller, contained an extremely short, simple sequence of nucleotidesÑ TTGGGG —repeated over and over. (Nucleotides are the building blocks of DNA; they are generally denoted as single letters representing the chemical bases that distinguish one nucleotide from another. The base in T nucleotides is thymine; that in Gnucleotides is guanine.) 
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The Nobel Prize in Physiology or Medicine 2009 - for the discovery of "how chromosomes are protected by telomeres and the enzyme telomerase"

http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html


Press Release

2009-10-05
The Nobel Assembly at Karolinska Institutet has today decided to award

The Nobel Prize in Physiology or Medicine 2009

jointly to
Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak
for the discovery of
"how chromosomes are protected
by telomeres and the enzyme telomerase"

Summary

This year's Nobel Prize in Physiology or Medicine is awarded to three scientists who have solved a major problem in biology: how the chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation. The Nobel Laureates have shown that the solution is to be found in the ends of the chromosomes – the telomeres – and in an enzyme that forms them – telomerase.
The long, thread-like DNA molecules that carry our genes are packed into chromosomes, the telomeres being the caps on their ends. Elizabeth Blackburn and Jack Szostak discovered that a unique DNA sequence in the telomeres protects the chromosomes from degradation. Carol Greider and Elizabeth Blackburn identified telomerase, the enzyme that makes telomere DNA. These discoveries explained how the ends of the chromosomes are protected by the telomeres and that they are built by telomerase.
If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cellular senescence is delayed. This is the case in cancer cells, which can be considered to have eternal life. Certain inherited diseases, in contrast, are characterized by a defective telomerase, resulting in damaged cells. The award of the Nobel Prize recognizes the discovery of a fundamental mechanism in the cell, a discovery that has stimulated the development of new therapeutic strategies.

The mysterious telomere

The chromosomes contain our genome in their DNA molecules. As early as the 1930s,Hermann Muller (Nobel Prize 1946) and Barbara McClintock (Nobel Prize 1983) had observed that the structures at the ends of the chromosomes, the so-called telomeres, seemed to prevent the chromosomes from attaching to each other. They suspected that the telomeres could have a protective role, but how they operate remained an enigma.
When scientists began to understand how genes are copied, in the 1950s, another problem presented itself. When a cell is about to divide, the DNA molecules, which contain the four bases that form the genetic code, are copied, base by base, by DNA polymerase enzymes. However, for one of the two DNA strands, a problem exists in that the very end of the strand cannot be copied. Therefore, the chromosomes should be shortened every time a cell divides – but in fact that is not usually the case (Fig 1).
Both these problems were solved when this year's Nobel Laureates discovered how the telomere functions and found the enzyme that copies it.

Telomere DNA protects the chromosomes

In the early phase of her research career, Elizabeth Blackburn mapped DNA sequences. When studying the chromosomes of Tetrahymena, a unicellular ciliate organism, she identified a DNA sequence that was repeated several times at the ends of the chromosomes. The function of this sequence, CCCCAA, was unclear. At the same time, Jack Szostak had made the observation that a linear DNA molecule, a type of minichromosome, is rapidly degraded when introduced into yeast cells.
Blackburn presented her results at a conference in 1980. They caught Jack Szostak's interest and he and Blackburn decided to perform an experiment that would cross the boundaries between very distant species (Fig 2). From the DNA of Tetrahymena, Blackburn isolated the CCCCAA sequence. Szostak coupled it to the minichromosomes and put them back into yeast cells. The results, which were published in 1982, were striking – the telomere DNA sequence protected the minichromosomes from degradation. As telomere DNA from one organism,Tetrahymena, protected chromosomes in an entirely different one, yeast, this demonstrated the existence of a previously unrecognized fundamental mechanism. Later on, it became evident that telomere DNA with its characteristic sequence is present in most plants and animals, from amoeba to man.

An enzyme that builds telomeres

Carol Greider, then a graduate student, and her supervisor Blackburn started to investigate if the formation of telomere DNA could be due to an unknown enzyme. On Christmas Day, 1984, Greider discovered signs of enzymatic activity in a cell extract. Greider and Blackburn named the enzyme telomerase, purified it, and showed that it consists of RNA as well as protein (Fig 3). The RNA component turned out to contain the CCCCAA sequence. It serves as the template when the telomere is built, while the protein component is required for the construction work, i.e. the enzymatic activity. Telomerase extends telomere DNA, providing a platform that enables DNA polymerases to copy the entire length of the chromosome without missing the very end portion.

Telomeres delay ageing of the cell

Scientists now began to investigate what roles the telomere might play in the cell. Szostak's group identified yeast cells with mutations that led to a gradual shortening of the telomeres. Such cells grew poorly and eventually stopped dividing. Blackburn and her co-workers made mutations in the RNA of the telomerase and observed similar effects in Tetrahymena. In both cases, this led to premature cellular ageing – senescence. In contrast, functional telomeres instead prevent chromosomal damage and delay cellular senescence. Later on, Greider's group showed that the senescence of human cells is also delayed by telomerase. Research in this area has been intense and it is now known that the DNA sequence in the telomere attracts proteins that form a protective cap around the fragile ends of the DNA strands.

An important piece in the puzzle – human ageing, cancer, and stem cells

These discoveries had a major impact within the scientific community. Many scientists speculated that telomere shortening could be the reason for ageing, not only in the individual cells but also in the organism as a whole. But the ageing process has turned out to be complex and it is now thought to depend on several different factors, the telomere being one of them. Research in this area remains intense.
Most normal cells do not divide frequently, therefore their chromosomes are not at risk of shortening and they do not require high telomerase activity. In contrast, cancer cells have the ability to divide infinitely and yet preserve their telomeres. How do they escape cellular senescence? One explanation became apparent with the finding that cancer cells often have increased telomerase activity. It was therefore proposed that cancer might be treated by eradicating telomerase. Several studies are underway in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity.

Some inherited diseases are now known to be caused by telomerase defects, including certain forms of congenital aplastic anemia, in which insufficient cell divisions in the stem cells of the bone marrow lead to severe anemia. Certain inherited diseases of the skin and the lungs are also caused by telomerase defects.
In conclusion, the discoveries by Blackburn, Greider and Szostak have added a new dimension to our understanding of the cell, shed light on disease mechanisms, and stimulated the development of potential new therapies.

Elizabeth H. Blackburn has US and Australian citizenship. She was born in 1948 in Hobart, Tasmania, Australia. After undergraduate studies at the University of Melbourne, she received her PhD in 1975 from the University of Cambridge, England, and was a postdoctoral researcher at Yale University, New Haven, USA. She was on the faculty at the University of California, Berkeley, and since 1990 has been professor of biology and physiology at the University of California, San Francisco.
Carol W. Greider is a US citizen and was born in 1961 in San Diego, California, USA. She studied at the University of California in Santa Barbara and in Berkeley, where she obtained her PhD in 1987 with Blackburn as her supervisor. After postdoctoral research at Cold Spring Harbor Laboratory, she was appointed professor in the department of molecular biology and genetics at Johns Hopkins University School of Medicine in Baltimore in 1997.
Jack W. Szostak is a US citizen. He was born in 1952 in London, UK and grew up in Canada. He studied at McGill University in Montreal and at Cornell University in Ithaca, New York, where he received his PhD in 1977. He has been at Harvard Medical School since 1979 and is currently professor of genetics at Massachusetts General Hospital in Boston. He is also affiliated with the Howard Hughes Medical Institute.

References:
Szostak JW, Blackburn EH. Cloning yeast telomeres on linear plasmid vectors. Cell 1982; 29:245-255.
Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity inTetrahymena extracts. Cell 1985; 43:405-13.
Greider CW, Blackburn EH. A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 1989; 337:331-7.

The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of mankind.
Nobel Prize® is the registered trademark of the Nobel Foundation
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Monday, 29 November 2010

Ageing process 'reversed' in mice

reposted from: http://www.nhs.uk/news/2010/11November/Pages/ageing-process-reversed-in-mice.aspx
crabsallover highlights and key points



“Scientists have managed to reverse the ageing process in a ‘landmark’ study,” reported the Daily Express. The newspaper said that research has shown that targeting the telomerase enzyme proved it is possible to protect body tissue from degenerating.
This research is well-executed and has been described by experts in the field as an important, if not landmark, study. It found that restoring the activity of this enzyme, which protects cells against the damage that occurs as they age, can restore the function of ageing organs in mice.
However, this is research in mice and there is some debate over how applicable these findings are to humans. At present, it should be considered as proof-of-principle that activating telomerase in this way can restore function to cells. More research will probably follow into the effects of artificial induction of telomerase activity. It too soon to describe this as the ‘secret of youth’ and the researchers themselves say that there is more to ageing than the process investigated here.

Where did the story come from?

The study was carried out by researchers from Harvard Medical School in Boston. Funds were provided by the National Cancer Institute and the Belter Foundation. The study was published in the peer-reviewed medical journal Nature.
The research is reported accurately by The Guardian. The Express article may give the impression that a practical application of this research is closer than it actually is, only mentioning that the study is in mice towards the latter end of the article.

What kind of research was this?

This research investigated the ageing process in the laboratory. The researchers were interested in whether restoring the activity of a particular enzyme would affect the age-related decline in the condition of the organs of mice that had been engineered to age prematurely.
Ageing involves many complex cellular processes that drive age-related organ decline and the increased risk of disease. One of these processes involves damage to DNA that can lead to cell death. The DNA damage occurs through the normal course of cell division over a lifetime. At the end of each chromosome is a section of DNA called a telomere. The telomeres protect the DNA from deteriorating. When cells divide, the DNA replicates and each time it replicates, the telomeres at the end of the DNA strands get shorter. When the telomeres get too short, the cell detects this as damage to the DNA and cell death or failure to repair can follow.
Research has shown that an enzyme called telomerase can prevent the telomeres from shortening and may even elongate them. This enzyme is active in many cancer tumours, in which it enables the cancer cells to continue growing. It is a potential target for anti-cancer drugs. Telomerase is not usually active in normal body cells in humans, but the theory is that if it were, the ageing processes involving telomere shortening could be prevented or even reversed.
In this study, the researchers investigated the effects of activating telomerase in genetically modified mice with damaged telomeres and increased DNA damage. They also carried out some of the experiments on the mice cells in culture.

What did the research involve?

Genetically modified mice with no telomerase activity were bred. Researchers tested whether these mice showed premature ageing as would be expected as they lacked the enzyme needed to prevent or slow down telomere shortening. They cultured some of the mutant mice cells (fibroblasts) for four weeks in an environment that reactivated telomerase. Live mice were treated with the telomerase activator too, and the researchers investigated what effect this had on their organs and survival.
The researchers were particularly interested in the effects on brain health (because ageing in humans involves changes to cognition) and on smell (ageing in humans often means “a reduced ability in odour identification and discrimination”). Towards this end, they investigated the effects of inducing telomerase activity in neural stem cells (the cells that produce other brain cells) of these mutant mice and on cells specifically linked with the sense of smell.

What were the basic results?

The genetically modified mice had significantly reduced survival (44 weeks compared to the 87 weeks that normal mice are expected to live) and many of their organs were damaged. When the researchers exposed mouse cells in culture to telomerase, an increase in telomere length was observed. Live mice treated with telomerase also displayed growth in telomere length, and also had improved organ health, particularly in the fast-growing cells such as those in the intestines, the testes and the liver. After four weeks of treatment, the mouse survival improved.
In further experiments, mouse neural stem cells that were treated with a telomerase activator had a restored ability to produce brain cells (i.e. neurogenic capacity). Further detailed analyses of the brain cells showed that telomerase activation restored several of the cell features to normal. Olfactory and neural cells that generally had shorter telomeres and were dysfunctional before treatment had their function partially restored afterwards.

How did the researchers interpret the results?

The researchers say that their mouse model has demonstrated the effects of telomerase reactivation in adult cells and different organs, and that it can restore the length of telomeres and reduce DNA damage in mice. They speculate that this may mean that the organs retain some healthy stem cells that can be reactivated to reproduce normal cells. They conclude that their findings warrant further study, saying that “…this unprecedented reversal of age-related decline in the central nervous system and other organs vital to adult mammalian health justify exploration of telomere rejuvenation strategies for age-associated diseases.”

Conclusion

This is well-executed laboratory research in animals and has been described by experts in the field as an important, if not a landmark, study. However, this is research in mice and there is some debate over whether these findings can be applied to humans. At present, it should be considered as proof-of-principle that activating telomerase, an enzyme known to prevent the shortening of telomeres that has been linked to cell damage and ageing, can restore function to cells.
The findings help to explain further some of the complex cellular activities that occur as cells age.

More research will probably follow into the effects of artificial induction of telomerase activity. It is too soon to describe this as the “secret of youth”, as the Express does. The researchers themselves acknowledge that there is more to ageing than the process investigated here.

Links to the headlines

Links to the science

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