Exercise Boosts Telomerase, Reduces Erosion of Telomeres

Regular exercise is good for you, and a great weight of scientific studies back up that statement. Insofar as the degenerations of aging go, the present consensus appears to be that exercise in humans slows aging to around the same degree as calorie restriction in humans. Where else could you go to find a fairly cost-effective way of extending your healthy life expectancy by a decade or so? (Or from the glass half empty perspective, we might add lack of exercise and eating too much to the list of ways to shorten your healthy life expectancy by a decade or so - like smoking, for example). The multiple mechanisms involved in producing the benefits of calorie restriction and exercise are incompletely understood but known to overlap to some degree: hormesis, for example, heat shock proteins, and lower amounts of of visceral body fat. But on either side there are likely distinct processes at work. There is every reason to expect exercise and calorie restriction practiced together to produce greater benefits than just one or the other.

Here is something interesting noted in a recent research paper - though you might derive more value from the popular science release:

Long-term exercise training activates telomerase and reduces telomere shortening in human leukocytes. The age-dependent telomere loss was lower in the master athletes who had performed endurance exercising for several decades.

...

"The most significant finding of this study is that physical exercise of the professional athletes leads to activation of the important enzyme telomerase and stabilizes the telomere," said Ulrich Laufs, M.D., the study's lead author and professor of clinical and experimental medicine in the department of internal medicine at Saarland University in Homburg, Germany. "This is direct evidence of an anti-aging effect of physical exercise. Physical exercise could prevent the aging of the cardiovascular system, reflecting this molecular principle."

This is in one cell population amongst thousands, of course - and there still remain questions about telomere biology and its relationship to age-related degeneration. Is it more of a cause of aging or more of a marker of aging - is telomere shortening a consequence of mitochondrial DNA damage, for example? That damage is the villain in the mitochondrial free radical theory of aging. We know that exercise correlates with lower levels of mitochondrial DNA damage, and it looks much as though mitochondrial DNA damage correlates with shorter telomeres. At this point there are all sorts of plausible theories floating around - more plausible on the mitochondrial side of the pool from where I stand - but the telomere researchers and mitochondria researchers haven't hammered in that last stake to prove root causes beyond any reasonable debate.

This is one of the many areas in which the Strategies for Engineered Negligible Senescence approach shines. We have a list of items that change with aging: here (a) mitochondrial DNA, (b) telomere length. We could spend an age working on a complete understanding, or we could instead start work immediately on methods to reverse both changes. It researchers can reverse all the biochemical changes of aging we know of - and there is good reason to believe researchers know of all the important ones in some detail - then it doesn't matter which are secondary, which are primary, or how exactly they work and interconnect. If your goal is to reverse aging, or rather if your goal is primarily accomplishment rather than primarily knowledge accumulation, then you engineer your way though uncertainty towards the most likely and comprehensive fix for the problem at hand.

Consider: just as our ancestors didn't need a formal mathematics of architecture and precision materials science to engineer fine bridges, we who stand at the dawn of the biotech century don't need a complete understanding of human biochemistry in order to reverse the damage of aging. Our longevity therapies will be pretty clunky compared to what will come with complete understanding, but they will work, and billions will be saved from suffering and death because we didn't wait around when we could have been getting the job done.

ResearchBlogging.orgWerner, C., Furster, T., Widmann, T., Poss, J., Roggia, C., Hanhoun, M., Scharhag, J., Buchner, N., Meyer, T., Kindermann, W., Haendeler, J., Bohm, M., & Laufs, U. (2009). Physical Exercise Prevents Cellular Senescence in Circulating Leukocytes and in the Vessel Wall Circulation DOI: 10.1161/CIRCULATIONAHA.109.861005

Comments

The real question is does exercise cause global warming or does it prevent global warming? Either way I say it's settled science and there should be a whopping big grant in there for us to prove it.

Posted by: willis at December 8th, 2009 10:28 AM

Wait...does this mean excercise in cancer patients is counterproductive? Read carefully.

Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

The Pink Sheet Daily. 2009 Apr 28, S Haley

Among the therapies showcased at the recent American Association for Cancer Research meeting in Denver were a growing number aimed at attacking cancer from a new or at least a different angle, through the specialized tumor cells known as cancer stem cells.
Cancer stem cells, the very aggressive cancer cells believed responsible for tumor metastases, are not stem cells in the way embryonic stem cells have captured the scientific imagination, but they are a very small, defined population of cancer cells than can go forth and generate a new tumor. And there's a good chance that if their migration in the body can be stopped, cancers can be made more susceptible to chemotherapy and tumors eliminated entirely, with no nasty surprises years down the road.
When a tumor cell divides it creates one new cancer stem cell, which goes into a resting state, and progeny cells, which become the mass of the tumor. It is these resting cells that are thought to be responsible for not only metastasis but also chemoresistance. They have a very low proliferation rate - so antiproliferatives don't reach them entirely - they overexpress paths that carry drugs out of the cell, and they have more detoxifying enzymes than other tumor cells, Patrick A. Baeuerle, chief scientific officer at Micromet, a company working in the space, explained at the firm's R&D day April 24.
In fact, Baeuerle said, "there is good evidence" that chemotherapy actually enriches the environment for cancer stem cells. When the other cancer cells are eliminated, there are more stem cells to "very rapidly repopulate the tumor."
Micromet harnessing immune system with BiTE antibodies
Micromet's BiTE antibody MT110 can successfully direct the immune system's T-cells to eliminate human colorectal cancer stem cells in cell culture and in animal models, the company reported at AACR.
At the R&D day, Baeuerle explained the significance of MT110's efficacy "in a dish and in a mouse." Eradicating 100 percent of the cells is important because as few as 100 stem cells left in the body after treatment can give rise to a new tumor later on, he said. In both the Petri dish and mouse model, MT100 yielded complete inhibition - meaning there was no further colonization in culture and no tumor growth in the animals.
Using its bispecific T-cell engager (BiTE) technology, the biotech engineered an antibody able to tether resting T-cells to tumor cells, then deliver a cytotoxic payload. MT110 is specific for epithelial cell adhesion molecule (Ep-CAM), a target antigen highly expressed on the surface of cancer stem cells from a variety of tumor types. The biologic is in a Phase I dose-escalating clinical trial in patients with lung or gastrointestinal cancer.
Geron going after telomerase inhibition with imetelstat
Another company working in the cancer stem cell space, Geron, gave five presentations at AACR involving its telomerase inhibitor imetelstat (GRN 163L). It is being studied against cancer stem cells from non-small cell lung, breast, pancreatic, prostate and pediatric neural tumors. Imetelstat is a short chain oligonucleotide with a high affinity and specificity to the telomerase site, thus inhibiting enzyme activity.
Imetelstat currently is in six clinical dose-ranging/safety trials. The drug is being tried in combination with standard of care carboplatin and paclitaxel in a Phase I/II trial testing it against non-small cell lung cancer.
Preclinical data shared at AACR showed that continued treatment of NSCLC cell lines with imetelstat induced progressive decreases in telomere length, resulting in cell death. Treatment over several months resulted in "a dramatic decrease" in colonies in culture, investigators said. In addition, they noted "marked" changes in the number of genes associated with stem cell proliferation. Together, the results mean imetelstat will have to be administered over a sustained period and that the cancer stem cells responsible for NSCLC proliferation were indeed targeted by the drug, investigators said.
Geron also presented preclinical data against four human prostate cancer cell lines, in which tumors express high levels of telomerase activity, suggesting clinical trials could produce a positive result in that cancer. Telomerase is absent or expressed occasionally and only at low levels in normal adult tissue. In another presentation of research, in pediatric neural tumors, including neuroblastoma, preclinical data show telomerase is only active in the tumor's stem cells and that treatment resulted in inhibition of telomerase, loss of replicative potential, and cell aging. In addition, cells pre-treated with imetelstat appeared more susceptible to radiation.
Geron, in Menlo Park, Calif., is best known as the stalwart company that continued its research with human embryonic stem cells during the Bush administration ban on federally funded investigations in that area, a complication that hindered the ability of university researchers to participate in studies of Geron candidates.
In January, FDA lifted a clinical hold on Geron's regenerative stem cell therapy OPC1, allowing Geron to proceed with human trials in spinal cord injury.
Biotechs not alone: big pharma pursuing cancer stem cells, too
Big pharmas also have been edging into the cancer stem cell space, as the increasing emphasis on oncology portfolios increases demand for novel approaches.
In 2007 Sanofi-Aventis formed a collaboration with Chinese researchers at the Tianjin Institute of Hematology and Blood Diseases Hospital. That same year, GlaxoSmithKline and Redwood City, Calif.-based OncoMed formed a back-end loaded relationship worth up to $1.4 billion for the biotech if the cancer stem cell bet pays off. Then in 2008, Roche paid $190 million in cash to take over Canadian antibody company Arius Research and gain control of its cancer stem cell program.
That leaves plenty of big pharma firms focused on oncology that could be interested in the programs from Micromet and Geron.

Researchers target telomeres to attack tumors

5. May 2009 19:09

Hoping to develop more effective long-term attacks on cancer, researchers at the Indiana University School of Medicine are conducting the first human tests of a breast cancer drug regimen that includes a compound meant to force cancer cells to grow old and die.

The early stage clinical tests are an attempt to block a mechanism cancer cells use to avoid the aging process that affects most normal cells. If successful, the new therapy could enhance the effects of other cancer treatments.
"This is really a completely different way of trying to tackle the problem that hasn't been tested in the clinic before," said Kathy Miller, M.D., associate professor of medicine and Sheila D. Ward Scholar at the IU School of Medicine and medical oncologist at the Indiana University Melvin and Bren Simon Cancer Center.
The clinical test is a good example of how positive results in basic science experiments can push a promising compound from the laboratory to the bedside - a process known as "translational research."
The new approach is based on research into telomeres, the caps that protect the ends of the 46 chromosomes in each cell that contain our genetic information. The telomeres, which some compare to the tips of shoelaces, help prevent genomic instability. Each time a cell divides, the telomeres shorten. When they become too short, losing their protective ability, it's a signal to the cell to die, or to go into a state of permanently arrested growth called senescence.
Telomeres in cancer cells generally are shorter than those in normal cells. That offers a tempting target, except that cancer cells know a trick. Cancer cells produce an enzyme called telomerase, which provides maintenance services on the telomeres, preventing them from reaching the critically short stage that would set off the cell death signal.
So, researchers have figured, if you could block cancer cells from producing telomerase, you could make them easier to kill. But how to do that? Several approaches seemed possible, including one that Brittney-Shea Herbert, Ph.D., then a post-doctoral researcher, was working on 10 years ago at the University of Texas Southwest in Dallas. Her approach: Find a special type of chemical compound, called an oligonucleotide, that would block access to telomerase and prevent it from doing its job. She began working with a new compound, with the chemical name GRN163L, that had been developed by Geron Corp. of Menlo Park, Calif.
Dr. Herbert has continued to work with GRN163L - now called imetelstat sodium - in the laboratory since coming in 2003 to the IU School of Medicine, where she is an assistant professor of medical and molecular genetics. She has published work showing that imetelstat disrupts telomere maintenance, in the process suppressing both tumor growth and metastasis - the appearance of tumors in other tissues. Another study found that telomere damage in breast cancer cells treated with the compound caused the cells to be more susceptible to radiation treatment. Furthermore, she has shown that imetelstat can restore the sensitivity of Herceptin-resistant breast cancer cell lines in the laboratory.
"What's interesting about GRN163L is that it can get into almost any cancer cell type, including drug resistant cancer cells. That's been a problem: A lot of agents cannot be taken up into drug resistant cells. This telomerase inhibitor can be taken up in any cell type - you can target those cells. So that's why we hope this will be great for reducing recurrence and metastasis," said Dr. Herbert.
Such results have made imetelstat an attractive compound to test in conjunction with other anti-cancer drugs, which is what brought Drs. Miller and Herbert together. They are testing imetelstat with the drugs Taxol and Avastin, initially to determine the appropriate dose of imetelstat, test whether the three drugs are safe to give in combination, and to determine whether there are side effects that must be dealt with.
Assuming the first phase goes well a second phase of testing will begin more formal evaluation of how well the combination therapy works.
Dr. Miller's research has shown that Taxol and Avastin are more effective in combination than Taxol alone, shrinking tumors in about twice as many women and providing such benefits more than twice as long. The therapy doesn't cure metastatic disease, though. Eventually the tumors become resistant to the drugs and other treatments are necessary.
If, as expected, imetelstat doesn't raise side effects issues, and "if it makes the cells more sensitive to the effects of the Taxol and Avastin, and allows the benefits of that therapy to continue for a much longer period of time, that would be a big benefit for those ladies with metastatic disease. It would also then give us the support for looking at this agent even earlier in the course of disease," said Dr. Miller.
Dr. Herbert's research indicated that imetelstat can reduce metastatic spread of cancer, though it's not yet clear what the mechanism is. But, as Dr. Miller points out, for patients that will be a distinction with little difference.
"Whether it actually prevents the cells from spreading or they spread but can't grow to make clinically apparent tumors we don't know, but I can tell you my patients don't care," she said.
http://www.iupui.edu

Posted by: Rich Reillyr at December 8th, 2009 5:39 PM

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