Telomeres, telomerase,cancer,aging and exercise

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teloTo better understand telomeres and telomerase, let’s first review some basic principles of biology and genetics. The human body is an organism formed by adding many organ systems together. Those organ systems are made of individual organs. Each organ contains tissues designed for specific functions like absorption and secretion. Tissues are made of cells that have joined together to perform those special functions. Each cell is then made of smaller components called organelles, one of which is called the nucleus.

The nucleus contains structures called chromosomes that are actually “packages” of all the genetic information that is passed from parents to their children. The genetic information, or “genes,” is really just a series of bases called Adenine (A), Guanine (G), Cytosine (C), and Thymine (T). These base pairs make up our cellular alphabet and create the sequences, or instructions needed to form our bodies. In order to grow and age, our bodies must duplicate their cells. This process is called mitosis. Mitosis is a process that allows one “parent” cell to divide into two new “daughter” cells. During mitosis, cells make copies of their genetic material. Half of the genetic material goes to each new daughter cell. To make sure that information is successfully passed from one generation to the next, each chromosome has a special protective cap called a telomere located at the end of its “arms.” Telomeres are controlled by the presence of the enzyme telomerase.

A telomere is a repeating DNA sequence (for example, TTAGGG) at the end of the body’s chromosomes. The telomere can reach a length of 15,000 base pairs. Telomeres function by preventing chromosomes from losing base pair sequences at their ends. They also stop chromosomes from fusing to each other. However, each time a cell divides, some of the telomere is lost (usually 25-200 base pairs per division). When the telomere becomes too short, the chromosome reaches a “critical length” and can no longer replicate. This means that a cell becomes “old” and dies by a process called apoptosis. Telomere activity is controlled by two mechanisms: erosion and addition. Erosion, as mentioned, occurs each time a cell divides. Addition is determined by the activity of telomerase.

Telomerase, also called telomere terminal transferase, is an enzyme made of protein and RNA subunits that elongates chromosomes by adding TTAGGG sequences to the end of existing chromosomes. Telomerase is found in fetal tissues, adult germ cells, and also tumor cells. Telomerase activity is regulated during development and has a very low, almost undetectable activity in somatic (body) cells. Because these somatic cells do not regularly use telomerase, they age. The result of aging cells is an aging body. If telomerase is activated in a cell, the cell will continue to grow and divide. This “immortal cell” theory is important in two areas of research: aging and cancer.

Cellular aging, or senescence, is the process by which a cell becomes old and dies. It is due to the shortening of chromosomal telomeres to the point that the chromosome reaches a critical length. Cellular aging is analogous to a wind up clock. If the clock stays wound, a cell becomes immortal and constantly produces new cells. If the clock winds down, the cell stops producing new cells and dies. Our cells are constantly aging. Being able to make the body’s cells live forever certainly creates some exciting possibilities. Telomerase research could therefore yield important discoveries related to the aging process.

Cancer cells are a type of malignant cell. The malignant cells multiply until they form a tumor that grows uncontrollably. Telomerase has been detected in human cancer cells and is found to be 10-20 times more active than in normal body cells. This provides a selective growth advantage to many types of tumors. If telomerase activity was to be turned off, then telomeres in cancer cells would shorten, just like they do in normal body cells. This would prevent the cancer cells from dividing uncontrollably in their early stages of development. In the event that a tumor has already thoroughly developed, it may be removed and anti-telomerase therapy could be administered to prevent relapse. In essence, preventing telomerase from performing its function would change cancer cells from “immortal” to “mortal.”

Knowing what we have just learned about telomeres and telomerase, it can be said that scientists are on the verge of discovering many of telomerase’s secrets. In the future, their research in the area of telomerase could uncover valuable information to combat aging, fight cancer, and even improve the quality of medical treatment in other areas such as skin grafts for burn victims, bone marrow transplants, and heart disease. Who knows how far this could go?

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Exercise is good for you

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.org

Werner, 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

 

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