Telomeres,+Aging,+and+Cancer

=Telomeres, Aging and Cancer=


 * Introduction**

The connotation that telomeres have gathered in the last two decades of their discovery is usually associated with their influence on the metabolic aging processes. The purpose of this project is to understand the relationship between telomeres, aging, and cancer with the goal of being able to shed some light on the misconceptions that have originated between the effect that telomeres’ rehabilitation and dysfunction have on aging and cancer. Studies show that the role that telomeres play is more complex than previously understood and requires a wider breadth of knowledge in order to not be misguided by one side of telomere research. Laying out the positive and negative characteristics that telomeres contain emphasizes the difficulty of making decisions about the role that telomeres play in our health, and the potential they could have on addressing age-related illnesses such as Hutchinson-Gilford Syndrome, Cockayne Syndrome, and Werner Syndrome, among many others, when fully understood.


 * What are Telomeres?**

Telomeres are non-coding DNA sequence repeats that cap the ends of chromosome to prevent DNA deterioration, analogous to the plastic bit of shoelaces. When DNA replication occurs chromosomal ends shorten each time due to the fact that DNA enzyme is not capable to continue duplication all the way to the end of the chromosome, which results on leaving the lagging strand incomplete and subjected to being loss. However, with the presence of telomeres this semi-incomplete DNA replication is compensated since no longer valuable DNA is located at the end of the chromosomes, rather is the non-coding telomere DNA what is being affected. Thus, as each replication occur the protective chromosomal caps at the ends shrink down and potentially expose valuable DNA. Telomerase enzyme prevents the degradation of telomeres by replenishing the non-coding repeat of DNA sequence affected after replication and as results ensuring that no valuable DNA is potentially harmed. However, in humans and other eukaryotes telomerase is not activated after development, resulting in the continuous degradation of telomeres at each chromosomal replication.


 * Research**

Researchers knowing that telomerase enzyme can replenish telomeres are diverting their attention on ways to re-activate telomerase with the purpose of finding a way in which they can prevent the continuous degradation of valuable DNA. Dr. Mariela Jaskelioff and colleges in their research “Tolomerase Reactivation Reverses Tissue Degeneration in Aged Telomerase-Deficient Mice” illustrates how the re-activation of telomerase has the potential to alleviate degenerated tissue and cellular mechanisms affected by age related disorders. This study was executed by studying the reactivation of telomerase in mice that were previously identified as having dysfunctional telomeres.In this [|study] the reactivation of telomeres was done by engineering mice in which inactivated telomeres could be switched to active by administering a chemical called 4-OHT. This chemical has the faculties to allow telomeres to be turned on and off. Thus, allowing to see the effects the reactivation of telomerase has on mice by comparing tissue before and after it was treated. Results from this research indicates that the reactivation of telomerase contributes to:


 * Reduction of DNA damage signaling and associated cellular checkpoint responses
 * Allow resumption of prolifiration in cells in quiescent sta
 * Reduce apoptosis of germ cells and intestinal crypt cells
 * Eliminates degenerative phenotypes across multiple organs (testes, spleens, and intestines)
 * Improved neurogenesis in the brain
 * Alleviate myelin levels in neurons
 * Increased repopulation of white matter structure in the brain

These results support the hypothesis that the reactivation of telomerase enzyme can halt or possible reverse the degeneration of multiple systems. However, it was unexpected to find the reactivation of telomerase to yield such noticeable effects. One example of how striking the findings in this study are can be perceived by looking at the portion of the experiment that addresses the recuperation of degenerated organs.

Mice with dysfunctional telomeres were observed to show extensive tissue atrophy in highly proliferative organs. Testes were notably smaller with reduced fecundity as result of extreme cell atrophy due to the apoptic elimination of germ cells. Intestinal crypt depletion and villus atrophy, coupled by numerous instances apoptosis in crypt cells and and increase of of 53BP1 was also present in mice with dysfunctional telomeres. Recall that P53 is a cellular check point that provokes apoptosis, the impairment of proliferation, and senescence in cells that show mutagenic characteristics. The figure below represents the extent telomerase reactivation has on damaged organs affected by the deficit of telomeres. Cells with intact telomeres are represented as G0 and those that are labeled as G4 possess dysfunctional telomeres.Vehicle treatment was determined to be the condition in which 4-OHT was not given, while 4-OHT represents the treatment in which the reactivation of telomerase occurs.In this illustration, it can be seen that damaged cells from the testes, spleen, and intestinal crypts show a significant improvement in the presence of 4-OHT in comparison to conditions where telomerase is inactive. As it is demonstrated in images a, b, and c cells there is a noticeable difference between tissue with dysfunctional telomeres, G4, in comparison to tissue with functional telomeres, G0. Organ tissue with dysfunctional telomeres demonstrates a degenerative morphology, however, when 4-OHT was administered deteriorated tissue reverts back to conditions seen on normal cells. The last can be seen when looking at the 4-OHT treatment of all dysfunctional tissue sample (G4) and noticing how similar after treatment they become to the normal tissue sample (G0). Interestingly, however, 4-OHT seems to have no effect on normal tissue (G0). Thus, indicating that the reactivation on telomerase has no effect in tissue that does not present instances of damages or age related characteristics. Furthermore, as indicated in graph d and h, we can see that this same patter of degenerative tissue returning back to normal conditions is as well illustrated in the weight of the organs. Organ weight of dysfunctional telomeres demonstrate to have abnormally low telomeres in comparison to healthy organs. Nevertheless, when telomeres reactivation was induced there was a notorious change in organ weight to the point that it closely resembled the weight of healthy organs. Once again the reactivation of telomeres seems to have no effect on the healthy organs.

In addition, after treatment there is an significant decrease on the expression of 53PB1 per cells in comparison to the high levels observed on cells with dysfunctional telomeres before telomerase was reactivated. Decrease of 53PB1 reaches levels similar to does seen in conditions where telomeres are functional. This decrease might indicate that when telomeres activation takes place there are fewer incidents in which P531 needs to be expressed to induce apoptosis, cell proliferation and senescence since cells seems to have regain healthy conditions. Once again, 4-OHT has no effect on healthy conditions. It might be suggested by looking at graph I that in fact apoptosis is decrease with the reactivation of telomeres by looking at the decrease of apoptosis in crypt cells. However, although the decrease in crypt cells apoptosis is significant, unlike the other results it does not resemble closely the conditions seen in healthy cells. This indicates that indeed the reactivation of telomerase has an effect on the apoptosis of cells, but is not as notably as the change seen in tissue and organ weight. In addition, when reactivation of telomerase occur survival of mice pups significantly increase back to levels seen in mice that have functional telomeres.

Thus, the results in this study provide evidence of the significant role telomerase has on maintaining the stability and integrity of our genome. However, it is important to realize that this study as most studies about telomerase reactivation fails to address the consequences telomerase reactivation can have in the long run. For instance, the fate of the mice in the study is not known; it could be possible that the rejuvenation of the cells was followed by cancerous circumstances. After all, cancer formation can be possible if cancerous cells acquire the mechanism to restore and stabilize telomerase to avoid death. Unfortunately, when looking at these kinds of studies that offer such an striking evidence of the potential telomeres could have when treating degenerated tissue, do not bother to understand all aspects related to telomeres. Consequently, leading people to believe that the reactivation of telomerase can serve as a rejuvenating tool without no side effects. 
 * TA-65**

Based on this study, we can begin to conclude that the reactivation of telomerase would be considered to have a positive effect on the metabolic aging process, leading researchers to believe that we could harness the advantages of telomeres in order to use as an anti-aging cure. In 2002, the biotech company, Geron Corp. produced a drug called TA-65 (TA stands for telomerase activator), which is created from astragalus, an herb that is often used as an immune system enhanver in traditional Chinese medicine. According to the [|website] that fosters this drug and multiple clients, this nutritional supplement is "proven" to do the following:


 * improve eyesight
 * maximize bone density
 * strengthen the immune system
 * enhance sexual performance
 * increase brain speed
 * produce younger looking skin

While these effects look promising, when given a closer look at this so-called "miracle drug", we could not find any scientific reseaerch to back up these claims. It has only been tested for five years, and as we learned in class, it takes many more years of tests and trials before a drug like this could possibly be released to the public with conclusive results. Since this is not considered a drug, but rather a supplement, it does not need FDA approval, even though it is changing our molecular composition, and because it needs no approval, the efficiency cannot be sufficiently tested. The website boasts that TA-65 has been used since 2005 with no reported adverse side-effects, but this is much too short of a time period to be conclusive, especially since its effets on the human body would most likely be associated with long-term effects. Because it is so new, we do not yet know these effects on our health--people using this drug could unknowingly be triggering molecular pathways that could possibly lead to cancer. When this supplement was first released to the public in 2007, patients spent $25,000 a year for the drug and accompanying tests. Now they can spend $2-4,000 for a six-month supply. While the high cost may comfort some, seeing it as proof that the drug works, this is not worth the money that people spend on it, with the supplement showing no conclusive results and not nearly as much scientific research and testing as needed.



As we grow older and our telomeres shorten, the structure gets damaged and the chromosomes become prone to mutation. At this point, when the telomeres are dysfunctional, the cell generally has three options depending on the checkpoints that are still intact. p53 and pRB are both checkpoints that serve to regulate pathways and, if needed, cause cell cycle arrest or apoptosis. These three fates are senescence, apoptosis, and genomic instability.
 * Telomeres and Cancer**

Senescence: When telomerase is critically shortened or becomes damaged, the cell’s first defense is to stop the cell cycle so that the cell can go into senescence. This is an irreversible suspension in the cell where it can no longer proliferate, but it is still viable. Most normal cells do this if both their p53 and pRB checkpoints are still functional.

Apoptosis: If only the p53 pathway is intact, but for some reason the pRB is damaged, the cell will go through genetically programmed cell death. This is usually the cell’s second defense against cancer because even though it causes the cell to die, it will protect against the DNA getting any mutations that might be cancerous.

Genomic Instability: If the pRB and the p53 pathways both become damaged or mutated somehow, then the cell cannot enter senescence or perform apoptosis, and they develop genetic instability which puts them at high risk for any kind of mutations that may occur. In an article entitled “Telomeres, aging and cancer: In search of a happy ending”, the authors look at mice that are lacking p53 and ones that are telomerase-deficient. When these two mice are crossed, it is shown that cancer development and progression are increased dramatically. Furthermore, we see that p53 and telomerase deficiency drive the development of epithelial tumors specifically, which are known to be the most common age-associated cancers in humans. Because of this research, it is assumed that repression of telomerase would likely ensure that cells would senesce when telomeres become dysfunctional instead of becoming unstable and at risk for becoming cancerous. While there is a multitude of information on how the increased activation of telomerase would be advantageous to us, especially when it comes to age-related diseases, the less known side of telomerase is quite a bit different. One of the hallmarks of cancer is enabling replicative immortality, and the way that cancer cells do this is by the constant activation of telomerase. In human cells, telomerase is developmentally regulated and the gene is turned off, therefore the telomeres at the ends of chromosomes constantly become shorter as we age. This, however, is not the case in cancer cells, which are able to activate telomerase and keep the gene turned on indefinitely so that the cells become immortal with virtually an endless supply of telomeres. Cancer cells will delay the activation of telomerase until the telomeres get so short that they reach the point of genomic instability, known as the crisis point, then suddenly turn back on telomerase so that they can grow forever. This is a significant factor in the growth of malignant cancer cells, as we see that an increase in telomerase occurs in 90% of all cancer cells. Furthermore in the study, the evidence points out that there are important reasons why telomerase is more likely to promote cancer than to prevent it. One is an observation that the expression of telomerase is more pronounced in mice tissue than in that of humans. This is significant due to the fact that mice are far more cancer prone than humans are. The other reason why increased telomerase activation is a disadvantage is that telomerase usually cooperates with oncogenic changes which promote the formation of tumors. In an epidermal study involving mice, epidermal wound healing was found to be much improved due to the increased telomeres, but at the same time, it also increased the rate of skin cancer.


 * Problems with studying Telomeres**

There seems to be so much research involved in studying telomeres, telomerase reactivation, and its role in cancer and the metabolic aging process, so why is the science so inconclusive? The answer is based on the complexity telomeres and their varying roles in specific organisms. For obvious reasons, we cannot test the effects of increased telomere levels and telomerase activation in humans, and especially not their roles in either preventing or promoting cancer. For this reason, telomere research is typically done on rats, though this is a problem because their bodies age differently than humans. In studies where mice lacked telomerase, we saw that the telomeres still became shorter over time, as expected but at a much slower rate. This was because mice have much longer telomeres than in humans, so in order for them to be comparable to humans, the mice had to go through 4-6 generations so that the telomeres were the same length as ours. Though we know this, it has implications for further research due to the processes of aging of which we are not aware, and therefore it can be difficult to make decisive conclusions of human aging based on animal research.


 * Conclusion**

Based on this research, we can see that telomeres are not just black and white, but have a complex system to protect the body whether it be from cancer, aging, or cell death. With little to no telomerase activation and shortened or damaged telomeres comes DNA damage, leading to senescence, apoptosis, and genomic instability. The advantages that are shown from telomerase activation seem endless in relation to cell growth and proliferation and even inspire scientists to create a "miracle drug" that can supposedly utilize these aspects to halt or reverse the aging process. On the opposite side of the spectrum, however, it seems that telomeres have their downsides as well. It is possible that given their relationship with cancer in rats, telomerase can promote cancer rather than promoting the immune system to protect it. Cancer cells are able to use telomeres to proliferate and grow exponentially as normal cells cannot. So what can we conclude from all of this? The answer is not a whole lot. There is not enough conclusive information to say whether or not the advantages telomerase reactivation would outweigh the disadvantages. We can say, though, that it is clear that telomeres are a touchy subject and the body seems to be able to strike a stable balance between too little and too much telomerase in order for its immune system to work properly.

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5) @http://morelife.org/references/full_papers/11850775.pdf

6) @http://articles.latimes.com/2010/dec/20/health/la-he-skeptic-telomeres-20101220

7) @http://www.tasciences.com/