

Wednesday, 9 November 2011

Is Human Immortality A Scientific Reality?

Is Human Immortality A Scientific Reality?
If you're alive in 20 years, you may be able to live forever.

By Gary Vey ©2011 Viewzone



Today's quest for the fountain of youth is taking scientists inside the genetic structure of cells and paying less attention to the role of stress and diet on life spans. Would-be immortals flock to anti-aging clinics and shell out as much as $20,000 a year for treatments that include hormone therapy, DNA analysis, even anti-aging cosmetic surgery. These experimental therapies offer no guarantees of immortality -- just the promise of prolonging life.

"Anti-aging medicine is not about stretching out the last years of life. It's about stretching out the middle years of life... and actually compressing those last years few years of life so that diseases of aging happen very, very late in the life cycle, just before death, or don't happen at all." -- Dr. Klatz.

Why do we age and die?

The cause of what we call "aging" is now being understood. This new understanding may soon move anti-aging cosmetics and surgery to the ranks of snake oil and Siberian yogurt as life-extension fads -- but not yet. There are a few obstacles that need to be addressed.

Just when you thought that holographic TV and outer space travel were on the future horizon of modern technology, immortality has silently been revealing itself to scientists like Doctor John Langmore [right] of the University of Michigan's Department of Biology.



Perhaps the best analogy I have heard is to compare the telomeres to the white margin surrounding an important type written document. In this analogy, the printed text is the vital DNA code while the white space is the "blank" telomeres. Imagine that this paper is repeatedly slapped on a copy machine, a copy is made, and then that copy is used to make another copy. Each time the paper is subject to errors of alignment and these errors accumulate. After enough copying, it is probable that the white space will diminish and some of the actual text will not be copied. That's what happens inside our cells and it is the reason we get old and die.

As any cell gets older, it is under attack by oxides and free-radicals in the body and environment. We survive as living beings because our cells have the ability to duplicate and replace themselves before being killed by these natural causes. Each time our cells divide, the DNA molecule makes a new copy of itself.

[Right: DNA is a complex molecule that resembles a spiral ladder. When it divides, it splits along the "rungs" then each half of this "ladder" rebuilds the missing half -- voila! -- two DNA molecules. Now the cell can divide. The old cell dies and the new cell continues on.]


Telomeres -- programmed to die!


Some cells in our body have a very high hayflick limit. Cells that line the inside of your mouth and intestines, for example, are constantly being worn away and replaced. Indeed these cells appear to have the ability to regrow telomeres even in aged bodies. Scientists were curious why some cells shut down telomere growth with age, and some do not.

Dr. Langmore used physical, biochemical, and genetic techniques to study the structure and function of telomeres. His group developed a cell-free system to reconstitute functional model telomeres using synthetic DNA, and studied the mechanism by which telomeres normally stabilize chromosomes and how shortening of the telomeres could cause instability.

The protein factors responsible for stabilizing the ends of chromosomes are being identified, cloned, and studied. Electron microscopy is used to directly visualize the structure of the model telomeres. Dr. Langmore's group used new enzymatic assays to determine the structure of telomere DNA in normal and abnormal cells grown in vivo and in vitro, in order to address specific hypotheses about the role of telomeres in aging and cancer. It's exciting research, for sure, and there have been some promising discoveries.

Scientists have discovered an important enzyme that can turn the telomere production on the DNA molecule "on" and "off." It's called telomerase. Not surprisingly, it seems that as we get older, the amount of telomerase in our cells decreases.

The Cancer Problem

You might be wondering why biologists don't simply find a way to keep our body's telomeres long. This would prevent replication errors and humans could live indefinitely. The big problem is cancer.

Usually, if a cell makes an error in copying itself, the error will prevent the cell from duplicating itself in the future. So the mistake is limited. But with cancer, cells with errors somehow "turn on" the production of telomerase and make the mutant cell immortal. Now, aberrant cells can reproduce unchecked and outlive normal cells. This is the process that creates tumors.

Since we all have mutant, pre-cancerous cells in our bodies, nature has decided to shut off the telomerase as we age, thus preventing these mutant cells from growing telomeres. It's a kind of programmed death -- a trade off to reduce our lifespan in order to save us from being riddled with tumors. Nevertheless, some pre-cancerous cells manage to re-activate their telomeres and this has caused the research to focus more on blocking telomere production rather than trying to extend it.

[Right: A 3-d rendering of the telomerase enzyme.] The molecular structure shows an interesting "groove" (show in green) where the enzyme attaches to the end of the DNA molecule.

Ant-cancer researchers believe that by introducing a molecule to block this groove, the telomerase would become unable to attach itself to the DNA and thereby limit the length of telomere production. While this work holds hope for stopping tumor cells from reproducing forever, it does little to extend healthy cells from being rejuvinated. However, if the molecular "blocker" could specifically target only cancerous cells, without blocking telomerase activity in healthy cells, it could be a step towards human life extension if and when a pharmaceutical can be developed that activates telomerase in the human body. [4]

Interview with Dr. Langmore

Viewzone asked Dr. Langmore to give us his thoughts on the role of telomerase, and the possibilities of using it to repair and lengthen telomeres in human cells. His comments follow:

Telomeres are special, essential DNA sequences at both ends of each chromosome. Each time chromosomes replicate a small amount of the DNA at both ends is lost, by an uncertain mechanism. Because human telomeres shorten at a much faster rate than many lower organisms, we speculate that this telomere shortening probably has a beneficial effect for humans, namely mortality. The telomere hypothesis of aging postulates that as the telomeres naturally shorten during the lifetime of an individual, a signal or set of signals is given to the cells to cause the cells to cease growing (senesce). At birth, human telomeres are about 10,000 base pairs long, but by 100 years of age this has been reduced to about 5,000 base pairs.

Telomerase is actually an enzyme (a catalytic protein) that is able to arrest or reverse this shortening process. Normally, telomerase is only used to increase the length of telomeres during the formation of sperm and perhaps eggs, thus ensuring that our offspring inherit long "young" telomeres to propagate the species.

ViewZone: How is mortality in non-germ line cells a beneficial effect?

Dr. Langmore: The telomere hypothesis of cancer is that the function of telomere shortening is to cause cells that have lost normal control over growth to senesce (i.e. stop growing) before being able to replicate enough times to become a tumor, thus decreasing the frequency of cancer.

Immortal cells like cancer have an unfair advantage over normal human cells which are designed to senesce. But nature seems to have planned this human telomere shortening perhaps to prolong life by hindering the otherwise unchecked growth of non-immortal or benign tumors. Malignant, or immortal tumors can simply outlive the rest of the organism.

Malignant cancer cells are being studied because they appear to have altered the shortening of telomeres by turning "on" the telomerase. Thus it appears that some cancers and aging are both connected with the biology of telomeres.

It is possible that increasing telomerase activity in normal cells might stop the biological clock of aging, yet the side effect of this intervention might be an increase in the rate of cancer. Further understanding and refinement in the telomere hypothesis might lead to a way to slow the aging process and prevent or arrest cancer.

However telomeres function, they are an integral part in the very complex process of cell growth, involving many other factors as well. Telomerase might be the Achilles Heal of aging and cancer, but as our understanding of factors that interact with telomerase, factors that are responsible for telomere shortening in the first place, and non-telomerase mechanisms for increasing the length of telomeres, we might find that one of these factors is more easily manipulated to slow aging or prevent cancer. Also there are additional factors that affect aging and cancer, which might prove in the end to be more important than telomeres and telomerase.

ViewZone: Are telomeres unique to individual DNA? If so, does this preclude any universal treatment for aging?

Dr. Langmore: Different individuals have telomeres with exactly the same DNA sequence but of different lengths. It is too early to say whether there is any relationship between telomere length in an individual and his or her life expectancy, or whether a treatment that would artificially lengthen telomeres would arrest (or reverse) the aging process. One problem is that even in one individual the telomeres of different chromosomes have very different lengths. Therefore an individual might have on average long telomeres; but, he might have one chromosome with a very short telomere that could affect cell growth.

ViewZone: In the work of Shay and Wright (see below), increased telomere length was positively associated with telomerase. How significant is this?

Dr. Langmore: Shay, Wright and all their many collaborators stimulated telomerase activity in normal cells. This was expected to 1) Increase the length of telomeres and 2) Prolong the lifetime of the cells in tissue culture. The treatment did both, in perfect agreement with the telomere hypothesis of aging.

ViewZone: How much was cell lifetime prolonged due to this treatment that reactivated telomerase?

Dr. Langmore: The increased proliferation of the cells was perhaps equivalent to hundreds of years of human life.

Dr. Langmore received his Ph.D. degree from the University of Chicago in 1975. He has held postdoctoral fellowships at the Laboratory of Molecular Biology in Cambridge and at the University of Basel.

[Above:] One of the more surprising developments in telomere structure was the discovery by collaborative efforts from Jack Griffith's and Titia de Lange's groups that mammalian telomeres looped back on themselves to form large lariat-like structures, called t-loops (Griffith et al., 1999).

This structure may help to conceal the end of the molecule from DNA damage surveillance mechanisms and guard against recognition of the chromosome terminus as a double-strand break. [11]

More links to cancer

In the March 15 issue of the European Molecular Biology Organization (EMBO) Journal, Dr. Jerry Shay and Dr. Woodring Wright, both professors of cell biology and neuroscience at UT Southwestern Medical Center at Dallas, report manipulating the length of telomeres to alter the life span of human cells. Shay and Wright are the first to report this important finding. They received an Allied-Signal Award for Research on Aging to explore this line of research last year.

"By lengthening the telomere, we were able to extend the life of the cell hybrids," Wright explained. "This study is strong evidence that telomere length is the clock that counts cell divisions."

"The expression of the enzyme telomerase maintains stable telomere length. Telomerase is not detected in normal cells and telomeres shorten and then the cells stop dividing and enter a phase called cellular senescence."

Shay and Wright have shown in earlier studies that telomeres maintain their length in almost all human cancer cell lines. This correlated with inappropriate expression of telomerase and as a consequence allowed the cell to become "immortal." Cell immortality is a critical and perhaps rate-limiting step for almost all cancers to progress. Previous work by the UT Southwestern investigators showed that in a special group of advanced pediatric cancers the lack of telomerase activity correlated with critically shortened telomeres and cancer remission.

Naturally, the exploration of this enzyme is now the focus of much investigation, but for now the research is aimed at understanding how to turn telomeres "off" to limit the spread of "immortal" cancer cells.

Abnormally high levels of telomerase have been found in cancerous breast cells and have been evident in many kinds of tumors.[1]

Consequently, an idea gaining momentum is that the ability to measure and perhaps alter telomere length and/or telomerase activity may give physicians new diagnostic and treatment tools for managing the care of patients with cancer.

Shay and Wright tried to alter already-immortal cells by attempting to inhibit telomerase activity and cause telomeres to shorten. "Unexpectedly, we found the opposite result. Rather than inhibiting telomerase, our treatment caused the immortal cells to develop longer telomeres," Shay explained. "Although we were surprised with the result, we now know there is a causal relationship between telomere length and the proliferate capacity of cells.

"Essentially, we combined the tumor cells containing experimentally elongated telomeres with normal cells and extended the life span of those cell hybrids compared to similar hybrids using cells without experimentally elongated telomeres."

Shay and Wright said the mechanism that causes telomeres to lengthen is still unclear. However, Shay said, "Our observations increase confidence in the hypothesis that immortal cells and reactivated telomerase are essential components of human tumors. Ultimately, we may be able to regulate tumor cells by inhibiting telomerase activity."

The potential implications for research on human aging also are significant. "It is still speculative, but understanding the role of telomere shortening in cell aging may give us the information we need to increase the life span of an organism," Wright said. (News Releases from UT Southwestern)

A New Player: Progeren?

Scientists now believe that the protein called progerin, causing rapid aging symptons in progeria victims [Right], is the same protein that causes our own more standard aging.

Progerin stems from a gene mutation that shows up in abundance in the disease but in more manageable quantities in all of us. It causes extreme premature aging.

"When the telomeres become too short and frayed, this triggers the production of progerin, signaling to the body that the cell is at the end of its useful life." -- Dr. Francis Collins, director of the National Institutes of Health

Studies are underway to block the excess production of the protein in children with progeria, which may in turn lead to slowing our own aging and preventing age-related diseases such as cancer, heart disease, and Alzheimer's.[10]

Rust Never Sleeps

DNA damage occurs continuously in living cells. While most of this damage is repaired, some accumulates. The DNA Polymerases and other repair mechanisms cannot keep up with defects as fast as they are produced. In particular,DNA damage accumulates in non-dividing cells of mammals [13], but all cells eventually need to reproduce and let their "other half" carry on.

Most damage comes in the form of oxidative damage -- the same "rusting" process that oxidizes irong. Arteriosclerosis and heart disease are the results of this type of damage to the cells lining the blood vessels.

Without the ability to duplicate and repair itself, the cell "rusts" to death. In this way we gradually lose members of our youth -- one cell at a time. We wear out and become a mortal.

Is Long Life Inherited?

If your family has a history of living to an old age, it is likely that your telomeres are longer and therefore protect the critical DNA information when your cells make copies of themselves.

In a general population, the people who live longer usually have more offspring. So it follows that the number of people having longer telomeres would increase. But there's the cancer problem. The immortal cancerous cells that we all produce outlive normal cells and eventually express themselves in tumors, shortening life. These two opposing consequences of long telomeres, positive and negative, are balanced by natural selection. The compromise is currently programmed for an average life expectancy of 76 years.

Environmental Factors?

Our cells are bombarded by environmental poisons that can cause the genetic codes to break, regardless of the telomere length. The more toxic the environment is, the greater the chance for "broken" cells to reproduce themselves and the more beneficial it would be to have shorter telomeres to limit this kind of mutation.

What would happen if a population was forced to have offspring at a very young age, eliminating the impact of a toxic environment? This is exactly what happens to laboratory rats and mice who are artificially bred. Their breeding environment is usually free of toxins and highly controlled, thus favoring the expression of longer telomeres. This fact is important because rats and mice are traditionally used to test for toxicity of products in humans. In short: the rats may be too healthy to be our experimental surrogate.

Beware of Lab Rat Inferences

Bret S. Weinstein & Deborah Ciszek [University of Michigan] observed that captive-rodent breeding protocols, designed to increase reproductive output, simultaneously exert strong selection against reproductive senescence (old age) and virtually eliminate selection that would otherwise favor tumor suppression (i.e. having shorter telomeres). This appears to have greatly elongated the telomeres of laboratory mice. With their telomeric failsafe effectively disabled by forced breeding techniques, these animals are unreliable models of normal senescence and tumor formation. Safety tests employing these animals likely overestimate cancer risks and underestimate tissue damage and consequent accelerated aging.

In short: lab rats are bred in an artificial environment that does not allow for the changes of natural selection and so they have become more prone to cancer and artificially immune to the effects of premature aging. As such, their reaction to pathogens should not necessarily be relied upon to indicate human reactions to such things as food additives, radiation and environmental contaminants. This is a serious problem that has, so far, received little acknowledgement. While we effectively test products for causing cancer we risk the mistake of permitting products that can make us age faster.

Children of young mothers live longer

It has also been noted that children of young mothers seem to live longer than children of older mothers. This is because all of the eggs of a female are produced while she is still in her mother's womb. She is born with all of the egg cells that she will ever have. The telomeres of the early produced eggs are very long but become shortened as more are made. So a woman has a finite number of eggs, some with long telomeres and some with shorter telomeres. After birth, when the female reaches puberty, these long-telomere egg cells are the first to be released by the ovaries, and the first to become potential embryos. Thus, having children as near to puberty as possible increases the chance that the offspring will inherit long telomeres. It also explains why having children later in life increases the chance for birth defects or miscarriages. This is precisely what is happening to the laboratory rat and mice populations, who are forced to breed early, and explains why these lab animals have unusually long telomeres compared to animals in the general "wild" population.

It is possible to become immortal and younger

Many have wondered what benefit an older person would have from an immortality medicine. Would they have to be old forever? Thankfully, no. Scientists have already reversed aging, transforming the slow and feeble into the quick and virile.

Harvard scientists reverse the ageing process in mice


Laboratory mouse in a scientist's hand In mice, reactivating the enzyme telomerase led to the repair of damaged tissues and reversed the signs of ageing.


The surprise recovery of the animals has raised hopes among scientists that it may be possible to achieve a similar feat in humans -- or at least to slow down the ageing process.


"What we saw in these animals was not a slowing down or stabilisation of the ageing process. We saw a dramatic reversal â and that was unexpected," said Ronald DePinho, who led the study, which was published in the journal Nature.


So for humans to extend life we must do two things: first, eliminate the toxins in our environment that rust the cells. Remember the hayflick limit. A toxic environment can run through those allotted duplications at an accelerated rate.

Next we wait for a scientific breakthrough -- perhaps some pharmaceutical that will re-activate telomere production in healthy cells only. Understanding and controlling telomeres in healthy and cancerous cells will lead to a cure or prevention of cancer. If mortality still eludes us, at least that will greatly extend our lives.

The twenty-first century may well be the era in which humans learn the secrets of life extension, but it may also be a time to be reminded of the many dangers inherent in exploring and exploiting these god-like abilities. Environmental pollution, overpopulation, food shortages, and the concentration of wealth by the few are all factors that pre-destine human immortality to be a highly controversial issue.



[1] Steven E. Artandi, Dept of Hematology, Cancer Biology Program, Stanford University School of Medicine, Trends in Molecular Medicine, Volume 8, Issue 1, 1 January 2002, Pages 44-47

[2] Telomere elongation in immortal human cells without detectable telomerase activity, T M Bryan, A Englezou, J Gupta, S Bacchetti, and R R Reddel Cancer Research Group, Children's Medical Research Institute, Westmead, Sydney, NSW, Australia.

[3] Ohyashiki K, Ohyashiki J, Iwama H, Hayashi S, Shay J, Toyama K.,Telomerase reactivation in leukemia cells, Int J Oncol. , 1996 Mar;8(3):417-21.

[4] Thanks to Thomas R. Cech, Steven A. Jacobs and Elaine R. Podell of the Howard Hughes Medical Institute, University of Colorado at Boulder.

[5] Motonobu Katoh, Misaki Katoh, Michihiro Kameyama, Hiroyuki Kugoh, Motoyuki Shimizu, Mitsuo Oshimura, A repressor function for telomerase activity in telomerase-negative immortal cells, Molecular Carcinogenesis, Volume 21, Issue 1, pages 17â25, January 1998

[6] T M Bryan, A Englezou, J Gupta, S Bacchetti, and R R Reddel, Telomere elongation in immortal human cells without detectable telomerase activity, EMBO J. ,1995 September 1; 14(17): 4240â4248.

[7] Steven E. Artandi, Telomere shortening and cell fates in mouse models of neoplasia, Trends in Molecular Medicine,Volume 8, Issue 1, 1 January 2002, Pages 44-47

[8] Calvin B Harley and Bryant Villeponteau, Telomeres and telomerase in aging and cancer, Current Opinion in Genetics & Development, Volume 5, Issue 2, April 1995, Pages 249-255

[9] Fajkus et al., 1996; Fitzgerald et al., 1996; Heller et al., 1996

[10] http://www.frontsidebus.net/2011/06/15/slow-down-new-research-suggests-a-treatment-for-aging/

[11] The Plant Cell, Vol. 16, 794â803, April 2004, www.plantcell.org 2004 American Society of Plant Biologists, HISTORICAL PERSPECTIVE ESSAY: Plant Telomere Biology

Additional Reading & Comments

December 2010 Article

Harvard scientists reverse the ageing process in mice -- now for humans



















[from Korean Times Newspaper]

By Kim Tae-gyu
Staff Reporter

A team of South Korean scientists on Sunday claimed to have created a "cellular fountain of youth," or a small molecule, which enables human cells to avoid aging and dying.

The team, headed by Prof. Kim Tae-kook at the Korea Advanced Institute of Science and Technology, argued the newly-synthesized molecule, named CGK733, can even make cells younger.

The findings were featured by the Britain-based Nature Chemical Biology online early today and will be printed as a cover story in the journal’s offline edition early next month.


"We also found the synthetic compound can reverse aging, by revitalizing already-lethargic cells. Theoretically, this can give youth to the elderly via rejuvenating cells," the 41-year-old said.

Kim expected that the CGK733-empowered drugs that keep cells youthful far beyond their normal life span would be commercialized in less than 10 years.

Other researchers here heaped praises on the discovery but they were cautious about the practical therapeutic application of the new substance.

"Obviously, it is an innovative finding. But we need to see whether or not CGK733 could really rejuvenate cells inside human bodies without generating side effects," Prof. Kim Sung-hoon at Seoul National University said.

Prof. Kim Tae-kook, however, is confident about the commercial viability of CGK733, believing the efficiency of the material was created using state-of-the-art magnetic nano-probe technology.

"We have the magnet-associated technology to identify molecular targets inside living cells, which allowed us to examine the mechanisms of CGK733 directly," Kim said.

"Unlike other research teams that must make candidates materials for drugs without being able to see their intra-cell activities, we know the precise mechanism of CGK733. So we have the better chance of making a success of the substance," he continued.

Indeed, Kim basked in global recognition last June when he and his associates developed a technology dubbed MAGIC, short for magnetism-based interactive capture.

MAGIC uses fluorescent materials to check whether any drug can mix with targeted proteins inside the cell. The results were globally recognized by being printed by the U.S.-based journal Science at the time.

"MAGIC is kind of a source technology to see inside cells. Based on the method, we also found a pair of promising substances that can deal with cancers," Kim said.

Key Target Of Aging Regulator Found



The team, led by senior author Shelley Berger, Ph.D., Hilary Koprowski Professor at The Wistar Institute, demonstrated for the first time a molecular target for a member of this class, Sir2, in regulation of aging in yeast cells. Sir2 removes an acetyl group attached to a specific site (lysine at position 16 or K16) on histone H4Ã³histones are proteins that package and organize the long strands of DNA within the nucleus and also are central regulators in turning genes on and off. The study reveals that removal of this acetyl group by Sir2 near the chromosome ends -- the telomeres -- is important for yeast cells to maintain the ability to replicate. Researchers found that Sir2 levels decline as cells age, and there is a concomitant accumulation of the acetylation mark along with disrupted histone organization at telomeres.


"Some modifications on histones, like this acetylation on histone H4 lysine 16, are persistent and are maintained through generations of cell divisions. This DNA-independent inheritance is called epigenetics," Berger says. "Characteristic epigenetic features have been discovered for various developmental processes in recent years. Understanding epigenetic changes associated with aging is a hugely exciting direction in aging research. It will provide insights and ideas not only for new therapies to regulate cells that have lost control of proliferation, such as 'immortal' cells found in cancers, but also for new strategies to maintain health and fitness."

"We plan to continue to search for new targets of Sir2 and other aging regulators," says lead author Weiwei Dang, Ph.D., a postdoctoral scientist working with Berger. "We are designing unbiased screens for other aging targets and mechanisms in chromatin. Using yeast as our aging model enables us to do many discovery screens that are impossible with other, more complex organisms. Yet it is remarkable that many of these chromatin mechanisms associated with yeast could turn out to be relevant even for aging human cells."

Handle With Care: Telomeres Resemble DNA Fragile Sites







The research lays new groundwork for the study of common fragile sites throughout the genome, explains de Lange. "Fragile sites have always been hard to study because no specific DNA sequence preceeds or follows them," she says. "In contrast, telomeres represent fragile sites with a known sequence, which may help us understand how common fragile sites break throughout the genome -- and why."

Also see Blood Cancer Stopped By Shortening Chromosomes


And see



From the New Illuminati – http://nexusilluminati.blogspot.com

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