January 31, 2003
Telomere Length Indicates Mortality Risk

There has been considerable debate for years as to whether the shortening of telomere length that happens each time cells divide is linked to mortality. Skeptics have argued that people were dying of other factors before telomeres became short enough to become a rate-limiting factor on longevity. However, recent research by Richard Cawthon has found a correlation between telomere length and longevity in humans.

Dr. Richard M. Cawthon and his colleagues at the University of Utah in Salt Lake City discovered that initially healthy people older than 60 with shorter telomeres--snippets of genetic material that cap chromosomes--are more likely to die than people of the same age with longer caps at the end of the chromosomes, which are long strings of coiled DNA found in cells.

Risk of death from both infection and heart disease was higher for those with shorter telomeres.

In all, 101 donors died. People with shorter telomeres showed an 86 percent higher death rate. They ran a threefold higher risk of dying from heart disease and an eight-fold higher risk of death from infectious disease, almost entirely pneumonia.

The higher rate of death from infection involved only a small fraction of the total set of people in the study. Most people die from things other than infection. Still, the results may demonstrate that the immune system requires a lot of cell replication to handle pathogens and over the years immune cells may have their telomeres wear down a lot as a result.

Telomere length matters for cells that have to divide. Heart muscle cells do not normally divide. Also, while regular muscle has a type of muscle stem cell that can generate replacement muscle cells the heart muscle does not have stem cells closely associated with them (at least not to my knowledge). Therefore the higher heart disease death rate for people with shorter telomeres brings up the question of why. Is it that people with shorter telomeres can't easily grow new blood vessels to keep the heart muscle cells well fed? Or do stem cells come from other parts of the body travel to the heart to form replacements for damaged and dead heart muscle cells?

The reduction in the ability of immune cells to rapidly divide is probably what causes the big increase in mortality from infection.

This was associated with a 3.18-fold increase in risk of death from heart disease for those in the bottom half of telomere length, to an 8.54-fold increased risk of death from infectious diseases for people in the bottom quartile of telomere length.

A blood test for telomeres could make longevity predictions more accurate. The implications of these results is dramatic for medical insurance and life insurance.

The test, which can produce a result in less than six hours from one drop of blood, could revolutionise the life insurance and health industries.

That means higher insurance rates for people with shorter telomeres or even denial of coverage while those with longer telomeres would get lower rates. Are you curious to find out for yourself how short or long your telomeres are?

There are even more subtle effects that could flow from a more accurate way of predicting longevity. Suppose you are an administrator for a defined benefit pension plan. You could reasonably argue that people with longer telomeres should have to work longer than people with shorter telomeres to earn a given level of benefits once retired.

Why do telomeres get short as we age? Why don't cells just turn on their telomerase enzymes and grow their telomeres? Once telomeres get short enough they prevent cells from dividing. Why would cells be designed to get to a point where they can no longer divide? One theory is that shortening of telomeres prevents old cells which are accumulating damage from becoming cancerous.

Judith Campisi of the Lawrence Berkeley Laboratory has a more sophisticated version of the popular theory that cellular aging evolved in part as a defense against cancer.

Epidemiologists and practicing physicians have long noted that cancer rates soar in people over 50, an observation usually attributed to the build-up of deleterious genetic mutations with age. But Dr. Campisi puts at least part of the blame on the accumulation of cells with a senescent phenotype, which hang around in certain tissues long after they've undergone changes in morphology, behavior and function. They secrete many different molecules, some of which appear to have a "field effect" that promotes malignant changes in nearby cells.

Support for this idea comes from a series of experiments in which preneoplastic epithelial cells were grown either on a lawn of presenescent stromal cells or one where 10-15% of cells were senescent. Dr. Campisi and her colleagues saw significantly more premalignant changes in cells exposed to senescent neighbors. The investigators obtained similar results in nude mice, where they observed a direct relationship between exposure to senescent cells and the size and number of tumors that developed. In mice, a neoplastic mutation was needed as a starting point for oncogenesis; after that, senescence appeared to drive tumor development.

Dr. Campisi speculates that cellular senescence evolved as a cancer suppression mechanism at a time when the life expectancy for humans was far shorter than it is today. Now that people live so much longer, senescence may be an example of antagonistic pleiotropy: a trait selected to optimize fitness early in life turns out to have unselected deleterious effects later on. Although this may sound like depressing news, Dr. Campisi sees it differently. She believes that additional research will discover small molecules that can counteract damaging secretions from old cells that have overstayed their welcome.

An implication of Campisi's work is to make aging rejuvenation harder to do. The senescent cells need to either be induced to die or somehow (drugs or gene therapy perhaps) induced to not secrete the kinds of molecules that they make that drive tumor development. A lot of cancers show up in organs. One way to get rid of the senescent cells that are driving tumor development is to get rid of the organs that contain them. So one more radical strategy for reducing the risk of cancer would be to grow replacements for those organs that posed the greatest cancer risk for each individual.

Short telomeres can cause all sorts of problems.

BOSTON - Scientists at Dana-Farber Cancer Institute and their colleagues have found that much of the widespread damage that the rare genetic disease ataxia telangiectasia, or AT, wreaks on the body results from the progressive shortening of telomeres, the structures that cap the ends of a cell's chromosomes.

In genetically altered mice, the researchers found that the shortening of telomeres led to a "crisis" that disrupted chromosomes "like a hand grenade thrown into the cell," as one scientist put it. The resulting cellular chaos was manifested throughout the rodents' bodies by the loss of reparative stem cells that different organs normally have in reserve, producing symptoms of premature aging such as hair loss and slow wound healing, and early death.

The report by Kwok-Kin Wong, MD, PhD, and Ronald A. DePinho, MD, of Dana-Farber and their collaborators was posted by Nature today on its website as an advance online publication, and it will appear in a forthcoming print issue of the journal.

"There are significant implications for humans" in the discovery, said DePinho, whose laboratory has made a number of fundamental findings about telomeres and their role in aging, cancer and problems like liver cirrhosis. "It suggests that much of the problems in AT are related to eroding telomeres. It provides us with a point of attack." For example, it might be possible someday to restore telomere function with drugs and potentially reduce some of the ravages of the disease, DePinho says.

Short telomeres are harmful in all sorts of ways. Long telomeres are a cancer risk.

Aside from perhaps providing for a new blood test to predict longevity does this latest result provide any sort of guide for the development of anti-aging treatments? To put it another way: Does it make sense to try to develop treatments that will lengthen telomeres? One potential risk of such treatments is cancer. The cells that have short telomeres are probably more at risk of becoming cancerous than cells in the same body that have longer telomeres (cells in the same body and cell type will not all have the same telomere length). Whether telomere lengthening would be a net benefit is hard to know and would probably depend on each individual's risk factors.

If a therapy (probably a gene therapy though not necessarily) to lengthen telomeres is delivered in the body then many different cells will get their telomeres lengthened. Some of the cells will be ones which have accumulated mutations that put them at risk for becoming cancerous. This argues against generalized therapies to lengthen telomeres throughout the body.

One less risky approach is to develop the ability to make high quality rejuvenated cells with lengthened telomeres outside of the body and then to deliver those cells back into the body as cell therapies. Cells taken out of the body could be treated to increase telomere length. A further step would be needed in order to reduce the risk of cancer due to accumulation of mutations. Individual cells whose telomeres were lengthened could be grown up into much larger numbers of cells. From that larger number of cells some could be sacrificed to do integrity testing of the genes that are most crucial for prevention of cancer. In other words the DNA could be sequenced or otherwise checked for mutations - especially in genes that regulate cell division. Cell lines that were found to have no mutations in crucial areas could then be further developed to eventually be injected back into the body to provide rejuvenated cells of the desired type.

In order to do the most thorough possible testing to screen out harmful mutations the development of much faster and cheaper DNA sequencing technology is needed. See the FuturePundit category archive for Biotech Advance Rates for a number of posts on the development of technologies that promise to reduce the cost of DNA sequencing by orders of magnitude.

Gene therapy to cell lines would also be helpful. There are naturally occurring genetic variations that increase the risk of cancer. More genetic risk factors for cancer will be found with time. Gene therapy to cell lines could be done to change cancer risk factor genes of cells to versions that make the cells less likely to turn cancerous.

In summary, short telomeres are probably a mortality risk. But telomere lengthening will bring risks as well as benefits. Development of therapies that increase telomere length for cells in the body (i.e. in situ therapies) might be beneficial for some portion of the population. The benefit would be greater if the therapy could be targeted to specific cell types. It would be greater still if it could be applied to cells outside of the body which are then carefully screened and treated in order to reduce the cancer risk before the cells are returned to the body. Telomere lengthening is unlikely to be applied systemically to increase telomere lengths for all the cells in the body or for all people.

Update: Illustrating the importance of short telomeres as a way to prevent cancer some scientists have recently discovered a regulatory site that controls telomerase expression. The suspicion is that this site gets mutated to enable the growth of cancers. They hope their finding can be used to develop a drug that will turn off telomerase in cancer cells.

The scientists, whose findings are reported in the journal Cancer Research, believe that a drug that targets the gene and the way it is packaged could switch off telomerase in cancerous cells.

Because telomerase is active in about 85-90 percent of cancers, a drug that blocks its production could potentially be effective against many different types of cancer.

From the BBC report Professor Robert Newbold of Brunel University and lead researcher for this study says blocking the expression of telomerase could stop cancer growth.

"Now we understand more fully how tumours activate telomerase we can begin to develop drugs that target this process to restore mortality to cancer cells and stop them from growing and dividing indefinitely."

Share |      Randall Parker, 2003 January 31 09:29 PM  Aging Reversal


Comments
Charlie Murtaugh said at February 2, 2003 1:54 PM:

Good post -- I've been meaning to write something about this myself. I suspect, though, that those short-telomere people also had other health conditions that would already allow an insurance co. to rate them as heart-attack or other risks. E.g. a chronic history of illness, which would cause increased cellular turnover and thus lower avg. telomere length.

stein said at April 3, 2004 12:09 PM:

Any companies that presently make a teleomerate length test product?????

Richard said at September 14, 2008 11:08 PM:

What do you know about a Dr. Alan Sears anti aging therapy TA-65? Is his work legitimate?

D Adams said at March 28, 2009 9:52 PM:

Who or what labs test telomers?
How much?
Can I have these test done without doctor?
What type of doctor? neuro or pedatric!
www.23andme.com test $399 for other illnesses etc.

But who and how much for stress or illness and mortality.
What impact if any does this have legally.
Intentional inflection of emotional diress from chronic abuse or stress.

anonymous said at August 5, 2009 2:41 PM:

I found SpectraCell telomere testing for anti-aging; obesity, hypertention, diabetes. They also test for vitamin deficiencies. decodeme.com and 23andme.com test for DNA illnesses. TA-65 telomere, starving or calorie restriction invokes the DNA gene, oxidative stress, telomerase, leukocytes, stress. Dr. Blackburn psychology or Dr. Sapolsky
both have studies on social stresses. I did mine to find out about blindness and when! Check it out! cost $350.-ish?

thomas t samaras said at January 28, 2012 4:35 PM:

A note about today's life expectancy vs. earlier years. Our increased life expectancy is often cited as an indicator that we live much longer today than in the past; e.g., in 1900 the average male life expectancy was about 49 years while today its about 76 years. The average life expectancy of the past was low because many infants and women died during childbirth. In addition, many young children died before 10 years of age. However, the ones that survived lived to respectable ages. For example, a 75 year old in 2007 can expect to live only 2 years longer than a 75 year old in 1900. Therefore, there were many people that lived to advanced ages if they survived to 20 or more years. Therefore, I don't think this would have much to do with telomere length except for the impact of a 60 hour work week, poor medical care, injuries and other undesirable life style factors, such as mental and physical stress.

Increasing body size is a major culprit in reducing longevity. It takes more cells to create a bigger body and more cell doublings to maintain a larger body over one's life time. For example, geneticist de Malgalhaes reported in 2002 that within a species, the smaller individual lives longer than the bigger one because it requires many more cell doublings to support a bigger body. For example, studies in Spain and Sardinia found that shorter people have better long-term survival than taller ones. More information on the relation of body size to longevity can be obtained from www.humanbodysize.com

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