I guess just about everyone in the world has heard of DNA. I presume everyone knows that DNA is
what genes are made of. And I
suppose everyone knows what genes are.
I suspect, however, that many people don’t know what a “chromosome”
is.
Simply put, a chromosome is a combination of DNA and
protein, and under a microscope it looks like a rod. Humans have 46.
Chimpanzees have 48. Corn
has 20. And so on. You might think of a chromosome as a “carrier”
for DNA.
When I studied genetics about 40 years ago, all we knew
about telomeres was that they are the tips found on either end of each rod-like
chromosome, but we didn’t know WHY they are there. Scientists now know a whole lot more, of course, and in 2009
there was even a Nobel Prize awarded for a discovery having to do with
telomeres.
Today it is known that telomeres serve essentially the same
function as an “aglet”, that little plastic sleeve at the end of a shoelace. Both telomeres and aglets protect the
ends of things from degradation, and what telomeres protect are chromosomes. What happens is that every time a cell
divides, the chromosomes divide too—along with the DNA that makes up the
chromosomes. Because of the way
DNA is replicated, the ends of each DNA strand get chopped off with each cell
division, which results in the loss of some DNA . So a telomere is
essentially some “disposable” DNA that is added as a buffer to the end of each DNA
strand so that non-essential DNA gets chopped off rather than the critical DNA that
makes up the main part of the strand. And then, to complete the process, there is an enzyme called
telomerase that adds this buffer-DNA back on to the end of the telomere.
But unfortunately this system isn’t perfect, and eventually
telomeres get shortened to the point that critical DNA is no longer
protected. When this happens, the
critical DNA is said to be “exposed,” and it can combine randomly with DNA from
other chromosomes. This leads to
chromosomal abnormalities and is the reason ALL cells eventually die: they can no longer divide properly. In fact, current theories about the aging
process assume there is a finite limit to the number of times a cell can
divide.
A small percentage of cancers (5-10%) have the ability to
activate telomerase and thus add DNA to the end of their chromosomes. This continual “rejuvenation” can make cancerous
cells immortal—that is, they do not die. Cell aging, therefore, represents a critical balance between
keeping cells dividing properly, using telomeres, but NOT allowing them to
continue dividing if they become defective (cancerous)
So basically, a lot of human-telomere biology can be summed
up as follows: long telomeres are
good, short telomeres are bad. This
is because long telomeres allow cells to divide more times than cells with
short telomeres.
It is not surprising, therefore, that short telomere length
has been correlated with many age-related disease conditions: cardiovascular
disease, hypertension, arthrosclerosis, Alzheimer’s, Parkinson’s, dementia,
diabetes, osteoporosis, and cancer.
In fact, the literature supporting these associations is very extensive.
Further, some pretty incredible results have been obtained by
lengthening telomeres in mice, actually reversing some of the characteristics
associated with the aging process.
The mice used in these studies are strains that don’t produce telomerase,
so their telomeres are very short.
They show tissue atrophy, reduced testis size, deteriorated spleens and
intestines, reduced fertility, diminished sense of smell, smaller brain size,
and a lifespan only about half as long as that of normal mice. But guess what—a 2011 study showed that
after these mice were injected with 4-OHT (a drug that induces production of
telomerase, which in turn results in elongated telomeres), indications of aging
actually REVERSED: testes grew,
fertility increased, brains became larger.
It seemed to be the fountain of youth . . . at least until it was reported in 2012
that mice receiving the 4-OHT injections had higher rates of cancer. This result is consistent with observations
in many other studies correlating longer telomeres with increased cancer. Apparently the researchers had reversed
aging, but in the process, they had raised cancer rates. (Some scientists think that inhibiting
telomerase is a viable way to treat cancer—the theory being that if you can
shorten telomeres, the cancer cells will die.)
And then (of course), there are telomere studies with
results that are truly puzzling.
For example, 1,091 Scots born in 1936 (548 men and 543 women) were
examined in 1947 at age 11 then again in 2006 at age 70. The subjects were given cognitive
tests, a physical examination, and their telomeres were examined. As reported in 2012, telomeres were
statistically longer in men than women, and longer telomeres were associated (in
women only) with higher cognitive scores and lower levels of C-reactive
protein, a molecule associated with inflammation. Telomere length was not associated with any other measures
of aging.
And then in 2011, a paper that reported on 60 mammalian
species showed an INVERSE relationship between telomere length and lifespan—in
other words, species with the longest telomeres had the shortest lifespans. Moreover, the longest lifespans were
not correlated with telomerase activity.
So what’s going on?
Well, there have been over 16,000 publications relating to
telomeres and aging, and there are bound to be inconsistencies. And, of course, what’s going on with
mice may not relate to what’s going on with humans. And what’s going on with most mammalian species may not have
anything to do with humans. But
even so, these studies do seem to contradict everything we think we know about
the relationship between telomeres and aging.
In spite of these findings, at least one of the three winners
of the 2009 Nobel Prize, Elizabeth Blackburn, thinks that telomeres “are an
integrative indicator of health.” She has been involved in the formation of
Telome Health in San Francisco, which will measure telomere length of your
white blood cells (if requested by a researcher). The Telome Health website (http://www.telomehealth.com/index.html)
asserts that telomere length is an indicator of aging and health and believes
that telomeres can serve as biomarkers that would be useful to pharmaceutical
companies in assessing drug response.
The company’s website lists 155 publications supporting their claims. (And, near and dear to my heart, their
foundational patents were licensed from the University of Utah. A great example of University
technology leading to the formation of a new company!)
However, as is often the case with emerging scientific
disciplines, not everybody agrees that measuring one’s telomere length is
useful. Carol Greider, who shared
the Nobel Prize with Blackburn in 2009, was quoted in 2011 as saying that
telomere length is not particularly helpful in assessing health and well-being
because telomere length is so variable. “Do I think it is useful to have a bunch of companies
offering to measure telomere length so people can find out how old they are? No.”
In 2010, another telomere researcher, Maria Blasco of the
Spanish National Cancer Centre in Madrid, Spain, founded a company called Life
Length that also measures telomeres.
Well, actually, it reports the percentage of short telomeres, a metric
that Blasco apparently thinks is a
better indicator of health than “average telomere length,” which is the metric used
by Telome Health. Life Length’s website
(http://www.lifelength.com/index-eng2.html)
is exceedingly thorough, and like Telome Health, it makes a compelling case for
telomere analysis.
As an indication of how small the world of telomere science
really is, Calvin Hartley from Telome Health has collaborated with Maria Blasco
of Life Length. In a 2011 paper, they
reported on a telomerase activator called TA-65 that is purified from the root
of Astragalus membranaceus. They showed that in mice with short
telomeres, injections of TA-65 resulted in increased telomere length and improved
glucose tolerance, bone density, and skin fitness—and best of all, the rate of
cancer did not increase. A
similar study using human cells that was published in 2013 also reported that TA-65
increased telomere length.
It turns out you can actually buy TA-65—it is sold, for
example, by Telomerase Activation Sciences, Rev Genetics, and Life Meds, to
name just a few. Apparently TA-65
was discovered by Geron Corporation, a California company that was an early
pioneer in stem cell commercialization.
It is sold as a “neutraceutical” and thus has NOT been subjected to the
kind of testing that is mandated by the FDA for pharmaceuticals. In other words, there have been no
large scale clinical trials, efficacy has not been proven, and no one has
determined the optimal dose.
Interestingly, a class-action lawsuit was filed in 2012
against Telomerase Activation Sciences by one of its former employees, who
claims that he got prostate cancer while taking TA-65. (Unfortunately, I haven’t been able to
find out anything else about this case.)
Although the current research results are intriguing, at
this point I’d look at telomere testing the same way you might look at getting
your cholesterol or your blood pressure checked. It is just another test that MAY be an important
indicator of your health. But I’d
shy away from chemicals purporting to make your telomeres longer until we have
results from large-scale clinical trials indicating that that these compounds are safe and effective—and won’t give you cancer.
All this is making me want to talk about neutraceuticals,
natural product claims, the role of the FDA, statistical tests, clinical
trials, and how we know if something is “true,” but I’ll leave that for another
time.
Useful references:
http://www.nature.com/nature/journal/v469/n7328/full/nature09603.html
http://www.nature.com/news/lawsuit-challenges-anti-ageing-claims-1.11090
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