December 05, 2010
Telomere Lengthening Rejuvenates Mice

Scientists at the Dana Farber Cancer Institute found that engineering mice to suppress the telomerase enzyme (which makes telomere caps on chromosomes) caused the mice to prematurely age and activating the enzyme in prematurely aged mice caused some of their aging to reverse. But read on for why we can't easily exploit this insight.

Scientists at Dana-Farber Cancer Institute say they have for the first time partially reversed age-related degeneration in mice, resulting in new growth of the brain and testes, improved fertility, and the return of a lost cognitive function.

In a report posted online by the journal Nature in advance of print publication, researchers led by Ronald A. DePinho, MD, said they achieved the milestone in aging science by engineering mice with a controllable telomerase gene. The telomerase enzyme maintains the protective caps called telomeres that shield the ends of chromosomes.

I wasn't going to do a post on this report because it was pretty much along the lines of my expectations. Also, it does not suggest any obvious easy ways to do full body rejuvenation. But since enough people have asked me here's my take:

If we found a way to turn on telomerase to make all our telomeres longer we'd increase the amount of repair done in our bodies. Lengthened telomeres would at least slow and, for a time, partially reverse aging in some parts of the body. That sounds great. But doing this might not cut all cause mortality. Why? Longer telomeres in aged cells will increase our odds of developing and dying from cancer.

The problem is that telomere shortening is an anti-cancer strategy for the body. Using drugs or gene therapy to lengthen telomeres would enable dormant cancer cells or pre-cancerous cells to grow. Whether the net result would be longer or shorter life would depend on each individual. But probably on average the net result would be shorter life because otherwise we'd already have more active telomerase (since longevity-lengthening mutations would be selected for, all else equals). In other words, our telomeres get shorter as we age in order to stop cancer cells. But their shortening also prevents other cellular division which accelerates aging. So telomere shortening with each division of a cell is a trade-off.

In spite of the cancer risk from longer telomeres I would be more excited by a study that found a way to activate telomerase in human cells in the body. Why? Because some people who have degenerative conditions face such high risks of death from organ failure that for most of them telomere lengthening would cut their death risk from organ failure by more than they'd increase their death risk from cancer. Basically, they face a bigger risk of death from unrepaired failing tissue than they do from cancer. So the trade-off for them comes down on the side of greater benefit from lengthening their telomeres.

When telomeres get too short their shortness tells cells to die or at least to stop dividing. But you need a constant supply of dividing cells in your skin and intestinal tract among other places. So widespread telomere shortening in an organism causes shrinking organs and declining function as cells die and are not replaced.

Loss of telomeres sends a cascade of signals that cause cells to stop dividing or self-destruct, stem cells to go into retirement, organs to atrophy, and brain cells to die. Generally, the shortening of telomeres in normal tissues shows a steady decline, except in the case of cancer, where they are maintained.

The experiments used mice that had been engineered to develop severe DNA and tissue damage as a result of abnormal, premature aging. These animals had short, dysfunctional telomeres and suffered a variety of age-related afflictions that progressed in successive generations of mice.

Among the conditions were testes reduced in size and depleted of sperm, atrophied spleens, damage to the intestines, and shrinkage of the brain along with an inability to grow new brain cells.

In order to do full body rejuvenation we need a cure for cancer that has mild side effects. Given a reliable way to wipe out or normalize cancer cells the risks of telomerase activation would go way down.

We could use telomere lengthening for a wider range of people sooner if the telomere lengthening therapy could be delivered more selectively to single organs or cell types. Figuring out ways to do that will take a while. Stem cell therapies where newer undamaged cells with long telomeres are introduced might become workable sooner.

Also check out some of my earlier posts on telomeres and aging: Telomere Length Indicates Mortality Risk, Chronic Stress Accelerates Aging As Measured By Telomere Length, and Sedentary Lifestyles Age Chromosome Telomeres Faster.

Share |      Randall Parker, 2010 December 05 01:49 PM  Aging Reversal


Comments
PacRim Jim said at December 5, 2010 2:34 PM:

Knowing what needs doing is halfway there.
The human mind won't be deterred from its ultimate prize: (relative) immortality.
Most of us will not reach the finish line, however.
At least we'll have the satisfaction of knowing we're the last generation of humans to die a natural death.
Wahoo, I guess.

James Bowery said at December 5, 2010 4:22 PM:

It's a good thing that governments prevent humans from voluntarily trying various telomere therapies, otherwise the poor little baby humans might hurt themselves.

ninda said at December 5, 2010 5:27 PM:

We need nanobots to be injected in our bloodstreams in order to detect and destroy cancer cells. Or find a way to upgrade our immune systems so they can do the same.

Wolf-Dog said at December 5, 2010 6:58 PM:

Already there is significant progress in training the human immune system to attach cancer cells, and in the future the cancerous side-effects won't be the main problem for new drugs.

But what I don't understand in this article is how exactly the telomere therapy is supposed to work. The article seems to talk about genetically engineered mice, but how about existing mice? What kind of drug or gene therapy can be injected to mice or humans to achieve the same telomere improvement?

Peter said at December 5, 2010 9:40 PM:

Cancer cells have short telomeres that regenerate just enough to prevent the cell from dying. Cells with long heathy telomeres don't turn cancerous, see germ cells. Telomere length affects genetic expression in the region of the gene near the caps. Long telomeres have a "sleeve" that turns off certain genes, probably oncogenes. If the telomere can be elongated properly, I would bet the oncogenes would be silenced, just as they are in youth.

Brett Bellmore said at December 6, 2010 3:04 AM:

I've suggested in the past, that we could virally add new apoptosis triggers to existing cells. This could be done by the same virus that restores the telomeres. (Alternatively, we could use something like an altered intracellular parasite to deliver a synthetic chromosome, if the amount of genetic material was too great to be delivered by a virus, or to avoid disruption of existing genes.) At first glance, the ability to direct all the cells you rejuvenated to die would appear not terribly useful.

But the triggering mechanism could be permuted in a fashion similar to that used to generate antibodies, leading to millions or even billions of distinct trigger molecules. This means that you could identify the particular post treatment cell line a new cancer descended from, and cause all members of that cell line to die. It would probably be a pretty effective cancer treatment for cancers which were very small at the time the telomere lengthening took place.

Lou Pagnucco said at December 6, 2010 12:05 PM:

Since number of moles is strongly associated with telomere length in several tissues
("Nevus Size and Number Are Associated with Telomere Length
and Represent Potential Markers of a Decreased Senescence In vivo"
http://cebp.aacrjournals.org/content/16/7/1499.abstract ),
it would be interesting to know whether there is correlation with longevity.
This seems easy to answer.

Some papers indicate that telomerase overexpression can accelerate cell senescence.

Additionally, enhancing telomerase activity may impair wound healing -
http://www.ncbi.nlm.nih.gov/pubmed/12565817
Perhaps, telomere shortening is a price to be paid to repair injury.

Flash Program said at December 6, 2010 5:26 PM:

There are humans that have very peculiar tastes like constantly consuming heavily burnt meat(high on carcinogens) and are also heavy smokers. Can we presume such individuals if they reach say 90 years without dying of cancer, that they were lucky to not acquire cancerous changes to their cells, or should we assume the more likely explanation that their immune system is able to fend off such cancerous cells? In such individuals might some form of telomerase therapy not provide benefits with low or negligible risks?

It is also possible that like famine epigenetic changes being inherited, exposure to high carcinogen environments in one generation might confer epigenetic changes in the following generation, changes to modulate the organism's defensive responses to such environment.


Immune response to even aggressive cancer tissue implantation has been seen in some mice. Some animals like whales have exponentially more cells and are high up the food chain, ensuring decades of exposure to all sorts of contaminants in the environment(due to their size they require massive amounts of matter going through their system). Yet evidence suggest lifespans of near 200 years on some species of whales. Likewise some of the negligible senescence organisms seem to exhibit constant growth. It is likely that the constant regeneration of such creatures is aided by a better immune system able to deal with cancer.

jeffrey dach md said at December 7, 2010 6:37 AM:

What Activates Telomerase ? Whether you happen to be a human being or a mouse, then the most logical and effective way to increase telomerase activity, lengthen the telomeres and reverse aging is with the human bioidentical hormone, 17-Beta-Estradiol, also known as estrogen.

In 1999, Kyo demonstrated that 17-Beta-Estradiol activates telomerase via direct and indirect effects on the hTERT promoter region. This was confirmed in 2000 by Silvia Misiti and again in 2009 by Rodrigo T. Calado from the NIH

A recent December 2010 study from Imanishi from Japan showed that 17-Beta-Estradiol (estrogen) augments telomerase activity, thereby accelerating recovery after injury and reducing the effects of aging (reducing senescence). If this isn't a description of anti-aging effects, I don't know what is.

An important study in Circulation 2006 found that 17-Beta Estradiol enhances recovery after heart attacks by augmenting incorporation of endothelial stem cells and inducing new collateral vessels in the ischemic myocardium. This beneficial effect is related to telomerase activation of the Endothelial Progentior cells.

For more see:
http://jeffreydach.com/2010/12/03/anti-aging-breakthrough-with-telomerase-knockout-mice-by-jeffrey-dach-md.aspx

jeffrey dach md

Lou Pagnucco said at December 7, 2010 8:58 PM:

Just published -

"Effects of a growth hormone-releasing hormone antagonist on telomerase activity, oxidative stress, longevity, and aging in mice"
http://www.pnas.org/content/early/2010/12/02/1016369107.abstract

Reducing growth hormone increased telomerase activity, and average (but not maximum) longevity in mice.
Tumor incidence dropped from 10% to 1.7%.

Randall Parker said at December 7, 2010 9:32 PM:

jeffrey dach md,

Replacement estrogen therapy also increases the incidence of cancer.

Lou,

Interesting report. I find it interesting that there's even such things known as GHRH agonists and that they'd be used rather than GHRH itself. Did you know that there's a test of the pituitary's ability to release growth hormone that uses GHRH and arginine to stimulate the pituitary to release the GH.

So if the pituitary is stimulated to release GH rather than injection of GH (as some aging men do) does the pituitary GH cause less in the way of undesirable side effects?

Randall Parker said at December 7, 2010 10:52 PM:

Lou,

Why do you supposed increased telomerase activity and decreased tumor incidence came together?

Lou Pagnucco said at December 8, 2010 9:31 AM:

Randall,

Read the title again - they used a GRHR "antagonist", not an "agonist".

On why increasing telomerase may have reduced cancer, I can only offer a (very likely wrong) conjecture -
Increasing telomerase appears to reverse the senescent phenotype in some cells (like fibroblasts).
Maybe this reduces the extracellular matrix degrading enzymes they excrete, making cancer promotion more difficult.

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