May 16, 2012
Telomerase Gene Therapy Boosts Mouse Longevity

Longer telomere caps on chromosomes enable cells to divide more times, replace lost cells, and do repairs. Lengthening the caps on telomeres increases life expectancy in mice.

A number of studies have shown that it is possible to lengthen the average life of individuals of many species, including mammals, by acting on specific genes. To date, however, this has meant altering the animals' genes permanently from the embryonic stage – an approach impracticable in humans. Researchers at the Spanish National Cancer Research Centre (CNIO), led by its director María Blasco, have proved that mouse lifespan can be extended by the application in adult life of a single treatment acting directly on the animal's genes. And they have done so using gene therapy, a strategy never before employed to combat ageing. The therapy has been found to be safe and effective in mice.

The results are published today in the journal EMBO Molecular Medicine. The CNIO team, in collaboration with Eduard Ayuso and Fátima Bosch of the Centre of Animal Biotechnology and Gene Therapy at the Universitat Autònoma de Barcelona (UAB), treated adult (one-year-old) and aged (two-year-old) mice, with the gene therapy delivering a "rejuvenating" effect in both cases, according to the authors.

Mice treated at the age of one lived longer by 24% on average, and those treated at the age of two, by 13%. The therapy, furthermore, produced an appreciable improvement in the animals' health, delaying the onset of age-related diseases – like osteoporosis and insulin resistance – and achieving improved readings on ageing indicators like neuromuscular coordination.

This is an interesting result for a number of reasons. First off, why don't mice just have longer telomeres at the start? If the increased life expectancy has no cost in fitness why aren't mouse telomeres longer already?

Second, I am surprised that the longer telomeres didn't enable more cancer growth and therefore cause shorter life expectancy. Telomere shortening every time a cell divides acts like a counter on the max number of times a cell can divide. This functions as a defense against cancer. Some cancers mutate their way past this defense (e.g. by turning on telomerase to make telomeres longer). But presumably others get stopped by cells with telomeres too short to allow further cell division.

The researchers address the cancer issue in a way that suggests to me this would not work for humans.

In 2007, Blasco's group proved that it was feasible to prolong the lives of transgenic mice, whose genome had been permanently altered at the embryonic stage, by causing their cells to express telomerase and, also, extra copies of cancer-resistant genes. These animals live 40% longer than is normal and do not develop cancer.

The mice subjected to the gene therapy now under test are likewise free of cancer. Researchers believe this is because the therapy begins when the animals are adult so do not have time to accumulate sufficient number of aberrant divisions for tumours to appear.

Mice do not live that long to begin with. Humans at middle age given telomerase gene therapy would have decades in which to accumulate aberrant cells that can turn cancerous. So

Third, on the bright side the gene therapy was able to reach a large enough fraction of the cells in the bodies of mice to make a big difference. Very good news because we have need for lots of types of gene therapy to do rejuvenation of our bodies. I wonder what fraction of all the cells in the mice got the gene therapy.

As for the implications for humans: Keep in mind that we already live many times longer than mice. We've got an assortment of optimizations for longer life that might reduce the value of longer telomeres and our cancer risk from longer telomeres might be greater than for mice.

But even if telomere lengthening would boost our all cause mortality today that does not mean this must always be so. Once cancer becomes easily curable the risks from longer telomeres will go way down and we'll left with just the benefits. So gene therapy for telomere lengthening will likely become a useful technique for life extension in about 10 to 20 years.

We will gain another and safer way to get the benefits of longer telomeres: Cell therapy. Separate out cells. Then test different cell lines for mutations. Then extend the telomeres of the safest cells. Then grow up those cells in large numbers and inject those cells back into the body.

Share |      Randall Parker, 2012 May 16 07:16 PM  Life Extension Gene Therapy


Comments
Wolf-Dog said at May 16, 2012 8:36 PM:

"We will gain another and safer way to get the benefits of longer telomeres: Cell therapy. Separate out cells. Then test different cell lines for mutations. Then extend the telomeres of the safest cells. Then grow up those cells in large numbers and inject those cells back into the body."
---------------------

This sounds like a very good idea, but when these specific cells are injected into the body, how do they go to their correct location they were supposed to be?

PacRim Jim said at May 16, 2012 11:22 PM:

If an effective rejuvenation therapy becomes available, but at a price few can afford, there would be riots such as America has never experienced.
Consideration should be given now as to how this long-dreamed-of gift can be provided to one and all, at an equitable price.
It's no exaggeration that is will be a matter of national security, which is the first duty of any government.
(Is it unreasonable to wish for an international Manhattan Project for human bioremediation? An international life extension program would be the best antiwar project imaginable.)

Tim said at May 17, 2012 9:18 AM:

Why do you assume the worse case scenario, just out of habit? It would be unlikely do occur that dramatically anyway. Most likely medical treatments of various expense slowly causing an overall life expectancy increase to actuarial escape velocity,(greater than one yr per yr increase in life expectancy). Furthermore the pop most likely to riot the young urban poor wouldn't really be effected. If one is under 30 you don't need longevity treatments, you have other concerns.

Art De Vany said at May 17, 2012 7:04 PM:

If this ever works, new forms of cancer will exploit it in the same way some cancers exploit our genes and metabolism to direct nutrients to themselves. Do not forget the second stage beyond the intervention as the various forms of cancer evolve. First stage, possible cure or solution. Second stage, adaptation and exploitation of the cure or solution.

Seerak said at May 18, 2012 4:03 AM:

First off, why don't mice just have longer telomeres at the start? If the increased life expectancy has no cost in fitness why aren't mouse telomeres longer already?

Gene churn. The mouse species is better served by constant genetic turnover, than by persistence of specific individuals.

Sexual reproduction and death both have the same purpose: to keep shuffling the deck of genetic cards in order to prevent overspecialization. So long as there are always outliers present in the species at any given time, the "bell curve" of genetic variation ensures that if conditions suddenly change enough such that the most successful genetic combinations are suddenly ill suited to survive, enough of the formerly disadvantaged oddballs will find themselves in the sweet spot, and take advantage of it to domlinate and keep the species adapted and successful. Gene churn keeps the species as a whole adaptable, fleet of genetic foot for when conditions change.

Without death from aging, there is only death from accident, disease or competition; the genetic bell curve narrows to the most successful individuals, resulting in a sort of genetic near-monoculture that could get wiped out by even a minor climate shift (as happened to the low-churn dinosaurs, who lost out to the high-churn mammals when the asteroid hit the fan.)

Without sex, the genetic library is highly static, with only mutation as a source of genetic innovation over many generations -- not only is it slow, but the vast majority of mutations are immediately fatal to the cell, and of the ones that aren't, many are fatal or crippling to the organism (e.g. the ones that lead to cancer). Relatively rare is the de novo mutation that confers substantial survival advantage. Moreover, mutation is completely random, whereas gene churn has a kind of apparent goal-directed quality to it. It can quickly emphasize useful traits while de-emphasizing (but not deleting) those that have become less useful by means of natural selection from the genetic library over just a few generations.

Sex (versus asexual reproduction) forces new combinations into existence with each generation, widening the bell curve; mortality forces the retirement of all combinations, even the most successful ones, permitting the "reserve" of genetic variety in the individuals at the bell curve's fringes to have some breathing space. Consider the sclerosis of university departments due to tenure, and you get a hint of why mortality serves the species better than immortalizing the currently successful individuals.

Nick G said at May 19, 2012 9:00 AM:

Seerak,

That makes sense. Some implications:

1) if death has positive benefits, that suggests that humans have death clocks, instead of a lack of longevity adaptations due to low selective pressures late in life. That would make longevity interventions easier.

2) genetic therapy is a lot more efficient and faster than adaptation over several generations due to response to environmental pressures.

j said at July 6, 2014 9:12 AM:

this is amazing.I am interested in this type of research.Can anyone tell me how I can get involved?Are the people who perform these experiments,Genetic engineers??????/

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