Miércoles 26 de Noviembre de 2008, Ip nº 256

Enzyme takes us a step closer to eternal youth
Por Linda Geddes

Could artificially raising levels of a key enzyme hold back the effects of ageing? It has long been a hope but now two lab experiments - one with human cells and one in animals - are providing the first evidence that this may actually be possible.

The enzyme in question is telomerase, which is present naturally in some mammalian cells. Its function is to maintain the protective caps called telomeres at the ends of our chromosomes, which unravel with each cell division as we get older. It has been suggested that this shortening triggers some of the negative effects of ageing at a cellular level. As a result, telomerase has been hailed by some as a potential elixir of life.

One of the latest studies confirms that at least one type of human cell can indeed be restored to a youthful state by boosting telomerase levels. The other suggests that boosting telomerase can result in longer life in animals. While an elixir of life in people remains a very long way off, the prospect of boosting telomerase to fight disease, including age-related diseases, may be much closer.

With the aim of fighting HIV, immunologist Rita Effros at the University of California, Los Angeles, previously inserted part of the telomerase gene into immune cells called killer T-cells. While this did indeed boost their ability to fight viral infections, such gene therapy is considered too dangerous to be used in practice.

So in her latest experiments, Effros has turned to a drug called TAT2, developed by Geron of Menlo Park, California, that boosts telomerase production without altering anyone's DNA. When killer T-cells from people with HIV were exposed to TAT2, it enhanced the cells' ability to fight the virus, suggesting that TAT2 might be used to supplement existing anti-retroviral drugs by boosting the immune systems of people with HIV (The Journal of Immunology, vol 181, p 7400).

This idea is supported by a previous study which indicated that some people with HIV who go for years without developing AIDS have killer T-cells with high telomerase activity and longer telomeres. Since T-cells fight many viruses, TAT2 might eventually be deployed to boost resistance to a whole range of diseases.

TAT2 also increased the cells' ability to divide and stopped their telomeres from shortening, which raises the possibility that it might be used to wind back the clock of other ageing cells and provide more general treatments for ageing.

Aubrey de Grey of the Virginia-based Methuselah Foundation, which promotes research into extending lifespan, certainly sees the study as a big step in that direction. "It is what we would have hoped," he says. He is particularly interested in the fact that the cells seemed to be "fully functional" in their new role as youthful immune cells, raising hopes that telomerase might wind back the cellular clock more generally.

Some safety concerns remain, however, not least because cancer cells produce telomerase at higher than normal rates. "With anything that boosts telomerase, you may have unwanted cell growth like in cancers," says Arne Akbar, an immunologist at University College London.

However, when TAT2 was added to tumour cells it did not affect the amount of telomerase they produced. Nor did it change the growth characteristics of immune cells that were cultured with a virus that can trigger cancer. "We are fairly confident at this point that TAT2 won't enhance cancer development," says Effros, although further trials are needed to confirm this.

Telomerase is extracted from the Astragalus plant, which is used in Chinese medicine without any obvious adverse effects. While this may help pave the way to pilot studies in humans in the near future, Effros warns against taking large doses of Astragalus to try and mimic the TAT2 effect. "Uncontrolled use of any herbal drug is not wise and I would not advocate it," she says.

Even if telomerase proves successful at holding back some of the effects of ageing at a cellular level, it is still a big jump from there to something that stops a person as a whole from ageing. Yet this prospect too has been brought a step closer with an announcement last week from Maria Blasco at the Spanish National Cancer Centre in Madrid and her colleagues.

Telomerase has previously been shown capable of turning "a normal, mortal cell into an immortal cell", as Blasco puts it. But whether this translates into delaying ageing in live mammals has previously been difficult to test, as high levels of telomerase tend to promote cancer, which shortens their lives.

So Blasco's team bred mice engineered to be resistant to cancer with mice engineered to produce 10 times the normal levels of telomerase in epithelial tissue, which lines the cavities and surfaces of the body. These animals lived up to 50 per cent longer than normal mice (Cell, DOI: 10.1016/j.cell.2008.09.034). "You can delay the ageing of mice and increase their lifespan," says Blasco.

Blasco's mice also had less subcutaneous fat, healthier epithelial tissue and improved neuromuscular coordination and glucose tolerance, which are all signs of youth. Boosting telomerase also seemed to have beneficial effects on the animals' brains and muscles, even though the enzyme was not expressed in these tissues.

Effros warns against concluding that this means we can prevent ageing in humans. "I think it is very hard to extrapolate data from mouse ageing to human ageing," she says. In particular, she points out that all mice have longer telomeres than humans, and the lab mice are bred in sterile conditions.

Blasco, however, is optimistic that a similar approach may eventually extend human lifespans. She suggests that the treatment could be combined with cancer drugs to offset any enhanced cancer risk.

"We're learning to control cell division in a manner that gets the best of both worlds," says de Grey, "allowing it to happen when we need it, and not to happen when we don't."

  19/11/2008. New Scientist Magazine.