DNA breakthrough may be key to living longer

Mankind has always been obsessed with its mortality or, rather, its potential for immortality.
A youthful Elizabeth Taylor on the set of the movie Cleopatra in Rome in 1962
A youthful Elizabeth Taylor on the set of the movie Cleopatra in Rome in 1962

Mankind has always been obsessed with its mortality or, rather, its potential for immortality. Since the days of ancient Egypt, when Cleopatra bathed in asses' milk to retain her youthful looks, there has been a plethora of creams, oils, potions and medicines developed with the promise of preventing the onset of the ageing process. Today, it is a multibillion-dollar global industry and, whereas in the past anecdotal evidence was enough to push "miracle" products, today big science ploughs huge sums into finding clear evidence of ways to promote longevity.

Anti-ageing medicine is at the forefront of applying the latest scientific advances and state-of-the-art techniques in the search for the elixir of youth. Research includes work using stem cells, gene therapy and biotechnology. And some of the results are promising. One major breakthrough occurred recently, with the findings published in the journal Nature Medicine. Researchers at Yeshiva University in New York found that genetic manipulation of specific parts of the DNA of older mice results in their livers functioning as well as those in younger mice.

The genes that were studied allow the animals to remove rogue, malfunctioning proteins from cells, leaving them to operate properly. Dr Ana Maria Cuervo, an associate professor at the Institute for Ageing Research at Yeshiva, led the research team. "Protein clearance is universal in all organisms and all tissues and cells," she said. "There are different surveillance mechanisms inside cells that take care of identifying abnormal or damaged proteins and eliminate them before they accumulate and become toxic for the cells."

All organisms contain two main surveillance systems: proteosomes and lysosomes. Proteosomes are enzymes designed specifically to remove unusable proteins from cells. Lysosomes are more complex; they contain digestive enzymes that can break down various potentially toxic products, including proteins in cells. Dr Cuervo's ongoing research is dedicated to the latter. "Our interest is to characterise how lysosomes identify the damaged proteins and remove them," she said. "We have been studying one of these mechanisms of disposal in lysosomes called chaperone-mediated autophagy (CMA). We found that CMA decreased with age, so we wanted to know if the decrease of CMA with age was caused by, or just mere consequence of, ageing."

Dr Cuervo discovered that a decline in CMA function contributed to the ageing process, rather than being a consequence of it. "In this work, we have repaired the defect of one of those surveillance mechanisms in [the] liver of old mice. We have found that by maintaining this system active until late in life, the liver of those animals was free of toxic or damaged products, was better prepared to respond to any stress and also functioned better," she said.

"This study provides, for the first time, convincing evidence that part of the loss of function with age is due to the accumulation of those damaged products and to the failure of the cellular surveillance systems that usually take care of their remova - proof that if you keep the cell clean they keep working properly until late in life." It is a major step forward in the prospect of preventing, or at least slowing, the ageing process. However, because the research involved altering the genetic function, the search is now on to find a product that can be used in a practical, safe way to create the same outcome.

"To repair the defect we used gene manipulation, but of course that is not something that you want to use," Dr Cuervo. "Our idea is that now we know that if we repair the defect it is enough to return all the system to its 'youth', we will start screenings of compounds that could have the same effect. "Through other projects in our laboratory we have a good idea of the reasons [behind] the defect, so we are looking for stabilising compounds that will mimic our gene manipulation."

Furthermore, at the moment this research is being restricted to mice. There are no plans to study the effects of genetic manipulation of surveillance systems in the cells of humans. At least, not at the moment. "As for a time frame, the translation to humans is not going to happen tomorrow but, given the recent interest in the molecular basis of the cellular clearance mechanisms and the number of new labs interested in this process, the field is advancing at a very good pace and makes me confident that if we get enough attention from drug companies the translation may not be too far along the way," said Dr Cuervo.

Regardless of when this happens, the potential impact of these findings could be huge and particularly so for research into degenerative diseases, such as Parkinson's and Alzheimer's. "There is quite a long list of diseases related to the accumulation of proteins that misbehave. As we get old and in many age-related human pathologies, including devastating disorders such as Alzheimer's and Parkinson's disease, mutated or damaged proteins accumulate inside cells in the form of toxic products which end up killing these cells," she said.

"In theory, any mechanism that helps remove proteins should at least alleviate the conditions of the affected cells." The race is now on to find the mechanism that will do this, but for Dr Cuervo a single method is unlikely to be enough. "Ageing is a multi-factor process and as such I think that the ways to attack it should be multiple. Repairing the surveillance systems seems to be a good way of slowing down the ageing process, but there are going to be many other ways and the more we learn about the biology of ageing the closer we will be to designing an integrated intervention that could modify the different aspects of ageing," she said.

For scientists such as Dr Cuervo, the search is not for "miracles", elixirs and immortality, but for a way of making the most of the time we have. "For me, the goal of ageing research is not to make people live forever, but allow them to be healthy and functional until the last moment. On that respect I am very optimistic that the scientific community should find ways to improve function with interventions such as the one we used here." Peter Donnelly is a Science Correspondent for the Life Science Division at IIR Middle East.

Published: August 21, 2008 04:00 AM

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