13 July 2009

Prolonging life: gene therapy instead of starvation?

"The Kiss of Death" prolongs lifePyotr Smirnov, "Newspaper.
Ru»Fasting increases the life expectancy of nematode worms due to an increase in the level of the WWP1 enzyme.

Regular monitoring leads to the fact that even slightly modified proteins receive a kind of black mark in the form of ubiquitin and are sent for processing.

The fact that asceticism contributes to the prolongation of life was known long before the discovery of genes, proteins and other molecular aspects of life. Scientists, bearing in mind those who have absolutely no time to monitor their diet, have been trying for 70 years to explain the mechanism of this very longevity, and at the same time to find a recipe for rejuvenation.

During this time, it was possible to find several genes and transcription factors involved in the development of age-related changes, and even to discover relatively independent of starvation mechanisms for the development of these changes, "tied" to sirtuins, resveratrol and insulin-like growth factor. It was only a couple of years ago that we managed to catch on to the effect of starvation and partially explain it – it turned out that this phenomenon manifests itself in nematode worms only if they have an active copy of the pha-4 gene.

The same international team of authors led by Andrew Dillin from the Salk Institute for Biological Research in California found out that starving worms live 20-40% longer due to more sensitive recognition of aged proteins and their subsequent destruction.

The authors of the publication in Nature themselves noted that this connection was discovered by chance. Dillin and colleagues were studying the ubiquitin molecule. The addition of ubiquitin to proteins in the cytoplasm at least leads to a change in their localization, in the event that several "ubiquitous" are attached, the protein is doomed to disassembly. Scientists who discovered the role of this black mark in the late 70s even received a Nobel Prize five years ago for a phenomenon they called the "kiss of death."

Like most intracellular processes, this one also goes under the careful control of certain enzymes (in this case, ubiquitin ligases) that provide this very attachment. Actually, Dillin and his colleagues were studying the effects of one of the ubiquitin ligases, WWP1, when they discovered that a genetically programmed increase of 50% in the level of WWP1 prolongs the life of worms by 20%, which is comparable in effect to the above-mentioned fasting.

It only remained to confirm that in the case of starvation, exactly the same activation of WWP1 occurs, which scientists have demonstrated by the example of their favorite pets, the nematodes Caenorhabditis elegans. In the case of a decrease in the concentration of WWP1 (complete blocking of this enzyme is incompatible with life), the effect of fasting was practically not manifested, which finally confirms that calorie restriction stimulates WWP1, and not vice versa.

It is possible, however, that the authors were a little "modest" with the randomness of this finding, because the work of WWP1 is closely related to the pha-4 gene, described in detail by Dillin 2 years ago. But it is independent of the transcription factors daf-2 and daf-16, which adds, on the one hand, the significance of the discovery, and on the other hand, the complexity of the already confusing scheme of the theory of aging, which already has a dozen mechanisms.

The described mechanism fits best into the concept of "age-related accumulation of errors in proteins", according to which old proteins "wear out" with age, but do not break down, and new ones do not form. An increase in the level of WWP1 due to starvation or genetic modifications makes the "flaw detection" of proteins more thorough, as a result increasing the reliability and quality of work of all intracellular systems, and with them the whole organism. However, Dillin's finding does not contradict the theories of peroxidation, epigenetic control or accumulation of mutations in cells, so it is unlikely that he will have serious opponents.

The introduction of the discovery should not be expected in the near future, although the prospects are tempting: one injection of a genetically engineered vector with WWP1 will be enough to prolong life by 20%, and at the same time get rid of many age-related diseases. But this is only if scientists manage to achieve the same effect on mammals.

Portal "Eternal youth" http://vechnayamolodost.ru13.07.2009

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