Sirtuins are a target for old age pills
The universal path to old age?Alexey Levin, Voice of America
Harvard University researchers have identified a series of molecular transformations that lead to the decrepitude of all eukaryotes without exception. This is the name of organisms whose cells contain decorated nuclei. Eukaryotes include all higher animals and plants, as well as unicellular and multicellular algae, fungi and protozoa. Bacteria of all types, on the contrary, are devoid of nuclei – such organisms are called prokaryotes.
Life on our planet began with prokaryotes, which almost certainly originated more than three and a half billion years ago. Eukaryotes appeared one and a half to two billion years later, and about a billion years after their appearance they existed only in single-celled variants. The first multicellular organisms appeared on our planet relatively recently, 700-800 million years ago.
Eukaryotic nuclei consist of a special substance, chromatin, which is absent in prokaryotes. Chromatin is formed by nucleic acids and proteins. Among the latter, a special role belongs to proteins from the histone group. Nucleosomes are constructed from them, supporting structures on which DNA strands are wound.
Histones are directly involved in reading genetic information, in other words, its rewriting from DNA molecules to RNA molecules. With dense histone packaging, such overwriting does not occur, and the genes remain in a passive state. In order for a particular gene to start working, the histones associated with it must be loosened somewhat.
Various enzymes are involved in these processes, the work of which depends on the density of histone packaging. These include enzymes from the sirtuin group. They force histones to move into a state with a denser packing and thus make it difficult for genes to be switched on.
Sirtuins work in the cells of a great variety of eukaryotes – from unicellular organisms to mammals. About 10 years ago, David Sinclair and his colleagues from the Massachusetts Institute of Technology discovered that overproduction of sirtuin, which is encoded by the Sir2 gene, slows down the aging of yeast cells. More precisely, they found that its excess increases the number of divisions that cells can undergo during their lifetime. Further studies have shown that this enzyme not only changes the density of histone packing and thereby regulates the activity of genes, but also participates in the repair of DNA damage.
The discovery of this effect aroused great interest in the scientific community and resonated in the mass media. However, scientists have not known for a long time whether sirtuins act in the same capacity in the cells of higher eukaryotes, primarily mammals.
Now he will find an answer to this question, and a positive one. It is contained in an article by the same Sinclair (he now holds a chair at Harvard University), his postdoc Philipp Oberdoerffer [Philipp Oberdoerffer] and their co-authors, which will appear in the journal Cell on November 28. They studied how the health of mouse cells depends on the activity of the SIRT1 gene. This gene in mammals is responsible for the production of an enzyme similar to the yeast protein that encodes the Sir2 gene.
It turned out that the functions of both enzymes are very similar to each other. This allows us to assert (or at least assume) that sirtuins are involved in a very ancient mechanism of cellular aging, which biological evolution invented over a billion years ago.
This mechanism is based on the gradual weakening of the ability of sirtuins to simultaneously perform both of their main functions. As already mentioned, these enzymes condense the histone frameworks of nucleosomes and thereby prevent the inclusion of those genes whose products are not needed or even harmful to the cell at the moment. However, sirtuins at the same time help to eliminate DNA breakdowns caused by ultraviolet radiation or free radicals. When such defects appear, the molecules of these proteins urgently migrate from their original locations to hot spots. Such migration temporarily weakens the sirtuin control over histone structures and therefore increases the probability of abnormal inclusion of various genes.
As the experiments of the Sinclair group researchers have shown, the degree of this probability depends on age. DNA breakdowns do not occur very often in young animals, so Sirtuin repairmen usually have time to return to their duty station in time. However, with age, cells begin to produce more free radicals (mainly due to progressive fatigue of intracellular respiration organs, mitochondria). Because of this, sirtuins leave the places of permanent dislocation more often and for a longer time, and therefore they monitor the density of histones worse. The consequences are clear: the cells of elderly individuals are beginning to suffer more and more from the activation of unnecessary genes. Such an imbalance of the gene apparatus leads to the aging of the body.
In conclusion, it is worth recalling that the activity of the SIRT1 gene can be increased with the help of certain foods and special preparations. This task is performed by a strong antioxidant resveratrol, which is part of red grapes and red wines. Experiments carried out in different countries have shown that taking resveratrol prolongs the life of various vertebrates – from fish to mammals.
Currently, synthetic compounds that spur SIRT1 hundreds of times stronger than resveratrol are being successfully tested on animals. Hopefully, such substances can slow down the aging process in humans as well.
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28.11.2008