The mechanisms of aging are combined into a single biochemical pathway
The main molecular cause of deterioration of health in old age has been found
LifeSciencesToday based on the materials of the Harvard Gazette: The ‘core pathway’ of aging
Scientists of the Dana-Farber Cancer Institute, a branch of Harvard University, believe that they have managed to establish the main molecular cause of several diseases associated with old age, including energy withering, weakening of the functions of the heart and other organs and metabolic disorders such as diabetes.
"What we have found is a new aging pathway linking several age–related biological processes previously considered independent of each other," says Ronald A. DePinho, senior author of the article "Telomere dysfunction induces metabolic and mitochondrial compromise", published in the online edition of the journal Nature. The first author of the article, Ergun Sahin, is an employee of the de Pinho laboratory and a lecturer at Harvard Medical School.
Professor de Pinho of Harvard Medical School believes that, despite the fact that the studies were conducted on mice, "the results are most directly related to human aging, since this main pathway can be directly linked to almost all known genes involved in the aging process, as well as with targeted treatments currently available, aimed at to mitigate the effects of aging on health."
Scientists have found that the main cause of aging–related deterioration of health is failures in the work of telomeres - the end sections of chromosomes that protect against DNA damage. As the cell reaches a predetermined limit of divisions, telomeres shorten and wear out, making the ends of chromosomes vulnerable to accelerating and irreversible damage to their DNA.
Faced with an ever-increasing amount of DNA damage, cells activate the p53 gene, which sounds like an alarm signal and slows down their normal growth and division cycle, ordering them to stop until the damage is eliminated, or, if this does not happen, self-destruct.
Previously, scientists have already linked such an emergency stop and cell death with age-related damage to organs, whose cells quickly divide and rejuvenate thanks to the reserves of adult stem cells. Such tissues include, among others, the skin, the intestinal mucosa, as well as blood cells, which create trillions of new cells for every day of life.
However, the question remained unanswered about how cells with fewer divisions, such as in the heart or in the liver, maintain an equivalent level of aging. Scientists felt that if they could solve this mystery, they could take a fresh look at how DNA damage can lead to age-related deterioration of all organs.
New data show that telomere dysfunction and activation of the p53 gene cause a wave of cellular and tissue degeneration, which links telomeres with well-known aging mechanisms associated not just with rapid growth and division. In other words, telomere dysfunction is not the only culprit of age-related deterioration of health. According to de Pinho and his colleagues, this is a "thief in law".
In January 2011, in the journal Nature, de Pinho published a study in which he demonstrated the possibility of reversing the symptoms of extreme aging in mice by increasing the level of telomerase, an enzyme that supports telomere health. (For a short description of the results obtained, see the article "Telomere restoration restored youth to cells" – VM.)
Telomere dysfunction also causes a number of reactions leading to poor health and a decrease in life expectancy. For example, muscles suffer from the loss of mitochondria, the chemical energy stations of the cell, leading to a decrease in vitality and a decrease in the functions of the heart and other organs. The risk of metabolic disorders, such as diabetes, increases.
In addition, the process weakens the body's antioxidant defense against damaging molecules known as reactive oxygen species, or free radicals, that accumulate with age and under stress. Until now, some researchers consider the extinction of mitochondria or the accumulation of free radicals to be the main causes of age-related diseases. The new work combines these seemingly disparate mechanisms into a unified theory of aging.
Scientists have concluded that telomere dysfunction causes this wave of metabolic disorders and organ failure, because the activation of the p53 gene suppresses the functions of the two main regulators of metabolism – the PGC1-alpha (PGC1-alpha) and PGC1-beta (PGC1-beta) genes. Suppression of the functions of these regulators reduces the activity of metabolic processes necessary to provide the body with energy and counter stress. In experiments on mice, scientists have shown that turning off p53 activated the PGC1-alpha and PGC1-beta genes.
"This is the first study that directly links telomere dysfunction to mitochondrial regulators and antioxidant protection via the p53 gene," says de Pinho. "The discovery of this new way of aging brings together many ideas expressed by people and gives us a deeper understanding of the aging process."
Combining several major aging pathways under the umbrella of telomere dysfunction, he notes, these discoveries may provide new targets for therapy. These mechanisms may also underlie the relatively sudden and rapid extinction of the organism leading to the end of life.
"We think that telomere dysfunction, which weakens the protection against free radicals, or reactive oxygen species," says de Pinho, "exposes telomeres to accelerated rates of damage that cannot be repaired, thereby leading to even greater deterioration of the organs. In fact, it sets in motion a spiral of death."
Portal "Eternal youth" http://vechnayamolodost.ru14.02.2011