The TAO of Aging
Irreversible cessation of cell growth is known as "physiological aging", and the accumulation of cells that have entered such a state is considered one of the causes of aging of the body. Japanese researchers from Kobe University, working under the guidance of Professor Shinji Kamada, have found that the enzyme D-amino acid oxidase (D-amino acid oxidase, DAO) synthesized in the human body promotes the entry of cells into the phase of physiological aging through the production of reactive oxygen species. Drugs acting on this enzyme are potentially capable of suppressing this process, while inhibiting the mechanisms of aging and the development of age-related diseases.
Maintaining good health in old age is a very urgent problem, especially for countries such as Japan, whose population has been rapidly aging in recent years. The relationship between aging and physiological aging of cells is not completely clear today, but experiments on mouse models have shown that the destruction of cells that have stopped dividing slows down the aging process and prevents the development of diseases associated with it.
Discovered about 80 years ago, the enzyme D-amino acid oxidase catalyzes the oxidative deamination of D-amino acids. In their work, the authors induced the entry of cells into the phase of physiological aging by exposure to cancer cells with low concentrations of an antitumor drug that causes double-stranded DNA breaks of dividing cells. At the same time, they found that the increased expression of D-amino acid oxidase depends on the transcription factor p53, which has a pronounced ability to suppress tumor growth. Increased expression of D-amino acid oxidase was detected in cells whose physiological aging was induced by various influences, which indicates the important role of the enzyme in regulating this process.
D-amino acid oxidase oxidizes D-amino acids to alpha-amino acids, which is accompanied by the synthesis of reactive oxygen species as a by-product of the reaction. The accumulation of these highly reactive molecules is associated with both the aging of the body and the physiological aging of cells, so the researchers drew attention to the relationship between the oxidase of D-amino acids and active oxygen forms in the mechanisms of the entry of cells into the phase of physiological aging.
Knockout of the D-amino acid oxidase gene and suppression of its activity inhibited the entry of cells into the phase of physiological aging and the production of reactive oxygen species. The authors also found that mutant forms of oxidase that do not have enzymatic activity did not contribute to the physiological aging of cells and the production of reactive oxygen species. Based on these observations, they concluded that D-amino acid oxidase contributes to the loss of cells' ability to divide through the production of reactive oxygen species, which are by-products of the enzymatic reaction catalyzed by them.
Activation of the process of physiological aging of cells under the action of D-amino acid oxidase occurred only in cases when anticancer drugs caused double-stranded breaks of DNA molecules. The authors suggested that this is facilitated by a gene whose activity is induced by DNA damage. Further experiments have shown that DNA damage caused by telomere shortening, exposure to anticancer drugs or activation of oncogenes induces transcription of D-amino acid oxidase and genes regulated by the p53 protein, including the SLC52A1 transporter. D-amino acid oxidase is localized inside cellular peroxisomes, however, it has low activity due to an insufficient amount of the flavin-adenine dinucleotide co-enzyme. The SLC52A1 transporter delivers vitamin B2 into the cell, which is converted into flavin-adenine dinucleotide in the intracellular space, an increase in the concentration of which activates D-amino acid oxidase. The reactive oxygen species, which are by-products of its activity, damage cells by oxidizing DNA, proteins and fats, which contributes to their entry into the phase of physiological aging.
As their name implies, reactive oxygen species are very reactive and, according to modern ideas, contribute to the development of diseases such as Alzheimer's disease, Parkinson's disease, cancer and diabetes mellitus, and are also involved in the aging process. However, reactive oxygen species do not only harm the body. In low concentrations, they increase life expectancy, and are also used by the immune system to destroy pathogens of infectious diseases. It is obvious that the excessive production of these reactive molecules has a detrimental effect on the body, in particular, it is believed that reactive oxygen species synthesized under stress lead to the development of diseases and aging. The study revealed the mechanism that triggers the production of reactive oxygen species in situations where the process of physiological aging of cells is induced by stress.
The article by Taiki Nagano et al. d-amino acid oxidase promotes cellular senescence via the production of reactive oxygen species is published in the journal Life Science Alliance.
Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Kobe University: Enzyme that breaks down amino acids may promote aging.