Anti-oncogenes, aging and anti-aging: the more we know…
Physiological aging of a cell is a state of irreversible cessation of growth induced by various factors. The effectors of physiological aging of cultured cells are two proteins known for their ability to suppress tumor growth: p16 Ink4a – a cyclin–dependent kinase inhibitor, at a certain concentration blocking the transition of the cell from a resting state to the division phase, and p19 Arf - activator of the "guardian of the genome", the p53 gene, whose protein regulates the transcription of a number of genes, including genes for cell cycle control and cell viability.
In many tissues, the expression level of these proteins increases as the body ages. This fact served as the basis of the theory according to which the induction of the synthesis of these proteins stimulates the physiological aging of cells and the aging of the whole organism. However, proving this hypothesis turned out to be a very difficult task, because transgenic mice that do not have at least one of these genes die of cancer long before the symptoms of age-related pathologies manifest.
Scientists at the Mayo Clinic (Rochester, Minnesota), working under the guidance of Dr. Jan M. van Deursen, proposed to solve this problem by using mutant mice, whose body is characterized by abnormally low levels of the protein BubR1, necessary for normal cell division. In such mice, premature separation of sister chromosomes occurs during mitosis, which leads to premature aging of the body, manifested by many changes in various organs and tissues. This, as well as the fact that as the body ages naturally, many mouse tissues show a significant decrease in the expression of the p16 protein, indicates a possible role of the BubR1 gene in the processes of natural aging. In experiments on mice, the authors demonstrated that in response to the lack of BubR1 protein in certain tissues, the expression of protein products p16 and p19 increases. At the same time, experiments on additionally modified animals that do not have one of the genes (p16 or p19) have shown that p16 protein is an effector of physiological aging of cells and aging of the whole organism, and p19 protein suppresses these processes.
Based on the data obtained, the researchers claim that cellular stress associated with protein deficiency of BubR1 causes an increase in the level of protein p16 and exacerbates the symptoms of premature aging, which indicates the participation of BubR1 in the processes of natural aging. An interesting fact is that in fat and muscle tissues, especially susceptible to p16-associated aging at low levels of BubR1, in the absence of p16, there is an increased number of dividing cells and low expression of proteins-markers of physiological aging. This observation indicates that the role of p16 in the aging process is due to the accumulation of cells unable to divide.
Along with an increase in the level of p16 protein, a lack of BubR1 protein induces an increase in the expression of p19 protein in mouse tissues. However, its inactivation, on the contrary, accelerates the aging process. This contradicts the opinion that the p19 protein is an effector of physiological aging of cell cultures, however, it corresponds to recently published data according to which mice with additional copies of the p19 and p53 genes age more slowly and live much longer than ordinary animals. The muscle and adipose tissue of transgenic animals without the p19 gene contains a large number of non-dividing cells compared to the tissues of animals with the functional p19 gene. The authors believe that the effects of the p19 gene preventing cell aging are at least partially due to the negative regulation of the expression of the p16 gene. This confirms the fact that inactivation of p19 led to an increase in the expression of p16 in skeletal muscles, adipose tissue and eye tissues prone to premature aging and characterized by high levels of p19.
Despite the fact that inactivation of the p16 gene significantly delays the manifestation of certain aging symptoms in transgenic mice with low levels of the BubR1 protein, it does not completely eliminate them. Moreover, inactivation of this gene has virtually no effect on a number of symptoms, which indicates the existence of other aging effectors induced by BubR1 deficiency in addition to p16.
The article by Darren J. Baker et al. "Opposing roles for p16 Ink4a and p19 Arf in senescence and aging caused by BubR1 insufficiency" is published in Nature Cell Biology.