Who survives, he lives to old age
Mice with one of the variants of the p53 protein live longer, but are more likely to get cancer
Polina Loseva, "Elements"
Fig.1. A model of the p53 protein (shown in red and yellow) encircling a DNA strand (blue-green double helix). Image from the website pdb101.rcsb.org
The p53 protein is known as the "guardian of the genome". It is activated in case of DNA damage and other critical conditions of the cell, blocks its division and starts the apoptosis program. Thus, p53 prevents the tumor transformation of cells, and mutations and disturbances in its work lead to the appearance of tumors. This protein occurs in humans in two variants, which differ from each other in the strength of binding to DNA and, as a result, the ability to regulate intracellular processes. It turned out that mice with a "weaker" version of the p53 protein are more likely to get cancer, but they live longer than mice with a "stronger" version of it: "but those who survive live to old age." Apparently, we don't know everything about the functions of this protein.
Each cell of a multicellular organism faces not only the task of performing its functions, but also – which is sometimes more important – not to harm the body as a whole. The greatest harm that a cell can bring is tumor transformation and uncontrolled division. Transformed cells compete with healthy cells for resources (nutrients, body space) and almost always win and continue to divide, as they are insensitive to signals from outside. Therefore, cell cycle control systems are needed that will be sensitive to changes within the cell. Errors in DNA, incorrect divergence of chromosomes during division, accumulation of damaged proteins – all this signals that something is wrong with the cell. No matter what causes these problems, the main thing is to prevent such a cell from multiplying.
One of the main "controllers" of the cell cycle is the p53 protein (see: On the way to a detailed catalog of cancer genes, "Elements", 06.04.2015). It works as a transcription factor: it binds to DNA, affecting the work of different genes: it suppresses genes that stimulate cell division, and activates genes that inhibit division. It is to p53 that all signals about what is happening inside the cell are pulled together through different intermediary molecules. Depending on the amount of activated p53 in the cell, it either divides (if there is little of it), or does not divide (if there is a lot of it), or dies by apoptosis (if there is a lot).
Mutations in the TP53 gene encoding the p53 protein often lead to the development of cancer (Hollstein et al., 1991. p53 mutations in human cancers). In this case, the protein can not only break down, but also turn into an oncogene, that is, stimulate uncontrolled cell division (see: The main fighter against tumors, the TR53 gene can turn into an oncogene, "Elements", 11.11.2015).
The problem of oncogenesis is closely related to the problem of aging. On the one hand, cancer is an age–related disease, its frequency and severity increase with age. This means that the fight against cancer helps to increase the average duration and quality of life of older people. On the other hand, there are hypotheses that aging protects us from cancer (de Magalhães, Passos, 2018. Stress, cell senescence and organizational aging), so as soon as we learn to cope with aging, it attacks us with renewed vigor. And this is logical: with age, cells in the body divide less often and renew worse; if we allow them to divide, the frequency of tumor transformations will increase. It turns out that these two problems need to be solved simultaneously. And here the question arises: what role does the main protein of antitumor control, p53, play in aging?
In addition to mutations, p53 protein polymorphisms occur in humans. These are allelic variants that differ by one nucleotide in the TR53 gene. As a result, the 72nd amino acid in the protein turns out to be either arginine (R72 allele) or proline (P72 allele). This tiny difference affects the activity of the protein: the P72 variant binds worse to DNA and, consequently, regulates gene transcription less. It is still not clear whether the difference in the 72nd amino acid really affects the risk of developing tumors. Although some researchers note that carriers of the P72 allele are more likely to develop cancer. But at the same time, P72 is more often found in centenarians (Van Heemst et al., 2005. Variation in the human TP53 gene affects old age survival and cancer mortality). This suggests that the p53 protein plays a dual role in our lives.
Mice also collected a lot of statistics on the work of the p53 protein. Previously, scientists have tried to permanently increase its activity in cells: normally, the protein is activated by special signals, and in an experiment, you can make it active all the time. At the same time, the mice became more resistant to cancer, but they aged faster. You can do it in another way: add an additional copy of the TR53 gene to the cell. Then the protein will be activated by a signal, but there will be more of it in the cell. Mice with this modification do not get cancer and do not age. However, both of these models do not recreate the real conditions in which p53 works in the body.
Therefore, a group of scientists from Rutgers University (USA) and Zhejiang University (China), whose article was published recently in the journal eLife, used a line of Hupki mice (humanized p53 knock-in), which instead of the mouse gene TP53 has a human version of this gene (as they were derived, you can read here: Luo et al., 2001. Knock-in mice with a chimeric human/murine p53 gene develop normally and show wild-type p53 responses to DNA damaging agents: a new biomedical research tool). These mice were of two types: with alleles P72 and R72. The authors of the article crossed these mice with mice of two laboratory lines (C57BL/6J and 129SVsl). These lines are far apart from each other genetically, so they are often used to test the independence of experimental results from a combination of genes. The result was four types of mice, and all these mice were monitored to determine what their survival rate (the dependence of the number of live mice on time) and mortality, as well as the level and rate of aging.
Fig. 2. Survival graphs for mice of the 129SVsl line (here and in other figures, data on only one line of mice are given; data on the second line is in the article under discussion, they are similar). The black lines are mice with the R72 allele, the red lines are mice with the P72 allele. On the horizontal axis – the lifetime of mice (in days), on the vertical axis – the percentage of surviving mice. To the right of each graph, the number of mice in the sample and the median life expectancy are indicated. A – overall survival, B – survival among mice that did not die of cancer, C – survival among mice that died of cancer, D – survival among mice older than 18 months (by human standards – about 60 years). An image from the article under discussion in eLife.
Mice with the P72 allele (which works worse), as expected, were more likely to die from cancer. However, in all other respects they turned out to be "stronger": both the overall survival rate, and the average life expectancy, and survival among centenarians were higher. And mortality from other diseases is lower (Fig. 2).
Fig. 3. Bone condition as a sign of aging in mice. The results are given for line 129SVsl. A is a tomogram of the mouse skeleton, yellow indicates lordokyphosis. B is the measured angle of lordokyphosis at 6 and 18 months, the blue bars are mice with the R72 allele, the red ones are with P72. C is a tomogram of the skull of mice aged 6 and 18 months. An image from the article under discussion in eLife.
The aging rate was assessed by several parameters: according to the curvature of the cervical spine (lordokyphosis), according to bone density (the lower it is, the stronger osteoporosis, another violation of the bone structure accompanying aging, Fig. 3), by the thickness of the dermis and subcutaneous fat, which thin out over time, and, finally, by the rate of wound healing, which indicates the presence or absence of a stock of stem cells for regeneration (Fig. 4). All these parameters were measured in mice aged 6 and 18 (sometimes even 12) months. And on all points, the P72 mice overtook the R72 mice. This allows us to conclude that the aging of their body has been slowed down.
Fig. 4. Skin thickness and wound healing as a sign of aging in mice. The results are given for line 129SVsl. A – stained histological preparations of the skin (e – epidermis, d – dermis, a – adipose tissue, m – connective tissue under the skin), B – thickness of the dermis in micrometers, C – thickness of adipose tissue in micrometers, D – ability to heal wounds (as a percentage of the wound area). The blue bars are mice with the R72 allele, the red ones are with P72. An image from the article under discussion in eLife.
The state of stem cells can be assessed by the number of dividing blood stem cells. And here the carriers of the P72 allele were the winners. However, only in relative terms: with age, the number of dividing stem cells in them also decreased, but not as sharply as in carriers of the R72 allele (Fig. 5).
Fig. 5. Dividing stem cells in the blood of mice. D – mice of the 129SVsl line, E – mice of the C57BL/6J line. The blue bars are mice with the R72 allele, the red ones are with P72. On the vertical axis – the percentage of cells with markers characteristic of dividing stem cells. An image from the article under discussion in eLife.
To determine the regenerative abilities of the cells, the researchers irradiated other mice, killing all their blood stem cells, and then planted stem cells of the studied mice to them. With age, stem cells lost their ability to restore blood, but this only happened in mice with the R72 allele! In carriers of the P72 allele, the differences were insignificant (Fig. 6).
Fig. 6. Restoration of blood by the cells of the studied mice. On the vertical axis is the percentage of blood cells obtained from donor mice. On the horizontal axis – the age of the donor mouse. The blue bars are mice with the R72 allele, the red ones are with P72. An image from the article under discussion in eLife.
As a result of a detailed study of mice, it became clear that the difference between carriers of well-functioning and poorly functioning versions of the p53 protein is not limited to the likelihood of developing cancer. Changes somehow affect all organ systems and lead to delayed aging of the body. All these changes are associated with the renewal of the cellular composition. Apparently, the P72 allele, which allows excessive cell division, also contributes to "useful" division, which renews the body's resources. And the R72 allele, which prevents deviations from the norm, reduces the ability of tissues to regenerate. Thus, the p53 protein turns out to be a cog that holds the scales together, on one side of which is protection against aging, and on the other – protection against cancer. This could serve as a confirmation of the theory of pleiotropic antagonism (see Blagosklonny, 2010. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program), according to which the mechanisms that ensure survival in the reproductive period produce the opposite effect in old age: if it is more important for a young organism not to die from a tumor than to conserve resources, then resources are more critical for the old, and they are no longer there. Therefore, the activity of the p53 protein in youth negatively affects survival in old age.
Finally, the very fact that there are two allelic variants in the human population, P72 and R72, suggests that each of them must be valuable in some way, since it is not eliminated under the influence of natural selection. Another option is also possible: the p53 protein has some other functions that we don't know anything about, and it is their P72 allele that performs more successfully.
Source: Zhao et al., A polymorphism in the tumor suppressor p53 affects aging and longevity in mouse models // eLife. 2018.
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