Epigenetics and age
The work of the epigenetic clock
Sergey Kiselyov, XX2 century
Epigenetics is the interface that exists between the genetic code, which is a text, and the environment. If we open a book and see many letters that merge into one long page, we will not understand anything. And epigenetics is a kind of "punctuation marks" that make certain combinations of letters meaningful.
DNA methylation
The most well–known epigenetic mechanism is methylation of individual nucleotides of the genetic text, namely cytosine. The conformation of the nucleotide changes. Such methylation of the base can prevent the binding of transcription factors directly to DNA, thereby interfering with the operation of the gene. Or, on the contrary, the absence of methylation contributes to the work of a particular gene. It is because of this that our body is so diverse: the genome in all cells is the same, but the "punctuation marks" in each of them are arranged differently, so the genetic text can be expressed, for example, as hair or as blood, and so on. In blood, DNA methylation has a certain pattern, that is, the number of methyl groups and how they are located on DNA strands, and in skin cells, the DNA methylation pattern will be different. Hence such a variety of tissues, which gives one genome.
The genomes of identical twins are identical. Moreover, when twins are born, the methylation of their DNA is also exactly the same. But the longer they live, the more the reading of their genetic texts diverges, and with age, the pattern of DNA methylation even in identical twins changes.
Determining the age of a person
If the DNA methylation pattern changes, then maybe it has something to do with age? In the early 2000s, a number of studies were conducted that tried to find a link between DNA methylation and human age. In the first work, buccal (buccal) epithelial cells were taken and the DNA methylation pattern was looked at: how many methylated bases exist and how the distribution of methyl groups in DNA changes during life. It turned out that it changes in a certain way, and sections of DNA are preserved either methylated, that is, they have "punctuation marks", or unmethylated. And that changes with age. It turned out to be quite simple to accurately predict the age of a particular individual by the presence of these sites.
Some time later, another group of scientists conducted a study: although the cells of the mucous membrane are different from blood cells, but there, in the blood, they also found certain areas of DNA methylation, which can be used to determine a person's age. A few years later, a work was published that combined the results of previous studies: Steve Horvath studied various human tissues and cell lines that can also age in culture. 353 DNA sites were found in different tissues and cell lines, which were methylated in a certain way with age. By methylation of these DNA sites in the genome, the age can be determined with an accuracy of 3-4 years.
Thus, if we found the remains of a certain person and his DNA was preserved, then thanks to the analysis of DNA methylation, we can find out what age the person was when he died. In addition, it can also talk about the relative age of different people. For example, there was no fundamental difference in the sites and the rate of aging for different populations, nations, groups of people, but there was a difference in the rate of aging between men and women: men's age was less in DNA methylation than women's.
However, women suffer from another ailment: breast cells age faster than other tissues. Most likely, this is due to the reproductive function. When secretory cells are formed, they must be constantly updated, so accelerated metabolic processes are activated, and aging is probably associated with this. Therefore, breast cancer is more common in women.
Interestingly, only 353 DNA sites indicate the age of a person. To date, they seem rather meaningless, since they are not associated with any specific genes, that is, they reflect a number of independent events, when what is called the epigenetic landscape, in particular DNA methylation, undergoes global changes. The technology of cell reprogramming allows us to get an embryonic cell from a somatic cell, and if we take a somatic cell that has aged along 353 DNA methylation sites, then reprogramming returns this cell to youth – it becomes young and can again go through all the stages of aging along 353 methylation sites, which indicate epigenetic age.
In fact, there are a number of studies conducted on blood cells that also accurately reflect the rate of human aging, although some other marker sites are used for this. This means that the change in DNA methylation is global in nature and, most likely, is not related to the functioning of specific genes, but to general aging.
Epigenetic life expectancy
At the end of 2019, a scientific paper was published in which the DNA methylation of about a hundred different species of vertebrates, including those that live quite a few months, was analyzed. There were also animals that lived for hundreds of years. But it is clear that an animal that lives for so long is often a unique specimen, so the accuracy of predicting life expectancy is not very high.
And it turned out that for a person, the life expectancy predicted by DNA methylation is 38 years – this is his warranty period. There is no difference between men and women, it is about Homo sapiens. In addition, if the DNA of extinct species is preserved, we can also analyze its methylation. And the life expectancy of a Neanderthal predicted by DNA methylation was 37.5 years. This means that the increase in human life expectancy to 70 years or more, which we observe today, has not been reflected in the history of man as a biological species. The life expectancy of both Neanderthals and Homo sapiens was quite short and did not exceed 38 years, which are necessary for reproduction and feeding of offspring. And so far, even for us, the predicted age remains the same.
When will there be changes in our epigenome that will give a longer warranty period? This question is difficult to answer, because today a person isolates his epigenome from environmental conditions. Rather, environmental conditions have fundamentally changed: there was a floor, a ceiling, batteries, phones that we use, and maybe they also contribute something to our epigenome. But only a few decades have passed, and this is extremely small compared to the period of 50-100 thousand years during which the human epigenome was formed. This epigenome makes us a man of today, looking to the future, who wants to somehow change his epigenome and thereby extend his warranty period.
About the author: Sergey Kiselyov – Doctor of Biological Sciences, Professor, Head of the Epigenetics Laboratory of the N. I. Vavilov Institute of General Genetics of the Russian Academy of Sciences.
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