Zero point: the search continues
Signs of rejuvenation were found in mammalian embryos immediately after fertilization
Polina Loseva, N+1
Biologists from Harvard measured the epigenetic age in human and mouse embryos and found that it changes non-linearly during development. Immediately after fertilization, it decreases, that is, the cells become younger. At the same time, they shed the old methyl labels from their DNA and acquire new ones. Then, from about the second week of development in the mouse, the age increases again. It is at this moment, according to researchers, that the aging processes begin in the body. Two articles (the first, the second) devoted to this problem are published on the portal of non-censored bioRxiv preprints.
In biology textbooks, the life and development of a new organism – at least when it comes to animals – is usually counted from the moment of fertilization. But not all scientists agree with this. The zero point of human life can be determined in several ways: for example, by the time of the launch of the embryo's own genes or by the date of the first heartbeat. There is another option: if we assume that life is a movement from the beginning of aging to death, then the beginning of life will coincide with the beginning of aging.
Many gerontologists associate aging with the inevitable biochemical processes in the cell – the accumulation of molecular debris and mutations. From this point of view, aging (and with it life) should begin from the moment of fertilization – when a new cell is formed, which begins to accumulate its own defects. However, biologist Vadim Gladyshev from Harvard Medical School suggested that the body can pass the zero point of aging later. Since the germ cells of an adult organism participate in fertilization, they must bear the signs of its age, which must somehow be erased so that the embryo begins to develop from scratch. Therefore, after fertilization, rejuvenation processes should be started, which lead the embryo to its zero point.
The concept of "zero point of aging" (V. N. Gladyshev / Trends in Mol Med, 2020)
However, finding out where this point is is also not easy – because aging has many signs, definitions and criteria. You can, for example, measure it by the dynamics of mortality: if organisms in a population die more often at some point in their lives than in the previous one, then they have aged. But, at least with mammalian embryos, this criterion is very difficult to apply. Firstly, they develop inside the mother's body, where it is difficult to measure mortality. Secondly, in the early stages of development, they die "of old age" so rare that it is almost imperceptible against the background of mortality from developmental abnormalities and severe mutations.
Therefore, Gladyshev's group approached the problem from the other side: they measured the epigenetic age in mammalian embryos. It is evaluated by a set of labels (methyl groups) that appear and disappear on certain DNA sites during the life of the organism and make these sites more or less accessible for reading information. There are many models that "translate" a set of labels in a particular sample into relative age – they are called epigenetic clocks. The researchers used several epigenetic clocks developed by their predecessors, and also created two models of their own: one relies on tags on ribosomal genes in DNA, and the other allows you to calculate the epigenetic age of individual cells.
Using all these models, they examined databases on epigenetic markers in mouse embryos. It turned out that in the first days after fertilization, the epigenetic age of the embryos falls – regardless of what hours it is measured with – and reaches a minimum on the 8th day. But then – at least from the 10th day - it begins to grow again and does not stop doing this until the mouse is born. Thus, it can be assumed that in the first week of development, the mouse embryo becomes younger.
This reduces the biological age of cells in the mouse embryo by the eighth day of development. It was evaluated using an epigenetic clock trained on liver (b) cells or several tissues (Trapp et al. / bioRxiv, 2021)
The researchers measured the overall level of DNA methylation in the cells and noticed that it was minimal on day 4.5. That is, the number of tags on DNA also first falls, and then grows, but its minimum falls three days earlier than the "zero" of the epigenetic age. The authors of the work suggested that this change in methylation just reflects the process of getting rid of the embryo from the parental labels. First, the cell removes many methyl groups from its DNA, and then arranges them anew – and this is the essence of epigenetic rejuvenation.
It turned out to be more difficult to find the tipping point from which aging begins in human embryos – there is not so much data about them. Nevertheless, the researchers noticed that at least from the eighth week of development, the epigenetic age of the embryo is already significantly increasing. And in the culture of embryonic stem cells (which correspond to about a week of development), it is close to zero. This means that the starting point of human aging may lie between the first and eighth weeks of development, or rather, nothing can be confirmed yet. However, the authors of the work suggest that this may be the same stage of development as in mice on day 8 - in humans, it corresponds to the beginning of the third week of embryogenesis.
However, upon closer examination, the picture may be much more complicated. When the researchers were working out the determination of the age of individual cells, they noticed that some cells were out of the general trend. For example, among the liver cells of a 4-month-old mouse, there were both cells with an epigenetic age of 20 months, and quite "young", with an age of about zero. This may mean that every time we determine the "average age" of a tissue, we ignore the microscopic aging and rejuvenation processes that may occur in its individual parts. It can be assumed that the epigenetic age also varies heterogeneously within the embryos. This means that in individual cells, the beginning of aging (and with it the beginning of life) may occur on different days.
Epigenetic age of embryonic fibroblasts (left), young (middle) and old (right) liver cells. The dots correspond to individual cells that stand out from the general age of the tissue. (Trapp et al. / bioRxiv, 2021)
Earlier we wrote about other studies of epigenetic age: for example, that in children with autism spectrum disorders it turns out to be more chronological, and how it was reduced for the first time in an adult. And with the help of epigenetic clocks, biologists have learned to more accurately translate the dog's age into human age.
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