Harmful old ladies

Old cells harm others because of "jumping genes"

Kirill Stasevich, "Science and Life" Based on Nature: De Cecco et al., L1 drives IFN in senescent cells and promotes age-associated inflammation.

Over time, various defects accumulate in our cells – mutations appear in the genes, damaged proteins stop working as they should. The cell does not just cease to perform its functions, it can become a threat to others. Usually, in response to defects and damage, a cellular suicide program should be included: the cell destroys itself, and does it in such a way as to cause as little concern to others as possible. But it often happens otherwise: the suicide program does not work, and the cell continues to age. There is no benefit from it – if, for example, the fibroblast of the skin is in front of us, which should divide, help heal wounds, synthesize connective tissue proteins, etc., then the aged fibroblast no longer divides and cannot heal wounds. But it actively releases a whole set of molecules into the environment, including inflammatory signals, enzymes that break down other proteins, etc. – such a cocktail secreted by a decrepit cell has a bad effect on the surrounding tissue (we once wrote about how old cells harm the brain and that they generally shorten life). The composition of the "cocktail of old age" (which is called SASP – senescence-associated secretory phenotype, the secretory phenotype associated with aging) depends on various factors, changing during the life of an aging cell. However, it is still not entirely clear why, in general, old cells secrete inflammatory signals and other unpleasant substances from themselves. 

Researchers from Brown University and a number of other scientific centers in North America and Europe write in Nature that old cells are preparing their "cocktail of old age" because of "jumping genes", or retrotransposons, awakened in the genome. Jumping genes are called specific sequences in DNA that can copy themselves into new sections of the genome; they are therefore also called mobile genetic elements or "jumping DNA". They may not affect the well-being of the cell in any way if they copy themselves into those DNA zones that do not encode anything. But if a mobile genetic element invades the coding sequence, then the gene will most likely stop working as it should, and the cell may start major troubles.

Retrotransposons are one of the varieties of "jumping genes", and one of the most numerous, they account for about 42% of all DNA; it is believed that they were once retroviruses that were embedded in the genome, and so they remained in it. However, many of them have been inactive for a long time because they have received many mutations. On the other hand, the cell itself keeps under control those retrotransposons that can still cause trouble. There are various mechanisms that allow them to be kept inactive, but it is known that with aging, such sleeping "jumping genes" can wake up.

The authors found that one of the retrotransposons called LINE-1 becomes extremely active in old fibroblasts. We said that aging cells stop dividing. In fibroblasts that stopped dividing, the "jumping gene" LINE-1 woke up after 16 weeks, that is, it was already quite late in the aging stage. At this stage, there are two inflammatory proteins in the protein "senile cocktail", interferon-α and interferon-β. It is known that interferons are needed for antiviral protection: when a foreign – viral – DNA appears in the cytoplasm of a cell, the cell includes a special chain of signals, which includes interferons. The task of the antiviral system is to start apoptosis, a program of cell death, so that the cell digests itself along with the infection.

LINE-1 itself was activated because the ratio of two regulatory proteins that can work with the LINE-1 sequence changed in the cell: one regulatory protein, activating, became more, the other, suppressing, became less. (Both work not only with LINE-1, but also with other sites in DNA, it's just that LINE-1 turned out to be in the black because the proportion of these regulators changed in an aging cell.) Enzymes synthesizing RNA made a lot of RNA copies with LINE-1, and then, like any retrotransposon his RNA was transformed into DNA, then to be embedded in new places in the genome. But the cell felt that it had a lot of suspicious DNA in the cytoplasm outside the cell nucleus, and reacted to it like a virus – that is, it turned on interferon signals. If the cell were normal, it would also have a lot of a special enzyme that breaks down such extraneous DNA. But aging fibroblasts have very little of this enzyme, DNA with LINE-1 continued to accumulate in the cytoplasm, and the alarming interferon signal was getting stronger and stronger, stimulating other inflammatory molecules. If the activity of retrotransposon in old cells was somehow suppressed, then interferon signals were silent, and concomitant inflammatory molecules did not appear.

Experiments on mice have shown that if they suppress the activity of LINE-1 with an antiretroviral drug, the old cells will cook less of their unpleasant "cocktail". What is especially important, such animals turned out to be healthier in old age, without characteristic age-related problems: their muscles degraded less, their kidneys worked better, and the general inflammation was not so pronounced.

But all this applied to cells precisely at the late stage of aging. Even if the cells tried to suppress the activity of the "jumping gene" LINE-1 from the very beginning, they still began to age, with the difference that late old age turned out to be less inflammatory and healthier. That is, that protein "senile cocktail" really arose because of LINE-1, but LINE-1 itself, obviously, was showered as a result of some other processes that began at earlier stages.

One can imagine that with the help of certain drugs we make the aging of cells healthier and thereby protect ourselves from various age-related diseases. Moreover, it seems that such drugs can serve as antiretroviral drugs, which have long been in use in clinical medicine. On the other hand, there is an alternative – just kill the old cells. Both methods have pros and cons that need to be carefully evaluated and compared before proceeding to their direct use.

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