Everything according to plan

How the Aging Program Theory of the Second Century survives without evidence

Polina Loseva, N+1
For links, see the original article.

The idea that aging is a programmed process, not a random one, has been circulating in scientific circles since the end of the XIX century. For almost a hundred and fifty years, it has not become generally accepted. She did not have any rigorous empirical evidence. And yet they continue to argue about it and look for its confirmation. Why do we spend so much time discussing what we can't prove?

Death in the name of speed

 "Children are our future", "all the best for children" and other slogans appeal to the conscience of the older generation for a reason: in the conflict of fathers and children, fathers will always be stronger. They have experience and immunity behind them, even if we are not talking about a person with his complex social structure. Conditioned reflexes and immunological memory accumulated over many years of life give the older generation such an advantage for survival that the younger one cannot compete with. However, despite their solid odds, fathers always lose. Something else intervenes in the conflict.

The theory of programmed aging suggests that at some point in the body of fathers, the mechanism of dying turns on, which weakens them relative to children. In a population where individuals would not lose vitality and fertility with age, children would have to wait too long for a niche to be freed for them. To give way to the young, we need an aging program that will take fathers out of the game.

From the point of view of each individual individually, the acquisition of such a program looks crazy – why stop reproducing and start dying if you can produce even more offspring? Nevertheless, according to the adherents of the theory, the aging program works for the benefit of the population as a whole. By accelerating the change of generations, they say, the program accelerates evolution, giving organisms a chance to adapt faster to changing environmental conditions.

This idea is almost 130 years old – zoologist August Weissman was one of the first to voice it in 1891. Since then, a number of arguments have been found against the theory of programmed aging. So, one of its weak links is that the theory relies on group selection, which some scientists consider less significant than individual selection, while others doubt that it exists at all. In addition, it is not very clear what advantages for the population will be at the very beginning of the origin of such a program, because the fittest individuals will die – those who were able to reach old age.

August Weisman

These and many other arguments could be refuted in one fell swoop – by showing who and how exactly this program works. But it turned out to be difficult to do.

Death is voluntary-forced

Ideally, for a convincing proof, it would be necessary to pick up an example of an organism in which the program obviously works, and another that does not have it. There are no problems with the first one. Here is a male brown Australian marsupial mouse dying, barely having time to mate with a female. Pacific salmon does not just die immediately after spawning, but also feeds their bodies to aquatic invertebrates – food for their future children. The hand of evil fate is immediately visible. Traces of the aging program continue to be found in other organisms, for example, in the nematode C.elegans or baker's yeast.

It turned out to be much more difficult with the opposite examples – so far they have not been able to be cited. Living organisms are divided not into those who die and those who live forever, but into those whom the program kills quickly (like salmon or nematodes), and those who die just as inevitably, but slowly. However, in order to prove that this is indeed the case, and the aging program is not a marginal strategy, but a choice that sooner or later any population (and a person, apparently, including) makes, it was necessary to find some universal mechanisms at the heart of this program.

Pacific salmon (female from above, male from below) is one of the possible arguments in favor of the aging program. David Menke / United States Fish and Wildlife Service.

Such a mechanism was invented in 1997 by the Russian academician Vladimir Skulachev and gave him the name phenoptosis (by analogy with apoptosis, programmed cell death). Phenoptosis according to Skulachev is hara–kiri at the level of the whole organism, which consists of many suicides of individual cells. The scientist believes that oxidative stress and free radicals are to blame for everything – they damage intracellular molecules, which pushes cells to suicide.

However, the theory of phenoptosis lacks a concrete embodiment for full plausibility. Where is the "red button" that forces the body to turn on the dying mode? To answer this question, adherents of the theory of programmed aging have been looking for differences between rapidly and slowly dying species for decades, for example, between an ordinary mouse and a naked digger. There were a lot of differences, but which of them serves as the same button has not yet been determined.

Death as a version

For more than a hundred years, the aging program has not had a concrete incarnation. However, her idea has not gone away, and now they write about her even more than before. Some authors believe that this was due to the development of machine translation, thanks to which Western scientists have become more accessible to the work of Russian colleagues, among whom the theory of programmed aging is especially popular. But it's not just that: in the works devoted to aging, the Program begins to take on more and more new forms.

Vladimir Skulachev and his colleagues, after many years of desperate attempts, changed their approach to the problem. Now they claim that the aging program does not consist in the mechanism of dying as such, but in turning off the program of life. In other words, they suggest looking not for a red button that stops life, but for an organism's power cable that stops working. Now their main candidate is a system of protection against oxidative stress, which works worse in elderly organisms than in young ones, and in a mouse – worse than in a naked digger.

Other scientists, desperate to find an old age program, found a youth program instead. A number of modern theories consider aging as a continuation of development: those processes that started at the beginning of an organism's life to allow it to grow and multiply, at the end of life, bring its death closer. The theory of a quasi–program, for example, states directly: aging is a program of youth that no one turned off in time.

(A) Concentration and (B) activity of hexogenase – an enzyme supposedly controlling aging – in the cells of mice of different ages. Vyssokhih et al. / PNAS, 2020.

Those who do not believe in the Program at all consider aging a natural process that no one can control either from the outside or from the inside. Promoting the idea of aging as an inevitable deterioration of the body, they contrast it with the theory of programmed aging – and write about why the Program does not exist.

Anyway, everyone, or almost everyone, is talking about the Program. By 2020, in the Google Scholar search engine for 4 million articles on the query "aging", more than 3.5 million include the word "program". Not all of them, of course, are devoted to the Program – some, for example, describe the results of state programs aimed at studying aging. And yet the lack of evidence for the theory of programmed aging has not made it less popular. The program hides under different guises, and the less we know about it, the more we want to talk about it.

Death as an answer

The theory of programmed aging has a fat plus: it assumes the presence of an answer. Theories of wear suggest accepting the inevitable and do not give recipes for immortality. As Skulachev correctly notes, they are "extremely pessimistic about finding successful medicines." Therefore, the scientist suggests, it would be better to first study all possible ways of manifesting the Program before dismissing this theory for lack of evidence. The program inspires optimism in its supporters, and he lives even when traces of it cannot be found.

Yesterday, an article was published in the journal Science, the authors of which described two possible trajectories of yeast aging. Within the framework of the first, the yeast's nucleolus disintegrated – the region of the nucleus where the ribosome framework, protein synthesis machines, is produced – that is, the cause of aging was DNA damage. In the second, the nucleolus remained intact, but the mitochondria stuck together and failed, depriving the cell of energy. The first strategy from the point of view of longevity turned out to be more advantageous: it allowed the yeast to go through about 50 rounds of division, while as a result of the second, they stopped and died on the 30th.

How the "destinies" of cells following different "aging programs" diverge. Yang Li et al. / Science, 2020.

The researchers found two genes, the expression of which makes it possible to prohibit the cell from aging along the first or second pathway, respectively. And the overexpression of both genes directed the yeast along the third path – they also lasted about 50 rounds of division at most, but the average duration of their "life" (that is, reproduction) became twice as long, and the time between rounds of reproduction was 2-3 times shorter.

And here we have a new branch of conversations about the Program. Desperate to find traces of programmed aging, we try to program it ourselves, switching between life trajectories. The search for the Program has reached the next stage of development: even if it does not exist, it will have to be invented and launched.

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