“Counterclockwise”: how biologists are trying to find a pill for old age

Scientists have been looking for a cure for old age for more than a hundred years. We have learned how to prolong the life of animals, but with humans, everything turned out to be much more complicated. The scientific community has not agreed on what old age is. How to determine that it has already come: by age, mutations or diseases? Who is to blame for the fact that youth is not eternal? In her book Counterclockwise: What is Aging and How to Fight It, biologist and science journalist Polina Loseva tells how modern gerontologists and supporters of the “alternative approach” are trying to create a pill for old age.

Detour road: is it possible to speed up science

In early childhood, like all children, I really liked to dig and find treasures. I still love to dig, but that’s a completely different story. And then I strove to find them again and again and dreamed of becoming an archaeologist. But, being a well-read child, I already understood then that archeology is not limited to just working with a shovel. And so I asked my father if it was possible for me to become an archaeologist, not loving history – because I was not at all interested in reading about generals who went east, and then west, and then east again. My father shook his head sadly in response, and I did not become an archaeologist.

In gerontology, as in any field of science, there are those who love history and those who are only interested in digging. There are those who are trying to understand the mechanisms of aging and build the chain of events that underlies it, and those who immediately run to try one drug after another on mice, and in some cases right on themselves. After all, if you do not spend time studying the “materiel”, but only engage in excavations, then you can dig much more treasures in a short time, that is, extend and save many lives. Adherents of this second approach blame basic science for being slow and claim that they will be able to develop a cure for old age themselves in the near future, using only the “excavation method”.

Sometimes their “alternative” experiments really turn out to be faster than classical ones. But how to interpret the results they obtained is far from always clear – just as it is difficult to date a fragment of an ancient vessel and determine which civilization it belonged to if you do not know where and how it was unearthed.

Riot on the ship

We have already talked about some of the internal problems of gerontology in previous chapters: there are difficulties with the definition of aging, it takes a long time to study centenarians, and it is difficult to conduct a correct experiment on humans. And therefore, no matter how much I want to defend fundamental science, it is impossible not to admit: the search for cures for human old age has not yet led to any unambiguous success. There are animals that we have been able to extend the life of: mice – twice (3,9 years versus the usual two years), flies – four times, and the roundworm C. elegans – as much as ten. Nevertheless, in no case we are talking about the abolition of aging completely, and there is nothing to brag about with people yet.

And although gerontology is relatively young compared to physiology or medicine – for example, the US National Institute on Aging was founded only 55 years ago – there are those who are ready to demand more impressive results from this field of science.

The main fighter against classical gerontology was Aubrey de Grey, a scientist from Cambridge. He began his career as a mathematician, but at the age of 30 he retrained as a biologist. He immediately became interested in aging and received his doctorate for a book on the role of free radicals and mitochondria in aging (more about them in the chapter “Stress is to blame”), but later became disillusioned with basic research and moved to the other side of the barricades. Now, in his diatribes, de Gray accuses his former colleagues of deliberately holding back progress by arguing about theories of aging, instead of devoting all their energies to finding a cure.

Another root of this problem, according to de Grey, is “at the top”, where the people who allocate funds for research sit. Investors want easy and fast results. They can be impressed with specific stories – their relatives and friends who have suffered from age-related diseases. Therefore, financing the fight against individual ailments – whether it be cancer or atherosclerosis – is much easier and more profitable than trying to delay aging. The cure for atherosclerosis is very easy to check: the plaques in the vessels either disappear or not, and it takes very little time. But an investor who invests in the struggle for eternal youth is forced to wait as long as the experimenter – at least decades.

In some ways, de Gray is certainly right. Many gerontologists are really afraid to move on to practical research. Here is how, for example, developments are developing in the field of combating Alzheimer’s disease – one of the most mysterious age-related diseases. In late 2018, two gerontologists tried to figure out why many promising Alzheimer’s treatments don’t make it to clinical trials. They called their colleagues with this question, and they answered that they were simply afraid of failure.

Tremendous amounts of money are spent every year fighting the disease (including half of the National Institute on Aging’s annual budget), and journals publish dozens of articles about drug failures. In such a situation, everyone who launches a trial of their drug has a heavy responsibility: on the one hand, to justify the money invested, and on the other, to prevent side effects and deaths. After all, a patient with Alzheimer’s disease can live long enough, and if he dies in the process of testing the drug, the authors of the experiment will have to answer to his relatives, the media and investors. Not everyone is ready to shoulder such a responsibility. It can be assumed that the situation with aging studies in general is similar.

However, de Gray argues that there is still not enough money allocated to search for a cure for old age. In 2019, the budget for the National Institute on Aging was about $2019 billion. By comparison, the United States spent $34,8 billion on the fight against AIDS in 100. At the same time, only one million Americans have AIDS, and old age threatens everyone who can live to see it. De Gray has calculated that about XNUMX people around the world die every day from old age (more precisely, from its accompanying diseases) – and this price, according to him, we pay for every day of delay.

The turtle method

Fundamental science has something to say in its defense: how can you try some drugs on a person if we still have not agreed on how to measure the result? And how can aging be prevented if it is still unknown what causes it?

De Gray, however, proposes to approach the problem from a different, engineering point of view. In his speeches and works, he describes the human body as a complex machine and calls to treat it accordingly. Vintage cars, he says, last much longer than their creators intended, because we replace “aged” parts in them with new ones. It remains to learn how to perform the same manipulations with a person: we will fasten here, touch up there, re-grow worn-out organs, remove accumulated old cells, dissolve extracellular deposits of substances, and so on endlessly.

This approach allows you not to waste time searching for the causes of aging, but go straight to the repair. At the same time, de Gray is confident that aging can be, if not reversed, then postponed, regardless of whether we determine its causes or not. The scientist believes that for success it is enough that people age a little more slowly than the methods of combating aging have developed. If, say, we learn to increase the life of a 70-year-old person by another 25 years, and in 24 years we can invent a way to extend it by another 25, then death will never catch up with us, just as Achilles could not catch up with the tortoise.

De Gray opened the door to gerontology for many who want to fight aging. Among them there are also biologists who have become disillusioned with fundamental science, but most have neither biological nor medical education and come to this area from other specialties, bringing with them alternative views on the problem.

This community is very diverse. It includes, for example, biohackers – people who are trying to experiment on themselves, taking different combinations of drugs, often without a doctor’s prescription, and transhumanists who are working to “improve” a person. Each of them is moving towards immortality in their own way: someone takes medicines that are not fully proven, and someone, for example, tries to create “digital avatars” – their software counterparts, who are supposedly able to live longer than a biological body. In addition to lone experimenters, independent associations of specialists are constantly springing up in the community, collecting together data on the fight against aging and launching their own trials of different methods. In our country, these are, for example, the Science for Life Extension Foundation and the Life Extension Assistance Foundation.

Not all of them share the same views on aging as de Grey. Each current offers its own route, which is worth going to immortality. Nevertheless, they are all united by the desire to find workarounds that will help to overtake fundamental gerontology, leaving it alone with its insoluble difficulties.

Salvation Manifesto

Proponents of the “alternative approach” offer workarounds that they believe will help speed up the path to eternal life:

First, redistribute the money. To restore justice and raise the missing funds for aging research, de Gray founded his own SENS foundation. This acronym reflects his main approach to aging: “strategies of engineered negligible senescence”. It also resembles the English word “sense” – a sense that allows de Gray to endlessly play with words. For example, the title of one of his program articles, “Time to talk SENS”141, sounds ambiguous: both “It’s time to think it over” and “Time to talk about SENS”.

The idea of ​​the SENS Foundation is to shift the focus from theoretical to practical research and distribute funding between projects based only on how far they can bring us closer to discovering a cure for old age. Among the SENS projects, for example, is the Methuselah Mouse Award for a way to maximize the life of a laboratory mouse. This award, in particular, was received by the group of Andrzej Bartke, whose mice lived for 1 days – thanks to a mutation in the growth hormone receptor and a low-calorie diet.

The SENS Foundation exists on private donations. Therefore, de Gray spends a significant part of his time traveling around the world, speaking at conferences and agitating people. Despite this, he believes that there is still not enough money in the science of aging.

Second, join forces. There is an analogue of SENS in our country – this is the Science for Life Extension Foundation by Mikhail Batin. True, he follows a different strategy: not to be particularly distracted by mice, but immediately go to people. With the support of the foundation, the Open Longevity project was born, which is designed to unite the efforts of patients, doctors and gerontologists in search of a way to prolong life.

Open Longevity invites everyone to become participants in a “distributed” clinical trial: take tests for some markers that reflect their state of health, and then test some procedure on themselves, for example, one of the diet options. In the process, they can retake tests, consult doctors and send the results to gerontologists-analysts. Open Longevity simply provides a platform where all participants in an experiment can interact and share data.

Thus, the authors of the project hope to solve the problem of heterogeneity of people. Since we cannot standardize the experimental conditions and put hundreds of identical people in one cage in order to feed them the same food or treat them with the same drugs, we need to experiment on volunteers and collect more data about them. Then it will be possible then to build a model in which to take into account all possible factors, and already against their background to look for the effect of a particular diet or medication. This approach proposes to “drown out” the low quality of the experiment with a large amount of data.

Third, draw up a plan of action. In 2006, in the article “Time to talk about SENS”, de Gray, along with other gerontologists, formulated the main directions in which the science of aging should move. The meaning of the new concept was to leave aside the causes of aging, highlight its main features for the human body and develop a separate weapon against each of them. In other words, scientists tried to compile a list of the main problems in the human body that need to be repaired or replaced. In total, nine “targets” were designated:

For each of them, the authors of the article proposed their own repair plan. For example, they were going to restore the immune system with the help of the signaling substance interleukin-7, and planned to make up for the deficiency of cells in tissues by introducing new stem cells.

The SENS concept was not widely used, but it set a useful example – it is easier to fight the enemy when all his weak points are known. And seven years later, another program article was published – the fruit of the reflections of academic gerontologists – on which all research on aging is based today. The list of their points of attack on aging largely repeats de Grey’s list and is, in fact, an improved version of it:

In this sense, we can say that the “alternative” approach to aging has significantly pushed the “traditional” science. After all, as soon as a specific list of targets appears, one can begin targeted research, demand a report on each of the points and analyze what exactly this or that approach has given to combat this or that sign of aging. This is done, among other things, by the Life Extension Foundation. He keeps a strict record of how far we have come towards defeating each of the scourges individually, and builds a roadmap for clinical trials. Judging by this map, the situation looks far from hopeless – in the battle with each of the heads of the hydra, we are already gaining the first victories.

At the same time, it is important to remember that clinical trials of a drug do not guarantee its success. In the first phases, researchers only evaluate the safety of the drug or intervention in the body. Therefore, the news that the drug is going through the first phase should be read as “we have an idea what could be done about this sign of aging.” In later phases, life expectancy itself is also not measured – as we have already discussed, everything is not easy with this – but only side effects, for example, what happened to markers of biological age or how the course of individual diseases associated with one or another symptom has changed. So, for example, senolytics that have reached the second phase – drugs to destroy old cells – are used to treat joint pain, pulmonary fibrosis or diabetes, and the effectiveness is evaluated only in relation to these diseases, and not longevity in general.

Fight with words

However, we know that in real life, not a single tortoise ran away from Achilles. And the scientific community has something to counter the optimism of an alternative approach to aging.

Despite the fact that the list of factors that SENS proposes to fight does not differ much from the pillars of aging generally accepted in fundamental science, de Gray’s strategy raises many questions among scientists. Biologists refuse to believe in “engineering” methods and accuse de Grey of trying to skip several important stages of the scientific process at once – putting forward and testing hypotheses about exactly which targets of aging should be aimed at.

And the methods of “twisting” and “tinting” themselves, upon closer examination, do not look like weapons of victory. Interleukin-7, with the help of which de Gray is going to restore immunity, has not yet coped with the task in any living organism. Stem cells, with the help of which it is proposed to replenish the reserves of cells in our bodies, are still practically not used anywhere in this capacity, with rare exceptions. And the cultivation of artificial organs is still at the very beginning of its journey.

At the same time, the results that can be obtained by “cutting corners” are likely to be unacceptable for fundamental science. For example, now the movement of biohackers is growing in the world: they take different combinations of drugs and then tell what effect they have achieved. Even if some of them succeed and live long or even reverse their aging, it will be very difficult to replicate this result. Since each biohacker acts on his own, it is impossible to combine them into one sample and analyze the results, obtaining a statistically significant conclusion. In addition, you can not be sure that their result will be fair. When both the experimenter and the subject are the same person, he may be biased in assessing his own condition, because he is obviously interested in the success of his experiment. This is where the proponents of the alternative approach find themselves in a trap: trying to move forward for the benefit of all of humanity, they generate data that humanity will not be able to use later.

Surprisingly, despite the pronounced confrontation between the two camps, fundamental and “alternative”, there is quite a lot in common between them. They describe aging in a similar way and follow the same path: they make a list of targets, choose weapons against them, and launch clinical trials. Even the arsenal of these weapons is similar. The only difference is in their attitude to the problem: some move gradually, step by step, while others try to immediately jump to the finish line by taking on clinical trials.

But since money is needed for both, real battles unfold between representatives of the camps. In order to gain public attention, proponents of an alternative approach have to criticize their opponents and accuse them of inaction. In response, scientists claim that their opponents are acting in unscientific ways. In this dispute, the fact is quickly lost that both of them, in their forecasts and developments, are based, in general, on the same basic research. It also fades into the background that no serious success has yet been achieved in any of the other camps – and no one can present the world with test subjects with a reliably extended life.

Ultimately, each camp presents its own version of the “old age pill.” De Gray and his followers suggest using not one, but a dozen or more, and not all of these will be pills in the truest sense of the word: even surgical interventions like cell and organ transplants appear in their plan. Fundamental science seeks to find the cause and cut it at the root – which means that its plans are not to find a lot of pills for repair, but a small number of drugs to prevent these breakdowns.

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