Outsmart aging?

A scientific view of attempts to live forever

ИноСМИ.Ru Kendra Pierre-Louis, The Outline:
The case for defeating deathCan humans outsmart aging?
Here's what the science says. The translation was carried out by the Newochem project

Probably, in scientific circles, the most ardent opponent of death due to old age is Aubrey de Grey, a British biologist with a PhD from Cambridge University and long, long hair that he ties in a ponytail. In his opinion, aging is an unhealthy process – a kind of collection of undesirable side effects of the fact that we live. He draws an analogy between old age and malaria, because the latter also kills a lot of people. If you had the opportunity to cure her, wouldn't you have done it?

"Every day of my success in the fight against aging saves 100 thousand lives. One hundred thousand lives are 30 World Trade Centers," he said in 2014.

A group of qualified scientists studying a significant increase in life expectancy continues to grow: geneticist Craig Venter, who was one of the first to sequence the human genome; biochemist Cynthia Kenyon, who discovered that a mutation in just one gene doubled the worm's lifespan (Kenyon is now vice president of the aging research project at Calico, a subsidiary of Google); biologist Bill Andrews, who led the team that discovered the human gene for telomerase– an enzyme that is considered key in the aging process.

Among their promises are the health of 90–year-olds at the level of 50-year-olds (as stated by the Methuselah Foundation), life up to 150 years (according to Andrews) and the eternal biological age of 25 years (as Gray says).

We have been taught that death is natural and that trying to avoid it is a dream–driven madness. However, these researchers have made real discoveries. They have published their work in highly respected journals and have attracted serious funding. When these scientists declare that it is possible to live longer or even indefinitely, they want to believe.

After all, we have already doubled life expectancy at the beginning of the twentieth century. Who can say with all certainty that we can't do it now, when we know so much about aging? Maybe the idea of preventing death isn't so crazy after all?

What is aging?

Last December, a study at the Salk Institute alarmed the media. Scientists have experimented on mice with progeria, a disease that causes premature aging. The researchers were able to genetically modify the mice so that it was possible to "turn on" four genes associated with aging by exposing the mice to an antibiotic. Mice with progeria lived 30% longer. As it turned out, healthy mice after treatment became younger and recovered faster. "Our study shows that aging does not necessarily have to proceed in one direction," explained the lead researcher.

Every few months, scientists announce another discovery that demonstrates how a very specific set of changes has slowed down some aspects of aging in animals. Of course, each study becomes more informative when it appears as part of a single process of studying aging.

To evaluate the achievements of researchers in the study of this field, it is necessary to understand what "aging" means in a scientific context. In particular, aging refers to the deterioration or destruction of vital body functions associated with time – "the gradual depletion of the integrity of all organ systems," as Dan Belksi, associate professor of medicine at the Department of Geriatrics at Duke University School of Medicine, put it. We know that diseases such as Alzheimer's disease, diabetes, cardiovascular disease and cancer are caused - at least in part – by aging.

As we age, intracellular changes occur in our body that affect not only the heart and lungs, but also the muscles and nervous system. "These changes affect all kinds of systems of our body. And each of these systems individually begins to work a little worse when we get older, and gradually this contributes to the development of dysfunctions that lead to diseases, disability, and eventually death," Belksi concludes.

Now we understand that biological age does not always correspond to chronological age. Imagine twins: one drinks a lot, is malnourished, does not get enough sleep and never exercises, and the other does the opposite. The first of this pair is likely to age earlier, and he will develop aging-related diseases.

What happens to our organs depends on cells, so the biggest breakthrough in our knowledge about aging may have been understanding some of the pathways that affect aging at the cellular level.

The key lies in a process that scientists call signaling – through it, cells communicate with each other to regulate the simplest functions like cell repair or immune response. While errors in cellular signaling can cause autoimmune diseases, diabetes, and cancer, it turns out that modifying signaling pathways can also slow aging, at least in animals.

The researchers identified two age-related signaling pathways: insulin-like growth factor (IGF-1), which is associated with growth and metabolism, and Rapamycin Target, or TOR (Target of Rapamycin), which, in addition to growth, regulates cell movement and replication. The more we delve into the science of rejuvenation, the more often these abbreviations will occur.

It is assumed that if it is possible to slow down the biological clock sufficiently, it is possible to delay the onset of old age and the diseases that come with it. Death fighters like Peter Thiel, Larry Ellison, and Larry Page fund rejuvenation research and believe that such discoveries in combination with medications will turn into a combined solution and prolong life, perhaps forever.

Fasting, gene hacking and other interventions

Today, Cynthia Kenyon directs aging research at Calico. In 1993, she worked at the University of California at San Francisco, where I first thought about the fact that different animals have different life spans. Cynthia began to search for the genetic basis of life expectancy, digging into the genetic code of one of the species of roundworm called C. elegans.

And although in most cases we see parasites in roundworms (for example, in heartworms that live in dogs), C. elegans, according to Kenyon, do not exceed the size of a comma in this sentence and are not parasites. Kenyon chose this view for two reasons. Firstly, their average life expectancy is 2-3 weeks, which makes it easier to measure it. Secondly, an earlier study found a mutated strain of C. elegans, which for some mysterious reason lived longer than the rest.

Kenyon and a group of researchers in her lab set about changing genes in C. elegans individuals randomly to see if those could make the worms live longer. Over time, they found that damage to a single gene, called daf-2, doubles the lifespan of C. elegans. And the modified worms not only lived longer, but also aged more slowly. The two-week-old modified C. elegans moved faster and was much more agile than its natural counterpart. Kenyon found that it takes two days for a modified worm to age as much as a normal worm ages in one day.

The discovery was not limited to the worm C. elegans. When the researchers modified a similar gene in flies and mice, they also lived longer. The most interesting thing is that in worms, the daf-2 gene modifies the hormone receptor, which is very similar to the human IGF-1 receptor. Centenarians who have been able to live 100 years or longer are more likely than those who die earlier to have mutations that reduce the activity of IGF-1 receptors.

At the same time, similar yeast studies have shown that if the TOR signaling pathways are genetically altered to limit communication, yeast also lives longer. In general, the study suggests that if we find ways to stop all these signal transmissions, there is a chance to slow down aging.

Genetic modification of humans presents a number of ethical and practical problems, so most of the immediate focus of rejuvenation science is aimed at taming the TOR and IGF-1 signaling pathways without gene changes.

One of the ways to suppress the signal of TOR paths you won't like if you like to eat. Studies have shown that mice fed 65% less lived 60% longer. Fortunately, scientists have discovered other ways to intervene that work similarly. Rapamycin, a drug used against rejection during kidney transplantation, increased the lifespan of mice by 14%; a low dose of aspirin prolonged the life of the worm by 23%.

The authors of the rejuvenation theory are enthusiastic about chemical interventions, including the use of vitamin D, metformin and acarbose, which function in the IGF pathway discovered thanks to Kenyon's experiments. Vitamin D extended the life of worms by 31%, and metformin and acarbose, created for the treatment of type II diabetes, extended the life of mice by 5%. A separate British study found that diabetic patients treated with metformin lived longer than non-diabetic patients, although they should have died on average 8 years earlier. If the drug treated their diabetes, then they should have died at about the same age as healthy people, and not live longer than them.

A national clinical trial called "Metformin Aging Treatment", or TAME (Targeting Aging with Metformin), which aims to test the anti–aging effects of metformin on humans, has received approval from the FDA. "We want to show that delaying aging is also the best way to delay the disease," Dr. Nir Barzilai, one of the researchers in the project, explains to Nature magazine.

There is another strategy that does not affect the signaling pathways.

If you've ever wondered why it seems that children have energy just over the edge, while you barely live to the end of the working day, at least part of the difference lies in the mitochondria. Their mitochondria – cellular power plants – are more productive than yours. As we get older, for reasons that are not entirely clear, mitochondria stop working as well, causing changes that slowly accumulate at the organ level.

In the last few years, sirtuins, types of proteins that control the host of cellular processes, including mitochondrial processes associated with aging, have come to the fore. And although the role of sirtuins is still ambiguous, researchers have found that feeding sirtuins to the body can not only slow down aging, but also reverse it. Mice fed with sirtuin activators lived 16-20% longer. This year, the first clinical trial of nicotinamide mononucleotide (NMD) was launched in Japan.

All of the above: lifestyle, medical and genetic interventions – allowed earthworms to live 10 times longer, and mice – by 15-20%. This does not mean that any of these interventions will work on humans, but it gives scientists a starting point.

"Ten years ago, it would have been difficult for us to come up with anything other than physical activity and diet. Now we have about 10-15 different interventions that can work," concludes Brian Kennedy, a professor at the Buck Institute for Aging Research, who has been working on the issue for more than 20 years.

Wishful thinking

In theory, if we can find out which of these interventions work better in the human body than the others, and attach some cloned organs instead of the completely worn ones, this will allow us to develop an effective set of measures that, if not end aging, at least significantly slow it down. Unfortunately, today such a prospect is supported more by dreams than by actual science.

The rise and fall of the popularity of resveratrol, an extract most often found in grape plants, is an instructive story.

In many animal studies, resveratrol has been found to prolong the life of yeast by 70 percent and fish by 59 percent. Another study showed that resveratrol improves health and prolongs the life of mice on a high–calorie diet - which apparently explains the French paradox (among the French, a low level of cardiovascular diseases persists, despite a high-fat diet). Well, with him with a cake, everyone thought, let them drink wine. Sales of food supplements with resveratrol soared to $30 million dollars a year.

Unfortunately, the effect on humans has not been confirmed. A 2014 study published on JAMA, which examined the lives of elderly people from the famous Chianti wine region in Italy, showed that people with higher levels of resveratrol do not live any longer. Earlier studies on whether resveratrol can help prevent or treat cancer have yielded mixed results. "Nutritional support with resveratrol in animal cancer modeling led to positive, neutral, as well as negative outcomes, depending on the route of resveratrol administration, dose, tumor type, type and other factors," the authors of the 2014 report write.

One of the problems with aging experiments is that people live too long. A mouse lives for about two years; extending its life by 20 percent extends it by about five months. This is quite easy to learn and repeat under controlled conditions. It is much more difficult to repeat such experiments on humans.

Scientists would have to wait for their patients to die, which, along with their own mortality, becomes a problem. To properly conduct an experiment, it may take generations of scientists to study the life cycle of patients.

Researchers struggling with aging can adapt to work with the elderly, but this will make it impossible to test preventive technologies. At the same time, manipulations with young people pose an ethical problem. Testing, say, gene therapy on a healthy young person can be potentially risky.

The best solution would be to find a way to measure biological aging without having to wait for the patient to really age. To do this, researchers are looking for a marker that would reflect biological age.

There are several promising candidates for this role, for example, telomeres – processes at the ends of chromosomes that shorten as we age. Scientists are also looking for an epigenetic methylation clock. Our DNA or genes are basically unchanged, but the manifestation of parts of the genes changes over time depending on environmental factors. Epigenetics studies such changes. If genetics were written on a sheet of music, then DNA would be notes, and epigenetics would be a set of instructions – clock size, tempo – that would tell us how to play these notes. Epigenetic changes are made through methylation, or the addition of methyl groups to nuclear DNA, but as we age, DNA methylation slows down. The epigenetic methylation clock will help correlate what we know about methylation and epigenetics and compare it with biological age.

Among other potentially promising timers, there are profiles of inflammatory cytokines that characterize the properties of cytokines, proteins included in the cell signaling system that are associated with metabolic markers and markers of aging. They are similar to fingerprints that are left behind by cellular processes, such as aging.

Until a suitable metric is found, we won't know what, if any, anti-aging measures will work in humans.

Is death even natural?

Our knowledge about aging is a bit similar to our knowledge about sleep. This is a fundamental sign of life, but we don't know how it works. We see how people age, and we begin to understand how to distinguish the markers of aging, but we do not fully understand why we are aging. Is human aging a bug or a feature?

This year , scientists from Albert Einstein University has published a study based on existing data on the course of life. His conclusion is that the natural life cycle lasts about 115 years. Although most of us live to 70, the number of those who have lived to 100 is incredibly small. "We wanted to see what progress we had made or not made in terms of human longevity," wrote Brandon Millholland, lead author of the study.

The reason, according to the researchers, is not that death is the ultimate goal, but rather that aging is a byproduct of the genetic codes that outline our life – development, birth, growth, reproduction. The codes that give us life have imperfections that lead to death. And although scientists may try to extend life beyond natural limits, we will still end up being limited by them – as if we were trying to build a skyscraper on the foundation of a country house. It's not that no one can live longer than 115 – Millholland says that an average of one in ten thousand lives to 125 – it's just statistically incredible.

It may seem that this does not correspond to the history of mankind. The life expectancy of Americans has increased from 47 years at the beginning of the twentieth century to 78.7 years today, which is why it can be assumed that the cycle of human life changes easily. However, this is not the case. The increase in life expectancy, which is the average value of all life cycles, is largely due to a decrease in child mortality, since public health, hygiene and medicine have sharply reduced the number of children who did not live to their fifth birthday. People who lived to adulthood could well live up to 40, 50 or even 60 years, and sometimes longer. Thomas Jefferson died at 83, Ben Franklin at 84, and John Adams lived to 90. Jeanne Louise Calman from France, who died at 122, and who holds the record for the longest confirmed life span, was born in 1875. "Her record probably won't be broken for a very long time," Millholland said.

Meanwhile, doubling life expectancy is not enough for the growing anti-aging lobby. They are attracted to eternal life – longer than a 4000-year-old black coral or a 2000-year-old sponge, or a Cream pie, a 38-year-old cat. At the moment, there has not been a single study on the creation of an eternal organism, there are also no such studies found in the wild. The only ever-living living being known to man is a cancer cell, but it kills its host.

Most researchers of aging are not doing their job because they strive for eternal life. Kennedy first began observing yeast out of pure scientific curiosity, and continued his research after he realized that aging is the main risk factor for many chronic diseases. Belsky's work focuses on health inequality – in particular, on why people with low earnings are more likely to suffer from chronic diseases. One of the reasons: their so-called "biological aging" is going faster than the rest.

None of the gerontologists I talked to talked about eternal life – they are closer to slowing down aging and improving health. Even de Grey doesn't like the phrase "eternal life" – he calls it "religious".

There is one famous quote that is usually attributed to Ralph Waldo Emerson: "Why eternity to someone who does not know how to spend half an hour usefully?" For most of us, the goal is not in life expectancy, but in its quality. And if all this increased attention to eternal life leads to the financing of the right research, our life may eventually become longer and our health stronger.

Portal "Eternal youth" http://vechnayamolodost.ru  25.04.2017