A cure for old age: how scientists from around the world are trying to regain youth

Rapamycin, widely prescribed to prevent organ rejection after transplantation, increases the lifespan of middle-aged mice by as much as 60%. Drugs called senolytics help older mice stay alert long after their peers die. The diabetes drugs metformin and acarbose, extreme calorie restriction, and about 90 other interventions, one biotechnology investor estimates, are causing mice to live much longer than normal. The newest scheme is to hack the very process of aging by reprogramming old cells into a younger state only in humans. Writes about it National Geographic.

Photo: IStock

"If you are a mouse, you are lucky"

"If you're a mouse, you're in luck because there are many ways to extend your life," says Cynthia Kenyon, a molecular biologist whose breakthrough work decades ago catalyzed what has now become a plethora of research.

What about people? How long can scientists extend our lives? Between 1900 and 2020, human life expectancy more than doubled to 73,4 years. But this remarkable achievement came at a price: a staggering rise in chronic and degenerative diseases. Aging remains the biggest risk factor for cancer, heart disease, Alzheimer's disease, type 2 diabetes, arthritis, lung disease and almost every other serious disease. It's hard to imagine anyone wanting to live that much longer if that means a few more years of weakness.

But if these experiments in mice lead to drugs that address the molecular and biochemical problems that underlie many health problems in old age, or treatments that slow down—or, better yet, prevent—then, then many of us would have reached the age of 80 or 90 without the illnesses and ailments that can make those years a blessing.

Moreover, it will be possible to achieve what is considered the natural maximum human lifespan of 120 to 125 years. Few people come close to this age. In industrialized countries, about one in 6000 reaches the centenary mark, and one in five million survives the centennial milestone. World record holder Jeanne Calment of France died in 1997 at the age of 122 years and 164 days.

Human biology appears to be able to be optimized for longer lifespans. Unimaginable riches await whoever breaks the code. No wonder investors are pouring billions into trying. Google spearheaded spending growth with the launch of Calico Life Sciences in 2013, where Kenyon is vice president of aging research. Over the past few years, investments in the industry have come from tech moguls, cryptocurrency millionaires and, most recently, members of the Saudi royal family. It seems that everyone with money is betting on the next - or, in fact, the first - big discovery on aging.

This work is based on artificial intelligence, big data, cellular reprogramming and an increasingly fine understanding of millions of molecules. Some researchers even talk about "cure" aging.

People have been chasing dreams of eternal youth for centuries. But as recently as 30 years ago, the study of aging and longevity was such a scientific backwater that it was difficult for Cynthia Kenyon to hire young researchers to help with experiments that would open up this area. While working at the University of California, San Francisco, she changed one gene in tiny roundworms known as C.elegans and doubled their lifespan. The mutants also acted younger, gliding briskly under the microscope while their unchanged peers rolled around in clumps.

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Kenyon's startling discovery showed that aging is malleable and controlled by genes, cellular pathways, and biochemical signals.

“All this has moved from a foggy world to a familiar science that everyone understands,” she says. “And anyone could do it.”

However, delaying the death of worms and mice does not mean it will work in humans, too. At some point, senolytics, which kill the damaging cells that accumulate with age, were poised to become the first anti-aging therapy. But one of the first clinical trials, a long-awaited osteoarthritis treatment study, found it was no better than a placebo at reducing swelling or joint pain. Researchers and biotech companies are currently testing senolytics to treat early-onset Alzheimer's disease, long-term COVID-19, chronic kidney disease, frailty in cancer survivors, and a complication of diabetes that can lead to blindness. Clinical trials of other anti-aging compounds are also ongoing. But so far, none of the experimental drugs that have had such a blinding effect on mice have hit the market.

“There are many different approaches,” says Kenyon. We don't know if any of them will work. But maybe they will all work. The good news is that people literally accepted such science as real. They are excited about the possibilities. We just have to try a lot of things."

growth hormone and aging

Walt Crompton, a retired Silicon Valley biomedical engineer, is 69. He has lush white hair, a white beard and a dark vision of growing up.

“Look around you, more and more of your peers are dying with terrible diseases. You have a little pain, suddenly your knee hurts when you run, and blah blah blah. If not one, then the other,” he says.

With this mindset, it's no surprise that Crompton has become obsessed with research into aging and life extension. He read studies on mice. He helped in the longevity lab. He attended conferences where scientists talked about the "signs" of aging, the interconnected ways in which biology goes awry over time.

The protective caps on chromosomes, called telomeres, shorten. The genome becomes unstable and cancer-causing DNA mutations increase. Changes occur in the epigenome, the compounds that attach to DNA and regulate the activity of genes. Some cells become senescent, that is, stop functioning normally, but, like zombies, they do not die and release chemicals that cause inflammation. The disruption occurs in pathways that respond to nutrients, lipids, and cholesterol, disrupting metabolism. And the list goes on. There is no consensus on how these changes affect each other or which ones are most important.

At the conference, Crompton heard a scientist named Gregory Fahey explain his theory that immunological aging can be reversed by targeting the thymus, a small gland in the chest that stimulates the development of disease-fighting T cells. Fahey was looking for volunteers to test his idea that injections of recombinant human growth hormone, a drug that has been used for decades to treat short children, can rejuvenate the thymus gland and lower the body's defenses against disease. Fahey had injected himself with the drug sporadically for eight years, and with his thick dark brown hair and youthful enthusiasm, he looked enviably fit for a guy of retirement age. Crompton signed up.

Fahey, Chief Scientist at California-based Intervene Immune, is well known as a cryobiologist who developed a method for preserving kidneys by injecting them with ethylene glycol and storing them at -135°C (-211°F). He made a splash by rewarming a rabbit's brain in a near-perfect state, raising hope that a way would be found to allow the brains of mammals, including ours, to survive cryopreservation. But Fahey has been obsessed with the thymus for decades, ever since he read a study by scientists who revitalized the immune system of rats by implanting growth hormone-producing cells. He believes that most life-extending drugs in mice will disappoint us, because they "do nothing to keep your immune system from dying out."

Recombinant human growth hormone is not patented, so reusing it to fight aging will not bring financial benefits. Fahey tried to get other scientists interested in conducting clinical trials, but failed.

“I took matters into my own hands and started regenerating my own thymus based on what I could glean from the rat study,” he says.

Because the drug can raise the risk of type 2 diabetes, he added two pills: metformin and dehydroepiandrosterone, or DHEA, a hormone that improves blood sugar regulation.

Both are also considered anti-aging agents and they are commonly used for this purpose. Metformin, which is taken by 150 million people worldwide for diabetes, may reduce the incidence of neurodegenerative diseases and cancer. American scientists plan to conduct a study to find out if it prevents or delays major age-related diseases. But some long-lived scientists don't wait: they take metformin daily.

Crompton says he immediately felt the effects of Fahey's treatments.

“I felt like I could jump over tall buildings in one jump,” he remarked.

He dropped unwanted pounds without dieting. Another participant, 70-year-old Hank Pellissier, said his hair, previously gray, had turned brown.

Tests showed that T-cell production increased with the treatment, thymus fat disappeared, and kidney and prostate health improved. Most strikingly, men have lost an average of two and a half years of biological age, measured by the so-called epigenetic clock. It uses blood to measure chemical changes in DNA that change gene expression and mark the passage of time.

Fahey's study, published in 2019 in the journal Aging Cell, was too small to prove anything and was not placebo controlled. Nevertheless, the experiment offered a tempting suggestion that medical intervention could reduce a person's biological age. Steve Horvath, who developed the epigenetic clock, which is now an indispensable tool in longevity research, was impressed. The 55-year-old geneticist and biostatistician is now participating in a larger trial being run by Fahey.

Fahey, 72, signed up as a guinea pig and resumed hormone injections.

“Unfortunately, the clock is ticking. I have to do my job quickly to save not only everyone else, but also myself,” he says.

Scientists study healthy older adults and track centenarians to find out how they manage to ignore the aging process. Kristen Fortney, a 40-year-old biotech executive with a Ph.D. in medical biophysics, uses big data and computational wizardry to solve a problem. The development of most anti-aging drugs aims to correct what is going wrong; Fortney is trying to figure out what's going right.

“I have always believed that you need to copy what is already working. There are all these human examples of successful aging already… people who live to be a hundred years old and older and their muscles are still working, their brains are still working, so we know that this can be done,” explains Fortney.

Fortney's company, BioAge Labs in Richmond, Calif., analyzes blood and tissue stored in biobanks from Hawaii to Estonia. The samples are linked to electronic medical records, so Fortney and her colleagues are aware of the health implications behind every vial of blood and are looking for biomarkers that distinguish those who have aged well. The machines measure each sample against tens of thousands of variables, including 7000 proteins. Then, using artificial intelligence, the scientists identify possible drug targets and look through the waste heaps of pharmaceutical companies for drugs that were developed for other purposes and proved to be safe, but remained unreleased.

Fortney's team has tested dozens of drug candidates in mice, and two of them are in clinical trials. One targets the immune system and the other targets muscle mass and strength. Because the US Food and Drug Administration (FDA) only approves drugs if they prevent or treat disease, and the agency does not consider aging a disease, studies such as the Fortney trial examine the effect of drugs on aging. condition. But researchers almost always have big ambitions.

For example, Fortney is studying a compound codenamed BGE-117 to treat age-related muscle dysfunction because it acts on pathways involved in tissue regeneration, blood vessel remodeling and other critical processes.

Super Old Diggers

Naked mole rats can live in captivity for over 40 years, which is 10 times longer than the typical age for rodents of their size. Vera Gorbunova and Andrey Seluanov, both biologists at the University of Rochester, study naked mole rats in the hope of stealing their longevity adaptations for us.

“We find something new in every long-lived animal. Crazy stuff!" — рsays Gorbunova.

The mystery of the phenomenal longevity of some animals has led to research around the world. Researchers have survived Arctic storms and seasickness to capture, study, tag and release bowhead sharks, which live to be at least 250 years old, maybe even a few centuries longer. Scientists extracting Quahog clams from the bottom of the sea north of Iceland have pulled out a 507-year-old clam. University of Birmingham biologist João Pedro de Magalhães, looking for clues in DNA, sequenced the genome of the bowhead whale, a 120-pound (000 t) hippopotamus that was considered the champion of longevity among mammals but endangered by pollution and other threats. He also worked with Gorbunova and Seluanov to study the genome of the naked mole rat.

Rodent habitat in Rochester, New York is 90 degrees (+32,2 Celsius), dark and damp, like a burrow. Each colony - a queen, her consorts, and generations of her minions - inhabit their own perspex dwelling. It has wide tubes connecting three large canisters for sleeping, eating and excreting. If naked mole rats don't like food, colony manager Nancy Corson says, "they put it down the toilet."

They look charmingly outgoing when tumbling over each other and huddled together, but they are belligerently territorial. Researcher Rochelle Baffenstein, who once had more than 7500 and now 2000 people in her lab at the University of Illinois at Chicago, has found that old people die no more often than young people.

“Many of them die because they fight,” says Gorbunova. “It doesn’t depend on age.”

Gorbunova has other residents in the lab: Damaraland diggers, as well as Chilean degu rodents (for studying Alzheimer's disease) and African prickly mice, which have almost mythical abilities to regenerate skin and cartilage.

The large freezer is stocked with tissue from squirrels, rabbits, porcupines, beavers, wild mice, bats, and two dozen other species. She receives these specimens from exterminators, hunters, animal rights activists, state guards. She also catches some. And Volfi, the family German Shepherd, from time to time brings carcasses to the threshold of the house.

Bowhead whales have a thousand times more cells than we do, which should dramatically increase the risk of a cancer-causing mutation. But they don't get cancer. Research has shown that they are amazingly effective and accurate in repairing DNA and keeping cells healthy. Gorbunova discovered that other long-lived animals, including naked mole rats, have this superpower.

Bats are so adept at controlling inflammation that they can carry viruses without getting sick, a feat that received worldwide attention after they were suspected of being the source of the pandemic coronavirus.

“We were interested in bats even before COVID-19,” says Gorbunova. Scientists estimate that chronic inflammation, which often progresses with age, is a major factor in more than half of all deaths worldwide.

What about naked diggers? One of their anti-aging wonders is hyaluronan, a sticky sugar secreted by connective tissue. We also manufacture this substance and it is a staple in "anti-aging" skin creams. But Gorbunova and Seluanov found that the naked mole rat version has a different, heavier molecular structure than ours, much more of it, and it doesn't degrade as much as ours, and it's not manufactured in the same way as expensive facial products. Hyaluronan in naked mole rats not only makes their skin elastic enough to squeeze through tight tunnels, but, biologists have found, it also suppresses tumors.

The study of longevity inevitably makes scientists think about their own. After reaching a certain age, many do something to prevent molecular changes. Gorbunova, 51, says she eats seaweed because it activates the protein sirtuin 6, which promotes DNA repair and genomic stability.

Gorbunova does not study people, although we are also considered long-lived animals. We outlive all other primates, and not just because they are more likely to be eaten by lions. Gorbunova believes that within one generation we will have methods of treatment that prolong a person's life by 10-20 years. To go beyond that would require fundamentally changing the human operating system, and it might not be as wild as it sounds.

"I think it's possible," she says.

Cell Reprogramming

In 2006, Shinya Yamanaka, a Japanese stem cell researcher, figured out how to reprogram adult cells and return them to their embryonic state. This discovery revolutionized cell biology and the search for ways to treat human diseases, for which Yamanaka received the Nobel Prize. Now researchers are determined to use a technique called cellular reprogramming, or epigenetic reprogramming, to reverse aging and eradicate its accompanying diseases.

“The implications could be bigger than CRISPR,” says biologist David Sinclair, referring to the transformational gene-editing technology. “This is by far the biggest event since CRISPR in terms of the amount of money and the number of people involved.”

In early 2022, a group of high-profile tech entrepreneurs, including Jeff Bezos, shook up the close-knit world of aging research with the launch of Altos Labs, a $3 billion cell reprogramming venture. Yamanaka became an advisor, and other star scientists were poached from prestigious academic positions.

Such huge investments in technology, which are themselves in their infancy, either epitomize Silicon Valley arrogance or mark a smart bet on the future of medicine.

"People won't invest serious money if the science isn't solid," says Steve Horvath, who recently left UCLA to join Altos.

Yamanaka used four proteins known as transcription factors, which initiate and regulate gene expression, to erase the identity of mature cells, essentially reverting them to their original state. Juan Carlos Izpisua Belmonte, a biologist who studies organ regeneration, wanted to apply this method to aging. He wanted to use the Yamanaka factors to only partially reverse the clock, restoring the youthful resilience of cells while maintaining their identity as well as function.

He and his team at the Salk Institute for Biological Research in La Jolla, California, experimented with mice for several years until they found a protocol that rejuvenated the animals instead of killing them. They used partial reprogramming to prolong the lives of prematurely aged mice and accelerate healing in normal-aged mice. Izpisua Belmonte said at the time that experiments had shown that aging "does not have to be in one direction."

Now, as the scientific director of Altos, he no longer speaks publicly about making aging a two-way street. The company insists that it is not about slowing down aging, but about treating disease. Perhaps the proponents want to distance themselves from a long and dubious history of research, or they are aiming for something that the FDA would approve: treating disease, not aging.

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Sinclair, professor of genetics and co-director of the Paul F. Glenn Center for Biological Research on Aging at Harvard Medical School, is open about his mission to prevent aging, including his own. He founded and invested in more than a dozen technology commercialization companies and longevity molecules. At 53, he takes metformin and sprinkles his breakfast with resveratrol.

“At least once I try what people say,” he says. - I am curious. I like being an experimenter."

The professor lifts weights to keep his hormone levels up — he posted on Instagram that he has high testosterone levels. Sinclair recently switched to a vegan diet.

“It's not as boring as I thought,” says the professor. He closely monitors his biological age with InsideTracker, a company he consults that analyzes 43 biomarkers.

Sinclair modified Yamanaka's formula to eliminate one transcription factor that had been linked to cancer, and then used partial reprogramming in mice to repair damaged optic nerves.

“It was great,” he admits. “But I thought that if this is really a change in age, then we should be able to reverse age-related diseases.”

So he tried it on mice with a glaucoma-like condition and they got their sight back. But they weren't very old, so Sinclair decided to reprogram the cells of old mice suffering from age-related vision loss. A colleague, an ophthalmological researcher, bet him that it wouldn't work.

“And guess what? Sinclair asks. “So it was.”

Since the findings were published in Nature in December 2020, the professor has continued the research and says the benefits appear to be long-term. Meanwhile, he and the researchers in his lab are conducting mind-blowing experiments in which they accelerate the aging of mice by making them wrinkled and lethargic, or accelerate the aging of just one organ or all at once. By turning on aging, they hope to learn how to turn it off.

Sinclair targeted the optic nerve because it's one of the first places to age. Shortly after birth, we lose the ability to regenerate cells there. He believes that his research offers a revolutionary model for the treatment of spinal cord injuries and diseases of the central nervous system. If reversing cell age can bring back lost vision, he says, why not regain the ability to walk or remember?

five habits

No one knows when or if a revolutionary technology like cellular reprogramming will be able to do for humans what it has done so wonderfully for mice. But in the meantime, we can do a lot to cope with aging. Researchers at Harvard University, the Chan School of Public Health, studied decades of data from 123 US adults and found that five habits can increase life expectancy by 219 years for women and 14 years for men: proper nutrition, regular exercise, healthy weight, smoking cessation and avoiding alcohol.

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“If you’re going to do one thing that I don’t recommend, choose exercise,” advises Matt Kaberlein, professor of laboratory medicine and pathology and director of the Healthy Aging and Longevity Research Institute at the University of Washington.

His lab has developed a robotic platform called WormBot that simultaneously collects data from hundreds of parallel experiments to identify factors that influence the lifespan of C. elegans roundworm. He is also testing rapamycin in dogs. But no matter how busy he is, Kaberlein, 51, hits the makeshift gym in his garage three days a week and cycles through bench presses, squats, deadlifts and shoulder raises to maintain muscle mass.

“For most people over 50, muscle loss due to a sedentary lifestyle is usually one of the most important factors in future ill health,” he says.

Fitness experts argue endlessly about which exercise regimen is best for promoting health and strength in old age. Similarly, nutrition experts disagree on the optimal diet—time-restricted meals, intermittent fasting, keto, vegan, Mediterranean, and so on.

Animal studies provide compelling evidence that severe calorie restriction increases lifespan. It is notoriously difficult to determine if this is true for humans. Twenty years ago, the National Institute on Aging initiated a major study to measure the impact of a diet that cut calories by 25 percent. But even though the participants received counseling, software to track what they ate, and meals for a while, they cut calories by just 12 percent.

Becca Levy, professor of epidemiology and psychology at Yale University, points to another important, controllable influence on healthy longevity: our understanding of aging. In one study that was replicated around the world, Levy found that people in their 30s and 40s who had positive expectations of old age—for example, they equated it with wisdom rather than frailty—were more likely to have a good health decades later.

Another study found that older people who have a positive view of aging are much more likely to fully recover from a disabling injury. And in another, she found that a positive attitude towards old age was associated with a lower risk of developing Alzheimer's disease. Levy noticed that people with the brightest ideas about aging live an average of seven and a half years longer than those with the darkest.

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