The scientific secrets of a long life

Aging is not an inevitable fact of life – many animals have already found a way to delay death. Their clues can help us all enjoy a long and healthy life. For example, at least two hundred years. Can you imagine that? I am.

Just 30 years after the publication of Moby Dick, a group of Alaskan whalers tried to rein in their own giant out of the ocean. Their target was a male bowhead whale, the second largest mammal on Earth. This species is famous for its amazing durability: according to Inuit folklore, these whales live "two human lives" and are also released from the harpoons at the expense of their enormous power.

These whalers were armed with the latest technology, in particular a “spear bomb” that explodes when hit to pierce a thick layer of whale oil. However, this was not enough to defeat the whale. Three spear fragments hit him in the side, but - like Moby Dick - he escaped and left with only superficial wounds.

The whale continued to wander uncaught for another 120 years, until 2007, when a group of whalers finally caught him. She even found fragments of the very spear left in whale oil.



According to various estimates, these whales live at least 150 years and possibly up to 210 years. Aside from slightly shrivelled skin, excess fat and battle scars, whales show surprisingly few harmful effects of a long life. Which, in turn, is of great interest to doctors studying aging.

“They live much longer than humans, but they live in the wild without going to a doctor or benefiting from human society,” says João Pedro de Magalhaes from the University of Liverpool. Thus, they must be naturally protected from the diseases of old age. By studying these whales and other extremely long-lived creatures, de Magalhaes and colleagues hope that we can find new drugs that will similarly slow the decay of the human body and delay death. “Aging is a mystery, we know relatively little about its biological processes, and it remains the root cause of suffering and death in the modern world,” de Magalhaes said. If we could postpone it even for a moment, it would be an unprecedented miracle for man.

Vadim Gladyshev of Harvard University agrees with him. “This is a critical biological issue, as most chronic human diseases stem from aging.” Biomedical science is organized to focus on specific diseases like cancer, Alzheimer’s or diabetes, he says. “But if you delay aging, you can put off all the diseases associated with it.”

A variety of factors are associated with ageing. First, the environment: no one can live in a bubble, so our DNA and other molecular engineering are slowly damaged by harmful chemicals or radiation. Although our cells have the tools to repair, eventually the destruction becomes too extensive, leads to mutations, and cells grow into tumors.



We could also solve problems with our own metabolism: just as stoves need regular cleaning, our cells produce a lot of waste as energy is burned. Waste accumulates over time and can disrupt important biological processes. “The amount of damage accumulates and the body is unable to cope with it,” Gladyshev says.

Finally, the body faces organ regeneration problems: each chromosome has a bundle of DNA at the ends, called telomeres, which behave like plastic tips on shoelaces that prevent them from spreading. The telomere becomes shorter each time a cell divides, until it eventually becomes so short that the cell malfunctions or dies. With this outcome, we become vulnerable to various diseases.

Methuselah’s Menagerie All points to an unstoppable force pushing us to death – but several lines of evidence suggest that there are brakes that can slow this process. For example, a common diabetic drug, metformin, may slow aging slightly in mice. And simply altering a single gene involved in cellular metabolism in ringworms can extend its life much longer; and while it is unlikely that the same changes will help more complex organisms, all this hints that aging is quite manageable. “Aging is a surprisingly plastic process that can be controlled,” de Magalhaes says.

Scholars like Magalhaes and Gladyshev are searching for other candidates, using real-life Methuselahs as their guides (Methuselah is the longest-lived biblical character). Among mammals alone, life expectancy is very different, from shrews that live no longer than six months, to bowhead whales that live more than two hundred years. For some reason, natural selection has pushed certain creatures to develop their own elixirs of life.

“Metformin extends the lifespan of mice a little bit, but if you look at different creatures, the ability of natural selection to extend lifespan is much more powerful,” says de Magalhaes. They will likely develop other life-prolonging mechanisms, resisting cancer and other age-related diseases. Each of these can improve our health. Or, as Gladyshev notes, “Nature changes life expectancy constantly, the only question is how it does it.” Can we be guided by this mechanics, thereby prolonging the lifespan of people?”

The most interesting creatures are among the special centenarians; specific species can outlive, it seems, even the closest relatives. And they're not always as majestic as the bowhead whale. With its wrinkled and hairless skin, the naked mole rat looks nothing like the baby on the poster promoting a healthy lifestyle - but lives up to 30 years, much more than the 2-3 years that ordinary mice can afford. In addition, the naked mole rat is extremely resistant to cancer - thousands of individual mole rats studied in laboratories have not been diagnosed with a single case of cancer. Even when bathed in powerful carcinogens, they remained immune to cancer.

This may be partly explained by the fact that their cells stop growing when they become too dense – a mechanism that stops tumors from multiplying and takes growth under control. And it seems to stem from a particularly "heavy" version of a chemical known as hyaluronic acid. This molecule is part of the forests surrounding the cage and may have initially been involved in developing the elasticity of the naked mole rat's skin to make it easier to squeeze through tight burrows. Today, it seems to be part of a signaling system that stops cells from multiplying uncontrollably. In other words, even if the mutation allows a tumor to form, hyalurone stops its further development.

Gladyshev also studied Brandt’s bat, a tiny creature that lives over 40 years, despite weighing just over a cube of refined sugar. "Given its size, this case is the most extreme," Gladyshev says. He found unusual mutations around mouse receptors that enable hormone growth and insulin-like growth factor — changes that could lead us to think about how to control metabolism in animals, limiting the damage that usually comes with age.



Will the whale recorder reveal such hints? The whale’s enormous size — 20 meters long and up to a hundred tons in weight — poses some unique challenges for biologists like Magalhaes and Gladyshev. For example, if its cells burned energy at the same rate as mouse cells, the excess heat would boil the surrounding water, so evolution developed a slow metabolism and low body temperature in the whale.

Such a huge body also puts you at a huge risk of cancer, thanks to simple math: the more cells you have, the better the chances that you will develop harmful mutations. (In fact, one study even found that tall people are slightly more likely to develop cancer than short people, for this reason.) And the problem gets worse if you live longer, you experience "more cell divisions, so the likelihood of cancer goes up a lot," says Leonard Nunney of the University of California, Riverside, who studies the evolution of cancer.

Can any creatures live forever?

• The bowhead whale can live longer than two centuries, making it the oldest mammal. But how do you compare this to other types of organisms? A study of the seeds of the bristle pine tree, which lives up to 4,700 years, revealed no specific cellular mutations that could manifest over time.
• Colonial animals like corals can live more than 4,000 years. But individual polyps will not last more than a few years.
• The mollusk of mines is considered the oldest solitary animal. This oceanic centenarian was 507 years old when biologists extracted it from coastal waters near Iceland in 2006.

Based on the human rate of cancer, all large whales should be strewn with tumors before they are born — but they continue to live. This fact is known as the “Peto paradox” and suggests that whales, like naked mole rats, have tricks up their sleeves to cope with harmful mutations. If you put them in the context of other animals, they're actually long-lived. They should have some mechanisms to suppress tumor growth that we don't have.



It is these mechanisms, and much more, that Magalhaes is trying to find by peering into the whale's genome. He initially experimented with fabric. He eventually found a team that had already established ties with Inuit hunters. To preserve their traditions, indigenous societies around the Arctic catch and kill a limited number of bowhead whales each year. Although initially suspicious of outsiders, the hunters eventually agreed to help scientists take some of the tissue from the prey.

Even after collecting the material, the group faced the extraordinary task of building genetic sequences. Given the sheer volume of data, the task was akin to slicing hundreds or thousands of copies of Moby Dicks and then putting individual sequences into meaningful order.

The result was a series of findings that could pave the way for future medicine. Of particular interest, the researchers saw changes in a gene called ERCC1. This gene is known for encoding molecular tools that can patch small patches of damaged genomes. It seems that one mutation of bowhead whales has gone even further and may prevent the accumulation of harmful mutations that cause cancer.



The scientists also found changes in the PCNA gene, which is involved in cell proliferation. It encodes a protein that acts as a kind of clamp connecting molecular machines that cause DNA to replicate. Greenland whales have doubled sites with this gene, and their mutations seem to help interact with other parts of the tool involved in DNA repair. The scientists hypothesized that this one change could trigger cell growth without the damage that comes with years. Given other important adaptations, this could help whales reduce cellular stress, which in turn could lead to a long mammalian life.

On the other side of the Atlantic, at Harvard, Gladyshev recently conducted his own study of the "transcriptome" of bowhead whales; not only by studying genes, but also by studying their activity. If you see that certain genes are particularly active, you know that they can also play an important role in aging. The scientist found the same types of changes in the insulin signaling system that he noticed in Brandt’s bats. “Perhaps this is how the metabolic tuning of cells changes, somehow they become long-lived.” However, these findings require careful analysis.” The results lead to a “sign of longevity”, according to the scientist, and therefore can be used in further research.

These findings attracted the attention of important figures in medicine. Francis Collins, director of the U.S. National Institutes of Health, was impressed, writing that Gladyshev’s work brings us “right to the threshold of new discoveries about healthy and long life.”

Beyond this threshold, we can discover many possible ways to improve our treatment. Gladyshev says we could see if some kind of diet or exercise could help our bodies develop a lifespan similar to that of a whale. For example, some argue that fasting, or “calorie restriction,” slows down the aging process, and it would be interesting to compare metabolic changes to see if they resemble those that allow whales to live that long. In this sense, bowhead whales could be our guides to a long, happy life.



In addition, these long-lived creatures could inspire more radical treatments. The first step, de Magalhaes says, will be to grow human tissue with mutations seen in bowhead whales, Brandt bat and naked mole rat. “If we change human proteins to resemble animals, we can see changes in DNA,” he says. And I would like to take the genes of a bowhead whale and put them in mice to see if they live longer.

After these initial trials, the next hurdle will be finding a way to create the same changes in the extremely complex human body, perhaps with drugs that mimic genetic effects. In some cases, you can genetically modify organisms like yeast to grow the right proteins in large vats that will self-clean for human use, or find drugs that mimic these effects. In the future, gene therapy may even allow us to correct the DNA of living humans; we could borrow genetic mutations from bowhead whales that have been producing for millions of years. Given recent advances in gene therapy, “there is no reason to think this is impossible.”

Obviously, all the hardest things are ahead. Although we are relatively closely related in terms of evolution, what works for a whale or a naked mole rat may work limitedly or not at all in the case of a human body. “You can always find different ways in which different organisms suppress cancer — but whether they will be useful therapeutically, you can’t know that in advance,” says Nanni. The natural response to cancer was developed through a “happy process” in which a unique decision stemmed from the unique circumstances of each individual organism. In doing so, he welcomes a new approach to finding solutions in nature. “I think cancer biologists are beginning to realize that incorporating evolutionary ideas is going to be fruitful.”

De Magalhaes and Gladyshev harbor no illusions about the complexity of the path - but do not lose hope. "History is full of statements by experts who thought some things were impossible and ended up wrong," de Magalhaes says. Think about the state of medicine 120 years ago, when some of today’s bowhead whales were children. Then life-threatening infections were a habitual fact. Today, antibiotics are engaged in their successful treatment.

Ultimately, de Magalhaes sees aging as the ultimate disease—a disease that can be cured on its own. "We're not just extending the dilapidation period," he says. We want 70-year-olds to have the health of 50-year-olds, that’s the goal. Perhaps in the year 2120, we will look to the past, marveling at the first steps toward achieving this goal.

Source: hi-news.ru