Aging is not an inevitable fact of life - many animals have already found a way to delay the moment of death. Their tips can help us all enjoy long and healthy lives. For example, at least up to two hundred years. Can you imagine this? I am.
Just 30 years after the publication of Moby Dick, a group of Alaskan whalers attempted to rein in their own ocean giant. Their target was the male bowhead whale, the second largest mammal on Earth.
This species is famous for its amazing longevity: according to Inuit folklore, these whales live "two human lives", and are also freed from harpoons due to their immense strength.
These whalers were armed with the latest technology, in particular a "spear bomb" that explodes on impact to pierce through 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 broke free 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 that remained in the whale oil.
According to various estimates, these whales live for at least 150 years, and possibly up to 210 years. Aside from slightly wrinkled skin, excess fat, and battle scars, whales show surprisingly few ill effects from a long life. Which, in turn, is of great interest to physicians studying aging.
“They live much longer than humans, but they live in the wild without going to a doctor or taking advantage of the benefits of human society,” says João Pedro de Magalhaes of the University of Liverpool. "Thus, they must be naturally protected from the diseases of old age."
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By studying these whales and other extremely long-lived creatures, de Magalhaes and colleagues hope 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 the biological processes associated with it, and it remains the root cause of suffering and death in the modern world,” says de Magalhaes. "If we could put it off even for a little while, it would be an unprecedented miracle for a person."
Vadim Gladyshev from Harvard University agrees with him. “This is a critical biological issue, since most chronic human diseases stem from aging. Biomedical science is organized to focus on specific diseases such as cancer, Alzheimer's or diabetes,”he says. "But if you postpone aging, you can postpone all the diseases associated with it as well."
A variety of factors are associated with aging. First, the environment: no one can live in a bubble, so our DNA and other molecular engineering is 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 the cells grow into tumors.
We could also solve problems with our own metabolism: just like stoves need to be cleaned regularly, our cells generate a lot of waste as energy is burned. Waste builds up over time and can disrupt important biological processes. “The amount of damage accumulates and the body is unable to cope with it,” says Gladyshev.
Finally, the body is faced with the problems of organ regeneration: each chromosome has a bundle of DNA at the ends called telomeres, which behave like plastic tips on laces to prevent them from spreading.
The telomere gets shorter each time the cell divides until it eventually becomes so short that the cell malfunctions or dies. With this outcome, we become vulnerable to various diseases.
Menagerie of Methuselah
All indications are that some compelling force is pushing us towards death - but several lines of evidence suggest that there are brakes that can slow this process down. For example, a common diabetic drug, metformin, may slow aging slightly in mice.
And a simple change in one gene involved in cellular metabolism in annelids can greatly extend its life; and while the same changes are unlikely to help more complex organisms, all of this hints that aging is quite manageable. “Aging is surprisingly flexible and manageable,” says de Magalhaes.
Scientists like Magalhaes and Gladyshev are looking for other candidates, using real mafusaili as leaders (Methuselah is the longest-lived biblical character).
Among mammals alone, life expectancy is very different, from shrews, which live no longer than six months, to bowhead whales, which live more than two hundred years. For some reason, natural selection has pushed certain creatures to develop their own elixirs of life.
“Metformin lengthens the lifespan of mice a little, but when you look at different creatures, the ability of natural selection to increase lifespan is much more powerful,” says de Magalhaes. "They will most likely develop other life-prolonging mechanisms, resisting cancer and other age-related diseases."
And each of them can improve our medicine. Or, as Gladyshev notes, “nature changes life expectancy all the time, the only question is how it does it. Can we be guided by this mechanic, thereby extending the lifespan of people?"
The most interesting creatures are among the special centenarians; specific species can survive, it seems, even the closest relatives. And they are not always as majestic as the bowhead whale.
With its wrinkled and hairless skin, the naked mole rat does not at all look like a child in a health promotion poster - but lives up to 30 years, far more than the 2-3 years that regular mice can afford.
In addition, the naked mole rat is extremely resistant to cancer - not a single case of cancer has been identified in thousands of individual mole rats studied in laboratories. Even when bathed in strong carcinogens, they remained immune to cancer.
This can be partially explained by the fact that their cells stop growing when they become too dense - this mechanism stops tumor multiplication and takes control of growth. And it seems to stem from a particularly "heavy" version of a chemical known as hyaluronic acid.
This molecule is part of the scaffolding that surrounds the cage, and may initially have been involved in developing the elasticity of the naked mole rat's skin to make it easier for it to squeeze through tight burrows.
Today it appears to be part of a signaling system that stops cells from proliferating uncontrollably. In other words, even if the mutation allows the formation of a tumor, hyaluron stops its further development.
Gladyshev also studied Brandt's bat, a tiny creature that lives for over 40 years despite weighing a little more than a cube of refined sugar. “Considering its size, this is the most extreme case,” Gladyshev says.
He found unusual mutations around mice receptors that mediate 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 record-breaking whale pick up such hints? The huge size of the whale - 20 meters in length and up to hundreds of tons in weight - creates some unique problems of interest to biologists like Magalhaes and Gladyshev. For example, if its cells were burning energy at the same rate as the cells of mice, the excess heat would boil the surrounding water, so evolution has produced a slow metabolism and low body temperature in the whale.
Such a huge body also exposes you to a huge risk of cancer, thanks to simple math: the more cells you have, the higher 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 is compounded if you live longer, you experience "more cell division, so the chances of cancer go up dramatically," says Leonard Nanny of the University of California, Riverside, who studies the evolution of cancer.
Immortal zoo
Can any creatures live forever?
The bowhead whale can live longer than two centuries, making it the oldest mammal. But how does this compare to other types of organisms? A study of the seeds of the bristlecone pine, which lives up to 4,700 years, has not revealed any specific cellular mutations that might have developed over time.
Colonial animals like corals can live for over 4,000 years. But individual polyps won't last more than a few years.
The mine clam is considered the oldest solitary animal. This oceanic long-liver was 507 years old when biologists retrieved it from coastal waters near Iceland in 2006.
Based on the human rate of cancer development, all large whales should be covered with tumors before birth - but they continue to live and live. This fact is known as the "Peto paradox" and suggests that whales, like naked mole rats, have cunning evolutionary tricks up their sleeves to cope with harmful mutations.
If you put them in the context of other animals, they really will live long. They must have some mechanisms of suppressing the growth of tumors, which we do not have.
It is these mechanisms, and much more, that Magalhaes is trying to find by peering into the whale's genome. Initially, he tried to experiment with fabric. And eventually he found a team that had already made connections with the Inuit hunters.
To preserve their traditions, indigenous communities around the Arctic capture 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 was faced with the extraordinary task of genetic sequencing. Given the sheer volume of data, the task was akin to slicing hundreds or thousands of copies of Moby Dicks and then arranging the individual sequences in meaningful order.
The result was a series of findings that could pave the way for future medicine. Scientists saw particular interest in changes in a gene called ERCC1. This gene is known for coding molecular tools that can patch small sections of a damaged genome. It looks like one mutation in bowhead whales has gone a step further and may be preventing the accumulation of harmful mutations that cause cancer.
The scientists also discovered changes in the PCNA gene, which is involved in cell proliferation. It codes for a protein that acts as a kind of clamp that connects the molecular machines that trigger DNA replication. Bowhead whales have duplicated regions of this gene, and their mutations seem to help interact with other parts of the DNA repair tool.
Scientists have suggested that this one change can provoke cell growth without the damage that comes over the years. Considering other important adaptations, this could help whales reduce cellular stress, which in turn could lead to long mammalian life.
A sign of longevity
Across the Atlantic, at Harvard, Gladyshev recently carried out 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 setting 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 have attracted the attention of key figures in medicine. Francis Collins, director of the US National Institutes of Health, was impressed, writing that Gladyshev's work takes 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 argues that we could see if some kind of diet or exercise can help our bodies develop a whale-like life span.
For example, some have argued 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 so long. In this sense, bowhead whales could be our guides to a long and happy life.
In addition, these long-lived creatures could inspire us for more radical treatments. The first step, de Magalhaes says, will be to grow human tissue with mutations seen in bowhead whales, Brandt's 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 bowhead whale genes and put them in mice to see if they live longer."
After these initial tests, the next hurdle will be to find a way to create the same changes in an extremely complex human body, perhaps with drugs that mimic genetic effects.
In some cases, organisms such as yeast can be genetically modified to grow the proteins of interest in large vats that will self-purify for human use, or drugs can be found to mimic these effects.
In the future, gene therapy may even allow us to fix the DNA of living people; we could borrow genetic mutations from bowhead whales that they have been producing for millions of years. Given recent advances in gene therapy, "there is no reason to think that this is impossible."
Obviously, the most difficult thing is ahead. While we are relatively closely related from an evolutionary perspective, what works for the whale or naked mole rat may work limitedly or not at all for the human body.
“You can always find different ways in which different organisms suppress cancer - but whether they will be useful therapeutically, you cannot know in advance,” says Nanni.
The natural response to cancer was developed through a “happy process,” where a unique solution stemmed from the unique circumstances of each individual organism. With all this, he welcomes a new approach to finding solutions in nature.
"I think cancer biologists are beginning to understand that incorporating evolutionary ideas will be fruitful."
De Magalhaes and Gladyshev do not harbor any illusions about the complexity of the path - but they do not lose hope. “History is full of claims by experts who thought some things were impossible and ended up being wrong,” de Magalhaes says.
Think of the state of medicine 120 years ago, when some of today's bowhead whales were just children. Back then, life-threatening infections were commonplace. Today antibiotics are used to treat them successfully.
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 2120 we will look backward, wondering at the first steps towards this goal.