By: April Carson
Mutational clocks exist in the cells of all animals, which dictate how quickly their DNA changes. Animals also tend to perish once they have accumulated a specific number of mutations, according on new research.
Scientists have long believed that the number of mutations humans accumulate over time is a major factor in determining their lifespan. A new study provides evidence for this theory, finding that animals with more genetic variations tend to live shorter lives than those with fewer variations.
In long-lived animals, such as humans, these mutation clocks tick more slowly than they do in short-lived species like mice, which means that when it comes to accumulating a certain number of mutations, human beings reach that threshold at a later age than mice. According to the researchers, this finding may help explain an outstanding biological mystery.
"Mutations are the raw material of evolution, but they can also have deleterious effects," said study co-author Caleb Finch, a USC University Professor and American Federation for Aging Research (AFAR) longevity prize recipient. "So the question has been: Why do some species live 10 times longer than others? We think that part of the answer may lie in the different rates at which species accumulate mutations."
The enigma that is known as Peto's paradox has defied analysis since the 1970s. Scientists knew in the 1970s that animal cells accumulate mutations in their DNA over time, and that the number of changes increases the likeliness of those cells becoming cancerous. Because the chance of acquiring cancer-causing changes rises with time and as the total number of cells in an animal goes up, this suggests that the world's longest-living and biggest animals should have the highest risk of disease.
Surprisingly, large long-lived animals develop cancer at comparable rates as tiny short-lived organisms — Peto's paradox. Now, in a study published April 13 in the Nature journal, researchers have proposed a partial solution to this conundrum: Shorter and longer lived species both accumulate the same number of genetic mutations throughout their lifespans, but the long-lived creatures do so at a far slower rate.
"I was utterly amazed by how robust the connection is between life span and mutation rate in various species," said Alex Cagan, a Wellcome Sanger Institute employee scientist and lead author of the research. The results of this study explain part of Peto's paradox by demonstrating that having a long lifespan does not increase the chance of cancer-causing genetic mutations for animals. However, the researchers didn't find a significant link between animals' body masses and their mutational clocks, so their findings do not address why enormous creatures have low cancer occurrence.
The study's authors conclude that the data lend support to the notion that animals age, at least in part, owing to cell-level mutations accumulating over time.
According to Cagan, however, it is not clear how they contribute to the aging process.
In a study recently published in the journal Science, researchers from the University of Liverpool tested Peto's paradox by examining cancer-related genetic mutations in animals with different body sizes and lifespans.
Yes, you can tell a mammal is approaching the end of its species' lifespan when it has approximately 3,200 mutations in its colonic epithelial stem cells, according to our findings. But we believe that it's because the animal will die of mutation overload at around 3,201, according to Cagan. Rather, the researchers think that there might be some complexity in the link between animals' mutational clocks and age.
To see how quickly mutational clocks tick in different mammals, the team analyzed genetic material from 16 species: humans, black-and-white colobus monkeys, cats, cows, dogs, ferrets, giraffes, harbor porpoises, horses, lions, mice, naked mole-rats, rabbits, rats, ring-tailed lemurs and tigers.
Analysis revealed that the clock was indeed different from species to species. The mutational clocks ticked fastest in mice and slowest in ferrets, for example. And humans had a slower than predicted rate of mutations, meaning their long lives might not be due simply to random mistakes made by genes.
The researchers obtained DNA from "crypts," tiny folds in the gastrointestinal and colon lining, from each of these species. Each crypt's cells descend from a single stem cell, making them all clones of that stem cell. Crypt cells appear to acquire changes at a constant rate as an individual grows older, according on previous research.
The researchers examined over 200 crypt tissue samples from the 16 species; each contained a few hundred cells, according to Cagan. The team found that the rate of crypt cell division varied from species to species. For example, the rates for mice and rats were about twice as fast as those for humans and elephants.
"The slower the rate of crypt cell division, the longer an animal lives," Cagan said.
"The capacity to sequence the genomes of extremely small cell populations (e.g., those that exist within one crypt) is relatively new, so this work couldn't have been easily done 20 years ago," said Kamila Naxerova, an assistant professor at Harvard Medical School and a co-director of the Center for Systems Biology at Massachusetts General Hospital in Boston, who was not involved in the research.
By tracking the number of DNA variations present in each sample and taking into account the animal's age, researchers were able to estimate how swiftly these changes occurred over the creature's lifetime. The team was able to compare the total number of mutations in individuals of different ages, such as a 1-year-old mouse versus a 2-year-old mouse, to double-check the accuracy of their mutation rate estimates in some species, including dogs, mice, and cats.
The researchers discovered that, similarly to people, the crypt cells of other species accumulate errors at a constant rate each year. But what was intriguing was the enormous difference in mutation rates among species. The number of new mutations accumulated in human crypts each year was 47, whereas mouse crypts accumulated the most, with 796 annually.
With these findings, the researchers hope to be able to link specific sections of DNA with functional variants in greater detail and more efficiently—allowing for a faster pace of discovery. "This difference is far-reaching, given the significant genetic overlap between humans and mice," Naxerova and Gorelick write in an article published in Nature.
Overall, the species' mutation rate was inversely related to its lifespan, suggesting that as a species got older, the rate of new mutations per year decreased. As a result, they added, "the number of mutations at the end of an animal's life was roughly similar across species."
The new research doesn't offer any insight into why long-lived creatures' mutation clocks tick more slowly than those of short-lived ones. That said, a previous study, published in October 2021 in the journal Science Advances, offers one answer.
In a recent study, researchers examined fibroblasts — cells found in connective tissues that are present in the lungs of mice, guinea pigs, blind mole-rats, naked mole-rats, and humans — with a mutagen (or a chemical that damages DNA) and exposed these cells to it. "Our thinking was that cells from long-lived species might survive better with a mutagen than those from short-lived species," said Jan Vijg, a professor and chair of the Department of Genetics at the Albert Einstein College of Medicine, who coauthored the Science Advances article.
That's all they discovered. "Short-lived mouse cells accumulated a significant number of genetic changes within just a few days, whereas the same dose of mutagen in the very long-lived naked mole-rat or human did not result in any mutations," said Vijg, who was not part of the new Nature study. This implies that long-lived animals may be better at repairing DNA damage and preventing mutations than short-lived ones, which may help to explain why they accumulate changes at a slower rate.
Both recent studies had several limitations, according to Vijg. They each examined one cell type: intestinal crypt cells or lung fibroblasts. That said, comparisons of additional cell types are likely to reveal similar results, according to Vijg. "I anticipate that the findings would apply to most other somatic cells," Naxerova added.
The team's goal is to help patients who don't respond well to those therapies, or cannot take them. Dr. Cagan and his staff are currently conducting similar research in additional tissue types. They're also expanding their study beyond mammals to look at a wide range of vertebrates and invertebrates, with the aim of establishing whether the same relationship applies across the animal kingdom. Tissue samples from a super-rare Greenland shark that washed up in the United Kingdom and may have been about 100 years old when it died were recently acquired by the team, Mr. Degnan said. The species can live at least 272 years, according to scientists' estimates, Live Science previously reported.
To answer this question, Cagan's team is conducting research on the mechanisms of aging. Assuming it does contribute to aging in some manner, the aim of this study is to show how the consistent accumulation of changes contributes to aging — a hypothesis has been put forth.
According to their research, as all somatic cells acquire mutations over time, some of those cells will develop changes in critical genes that regulate cell behavior. These deformed cells become more efficient at performing their tasks but also grow faster than their neighbors, the theory indicates. And as these cells take control of tissues in the body, this will cause bodily systems to break down and result in disease and death, Cagan explained.
"The idea is that once you have a lot of mutations, it's not that every cell quits working since it has acquired a lot of errors," Mr. Johnston explained. Instead, particular cells' harmful mutations drive them to become rogue and take control of tissues, while simultaneously crowding out all the healthier, better-functioning cells. As a result, each species' mutational clock most likely determines the rate at which these rogue cell clonal expansions disrupt tissues until they render an animal unable to function.
"Selfish" cells might be utilized to describe these rogue ones, Naxerova and Gorelick wrote in their essay, since they spread harm to surrounding cells. According to Naxerova, there's evidence that such selfish cells could form in the haematopoietic system — the bodily system that generates blood — and contribute to chronic inflammation.
"It's possible that selfish clones in other organs contribute to disease and aging, but I believe this is primarily speculative for the time being," she added.
To combat the spread of these cells, Naxerova and Gorelick recommended using drugs that "directly target" them.
The study's findings were originally revealed on Live Science.
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