DNA Mutation Time Bombs May Dictate When Animals Die -

Animals carry “mutational clocks” in their cells that dictate how quickly their DNA picks up mutations. And across species, animals tend to die once they reach a certain number of mutations, according to new research.

It turns out that in long-lived mammals like humans, these mutational clocks run slower than in short-lived mammals like mice, which means that humans reach a threshold number of mutations at older than mice. This finding, the researchers say, could help solve a long-standing mystery in biology.

This mystery, known as Peto’s paradox, describes a puzzling phenomenon that has defied explanation since the 1970s. At that time, scientists knew that animal cells accumulated mutations in their DNA over time, and as the number of mutations increased, the risk of these cells becoming cancerous also increased. On paper, this suggests that the world who lives the longest and the biggest animal should face the highest risk of cancerbecause the risk of detecting carcinogenic mutations increases with time and as the total number of cells in an organism increases.

But curiously, large, long-lived animals develop cancer at similar rates to tiny, short-lived creatures – this is Peto’s paradox. Now, in a new study, published April 13 in the journal Naturescientists offer a potential partial solution to this puzzle: they found that both short-lived and long-lived mammals accumulate a similar number of genetic mutations over their lifetime, but long-lived animals lives do so at a much slower pace.

“I was really surprised” by the strength of the relationship between lifespan and mutation rate in different species, said Alex Cagan, a researcher at the Wellcome Sanger Institute in England and first author of the study. The results of the study help explain one aspect of Peto’s paradox, by showing that having a long lifespan does not put animals at higher risk for cancer-causing mutations. However, the authors did not find a strong link between the animals’ body masses and their mutational clocks, so their results do not answer the question of why large animals do not have high rates of cancer.

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The results support the theory that animals age, at least in part, due to the accumulation of mutations in their cells over time – although the study does not reveal exactly how mutations contribute to the aging process, Cagan said.

“Based on our results, yes, you can say that a mammal is near the end of its species lifespan when it has [approximately] 3,200 mutations in his colon epithelial stem cells,” which was the specific population of cells the team analyzed. “But we don’t think it’s because at 3,201 the animal will drop dead from mutation overload,” Cagan said. the authors think the relationship between animals’ mutational clocks and aging might be a bit more nuanced.

Ticking clocks

This light micrograph shows a cross section of crypts, fold-like structures that appear in the lining of the intestine. (Image credit: STEVE GSCHMEISSNER/SCIENTIFIC PHOTO LIBRARY via Getty Images)

To see how quickly mutational clocks are ticking in different mammals, the team analyzed the genetic material of 16 species: humans, black and white colobus monkeysOld cats, cows, dogs, ferrets, giraffes, harbor porpoises, horses, lions, mice, naked mole-rats, rabbits, rats, ring-tailed lemurs and tigers. Of these species, humans have the longest lifespan at around 80 years; Mice and rats had the shortest lifespan, between about 3 and 4 years.

From each of these species, the researchers collected DNA from “crypts,” which are tiny folds found in the lining of the small intestine and colon. The cells of each crypt all descend from the same stem cell, which means that they are all clones of this stem cell. Previous studies suggest that, at least in humans, crypt cells pick up mutations at a steady rate as a person ages.

In total, the researchers analyzed more than 200 crypt tissue samples from all 16 species; Each sample contained a few hundred cells, Cagan noted.

“The ability to sequence the genomes of very small populations of cells (for example those in a crypt) is quite new, so this study could not have been easily done 20 years ago,” said Kamila Naxerova. , assistant professor at Harvard Medical. School and principal investigator at the Massachusetts General Hospital Center for Systems Biology, who was not involved in the study.

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The team determined the total number of DNA mutations present in each sample and, taking into account the age of each animal, they were able to estimate how quickly these mutations occurred over the lifespan. of the organism. In some species, including dogs, mice and cats, the team had enough samples to compare the total number of mutations in individuals of different ages – for example, a one-year-old mouse versus a of 2 years – to double check the accuracy of their mutation rate estimates.

Through their analysis, the authors found that, just like in humans, the crypt cells of other mammals also accumulate mutations at a constant rate, year after year. But what was striking was that this mutation rate differed significantly between species. Human crypts accumulated the fewest number of new mutations each year, at just 47, while mouse crypts picked up the most, at 796 per year.

“This difference is staggering, given the large overall similarities between human and mouse genomes,” wrote Naxerov and Alexander Gorelick, a postdoctoral researcher at Harvard Medical School and Massachusetts General Hospital. commentary on the study.

Overall, each species’ mutation rate showed an inverse correlation with its lifespan, meaning that as an animal’s lifespan increased, the rate of new mutations per year decreased. This ultimately meant that “the total number of mutations at the end of an animal’s life was roughly similar across species,” Naxerova and Gorelick noted.

More mysteries to solve

(Image credit: Getty Images)

The new study does not indicate why the mutational clocks of long-lived animals are slower than those of short-lived animals, Cagan said. That said, an earlier study, published in October 2021 in the journal Scientists progressprovides an explanation.

In this study, scientists sampled fibroblasts – a type of cell found in connective tissue – from the lungs of mice, guinea pigs, blind mole rats, naked mole rats and humans, then exposed these cells to a mutagen or chemical that damages DNA. “Our reasoning was that cells from long-lived species can cope better with a mutagen than cells from short-lived species,” said Jan Vijg, professor and head of the department of genetics at the Albert Einstein College of Medicine and lead author. of the Science Advances report.

And that’s exactly what they found. “The cells of an ephemeral mouse quickly accumulated a lot of mutations, whereas at the very beginning long-lived naked mole-rat or human, the same dose of mutagen didn’t even induce mutations,” said Vijg, who was not involved in the new Nature study. This suggests that long-lived animals may be better at repairing DNA damage and preventing mutations than short-lived animals. animals, and this may partly explain why they accumulate mutations at a slower rate.

One limitation of the two recent studies is that they each included only one type of cell — intestinal crypt cells or lung fibroblasts, Vijg said. That said, analyzes of additional cell types would likely yield similar results, he said. “I would expect the results to generalize to most other somatic cells,” that is, cells that are neither eggs nor sperm, Naxerova agreed.

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Cagan and his team are now initiating such studies on other tissue types. At the same time, they are going beyond mammals to study a wide range of vertebrates and invertebrates, to see if the same relationship exists in the animal kingdom, he said. For example, the team recently got hold of tissue samples from a super rare greenland shark which washed up in the UK and was possibly around 100 years old when it died, he said. Scientists estimate that this species can live for at least 272 years, Live Science previously reported.

Selfish cells?

Through this research, Cagan’s team hopes to reveal how the constant accumulation of mutations actually contributes to aging — assuming it does, Cagan said. On that front, the team came up with a theory.

They suggest that, as all somatic cells pick up mutations over time, some of these cells will develop mutations in critical genes that normally regulate cell behavior. These corrupted cells become less efficient at their job but are able to multiply more efficiently than their neighbors, the theory suggests. And as these cells invade body tissues, it would ultimately cause organ systems to malfunction, leading to disease and death, Cagan said.

So “it’s not that every cell stops functioning because it’s accumulated a lot of mutations,” he said. Rather, problematic mutations in specific cells cause those cells to go rogue, take over tissues, and crowd out all the healthier, better-functioning cells. Therefore, each species’ mutational clock likely determines the rate at which these rogue cells take over, such that “it takes a lifetime before these clonal expansions of malfunctioning cells have so disrupted the tissues that the animal can no longer function”.

Such rogue cells could be described as “selfish” because they spread at the expense of the cells around them, Naxerov and Gorelick wrote in their commentary. Animal studies have proven that such selfish cells can emerge in the hematopoietic system — the body system that makes blood — and cause disease by contributing to chronic inflammation, Naxerov told Live Science.

“It could be that selfish clones in other organs contribute to disease and aging…as well, but I think that’s largely hypothetical at this point,” she said.

Originally posted on Live Science.

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