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've hit a certain number of mutations, new research finds.

It turns out that, in long-lived mammals like humans, these mutational clocks tick slower than they do in short-lived mammals like mice, meaning humans reach that threshold number of mutations at a later age than mice do. This discovery, the researchers said, could help solve a long-standing mystery in biology.

This mystery, known as Peto's paradox, describes a perplexing phenomenon that has defied explanation since the 1970s. At that time, scientists knew that animal cells accrued mutations in their DNA over time, and that as the number of mutations increased, so too did the risk of those cells turning cancerous. On paper, this suggests that the world's longest-living and largest animals should face the highest risk of cancer, because the chance of picking up cancer-causing mutations increases over time and as the total number of cells in an organism goes up.

But oddly enough, large, long-lived animals develop cancer at similar rates as tiny, short-lived creatures this is Peto's paradox. Now, in a new study, published April 13 in the journal Nature, scientists offer a partial potential solution to this puzzle: They discovered that short- and long-lived mammals both accumulate a similar number of genetic mutations over their lifespans, but the long-lived animals do so at a far slower rate.

"I was really surprised" at the strength of the relationship between lifespan and mutation rate in different species, said Alex Cagan, a staff scientist at the Wellcome Sanger Institute in England and first author of the study. The study results help explain one aspect of Peto's paradox, by showing that having a lengthy lifespan doesn't put animals at higher risk of cancer-causing mutations. However, the authors didn't find a strong link between animals' body masses and their mutational clocks, so their results don't address the question of why big animals don't have high rates of cancer.

Related: Scientists discover 4 distinct patterns of aging

The results do support the theory that animals age, at least in part, due to the build-up of mutations in their cells over time although the study doesn't reveal exactly how the mutations contribute to the aging process, Cagan said.

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

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. Of these species, humans have the longest lifespan at roughly 80 years; mice and rats had the shortest lifespans, 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 intestines and colon. The cells in each crypt all descend from a single stem cell, meaning they're all clones of that stem cell. Past studies suggest that, at least in humans, crypt cells pick up mutations at a constant rate as a person ages.

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

"The ability to sequence the genomes of very small cell populations (e.g. those that are found within one crypt) is fairly new, so this study could not have easily been done 20 years ago," said Kamila Naxerova, an assistant professor at Harvard Medical School and a principal investigator at the Massachusetts General Hospital Center for Systems Biology, who was not involved in the study.

Related: Anti-aging vaccine shows promise in mice will it work in humans?

The team determined the total number of DNA mutations present in each sample, and by taking each animal's age into account, they were able to estimate how quickly these mutations cropped up over the organism's lifespan. 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 instance, a 1-year-old mouse versus a 2-year-old mouse to double-check the accuracy of their mutation rate estimates.

Through their analysis, the authors discovered that, just like in humans, the crypt cells of other mammals also accrue mutations at a constant rate, year to year. But what was striking was that this mutation rate differed drastically between species. Human crypts accumulated the lowest number of new mutations each year, at only 47, while mouse crypts picked up the most, at a whopping 796 per year.

"This difference is staggering, given the large overall similarities between human and mouse genomes," Naxerov and Alexander Gorelick, a postdoctoral fellow at Harvard Medical School and Massachusetts General Hospital, wrote in an accompanying Nature commentary on the study.

Overall, the mutation rate of each species showed an inverse correlation to its lifespan, meaning that as an animal's lifespan increased the rate of new mutations per year decreased. That 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.

The new study doesn't hint at why long-lived animals' mutational clocks tick slower than those of short-lived animals, Cagan said. That said, an earlier study, published in October 2021 in the journal Science Advances, provides one explanation.

In that 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 and then exposed these cells to a mutagen, or a chemical that damages DNA. "Our reasoning was that cells from long-lived species may cope much better with a mutagen than cells from short-lived species," said Jan Vijg, a professor and chair of the Department of Genetics at the Albert Einstein College of Medicine and senior author of the Science Advances report.

And that's just what they found. "Cells from a short-lived mouse quickly accumulated a lot of mutations, while in the very long-lived naked mole-rat or human, the same dose of mutagen did not even induce any 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, and this may partially explain why they accumulate mutations at a slower rate.

One limitation of both recent studies is that they each included just one cell type intestinal crypt cells or lung fibroblasts, Vijg said. That said, analyses of additional cell types would likely turn up similar results, he said. "I would expect that the findings would generalize to most other somatic cells," meaning cells that aren't eggs or sperm, Naxerova agreed.

Related: Natural rates of aging are fixed, study suggests

Cagan and his team are launching such studies into additional tissue types now. At the same time, they're moving beyond mammals to study a wide range of vertebrates and invertebrates, to see if the same relationship holds across the animal kingdom, he said. For example, the team recently got a hold of tissue samples from a super-rare Greenland shark that washed ashore in the U.K. and may have been about 100 years old at the time of its death, he said. Scientists estimate that this species can live at least up to 272 years, Live Science previously reported.

Within that research, Cagan's team hopes to reveal how the steady accumulation of mutations actually contributes to aging assuming it does at all, Cagan said. On this front, the team has proposed a theory.

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

So "it's not that every cell stops working 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, the mutational clock of each species likely sets the pace at which these rogue cells take over, such that "it takes a lifetime before these clonal expansions of poorly functioning cells have disrupted the tissues so much that the animal can no longer function."

Such rogue cells could be described as "selfish," since they spread to the detriment of cells around them, Naxerov and Gorelick wrote in their commentary. There's evidence from animal studies that such selfish cells can emerge in the haematopoietic system the bodily system that makes blood and drive 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 this is largely hypothetical for now," she said.

Originally published on Live Science.

See more here:
Ticking time bombs of DNA mutation may dictate when animals die - Livescience.com

When it comes to health policy, former Utah Republican Sen. Orrin Hatch, who died Saturday at age 88, leaves a complex legacy of major legislative achievements, changing positions, compromises and fierce opposition. In many ways, though, Hatch's evolution and leadership on health policy during his four decades in the U.S. Senate mirror that of the Republican Party.

When he came to Washington as a neophyte politician after an upset victory in 1976, Hatch was a conservative firebrand, one of the early leaders of the "New Right" bent on dismantling the federal welfare state and banning abortion. A former trial lawyer, the new senator had never before held public office.

But the election of Ronald Reagan in 1980 and the Republican takeover of the Senate that made Hatch chairman of the powerful Labor and Human Resources Committee (now the Health, Education, Labor and Pensions Committee) turned him into something of a pragmatist. That pragmatism, it should be noted, was somewhat forced: Even though Hatch was technically the chair, there were enough moderate Republicans on the panel to give the ranking Democrat, Massachusetts' Edward Kennedy, effective control over what could be passed by the committee.

So Hatch learned to compromise and to legislate. In 1984, he negotiated with liberal Rep. Henry Waxman, D-Calif., what is still referred to as the "Hatch-Waxman Act." It's better known as the law that allowed, for the first time, approval of generic copies of brand-name drugs. Although far from a panacea, it is still the single-biggest advance in the fight to rein in high drug prices.

When the Democrats took back the Senate after the 1986 elections, Kennedy became chairman of the committee and Hatch, the ranking Republican. The two teamed up on a series of landmark legislative achievements, from the Ryan White program on AIDS treatment and the Americans with Disabilities Act to the first major federal child care law. And while Hatch was a strong foe of national health insurance, he and Kennedy ultimately pushed through Congress in 1997 the bill to create the Children's Health Insurance Program, which provides low-cost health insurance for low-income families who don't qualify for Medicaid.

The stridently anti-abortion Hatch was outspoken about his support for federal funding for research on embryonic stem cells derived from aborted fetuses. "I think it's the ultimate pro-life position, because I believe being pro-life is not just caring for the unborn but caring for those who are living," he told NPR in 2007.

Stay informed with WPR's email newsletter.

But like much of the Republican Party in Congress, Hatch returned to his conservative roots after the election of President Barack Obama in 2008. A supporter of the so-called individual mandate requiring people to have health insurance when it was the quasi-official GOP position in the early 1990s, Hatch became an outspoken foe. "Congress has never crossed the line between regulating what people choose to do and ordering them to do it," he said in 2010.

After moderate Utah Republican Sen. Robert Bennett was ousted in a primary in 2010 and replaced by conservative favorite Mike Lee, Hatch grew more conservative to win reelection in 2012. His final term in the Senate was marked by efforts to overturn the Affordable Care Act and further restrict abortion access. The devout Mormon, who in his spare time wrote lyrics for best-selling Christian music, even called the ACA "the stupidest, dumb-a** bill that I've ever seen. Now some of you may have loved it; if you do, you are one of the stupidest dumb-a** people I've ever met." He later apologized for the statement.

A former Kennedy aide, Jim Manley, told The Salt Lake Tribune that "no one epitomizes the rightward lurch of the Republican Party more than Sen. Hatch."

In one final twist, however, Hatch pushed as his successor the 2012 GOP presidential nominee, Mitt Romney. In just his first few years, Romney has become one of the most moderate Republicans in the chamber. That may prove to be Orrin Hatch's final legacy.

KHN (Kaiser Health News) is a national newsroom that produces in-depth journalism about health issues. It is an editorially independent operating program of KFF (Kaiser Family Foundation).

Read more from the original source:
Sen. Orrin Hatch's legacy tracks the GOP's evolution on health - Wisconsin Public Radio