Scientists prevent signs of aging in zebrafish by targeting the gut | Science

When it comes to slowing aging in humans, telomeres have long been a tempting target. These complex, repetitive sequences of DNA that cap the ends of chromosomes tick away the years by shortening each time a cell divides, eventually causing the cell to die.

The jury’s still out about whether reversing this shortening could be a molecular fountain of youth, but a new study in zebrafish is encouraging. When researchers lengthened telomeres in the gut cells of these tiny, translucent fish, they reversed signs of aging in the entire organism.

“It’s a really good paper,” says Ronald DePinho, a cancer biologist at the MD Anderson Cancer Center who studies telomeres and aging. The authors of the study, published this month in Nature Aging, suggest their data could support an old theory that the gut somehow controls aging in all tissues. DePinho isn’t totally sold yet, but he says it’s clear that the organ plays an important role in healthy aging.

During embryonic development, an enzyme called telomerase lengthens telomeres in order to allow cells to divide more often. But the gene for telomerase is largely shut off in most cells in adult humans; it only switches back on in cancerous cells that divide rapidly.

Researchers have long been interested in telomerase as an antiaging treatment. Some evidence suggests giving mice telomerase can reverse the symptoms of aging, curbing everything from the appearance of gray hair to cognitive decline. But treating people with telomerase would be risky because of the chance of causing cancer, as well as the difficulty of getting the enzyme into every cell in the body. Recent studies in humans have also suggested that, although short telomeres cause inflammation, long telomeres carry a higher risk of cancer.

To figure out whether a more targeted telomerase treatment would be more effective, Miguel Godinho Ferreira, an aging researcher at Côte d’Azur University and his colleagues turned to zebrafish. Ferreira says these swimmers—about the diameter of a penny—are a good model for aging because their telomeres are naturally about the same length as those of humans. (Mouse telomeres are much longer.)

The scientists disabled the gene for telomerase in the fish, which caused them to prematurely develop the DNA damage and metabolic problems that occur with aging. Their life expectancy also dropped by as much as 70%.

These aging effects were particularly apparent in the fish’s gastrointestinal tracts, the team found. That made sense, Ferreira says: Cells in the gut divide frequently in order to regenerate the organ’s lining, and therefore tend to have shorter telomeres than most other cell types.

close up of intestinal wall of fish without telomerase
The intestinal wall of fish without telomerase (left) becomes inflamed; restoring telomerase brings it back to health (right).Miguel Godinho Ferreira

Next, the researchers compared these fish’s gastrointestinal tracts with those of fish they had injected with pieces of messenger RNA encoding an enzyme that reactivates the disabled telomerase gene in the gut. These fish had also received a piece of DNA encoding an extra telomerase gene in the same organ. This lengthened telomeres in the gut and restored cells’ ability to proliferate and replace damaged tissue. Genes associated with aging were shut off, and there were fewer leaks in the gut wall.

The telomerase treatment also improved metabolism that had slowed because of aging in fish without telomerase. The collection of bacteria that live in the zebrafish’s guts—known as the microbiome and linked to inflammation and metabolic problems in aging humans—also shifted to become more like those found in younger fish.

But the antiaging effects weren’t limited to the gut. Zebrafish that made telomerase only in the gut had less DNA damage in their kidney marrow, which produces blood and immune cells; even cells in the males’ testes retained the ability to proliferate.

On average, treated fish lived 40% longer than those that lacked telomerase entirely and remained healthier during their old age with more cell proliferation in the kidneys and testes. When the researchers looked at the guts of normal elderly fish who had been engineered with an extra gene for telomerase in the gut, the extra amount of the enzyme also greatly improved their overall health and eliminated signs of aging in their guts.

It’s not surprising that telomere extension in the gut can improve fish’s life spans, given that mice without telomerase tend to have intestinal damage, says Maria Blasco, a telomere researcher at the Spanish National Cancer Research Centre. She says she’d like to see whether telomerase would have the same effect in aging fish that don’t have gut problems.

Ferreira adds that humans with mutations in the gene for telomerase are also prone to gut problems, including inflammatory bowel disease. But it’s unclear why activating telomerase in the gut improves the fish’s other organs as well. He suspects that when aging is reversed in the gut, the organ may release signaling molecules that affect the whole body by stopping inflammation that damages DNA in other organs. Some evidence suggests gut bacteria produce harmful chemicals that pass through leaks in aging gut tissue and damage the rest of the body; kick-starting cell proliferation in the gut through telomerase could prevent these leaks.

DePinho says the results imply that when a specific organ fails, it causes other, distant organs to develop problems including widespread inflammation or the wrong combination of gut bacteria. It’s not clear though, he says, whether the gut is the only organ whose failure—or improvement through telomerase treatment—can have long-distance effects on aging and overall health. The next step, he says, would be to figure out how exactly the gut is affecting the rest of the body, which could enable the development of a targeted human treatment in the future.

2023-05-19 17:09:02