Long-Living Wild Mouse May Hold Secret to Healthy Aging

When it comes to health, some of our animal neighbors have extraordinary advantages. Ostriches, for example, are highly resistant to viruses, while sharks rarely develop cancer. And species like naked mole rats and bowhead whales live for astonishingly long periods of time, decades and centuries, respectively.

Researchers are now starting to understand why another species—the golden spiny mouse—seems to be unhindered by the negative health effects that typically accompany aging.

Reporting Feb. 25 in Science Advances, researchers at Yale School of Medicine (YSM) have begun to uncover how this wild mouse, native to rocky deserts in the Middle East, resists physical, cognitive, and immunological decline while living six to seven times longer than other wild mice.

“Mice in the wild typically live around nine months,” says senior author Vishwa Deep Dixit, DVM, PhD, Waldemar Von Zedtwitz Professor of Pathology at YSM. “But some of these golden spiny mice are living out in the desert for up to five years. And that’s just what we’ve been able to observe; their maximum lifespan is unknown.”

They’re not only living longer, but also very active throughout their lifespans.

“In order to live that long, they have to forage, they have to avoid predators,” says Dixit, who is also a professor of comparative medicine and of immunobiology at YSM and director of the Yale Center for Research on Aging (Y-Age). “So it’s not like they’re living this long in a way that we would think of as ‘aged.’”

The question, says lead author Hee-Hoon Kim, PhD, a postdoctoral associate in Dixit’s lab, is why some species like the golden spiny mouse age so gracefully while others don’t.

In collaboration with researchers at Tel Aviv University, the researchers observed young and old golden spiny mice and compared them with closely related species.

They found a number of ways in which golden spiny mice excel, and three abilities stood out that could help explain their question of graceful aging.

First, this species was already known to repair its skin wounds without any sign of scarring. The researchers discovered that this isn’t limited to young mice; golden spiny mice maintain this ability through advanced age.

Secondly, the mice had healthy thymus glands well into old age. In humans, the thymus sits above the heart and produces a type of white blood cell that’s critical to immune system function. In all vertebrates, the thymus degenerates very rapidly with age.

“Aging of the thymus actually precedes aging of all the other organs,” says Dixit. “But even in very old golden spiny mice, the thymus is structurally and functionally intact. And perhaps this gives the mice a much stronger immune system into old age.”

The researchers also found that older golden spiny mice didn’t appear to have the declines in learning and memory one would expect of an aging animal.

“These are all of the major pathways that decline with age,” says Dixit. “Understanding how they’re maintained through age in this species could be of extreme importance.”

Chronic low-grade inflammation worsens as we age—a process known as “inflammaging.” Much of this occurs in fat tissue. The researchers looked at gene expression in golden spiny mouse fat tissue for clues as to how the mouse evades inflammaging, and they came across a protein called clusterin.

Clusterin helps get rid of misfolded proteins in the body, limiting their toxic effects. It has been linked to reduced neuroinflammation in Alzheimer’s disease and longer lifespan in many mammals, humans included (people 100 years or older tend to have higher concentrations of clusterin, for instance). In aged golden spiny mice, immune cells in fat tissue highly express the gene that codes for clusterin.

To test clusterin’s effects more directly, the researchers administered the protein to regular lab mice. They found that it conferred some of the healthy aging effects they observed in golden spiny mice—the lab mice experienced less motor decline and had healthier organs than mice that didn’t receive clusterin. They also showed signs of reduced inflammaging. The researchers observed these benefits in human white blood cells exposed to clusterin as well.

“We think that clusterin is one of the key operators of how golden spiny mice resist age-related decline,” says Kim. “This is a small start to a big narrative.”

Animals in the wild don’t die of old age. Often their ends are brought on by predators, lack of food, or infection. Because of this, healthy aging isn’t something natural selection can select for—not enough animals live long enough for healthy aging traits to confer an advantage to their species’ survival.

But golden spiny mice have made some adaptations that give them a better chance at longer life. Rather than being nocturnal, for instance, these mice are active in the daytime, allowing them to avoid food competition among other mouse species and the predators that come out at night when other mice are active.

Golden spiny mice are also resistant to toxins, and they can survive prolonged periods of starvation by downregulating their energy expenditures. This enables them to use less energy while still being active enough to seek out food. And the mice grant themselves a head start early in life. Pups are born more developed than other mice and multiple females take care of pups, giving them a higher chance of survival.

“So they have many ways of avoiding death,” says Dixit. “And we think that natural selection is then able to endow those healthy aging traits, which are then passed on from generation to generation.”

It’s clear, say the researchers, that golden spiny mice have metabolic pathways that control resilience to aging. And it seems other mice—and humans—may have these pathways too, they’ve just gone dormant for some reason or another. But they can be reactivated by proteins like clusterin.

These pathways, says Dixit, may be a way to enhance aging and longevity in humans. “We think that these are going to be stepping stones for new drugs in the future.”