Each day technicians at the Jackson Laboratory in Bar Harbor, Maine, check on special groups of mice in their care. The mice are all more than 600 days old, roughly 60 in human years; some are much older. A few may need help reaching their water dispensers, but many are how humans hope to be as we age: “curious, energetic, unbelievably active,” says Nadia Rosenthal, the lab’s scientific director. “It takes them a little longer to run from one side of the cage to the other,” but often “that’s the only difference.”
In medical research, lab mice and rats die for us in great numbers. Sacrificed during or after experiments, they leave us with information that, over the years, has helped us understand diseases, develop medicines and map the functions of particular genes. But some aging-focused research projects require something else from these animals: that they stay alive, and healthy, for as long as possible.
So in labs from North Dakota to Mumbai, select rodents grow old under heavy scrutiny. Tucked away from the world to avoid pathogens and other confounding variables, sleeping in piles and doing flexed-arm hangs, and soldiering on as their cage mates die, they’re helping to illuminate certain mysteries of aging and test the efficacy of life-extension methods that may eventually be used for humans. They are rarely sung heroes in our quest to understand, and perhaps soften, the ravages of time.
The world is full of creatures that age in ways humans might consider aspirational, including bowhead whales that enjoy a cancer-free life that can span two centuries and jellyfish that respond to stress by becoming polyps again. Researchers look into their methods to learn more about the evolutionary tweaks that allow for good health and long life spans.
Mice are not like that; they’re like us. “Their similarity to humans is profound,” Rosenthal says. In general, mice are good models for biomedical studies because of all they share with people: the same organs and physiological systems, undergirded by an almost identical set of genes. “We don’t have big ears and tails, and no fur,” she says, but “the inside is totally identical.”
Since at least the 1920s, researchers hoping to understand how and why aging occurs have watched ordinary lab mice go through it. Early on, the work was largely descriptive, says Richard Miller, a professor of pathology at the University of Michigan. “You’d get lots of papers saying the skin changes when the mouse gets old, and [the reflexes get] slower, and the heart changes and the bones change.”
In 1935 a group of researchers led by nutritionist and gerontologist Clive McCay made a breakthrough. They put a group of rats on a nutritious but calorie-restricted diet and found that they lived about 33% longer than average. This was the first demonstration “that aging could be slowed down,” Miller says. According to Roger McDonald and Jon Ramsey, writing in the Journal of Nutrition, it also established “a fundamental prerequisite for valid longevity studies”—that animals “must be given the opportunity to achieve old age.”
After that breakthrough came a small flurry of studies, establishing that one or another drug helped to extend life span in a group of mice. But, Miller says, the high cost of more systematic investigations—as well as the idea, once pervasive, that aging is too complicated to slow down—meant these were largely one-offs until 2002, when he and others began an ongoing project called the Interventions Testing Program (ITP).
For this study, which is funded by the National Institute on Aging, three labs in three states—at Maine’s Jackson Lab, the University of Michigan and the University of Texas Health Science Center in San Antonio—collectively raise hundreds of mice each year, in highly controlled conditions. A subset of these mice are given drugs that seem promising for life span extension and are supported to live for as long as they can.
Participants in the ITP belong to a lab mouse stock called UM-HET3, or HET3 for short. Many popular lab mouse types are inbred and thus genetically identical. Studying a whole group of these mice is “like studying one person”—of limited utility when trying to find interventions that might help the whole human population, says Rosenthal, a co-principal investigator in the ITP. While wild mice are naturally diverse, they’re difficult to work with: Lab veterinarians handling them sometimes wear protective chain-mail sleeves.
HET3s, who as pups range from brown to black in color before settling on a grayish shade called agouti, were bred to be the best of both worlds: robust yet mild-mannered Everymice. All HET3 mice share the same grandparents, and thus half their genes, but “a random half,” Miller says, making each cohort genetically diverse enough to be “a valuable model for people.”
With each population’s genes reasonably jumbled, the ITP researchers, veterinarians and lab techs work hard to make sure almost everything else about the life of each mouse is exactly the same for each cohort—enclosure to enclosure, lab to lab and year to year. This level of control allows them to test the efficacy of specific drugs and drug combinations. If a particular intervention extends mouse life span in many of these genetically diverse mice, and at all three sites, “you know you’ve really got something,” says Peter Reifsnyder, manager of the Harrison Lab, which supervises ITP studies done at the Jackson Laboratory.
Not everything can be successfully controlled for. ITP researchers are unsure why male mice that participate in the study in Michigan always live a bit longer than those in Maine and Texas, or why both male and female mice in Michigan weigh slightly less than their cross-state counterparts despite an identical diet. Miller speculates that there may be differences between the sites that matter to mice but are imperceptible to us—“maybe there’s a smell at Michigan that they like,” he says.
Over the years, the ITP has surfaced several promising life-span-increasing interventions. The most successful, mousewise, is a combination of the immunosuppressive drug rapamycin and the glucose regulator acarbose, which allowed mice in the ITP to live an average of 29% longer. Other stakeholders are now investigating these and other successful drugs further, in mice, different study animals or occasionally themselves, Miller says.
The Jackson Lab runs numerous mouse aging studies and sells pre-aged mice to other research groups. (A single 90-week-old HET3 mouse costs almost $600.) The mice are visited every day, and aged ones get considerations related to their status, says head veterinarian Linda Waterman: “Can they reach their food and water readily? Do they have soft bedding?” In geneticist Gary Churchill’s lab, technicians keep “a whole list of old-fashioned female names” to give mice when they turn 4, he says, a tradition that dates to around 2016, when two particularly long-lived mice, from a different study of genetically diverse mice, were christened Grace and Blanche.
This careful attention extends up to the very end of a mouse’s life. When mice in the ITP do eventually die, they’re put in fixative as quickly as possible so the researchers can study their tissues. If it seems a mouse will die in the next day or two, they may be humanely euthanized to prevent suffering and ensure their tissues are well-preserved.
The need to balance gathering accurate life span data with these concerns has led Reifsnyder to brainstorm potential ways to keep track of his charges’ body temperature, which dips before death. So far, “we haven’t come up with a best way of knowing exactly when a mouse is going to die,” he says, though it’s something he puts a lot of thought into.
Without a system, experience is key: “Most of the people who work at [the Jackson Laboratory] have a kind of a sense for when a mouse is experiencing well-being versus not,” says Rosenthal, who, she says, works with one technician who’s so attuned to her mice that she can predict their deaths. “It’s so important to spend a lot of time with your model organism, so that you really get to know.”
The world’s longest-living lab mice are a special class of rodents known as dwarf mice. These tiny titans have mutations that block the production or actions of growth hormone, thanks to natural gene misprints or genetic engineering.
Each dwarf mouse is about as big as an unshelled walnut, with a round face, snub nose and tiny feet. “The cutest things ever,” says Holly Brown-Borg, a biogerontologist at the University of North Dakota who works with a particular strain called Ames dwarf mice. And they’re very chill: Andrzej Bartke, director of geriatric medicine at the Southern Illinois University School of Medicine and a pioneer in the use of dwarf mice to study aging, has posed for headshots with one perched on his shoulder like a parrot.
For reasons experts are still untangling, these Zen mini-mice have an average life span that can stretch over 60% longer than that of their traditional relatives, including their siblings. (Their mutations are recessive, so a litter of mice may contain both normal-size mice and dwarf mutants.) Many dwarf mice live longer than four years, making them the equivalent of centenarian humans: rodent sages, each in the body of “a big baby mouse,” Bartke says.
Because lab mice are so rarely given the opportunity to age beyond their perceived usefulness, the dwarf mouse’s penchant for extralong life wasn’t discovered until the mid-1990s. Even then it was something of an accident, Brown-Borg says. As postdoctoral students in Bartke’s group, she and her husband, Kurt Borg, were looking for mice of a certain age for an immune system study when they realized that the lab’s spare dwarf mice were often older than the regular-size ones. This came after other work, by the geneticist Thomas Wagner, showed that mice with extra growth hormone had unusually short life spans. The group wondered whether the opposite was also true.
When Borg and Brown-Borg set aside some dwarf mice to see how far they could take things, the longest-lived made it past four years—long enough for the couple to finish their postdocs and get jobs. A few years later, in 2003, a genetically engineered dwarf mouse in Bartke’s lab lived to 4 years, 11 months and 21 days—roughly 180 in human years—winning the Methuselah Mouse Prize, an award once given to long-lived mice, and setting a lab mouse life span record that still hasn’t been broken. (This mouse was also “kind of forgotten—left over from some study,” Bartke says.)
Since these discoveries, researchers have been looking into the extent of the dwarf mouse’s special powers. “If we look for mechanisms related to health, these animals are probably teaching us many things,” says Bartke. They’ve found the little guys are better than normal mice at handling oxidative stress, a buildup of reactive molecules that can damage tissues. They have “exquisitely good regulation of blood sugar,” he says. Put on high-fat diets, they avoid fatty liver disease, and when mice bred to develop Alzheimer’s-like conditions are crossed with dwarf mice, their descendants are slower to experience the hallmarks of that disease.
“There’s something about their metabolism physiology that helps to slow or prevent some of these age-related diseases,” says Brown-Borg. “They not only live longer, but they live healthier.” Humans with similar genetic growth hormone deficiencies don’t seem to have unusually long life spans. So researchers focus on some of these other effects, trying to trace their relation to health and life.
Even during behavioral tests, dwarfs aren’t like other mice, Brown-Borg says. They amble through mazes and build nests under their running wheels. Dropped in a warm water bath, where normal-size mice furiously paddle, dwarfs “spread their legs out and float.” Although this attitude is harder to directly connect to their long life span, it does seem to contain a lesson.
Other researchers prefer to test life span extension possibilities in rats—also well-characterized lab animals that share genes and physiology with humans. The world’s oldest known lab rat died on March 3 of this year, in the animal facility of the Shobhaben Pratapbhai Patel School of Pharmacy and Technology in Mumbai. Her name was Sima, and she was a Sprague-Dawley rat, a snowy-furred, rosy-eyed albino strain. Three days before she passed away, she had turned 4, a milestone her caretakers celebrated with birthday cake.
Sima was the last of her cohort, a group of 16 Sprague-Dawley rats. She and the others had been procured at age 2 by Yuvan Research Inc., an anti-aging startup in Mountain View, California. Every two or three months, Sima and seven of her colleagues received injections of E5, a proprietary plasma mixture the company developed that’s made from the blood of young pigs. The other eight, the control group, got saline placebos.
According to data from the company, whether these rats were given E5 determined the course and length of their unusual retirement. (Although this data hasn’t yet been peer-reviewed or made public, another study with similar results was published earlier this year in GeroScience.) Compared with the control group, Sima and the rest of the experimental group had less inflammation, lower triglycerides and more glutathione, a liver product that prevents cell damage.
In data from the GeroScience study, rats on E5 solved and remembered mazes more effectively than those stuck with their own blood. In the unpublished study, they gripped a bar for longer, showing almost as much strength as young rats. Juiced up with the proprietary pig plasma, “these rats become younger, livelier,” says Akshay Sanghavi, the company’s chief executive officer. “We are able to reverse the biological age.”
Yuvan Research takes a different approach to anti-aging. Instead of testing many compounds that might extend life span, or digging into the traits that tend to accompany long life, they operate with the assumption that aging is programmed into mammalian cells, with certain forms of degradation set to begin right after puberty. They try to hack that process in an older animal by sending in signaling molecules from younger bodies—this can make cells “closer to the donor’s age,” Sanghavi says.
Scientists have been making rats swap blood since at least 1864, when a French physiologist named Paul Bert joined the circulatory systems of two albino rats through their flanks, a technique now called parabiosis. Over the years, researchers built on this idea, eventually stitching together rats of different ages and finding that young blood increased the old rats’ life spans, an idea now perhaps better known from conspiracy theories and the unusual behavior of tech mogul Bryan Johnson.
Yuvan Research originally sought to clean up young rat blood and transfer it into elderly rats, Sanghavi says, but they couldn’t find an easy way to do it. Instead, Sanghavi and his co-founder, the geneticist Harold Katcher, decided to create an injectable: “something that was in small doses but could be very powerful,” Sanghavi says. Switching to pig blood meant they could also see if their driving principle would work across species.
When Sima entered the study, she was known as Rat T6. Like Grace and Blanche before her, she received a name when she began outperforming the others in her cohort. In Sanskrit, Sima means “barrier” or “border,” which Sanghavi says references the natural limits of aging. “I could see that she was going to cross,” he says.
Life span studies, like those done with Sima and other record-setters, are just one type of aging research. Now that the extent of the unusual life span of dwarf mice is well-established, most of the studies involving them focus on other things. (In her lab, Brown-Borg always makes sure a few live out their natural extralong life, “just to make sure that it’s still happening,” she says.) Other investigations of the aging process may instead look into how interventions early in life affect aging rates, or compare different mice of the same age to see, for instance, how their genes influence how they get old. And in many cases, rodents make up just one step in a long testing process: Buoyed by their success with rats, Yuvan Research is moving on to beagles.
But where it’s possible and useful, mice, rats and those who care for them continue to chase that border. “For scientists interested in aging, end-of-life is just as important as beginning of life,” Rosenthal says. So in places like the Jackson Lab, where the infrastructure allows them to achieve economies of scale, “we can do big experiments with hundreds of mice and just let them live,” she says. “We can keep them in the cages for long periods of time, for years, and just wait for them to get older, and watch.”
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