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What bats, primates and even zebrafish tell us about human aging

Black-tailed marmosets cling to a branch with their tails at a zoological park near Tokyo. Marmosets are ideal research subjects because they have a similar metabolism and get similar age-related diseases as humans, one scientist says. (Itsuo Inouye/AP)

Scientists who want to understand why some of us live longer and healthier have traditionally focused on studying centenarians from the world’s “blue zones,” such as Okinawa, Japan, or Ikaria, Greece, where inhabitants routinely shatter longevity records.

Yet Irish bat biologist Emma Teeling thinks the answer can be found among bats in the storybook belfries of the Gothic cathedrals in Brittany, France. Every spring, she and her team travel there to trap hundreds of brown mouse-eared baby and mother bats to collect their blood so they can sequence their DNA. Given that the mothers repeatedly return to their birthplaces to deliver babies, the cathedrals offer a perfect setting to recatch the same bats and study how they’ve aged.

Teeling is convinced these tiny Myotis myotis bats, which weigh at most 1.6 ounces, have aging superpowers that offer clues for improving humans’ health. “Bats can tolerate viruses, rarely get cancer and don’t show signs of aging,” says Teeling of University College Dublin. “They also live way longer than expected, given their small body size.”

Of the 19 species of mammals that outlive humans when adjusted for body mass, 18 are bats. She documented one bat that was trapped as an adult and recaught 41 years later — a remarkable feat of aging considering the bat was about one-third the size of mice, which only live a couple of years.

“I wanted to understand the molecular mechanisms that kept them healthy,” says Teeling, who recently launched Bat1K, an initiative to sequence the genomes of all 1,300 bat species. Of particular interest are the bats’ telomeres, the protective end caps of chromosomes that in most mammals — including humans — shorten as they age.

Yet the telomeres of the Myotis myotis bats stayed the same size year after year, Telling’s team found. To solve the mystery, they compared the associated 225 genes in the bats’ cellular pathway with those of 52 other mammals and discovered two genes that existed only in the bats, and which they think might repair the DNA damage that occurs with aging.

In a paper published this month, they reported sequencing 1.7 trillion base pairs of RNA from 150 bats to find the small regulatory genes involved in those aging pathways. The future goal: “To manipulate those pathways in humans by drugs or potentially gene therapy and ultimately limit and slow down diseases associated with aging in humans,” Teeling says.

Marmosets, other primates

Animals have long been a fundamental part of medical research — more than 140,000 were used in the United States in 2017, according to the Agriculture Department — to test everything from drugs to surgical techniques before they’re tried out in humans. Yet a new wave of researchers are looking at certain animals’ unique biology to learn how we might live and thrive longer.

“Aging research has shifted its focus from increasing longevity to increasing our health span, which is how long people can live in a healthy way,” says Corinna Ross, a primatologist at the Texas Biomedical Research Institute in San Antonio. She studies aging in marmosets. “The goal isn’t to increase the number of 120-year-olds who are living in nursing homes. We want more 80- and 90-year-olds who are living independently.”

Scientists have historically depended on worms and rodents for aging studies, yet a 2017 paper by National Institute on Aging researchers makes the case to focus more on nonhuman primates that share 92 percent of genes with humans and have an “aging process that more closely resembles the human experience.”

Although in 2015 the National Institutes of Health announced it would stop using chimpanzees in biomedical studies, the researchers say that rhesus monkeys and marmosets are useful models to learn about the mechanisms that “lead to age-related decline seen universally, across species.”

For Ross, marmosets are ideal research subjects because they have a similar metabolism and get similar age-related diseases as humans. Marmosets can live up to 22 years, but they show signs of getting older, such as stretching more and leaping less often from branch to branch, as early as 10 years old.

“They age five times faster than humans. That means we can study aging interventions in a much shorter time frame than in humans,” Ross says. For example, she’s evaluating the effect on marmosets of an immunosuppressant drug called rapamycin that has been shown to extend the life span in mice, to see whether it might delay cognitive decline and frailty in the monkeys.

Such primates also provide a unique window into female aging because they have a similar reproductive cycle and offer opportunities to study what happens after menopause. Female rhesus monkeys in particular have a 28-day menstrual cycle and experience the end of their fertility about the same point in their life spans. (They live up to 40 years in captivity.)

Neuroscientist Yuko Hara was curious why some female rhesus monkeys were mentally sharper than other monkeys as they aged and whether estrogen might play a role. In her research at the Icahn School of Medicine at Mount Sinai, she and her team found that monkeys that were given hormone therapy following menopause had better cognitive performance than those who weren’t.

What was important about this research is that the monkeys were given different doses of hormones during the month to mimic the natural hormonal fluctuations of their previous menstrual cycles. Menopausal women, who take hormones, on the other hand, commonly take a constant dose of estrogen with progesterone.

“The monkeys didn’t have the same cognitive benefits when they took it at the same dose every day,” says Hara, who’s now at the Alzheimer’s Drug Discovery Foundation. “This could have implications on the best way to treat postmenopausal women in the future.”

Zeroing in on zebrafish

Given the genetic similarities of primates to humans, it’s not surprising they’re in high demand by scientists and accounted for a record 76,000 of animals in U.S. research studies in 2017. At the same time, the lowly two-inch striped zebrafish, which shares 70 percent of its genes with humans, is also gaining popularity.

“I’m not sure the world is aware these fish are amazing genetic models for humans. I tell people we’re walking fish,” says environmental biologist Keith Tierney at the University of Alberta in Canada. Although they have a short life span of only three years, they grow into adults within three months and give scientists the opportunity to see the effects of various interventions quickly.

Zebrafish also experience the same kind of muscle loss in old age that humans do. Tierney is starting a study that feeds zebrafish various diets (a vegetarian mix, an animal muscle protein mix and another with that trendy new protein source: crickets) to see how it impacts their athletic performance and muscle tone as they get older. “We put them in special zebrafish treadmills to see how fast they move and how much oxygen they use,” Tierney says. “The goal is to learn how to keep our human aging population healthy on less expensive green proteins, which are easier on [the] environment.”

The limits of such science

Despite the wisdom that animals can offer humans, some experts caution against drawing too many parallels, especially since many clinical trials of drugs that show promise in animals fail in humans.

“If we study the DNA of aging in a mouse, it’s not going to give us a predictive value for what happens in humans,” says Ray Greek, an anesthesiologist near Santa Barbara, Calif., and co-author of “Animal Models in Light of Evolution.” “There are too many differences between the species that have been fine-tuned through evolution. We need to change from using animals to studying humans directly.”

Other experts, such as Stanford epidemiologist John Ioannidis, argue that animal studies are necessary to test the safety and effectiveness of interventions before trying them out on humans. “The information we can get from animals before jumping to humans is invaluable,” he says.

Yet there are too many variables, including the complexity of diseases and types of animal, to divine which studies will be useful. One review in the BMJ medical journal documented animal interventions that had the opposite effect on humans. For example, a stroke medication helped animals, but made the condition worse in people.

For researcher Julie Mattison at the National Institute on Aging, animals won’t give us all the answers about how humans age, but they might point scientists in the right direction. Mattison, who studies the impact of intermittent fasting on people’s health and longevity, is designing a trial with rhesus monkeys to look at whether eating for fewer hours for several days at a time will improve their brain functioning, immunity and metabolism.

“Humans studies are often more expensive and complicated because you don’t have the same control and follow-up,” she says. In other words, monkeys don’t live in a world of processed foods, happy-hour invitations and truffle fries.

“The animal model gives us the opportunity to understand the mechanisms for why we might have these benefits,” Mattison says. “It’s easy to tell people to cut back on calories for a few days. But they need to understand what’s going on in their bodies and why a nutritional intervention like this could delay age-related diseases and help them live in good health longer.”

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