“Every mammal seems to have their own strategy for longevity and immunity that’s informed by their evolutionary history,” said Juan “Manny” Vazquez, assistant professor of biology at Penn State and co-lead author on the study. “The diseases that we complain about as humans — age-related muscle loss, metabolic disorders, cancer, aging — are all conditions that bats have evolved to deal with. By studying different animals, it can spark inspiration that could lead to breakthroughs for human health.”
After rodents, bats are the second largest group of mammals on Earth — roughly one in five mammals are bats — and they’ve evolved to have long lifespans and exceptional immune defenses, according to Vazquez, who is also a co-hire of Penn State’s Huck Institutes of the Life Sciences. The specific genus of bats, Myotis, is vast with more than 139 species inhabiting six continents that all descended from a common ancestor approximately 33 million years ago. Lifespan ranges from seven years to 42 years, a six-fold difference among species within the same genus that are otherwise identical in shape, size and even the organization of their DNA.
Generally, researchers have approached the study of longevity and immunity and cancer resistance in bats as separate questions, explained Elise Lauterbur, assistant professor of evolutionary biology at the University of Vermont and co-lead author on the paper. Here, the researchers noticed that the genes involved in aging overlapped with those that have evolved to combat viruses and suppress cancer. The researchers wanted to examine the genetic pathways involved in these processes together to understand how they have evolved to account for the similar genetic adaptations and their link to longevity.
“The remarkable immune systems of bats have long been of interest, and we are just scratching the surface of the insights we can gain from bat genomes into the immune innovations of these animals and their links to lifespan,” said Peter Sudmant, associate professor of integrative biology at the University of California, Berkeley, and co-senior author on the paper.
The researchers assembled near complete genomes for eight North American species of Myotis bats, the most detailed genome assemblies ever constructed in bats. These are standardized maps of the species’ genes and other chromosomal regions that allow researchers to look for genetic patterns and variations in DNA between species at a scale that previously wasn’t possible. They also conducted experiments in the laboratory using a cell culture model of bat cells to understand how the cells respond to DNA damage. The research team collected skin samples from the wings of the Myotis bats to derive the primary cell cultures and the genome assemblies.
“The genome is the first step towards unlocking biology; however, it's only the first step,” Sudmant said. “Here we begin by generating genomes of diverse species and then follow up on our genomic insights using experiments in bat cells. This approach to biology is extremely impactful as it enables us to explore the remarkable phenotypes, or characteristics, of species living at the extremes in a dish.”
The study showed that Myotis bats defend against viruses differently than other mammals. Researchers focused on the bats’ genes that contain instructions for proteins that engaged with viruses, called viral interacting proteins or VIPs, and that have an equivalent copy in humans. They looked at how they have evolved and found that bats showed the strongest signs of adaptation in proteins that interact with DNA viruses. Primates, rodents and other large mammals, on the other hand, have adapted to handle rapidly evolving RNA viruses.
“What we found in bats is that there’s a much stronger signature for making new genes to deal with RNA viruses. Bats have to evolve fast to handle RNA viruses because these types of viruses change quickly,” Vazquez said. They keep extra copies of these key immune genes through a phenomenon called copy number variation, to respond to changes in RNA viral loads. “Since DNA viruses are generally more stable and don’t evolve as quickly, bats can use existing DNA repair tools to tweak the proteins that interact with these viruses,” he said.
It’s not that humans don’t contract DNA viruses or that bats don’t battle RNA viruses. Instead, the mechanisms used to defend against the viruses aren't the same, which could explain why bats can coexist with viruses without getting sick.
“Different kinds of genetic changes could provide an advantage in responding to challenges posed by the different types of viruses,” Lauterbur said. “Understanding those differences could help us understand how immune systems balance the need to control viruses with the need to avoid excessive damage from the immune response itself.”
As Myotis bats have evolved over millions of years of natural selection to effectively fend off DNA viruses and repair DNA damage, their genomes have also been shaped to reduce their risk of cancer despite their long lifespan, the researchers explained.
“There are three main ways to stop cancer: You can prevent it. You can repair damaged DNA that could lead to mutations that may develop into cancer. Or you can just get rid of anything that’s damaged,” Vazquez said. Long-lived bats appear to favor the third option.
Using a cell model derived from the cells of the little brown bat, a bat common to North America and one of the longest-lived bats, the researchers found that these bat cells were extremely sensitive to DNA damage compared to other bat species. Rather than repairing the damage, cells were purged and replaced with new cells, reducing the risk of accumulating mutations that could lead to cancer. This type of response also has been seen in other animals with long lifespans including elephants, naked mole rats and bowhead whales.
This study is the culmination of seven years of research, Vazquez said. He plans to continue to investigate the evolution of longevity-associated traits. For example, future studies will investigate gene regulation and expression in bats, elephants, whales and other studies.
“What we found in this study is that there’s a lot of evolutionary pressure to develop adaptations to genes at the intersection of disease, cancer and longevity,” Vazquez said. “It’s an interesting finding because that means you don’t have to treat all these different biological challenges as separate problems. You can focus on the genes at the intersection of these processes.”
Lucie Etienne of the École Normale Supérieure in Lyon, France, and David Enard of the University of Arizona, Tucson, are also co-senior authors on the paper.
Funding from the National Institutes of Health’s National Institute on Aging under award number K99/R00AG088361 contributed to the Penn State portion of the research activities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
For a full list of authors and funding sources, see the paper.
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