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The idea fascinated Juan Manuel Vazquez while he was a graduate student at the University of Chicago. At the time, however, there was little published genomic information about bats that could help answer questions about longevity. After becoming a UC Berkeley postdoctoral fellow in 2020, he began searching across the Western U.S. for bat species that could provide tissue samples for DNA sequencing.

With help from Berkeley undergraduates, Vazquez traveled throughout the region, setting up mist nets over streams, ponds and rivers at night. The team captured bats, collected small biopsy samples and released the animals. Much of the work focused on the genus Myotis, which includes some species with exceptionally long lifespans. One Brandt's myotis, Myotis brandtii, was banded in Europe and then recaptured 50 years later.

Bat Genomes Reveal a Longevity Connection

In a new study published in Nature, Vazquez and his colleagues present the first analysis of eight Myotis genomes. Their results point to a strong connection between lifespan and immune function. The longer-lived bats had higher levels of genes associated with fighting cancer.

The findings suggest that longevity may depend in part on an immune system that remains highly effective against both infectious organisms and cancer. Researchers also found substantial overlap between genes associated with aging and genes involved in disease defense, suggesting that studying one process could help explain the other.

"Bats evolved to live for a long time without getting diseases, which suggests that we don't necessarily need to look at diseases of aging and diseases of infection as completely separate fields," Vazquez said. "We can look at these bats and try to understand how, in the same way you can improve your immune system to fight off viruses, maybe you can improve your immune system so it doesn't decline in old age. Or maybe bats can help us find ways to fight off tumors so our immune system doesn't get tired, and that can also help us deal with other stresses of life and not exhaust our immunity."

Damaged Bat Cells Choose Self-Destruction

As part of the study, Vazquez grew cells collected from bat wing biopsies in the laboratory. (He currently has cell cultures from 259 individuals representing 32 species.) He then exposed the cultured cells to toxic chemicals to see how they responded to severe damage.

The longest-lived bat in his sample, the widespread little brown bat (Myotis lucifugus), reacted in an unexpected way. Instead of switching on genes that produce DNA repair proteins, the cells increased the activity of genes that promote cell death.

"We found the literal opposite of what we expected if you treat the bats with a lethal dose of this chemical," he said. "The longest-lived bat in North America decides 'I can't save this ship' and immediately switches gears to prioritize killing off the cells that are damaged. The elephant, another cancer-resistant species that is long-lived, has the exact same strategy -- if you can't save the cell, kill the cell."

The result suggests that animals may have evolved very different strategies for preventing damaged cells from becoming dangerous. Understanding those strategies could provide valuable clues about longevity, according to Peter Sudmant, a Berkeley associate professor of integrative biology who studies the genetics of aging and lifespan.

"By looking across the diversity of life and the remarkable longevities of different species, we hope we can better understand the interplay between DNA damage and the immune system to enable us to have full and healthy life spans," he said.

"If you start looking at long-lived species like elephants, whales and bats, you start finding ways that nature has actually already resolved a lot of these problems in human health," Vazquez added.

Longevity, an Active Lifestyle and an Immune System on High Alert

Bats have been remarkably successful since they first appeared about 60 million years ago. Today, they account for 20% of all mammal species, occupy habitats on every continent except Antarctica, and have adapted to a wide range of ecological niches.

Among the 1,511 known bat species, about 139 belong to the Myotis genus. These bats are especially interesting because closely related species can have dramatically different lifespans. Brandt's myotis can survive for half a century, while the black Myotis, Myotis nigricans, of South and Central America, lives only about seven years. Vazquez compared the contrast to a hypothetical situation in which our close relative, Homo neanderthalensis, lived nine times longer than modern Homo sapiens.

Another unusual feature of bats is their immune system. Scientists have found that it operates at an unusually high level, helping bats control damaging inflammation while they live with persistent viral infections without becoming sick.

That ability allows healthy bats to host an extraordinary variety of viruses. Some of those viruses, including viruses related to the cause of COVID-19, can spill over into humans.

Researchers have proposed that bats' powerful immune systems may be connected to their intense physical activity. Vazquez compares the nightly flights bats make while hunting insects to running several ultramarathons every day.

"Bats have evolved this incredible fitness capacity, this incredible ability to deal with disease and this incredible ability to be able to prevent cancer," he said. "That means that, by understanding how bats have evolved to do all these things that other mammals haven't, we can find completely new and unexpected ways of dealing with the normal things that cause human diseases."

Longevity Genes Also Help Bats Fight Viruses

The new genomic analysis offers another intriguing connection. Whenever Vazquez identified a gene associated with bat lifespan, his collaborator Elise Lauterbur, then at the University of Arizona, had often identified the same gene as one involved in interactions between bats and viruses.

"There is way more overlap than you would expect just by random chance between the genes that are associated with longevity and genes that are associated with viral interactions," he said.

Researchers also found that Myotis bats possess an unusually large number of genes that produce proteins interacting with DNA viruses, such as herpes viruses, which carry their genetic information in DNA.

Those proteins can either assist viral infection or help protect the animal. One protective function, for example, can involve increasing production of interferon, an antiviral signaling protein that helps coordinate immune defenses.

"DNA viral interacting proteins were strongly enriched for selection in bats in contrast to most other mammals, where there is a very strong enrichment for selection for both DNA and RNA viral interacting proteins," Sudmant said.

Humans and other primates show a different pattern. They tend to have more genes producing proteins that interact with RNA viruses, including viruses such as COVID and HIV, compared with DNA viruses.

Why Bat Viruses Can Be So Dangerous to Humans

That evolutionary mismatch between bat and human immune defenses could help explain why some viruses that move from bats into people can cause serious zoonotic diseases.

"Humans and bats are badly suited to each other," Vazquez said. "That is one of the reasons why we have to be careful working with bats -- it's a two-way street for zoonoses. We don't want to give the bat something and we don't want to get something from the bat. That mismatch is definitely something we should look into more."

Vazquez is continuing to investigate the genetic mechanisms that control longevity using cell cultures in his new faculty position at Pennsylvania State University. Sudmant, meanwhile, is focusing more closely on how those cells regulate their immune responses.

"One thing that I'm really excited about is the trade-off between how a bat protects itself by producing proteins that attack the genomes of viruses but also protects its own genome from being attacked by those proteins," he said.

Sudmant currently maintains cell cultures from numerous primate species and is using them to investigate the genetics of longevity and the relationship between lifespan and DNA repair genes.

In addition to Vazquez, Sudmant and Lauterbur, now at the University of Vermont, other co-authors of the paper include Lucie Etienne of the École Normale Supérieure in Lyon, France, and David Enard of the University of Arizona in Tucson. The work was funded by the National Institutes of Health and the National Science Foundation.