This pattern differs from humans and other primates, which tend to have more genes producing proteins that interact with RNA viruses, including viruses such as COVID and HIV.

"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," said Peter Sudmant, a Berkeley associate professor of integrative biology who studies the genetics of aging and lifespan.

How do bat cells respond to severe damage?

Vazquez grew cells collected from bat wing biopsies in the laboratory — he currently maintains cell cultures from 259 individuals representing 32 species — and exposed the cultured cells to toxic chemicals to observe how they responded to severe damage.

The longest-lived bat in his sample, the widespread little brown bat (Myotis lucifugus), reacted unexpectedly. 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," Vazquez 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 have evolved very different strategies for preventing damaged cells from becoming dangerous, and understanding those strategies could provide valuable clues about longevity.

Could bats inspire new human therapies?

Vazquez argues that the findings blur the line between two fields usually treated separately.

"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," he 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."

The researchers urge caution, though. These are preliminary genomic findings, and any translation into human medicine remains far off. The study establishes correlations between genes and lifespan; it does not yet demonstrate causal mechanisms.

Still, the long evolutionary view is promising. Bats first appeared about 60 million years ago and now account for 20% of all mammal species, occupying habitats on every continent except Antarctica. Their immune systems operate at an unusually high level, helping them control damaging inflammation while living with persistent viral infections without becoming sick.

Researchers have proposed that this immune strength may connect to bats' 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."

Why can bat viruses be dangerous to humans?

The evolutionary mismatch between bat and human immune defenses could help explain why some viruses that move from bats into people cause serious zoonotic diseases. Healthy bats host an extraordinary variety of viruses, some of which — including viruses related to the cause of COVID-19 — can spill over into humans.

"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."

What comes next?

Vazquez is continuing to investigate the genetic mechanisms that control longevity using cell cultures in his new faculty position at Pennsylvania State University. Sudmant is focusing 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," Sudmant said.

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 National Institutes of Health and the National Science Foundation funded the work.