Bat DNA Holds Clues to Longevity and Disease Resistance

Long-lived bats combine powerful immune defenses with unusual strategies for eliminating damaged cells, potentially helping them avoid cancer and disease for decades. Researchers from the University of California, Berkeley, hope these genetic tricks could eventually reveal new ways to protect human health during aging.

Some of the best clues to living a long, healthy life may be hidden in the DNA of bats. These mammals can survive for remarkably long periods relative to their body size. The idea fascinated researcher Juan Manuel Vazquez. After becoming a UC Berkeley postdoctoral fellow in 2020, he began searching across the Western U.S. For bat species to provide tissue samples for DNA sequencing.

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

Genomic Links to Longevity and Immunity

In a new study published in Nature, Vazquez and 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 longevity may depend partly on an immune system that remains highly effective against both infectious organisms and cancer. Researchers found substantial overlap between genes associated with aging and genes involved in disease defense. Studying one process could help explain the other.

"Bats evolved to live for a long time without getting diseases," 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."

A Strategy of Cellular Self-Destruction

As part of the study, Vazquez grew cells from bat wing biopsies in the lab. He currently has cell cultures from 259 individuals representing 32 species. He exposed the cultured cells to toxic chemicals to see their response 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 activity of genes that promote cell death.

"We found the literal opposite of what we expected," Vazquez explained. "The longest-lived bat in North America decides 'I can't save this ship' and immediately switches gears to prioritize killing off the damaged cells." He noted the elephant, another cancer-resistant, long-lived species, uses the exact same strategy.

The result suggests animals may have evolved 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.

An Active Life and a Hyper-Alert Immune System

Bats account for 20% of all mammal species and occupy habitats on every continent except Antarctica. 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.

Vazquez compared this contrast to a hypothetical situation where Neanderthals lived nine times longer than modern humans. Another unusual feature is the bat immune system. Scientists found it operates at an unusually high level, helping bats control damaging inflammation while living with persistent viral infections without becoming sick.

That ability allows healthy bats to host an extraordinary variety of viruses. Some, including viruses related to the cause of COVID-19, can spill over into humans. Researchers propose bats' powerful immune systems may connect to their intense physical activity. Vazquez compares nightly insect-hunting flights to running several ultramarathons daily.

Longevity Genes and Viral Defense

The new genomic analysis offers another intriguing connection. Whenever Vazquez identified a gene associated with bat lifespan, his collaborator Elise Lauterbur 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 Myotis bats possess an unusually large number of genes producing proteins that interact with DNA viruses, such as herpes viruses. Those proteins can either assist viral infection or help protect the animal. One protective function can involve increasing production of interferon, an antiviral signaling protein.

"DNA viral interacting proteins were strongly enriched for selection in bats in contrast to most other mammals," Sudmant said. Humans and other primates show a different pattern, tending to have more genes producing proteins that interact with RNA viruses.

This evolutionary mismatch between bat and human immune defenses could help explain why some viruses moving from bats into people cause serious zoonotic diseases. "Humans and bats are badly suited to each other," Vazquez said. "That mismatch is definitely something we should look into more."

Vazquez continues investigating genetic mechanisms controlling longevity at Pennsylvania State University. Sudmant is focusing more closely on how bat cells regulate their immune responses, particularly the trade-off in producing proteins that attack virus genomes while protecting their own.