Some of the best clues to living a long, healthy life may be hidden in the DNA of bats, mammals that can survive for remarkably long periods relative to their body size.
The idea fascinated Juan Manuel Vázquez when he was a graduate student at the University of Chicago. At the time, however, there was little published genomic information on bats that could help answer questions about longevity. After becoming a UC Berkeley postdoctoral fellow in 2020, he began searching across the western US for bat species that could provide tissue samples for DNA sequencing.
With the help of Berkeley college students, Vázquez 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 gender. myotiswhich includes some species with exceptionally long lifespans. A Brandt myotis, Myotis brandtiiIt was ringed in Europe and then recaptured 50 years later.
Bat genomes reveal connection to longevity
In a new study published in NatureVázquez and his colleagues present the first analysis of eight myotis genomes. Their results point to a strong connection between life expectancy and immune function. 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. The researchers also found substantial overlap between genes associated with aging and genes involved in defense against disease, suggesting that studying one process could help explain the other.
“Bats evolved to live for a long time without contracting diseases, which suggests that we don’t necessarily need to consider diseases of aging and infectious diseases as completely separate fields,” Vázquez said. “We can look at these bats and try to understand how, in the same way that you can improve your immune system to fight viruses, maybe you can improve your immune system so that it doesn’t decline with age. Or maybe bats can help us find ways to fight tumors so that our immune system doesn’t get tired, and that can also help us deal with other stresses of life and not deplete our immunity.”
Damaged bat cells choose self-destruct
As part of the study, Vázquez grew cells collected from bat wing biopsies in the laboratory. (Currently it has cell cultures of 259 individuals representing 32 species). He then exposed the cultured cells to toxic chemicals to see how they responded to severe damage.
The oldest bat in his sample, the widespread little brown bat (Myotis lucifugus), reacted unexpectedly. Instead of turning on genes that produce DNA repair proteins, the cells increased the activity of genes that promote cell death.
“We found literally the opposite of what we expected if you treated 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 changes course to prioritize eliminating damaged cells. The elephant, another long-lived, cancer-resistant species, has exactly the same strategy: If you can’t save the cell, kill it.”
The result suggests that the animals may have developed very different strategies to prevent damaged cells from becoming dangerous. Understanding those strategies could provide valuable clues about longevity, according to Peter Sudmant, an associate professor of integrative biology at Berkeley who studies the genetics of aging and lifespan.
“By looking at the diversity of life and the remarkable longevity of different species, we hope to better understand the interaction between DNA damage and the immune system to allow us to live full and healthy lives,” he said.
“If you start looking at long-lived species like elephants, whales and bats, you start to find ways that nature has already solved many of these problems in human health,” Vázquez 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 represent 20% of all mammal species, occupy habitats on all continents except Antarctica and have adapted to a wide range of ecological niches.
Among the 1,511 known species of bats, about 139 belong to the myotis gender. These bats are especially interesting because closely related species can have dramatically different lifespans. Brandt’s myotis can survive half a century, while black myotis, miotis nigricansfrom South and Central America, lives only about seven years. Vázquez compared the contrast to a hypothetical situation in which our close relative, Homo neanderthalensislived nine times longer than moderns Homo sapiens.
Another unusual feature of bats is their immune system. Scientists have discovered that it works at an unusually high level, helping bats control harmful inflammation while living with persistent viral infections without getting sick.
This ability allows healthy bats to harbor an extraordinary variety of viruses. Some of those viruses, including those linked to the cause of COVID-19, can be transmitted to humans.
Researchers have proposed that bats’ powerful immune systems may be related to their intense physical activity. Vázquez compares the night flights that bats make while hunting for insects to running several ultramarathons every day.
“Bats have evolved this incredible fitness ability, 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 done, we can find completely new and unexpected ways to deal with the normal things that cause human diseases.”
Longevity genes also help bats fight viruses
The new genomic analysis offers another intriguing connection. Each time Vázquez identified a gene associated with bat lifespan, his collaborator Elise Lauterbur, then at the University of Arizona, often identified the same gene as one involved in interactions between bats and viruses.
“There is much more overlap than would be expected simply by chance between genes associated with longevity and genes associated with viral interactions,” he said.
The researchers also found that myotis Bats possess an unusually large number of genes that produce proteins that interact with DNA viruses, such as herpes viruses, that carry their genetic information in DNA.
Those proteins can help viral infection or help protect the animal. A protective function, for example, may involve increasing the production of interferon, an antiviral signaling protein that helps coordinate immune defenses.
“Proteins that interact with viral DNA were strongly enriched for selection in bats, unlike most other mammals, where there is very strong enrichment for selection for proteins that interact with DNA and RNA,” Sudmant said.
Humans and other primates show a different pattern. They tend to have more genes that make proteins that interact with RNA viruses, including viruses like COVID and HIV, compared to DNA viruses.
Why bat viruses can be so dangerous to humans
That evolutionary mismatch between the immune defenses of bats and humans could help explain why some viruses that jump from bats to people can cause serious zoonotic diseases.
“Humans and bats do not adapt well to each other,” Vázquez said. “That’s one of the reasons we have to be careful when working with bats: It’s a two-way street for zoonoses. We don’t want to give something to the bat and we don’t want to get something from the bat. That mismatch is definitely something we should investigate more.”
Vázquez continues to investigate the genetic mechanisms that control longevity using cell cultures in his new faculty position at Pennsylvania State University. Meanwhile, Sudmant is focusing more closely on how those cells regulate their immune responses.
“One thing I’m really excited about is the balance between how a bat protects itself by producing proteins that attack the genomes of viruses and also protects its own genome from attack by those proteins,” he said.
Currently, Sudmant maintains cell cultures of numerous primate species and uses them to investigate the genetics of longevity and the relationship between lifespan and DNA repair genes.
In addition to Vázquez, 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.