Understanding the Aging Brain Through Its Genetic Roots
Understanding how the brain changes over time, and why those changes lead to disease, remains one of the most difficult challenges in science. For Josh Dubnau, professor in the Department of Anesthesiology in the Renaissance School of Medicine at Stony Brook University, that challenge begins at the level of DNA. With a secondary appointment in Neurobiology and Behavior, his work sits at the intersection of genetics, brain function and disease.
Dubnau approaches neuroscience through genetics, studying how changes in DNA shape brain function over time. “As a geneticist, you’re making manipulations at the DNA level and observing the effects on the organism,” he explains. “It’s about connecting that path from genes to behavior.”
Early in his career, Dubnau’s lab made a discovery that would reshape the direction of his research. While studying how genes influence learning and memory, his team found that genes known for suppressing virus-like elements in the genome were influencing cognitive function.
“That was kind of a head-scratcher,” Dubnau says. “What initially looked like a memory defect turned out to be a very rapid, age-dependent cognitive impairment. That set me off on the path of studying this.”
That finding led his lab to focus on retrotransposons, often described as “jumping genes.” These ancient genetic elements, closely related to retroviruses like HIV, are embedded in our DNA and typically remain inactive, but can become active with age or stress, copying and inserting themselves into new parts of the genome.
“The central question we’re trying to answer,” he says, “is what role these ancient, virus-like elements in our genome play in neurodegeneration.”
Over time, the cellular systems that suppress these elements begin to fail. As a result, retrotransposons can become increasingly active in the aging brain, potentially causing DNA damage, inflammation and other forms of cellular stress. Dubnau coined the term “retrotransposon storm” to describe this surge of activity, reflecting the idea that the brain becomes collateral damage in a long-running genetic conflict.
His research suggests that this process may contribute to neurodegenerative diseases including ALS, frontotemporal dementia and Alzheimer’s disease. Rather than treating these conditions as entirely separate, Dubnau emphasizes that they often share underlying biological mechanisms.
One important piece of that shared biology is a protein called TDP-43. In healthy cells, it helps regulate gene activity inside the nucleus. In disease states, it moves out of the nucleus and forms clumps in the cytoplasm, disrupting normal cellular function. The location of this damage in the brain helps determine how the disease presents, affecting movement in some cases and memory or cognition in others.
These discoveries also point to possible treatments. Because retrotransposons are so similar to viruses, drugs originally developed for HIV may offer a way to suppress their activity. Researchers are now exploring whether these existing therapies could be used to slow neurodegeneration.
A key part of Dubnau’s research relies on Drosophila melanogaster, the common fruit fly. Though simple, fruit flies share many genes with humans, making them a powerful system for studying processes like memory and aging. For more than a century, scientists have used fruit flies to uncover fundamental principles of genetics, many of which continue to inform modern biomedical research.
Dubnau’s path to neuroscience reflects this integration of disciplines. Initially drawn to behavior, he trained as a geneticist in graduate school, studying embryonic development. His perspective shifted when he realized that the same genetic tools could be used to study the brain, allowing him to connect molecular changes directly to behavior.
At the same time, Dubnau emphasizes that breakthroughs like these depend on basic science. Many of the most important discoveries in biology did not begin with a direct focus on disease. “You don’t get effective treatments without first understanding how the system works,” he says. “That foundation in basic science is essential.”
This approach is reflected in his role as director of the Center for Developmental Genetics at Stony Brook. The center brings together researchers who share common tools and approaches, from genetics and imaging to biochemistry, creating an environment where collaboration happens naturally across disciplines.
For Dubnau, the most rewarding part of the job is still the day-to-day process of discovery. “It’s sitting with a student, looking at their data and figuring out the next experiment,” he says. “That’s the part I enjoy the most.”
By revealing how hidden genetic activity shapes the aging brain, Dubnau’s work is helping redefine how scientists understand neurodegenerative disease and opening new paths toward potential treatments.
—Minji Kang