When mice reach old age, something surprising happens inside their cells: the genes that take longer to activate start getting left behind.
Scientists at Northwestern Medicine discovered that aging changes how cells read their DNA, flipping a preference toward short, quick genes while leaving longer genes—especially those involved in brain development—struggling to keep up. The findings, published in the Proceedings of the National Academy of Sciences, could one day help researchers develop drugs that slow or reverse aging at the cellular level.
"Our cells have thousands of genes, and they don't all behave the same way as we get older," said Ali Shilatifard, Ph.D., the study's senior author and chair of Biochemistry and Molecular Genetics at Northwestern. "We're starting to understand which ones are vulnerable, and why."
The research team examined tissue from the liver, kidney, and brain of young mice (11 weeks old) and old mice (72 weeks old). They also looked at similar data from human tissue samples. Using a technique called RNA sequencing, they found that older tissues showed less overall gene activity. But the most striking pattern was a shift toward shorter genes—those that can be switched on quickly without much effort from the cell's machinery.
In the aging mouse brain, long genes involved in neurodevelopment became less active, while short stress-response genes ramped up. The scientists also found that two key helpers of RNA polymerase II—the molecular machine that copies DNA into RNA—interact less with each other in aged tissues. One of those helpers, an elongation factor called SPT6, was actually found at lower levels in older cells.
"Longer genes may be at a disadvantage because they have more room for errors," said Marta Iwanaszko, Ph.D., a co-author who designed the study's computational analysis. Long-read RNA sequencing of aged mouse brains revealed a rise in splicing mistakes—essentially, garbled instructions when the cell pieces together gene segments.
Saeid Parast, Ph.D., a postdoctoral fellow and co-first author, said the team is now studying how specific elongation factors balance aging. "ELOA may drive stress gene expression while the loss of SPT6 shuts down long neuronal genes," he explained.
The researchers acknowledge there's more to learn. The current study didn't measure whether the decline in elongation factors actually causes the loss of long gene activity, or is simply linked to it. But the potential is exciting: understanding how to keep RNA polymerase II working smoothly on longer genes could open doors to therapies that protect the brain and other organs as people age.
"A more thorough understanding of elongation control in aging could enable approaches to maintain or increase RNAPII processivity in hope of preventing or reversing aging at the cellular level," the authors wrote.