STANFORD — Scientists at Stanford University discovered that the cellular machinery responsible for building proteins begins to jam and malfunction over time in aging brains. In older killifish brains, ribosomes frequently stalled or collided with one another during translation elongation, leading to reduced production of healthy proteins and increased protein aggregation.

The research points to breakdowns in proteostasis—the system that helps cells correctly build, maintain, and dispose of proteins—as a key factor in age-related cognitive decline and neurodegenerative diseases like Alzheimer’s. The discovery may explain “protein-transcript decoupling,” a phenomenon in aging organisms where changes in mRNA levels no longer correspond to changes in protein levels.

The study focused on the turquoise killifish (Nothobranchius furzeri), which has an extremely short lifespan and rapidly develops age-related problems. The researchers compared young, adult, and old killifish, examining amino acid levels, transfer RNA, messenger RNA (mRNA), proteins, and other components involved in cellular protein manufacturing.

“We know that many processes become more dysfunctional with aging, but we really don't understand the fundamental molecular principles of why we age,” said study author Judith Frydman, the Donald Kennedy Chair in the School of Humanities and Sciences at Stanford. “Our new study begins to provide a mechanistic explanation for a phenomenon widely seen during aging, which is increased aggregation and dysfunction in the processes that make proteins.”

“Showing that the process of protein production loses fidelity with aging provides a kind of underlying rationale for why all these other processes start to malfunction with age,” Frydman said.

Jae Ho Lee, co-lead author of the paper and now an assistant professor at Stony Brook University, worked on the study as a postdoctoral scholar in the Frydman lab. “Our results show that changes in the speed of ribosome movement along the mRNA can have a profound impact on protein homeostasis — and highlight the essential nature of 'regulated' translation elongation speed of different mRNAs in the context of aging,” Lee said. He added, “This work provides new insights on protein biogenesis, function, and homeostasis in general, as well as a new potential target for intervention for aging-associated diseases.”

The researchers plan to investigate whether ribosome dysfunction directly contributes to human neurodegenerative diseases and whether therapies targeting protein production could protect the aging brain. The study was published in the journal Science.