A new study led by Stanford University researchers has identified a specific mechanism that contributes to brain aging, with potential implications for neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and ALS. The research, published July 30 in Science, used the turquoise killifish—a vertebrate known for its short lifespan—as a model to investigate how protein dysfunction develops in brain cells.
The team found that disruptions in proteostasis—the balance of protein synthesis and degradation—are central to the aging process in brain cells. These disruptions can lead to harmful protein aggregation, which is linked to several neurodegenerative conditions. According to Judith Frydman, Donald Kennedy Chair in the School of Humanities and Sciences at Stanford and senior author of the study, “We know that many processes become more dysfunctional with aging, but we really don’t understand the fundamental molecular principles of why we age. 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.”
The use of killifish allowed researchers to observe accelerated aging processes more quickly than would be possible with longer-lived animals like mice. By comparing young, adult, and old fish brains, they examined amino acid concentrations and levels of transfer RNA (tRNA), messenger RNA (mRNA), and proteins.
Frydman’s lab had previously studied proteostasis using simpler organisms such as yeast and roundworms. The current findings show similar mechanisms are present in more complex vertebrates like killifish—and likely humans as well. “With aging, problems mysteriously emerge at many levels – at the mechanistic, cellular, and organ level – but one commonality is that all those processes are mediated by proteins,” Frydman said. “This study confirms that during aging, the central machinery that makes proteins starts to have quality problems.”
Researchers pinpointed translation elongation—a step where ribosomes synthesize proteins from mRNA—as a critical point where dysfunction occurs with age. In older fish brains, ribosomes were observed colliding or stalling on mRNA strands; this impaired process resulted in lower protein production and increased aggregation.
Jae Ho Lee, co-lead author who worked on this project while at Stanford before joining Stony Brook University as an assistant professor noted: “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.”
The study also offers an explanation for “protein-transcript decoupling,” where changes in mRNA levels no longer match changes in corresponding protein levels among aged individuals—a hallmark observed across species including humans. Many affected proteins are involved with genome maintenance; thus these observations may clarify why such functions decline over time.
“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,” said Frydman. “And, of course, the key to solving a problem is to understand why it’s gone wrong. Otherwise you’re just fumbling in the dark.”
Looking ahead, researchers plan further studies into how ribosome dysfunction could contribute directly to human neurodegenerative disorders and whether improving translation efficiency or ribosome quality control might help restore proteostasis or slow cognitive decline.
“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,” Lee added.
Frydman holds appointments across multiple Stanford units including Bio-X; Cancer Institute; Wu Tsai Neurosciences Institute; Sarafan ChEM-H; she also co-directs Stanford’s Paul F. Glenn Center for Biology of Aging Research.
Additional collaborators came from institutions across Germany (including Fritz Lipmann Institute [FLI], Max Planck Institute), Italy (Stazione Zoologica Anton Dohrn), UK (University of Cambridge), among others. Funding sources included organizations such as FLI Proteomics Core Facilities; National Institutes of Health; Chan Zuckerberg Initiative Neurodegeneration Challenge Network; European Research Council; UK Medical Research Council; Next Generation EU programs; German Research Council through ProMoAge Training Group; Else Kröner Fresenius Stiftung; Max Planck Society.
