Aging Brains Face Protein Production Errors
Stanford Study Uncovers Molecular Cause of Neurodegeneration Decline
Researchers have pinpointed a critical mechanism behind the protein production failures that plague aging brains, a discovery that could pave the way for new therapies against neurodegenerative diseases and age-related cognitive decline.
Unlocking the Aging Brain’s Protein Problem
Aging significantly impairs how cells maintain and produce functional proteins, a process known as proteostasis. This breakdown is particularly damaging to brain cells, contributing to the buildup of abnormal protein clumps seen in diseases like Alzheimer’s. A new study in Science by Stanford University researchers has illuminated the sequence of events leading to this decline in aging brains.
The findings, derived from studies on the turquoise killifish, Nothobranchius furzeri, offer a foundational understanding for developing interventions. These could combat neurodegenerative conditions and the universal process of mental ability reduction that accompanies aging.
“We know that many processes become more dysfunctional with aging, but we really don’t understand the fundamental molecular principles of why we age.”
—Judith Frydman, Donald Kennedy Chair in the School of Humanities and Sciences at Stanford
Judith Frydman, a lead author on the study, emphasized that the research begins to provide a mechanistic explanation for increased protein aggregation and dysfunction observed as organisms age.
A Model for Accelerated Aging
The turquoise killifish, a species with one of the shortest lifespans among vertebrates studied in captivity, develops age-related issues rapidly. This makes it an ideal model for investigating the intricacies of brain aging, a process that would be far more challenging to study in longer-lived animals like mice.
The research team meticulously examined proteostasis in the brains of young, adult, and old killifish. They analyzed key components of protein synthesis, including amino acid concentrations and the levels of various RNA and protein molecules.
Proteostasis is crucial for balancing protein creation and breakdown, preventing the formation of harmful protein aggregates that can result from errors in protein folding. The disruption of this system is recognized as a hallmark of aging.
Frydman‘s previous work in simpler organisms like yeast and roundworms had already indicated that aging processes observed in these models were mirrored in more complex vertebrates, including humans. This new study confirms that the fundamental machinery of protein production experiences quality issues with age.
Pinpointing the Ribosomal Roadblock
The study identified a critical disruption during the “translation elongation” phase of protein synthesis. This is the stage where ribosomes, the cell’s protein-making machinery, move along messenger RNA (mRNA) to assemble amino acids into proteins.
In the aging fish brains, researchers observed ribosomes colliding and stalling. These disruptions resulted in both diminished protein levels and the accumulation of misfolded proteins. According to the Centers for Disease Control and Prevention, Alzheimer’s disease, a leading cause of dementia, affects millions worldwide, with the risk increasing significantly with age (CDC, 2024).
Jae Ho Lee, a co-lead author and now an assistant professor at Stony Brook University, noted that alterations in ribosome movement speed along mRNA have a substantial impact on protein homeostasis. He highlighted the vital role of “regulated” translation elongation speed for various mRNAs in the context of aging.
This discovery also sheds light on “protein-transcript decoupling,” a common aging phenomenon where changes in mRNA levels no longer accurately predict changes in protein levels. The research suggests that the aging-related synthesis issues, including ribosome malfunctions, can explain this decoupling. Since many of the affected proteins are involved in maintaining genome integrity, these findings help explain why these crucial processes decline with age.
“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 stated. “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.”
Future Directions in Aging Research
The researchers plan to investigate how ribosome dysfunction, identified as a key factor in declining proteostasis, directly contributes to age-related neurodegenerative disorders in humans. They also aim to explore whether targeting translation efficiency or ribosome quality control could restore proteostasis in brain cells and potentially delay age-related 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.
The team is also delving into the causes of age-related cognitive decline and how manipulating these processes might influence longevity across different species.
