Stanford Scientists Uncover the Molecular Mistake That May Trigger Brain Aging

Scientists have identified a critical breakdown in the cellular machinery that produces proteins in aging brains.

Aging and neurodegenerative disease can interfere with a cell’s ability to produce properly functioning proteins. This process, known as “proteostasis,” or protein homeostasis, keeps protein production and maintenance in balance. Brain cells appear especially vulnerable when this system begins to break down. Disruptions in proteostasis are closely associated with the buildup of protein aggregates that are commonly seen in neurodegenerative disorders.

In a study published in Science, researchers at Stanford University identified a sequence of molecular events that contributes to the loss of proteostasis in aging brains.

The discovery comes from experiments involving the turquoise killifish and offers insight that could eventually guide the development of therapies aimed at preventing or slowing neurodegenerative diseases in humans. The findings may also help explain the gradual decline in cognitive function that occurs during 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,” 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.”

Locating the problem

The turquoise killifish, Nothobranchius furzeri, is a brightly colored species adapted to survive in temporary freshwater pools across the African savanna. Because these fish have the shortest lifespan of any vertebrate bred in captivity, they develop age related biological changes quickly. This rapid life cycle makes them a valuable model for studying aging.

By contrast, studying similar changes in animals with longer lifespans, such as mice, would require far more time.

To investigate how aging affects the brain, the research team carried out a detailed analysis of proteostasis in killifish at different stages of life. They compared young, adult, and old individuals and examined several components involved in protein production. These included amino acid levels, transfer RNA, messenger RNA (mRNA), proteins, and other related factors.

Inside cells, proteostasis maintains equilibrium between the creation of new proteins and the breakdown of old or damaged ones. The system also helps prevent proteins from forming aggregates, which are harmful clumps that can arise when proteins fold incorrectly.

Loss of proteostasis and the accumulation of protein aggregates are considered hallmarks of aging. Scientists have long suspected that these processes connect normal brain aging with neurodegenerative diseases associated with protein aggregation, including Alzheimer’s disease.

Frydman’s laboratory studies how cells maintain proteostasis. Earlier work from the group examined this process in simpler organisms such as yeast and roundworms. The new research demonstrates that many of the same aging-related mechanisms found in those organisms also occur in more complex vertebrates such as killifish and likely humans.

“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.”

Ribosome Traffic Jams in Aging Brains

The researchers eventually traced the disruption to a particular step in protein synthesis called translation elongation.

During this stage, ribosomes act as molecular machines that translate genetic instructions carried by mRNA into proteins. As the ribosome moves along the mRNA strand, it adds amino acids one at a time to build a protein.

In the brains of older killifish, however, the team observed that ribosomes frequently collided with one another and stalled while moving along the mRNA. These disruptions reduced the production of proteins and contributed to the formation of protein aggregates.

“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,” said Jae Ho Lee, co-lead author of the paper who worked on this as a postdoctoral scholar in the Frydman lab. He is now an assistant professor at Stony Brook University.

Solving a Longstanding Aging Puzzle

The finding helped to illuminate another aging mystery. One of the hallmarks of aging in all organisms, including humans, is called “protein-transcript decoupling.” In this phenomenon, changes in levels of some mRNA no longer correlate to changes in protein levels in aged individuals. The new study shows that changes in protein synthesis during aging, including ribosomes, can explain the “protein-transcript decoupling.” Since many of the affected proteins are involved in genome maintenance and integrity, these new observations rationalize why these processes decline during aging.

“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.”

Future aging research

As a next step, the researchers will explore directly how ribosome dysfunction – which they identified as a key culprit of declining proteostasis – may contribute to age-related neurodegenerative disorders in people. They also want to know whether targeting translation efficiency or ribosome quality control in treatments can restore proteostasis in brain cells and even delay aging-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,” said Lee.

Additionally, the research team is probing what leads to cognitive decline as we age and how modulating such processes may shape longevity in a range of different species.

Reference: “Altered translation elongation contributes to key hallmarks of aging in the killifish brain” by Domenico Di Fraia, Antonio Marino, Jae Ho Lee, Erika Kelmer Sacramento, Mario Baumgart, Sara Bagnoli, Till Balla, Felix Schalk, Stephan Kamrad, Rui Guan, Cinzia Caterino, Chiara Giannuzzi, Pedro Tomaz da Silva, Amit Kumar Sahu, Hanna Gut, Giacomo Siano, Max Tiessen, Eva Terzibasi-Tozzini, Eugenio F. Fornasiero, Julien Gagneur, Christoph Englert, Kiran R. Patil, Clara Correia-Melo, Danny D. Nedialkova, Judith Frydman, Alessandro Cellerino and Alessandro Ori, 31 July 2025, Science.
DOI: 10.1126/science.adk3079

This research was funded by the FLI Proteomics, Sequencing, and Life Science Computing Core Facilities, the Fish Facility, the Stanford Genomics Facility, the Paul F. Glenn Center for Biology of Aging Research at Stanford University, the National Institute of Aging, the NGS Facility in the Department of Totipotency at the Max Planck Institute of Biochemistry, the German Research Council through the Research Training Group ProMoAge, the Else Kröner Fresenius Stiftung, the Fritz- Thyssen Foundation, the Chan Zuckerberg Initiative Neurodegeneration Challenge Network, the NCL Stiftung, the National Institutes of Health, the German Research Council, Next Generation EU (PNRR), “Tuscany Health Ecosystem,” the Italian Ministry of University and Research (MIUR), a CZI Collaborative Pairs Pilot Project Award, the SFB1286 (Göttingen, Germany), the Max Planck Society, the European Research Council, and the UK Medical Research Council. The FLI is a member of the Leibniz Association and is financially supported by the Federal Government of Germany and the State of Thuringia.

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