Scientists at Stanford University have discovered an important clue to why the brain deteriorates as we age. Their research points to a breakdown in the cell’s protein production system, a process that is thought to potentially cause widespread dysfunction associated with cognitive decline and neurodegenerative diseases such as Alzheimer’s disease.
This research sciencefocused on how aging disrupts “proteostasis,” or protein homeostasis. This system helps cells build, maintain, and dispose of proteins correctly. When proteostasis fails, damaged proteins accumulate into harmful clumps that can interfere with normal brain function.
Researchers say the findings provide one of the clearest explanations yet for why aging brains become increasingly vulnerable to disease and decline in mental performance.
“We know that many processes become dysfunctional as we age, but we don’t really understand the fundamental molecular principles of why we age,” said study author Judith Friedman, Donald Kennedy Dean of the School of Humanities and Sciences at Stanford University. “Our new research begins to provide a mechanistic explanation for a widespread phenomenon during aging: increased aggregation and dysfunction in the process of making proteins.”
A tiny fish with big clues about aging
To investigate what’s happening in the aging brain, researchers focused on turquoise killifish. Nosobranchius furzeri. These colorful fish, which live in ephemeral freshwater pools in the African savanna, are ideal for aging research because they have very short lifespans and rapidly develop many age-related problems.
Mice and other mammals age much more slowly, so studying the biological causes of aging can take years. Medaka allows scientists to observe the same process on a faster timeline.
The research team compared young, adult, and old fish to examine different aspects of protein production in brain cells. The researchers measured amino acid levels, transfer RNA, messenger RNA (mRNA), protein, and other components involved in the production of cellular proteins.
How protein production begins to collapse
Proteostasis relies on a careful balance between protein production and removal of damaged proteins. It also helps prevent proteins from folding incorrectly or sticking together in toxic aggregates. These protein clumps are strongly associated with neurodegenerative diseases, including Alzheimer’s disease.
Friedman’s lab has spent years studying how cells maintain proteostasis in simpler organisms such as yeast and roundworms. New findings show that similar aging mechanisms occur in more complex vertebrates such as medaka and humans.
“As we age, problems mysteriously emerge at many levels, including the mechanistic, cellular, and organ level, but one thing they all have in common is that all of these processes are mediated by proteins,” Friedman said. “This study confirms that as we age, the core machinery that makes proteins begins to experience quality problems.”
The researchers identified a problem with a particular step in protein synthesis known as translation elongation. During this process, ribosomes move along the mRNA chain and add amino acids one at a time to assemble the protein.
In the brains of older fish, ribosomes often stalled and collided with each other. The “traffic jam” of these molecules reduced the production of healthy proteins and increased protein aggregation.
“Our results show that changes in the rate of ribosome movement along an mRNA can have a profound impact on protein homeostasis, and highlight the nature of age-related ‘regulation’ of translation elongation rates for various mRNAs,” said Jae Ho Lee, a postdoctoral fellow in the Friedman lab and co-first author of the paper. He is currently an assistant professor at Stony Brook University.
Solving another mystery of aging
The discovery may also help explain another puzzling feature of aging called protein-transcript decoupling. In aging organisms, changes in mRNA levels often no longer match changes in protein levels, even though mRNA carries the necessary instructions to build proteins.
Researchers at Stanford University have discovered that age-related disruptions in protein synthesis, particularly involving ribosomes, may explain why this cleavage occurs.
Many of the proteins affected by these disorders are involved in maintaining genome stability and cellular integrity. Weakening of these systems can lead to widespread age-related dysfunction.
“Showing that the protein production process loses fidelity with age provides some kind of fundamental rationale for why all these other processes start to malfunction with age,” Friedman said. “And, of course, the key to solving a problem is understanding why it happened. Otherwise, you’re just groping in the dark.”
Possible new target for Alzheimer’s disease and cognitive decline
The researchers now plan to investigate whether ribosome dysfunction directly contributes to human neurodegenerative diseases and whether treatments aimed at improving protein production can help protect the aging brain.
They are particularly interested in exploring whether increasing translation efficiency or improving ribosome quality control can restore a healthier protein balance in brain cells and potentially slow cognitive decline.
“This study not only provides new insights into protein biosynthesis, function and homeostasis in general, but also provides new potential targets for intervention in age-related diseases,” Professor Lee said.
The research team is also studying how these molecular processes influence lifespan and cognitive aging across multiple species.
Friedman is a Professor of Biology in the College of Humanities and Sciences, a Professor of Genetics in the School of Medicine, a member of Stanford Bio-X, the Stanford Cancer Institute, the Wu Tsai Institute for Neuroscience, and a faculty fellow at Sarafan ChEM-H. Friedman is also co-director of the Paul F. Glenn Center for the Biology of Aging at Stanford University. Further research in the Friedman lab on the mechanisms of human neuronal aging and its association with Alzheimer’s disease is funded by the Knight Initiative for Brain Resilience.
