Aging and neurodegeneration are both known to disrupt the production of functional proteins in cells - a process called "proteostasis," or protein homeostasis. Brain cells in particular fall prey to proteostasis disruptions, which are linked to the accumulation of protein aggregates in neurodegenerative diseases. In a new study published July 30 in Science, Stanford researchers have discovered the cascade of events that leads to declining proteostasis in aging brains.
The findings, based on study of the turquoise killifish, lay the foundation for developing therapies that can combat and prevent neurodegenerative diseases in people - and the gradual decline in mental abilities we will all face one day.
"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 vibrantly colorful fish that adapted to thrive in the ephemeral freshwater pools of the African savanna. Killifish, the shortest-lived vertebrates bred in captivity, develop many issues as they grow old and provide a great model of accelerated aging. Studying why and how the brain ages would be harder in longer-lived animals, such as mice.
To make their new discovery, the researchers conducted a comprehensive investigation of proteostasis in the brains of aging killifish. The scientists compared young, adult, and old killifish. They looked at various players in protein production, such as amino acid concentrations, levels of transfer RNA, messenger RNA (mRNA), proteins, and more.
In cells, proteostasis balances protein synthesis and degradation and also prevents protein aggregation - harmful clumps of proteins that can result from errors in protein folding. Proteostasis dysfunction and aggregation are part of a series of molecular and cellular changes classified as aging hallmarks. Proteostasis has received attention as a likely link between brain aging and neurodegenerative diseases tied to protein aggregation, like Alzheimer's.
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 FrydmanDonald Kennedy Chair in the School of Humanities and Sciences
Frydman's lab explores how cells achieve proteostasis and has previously focused on how aging affects proteostasis in the simple models of aging provided by yeast and roundworms. The new study confirms that aging processes observed in those simple organisms reflect those in more complex vertebrates like killifish - and 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."
Ultimately, the team located the disruption at a specific stage of protein synthesis called translation elongation. In this step, the ribosome enacts its role as the cellular machinery responsible for converting mRNA into proteins by moving along the mRNA and adding amino acids one by one. In the aging fish brains, the researchers documented ribosomes colliding and stalling, which both resulted in reduced levels of proteins and protein aggregation.
"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.
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.
