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.
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.
