Breakdown of Protein Production May Contribute to Brain Aging

The underlying factors contributing to cellular senescence may have been uncovered, revealing insights into various aging processes at the cellular level.

Studies on the brains of a type of freshwater fish known as Killifish reveal that as these fish age, their internal protein factories begin to malfunction, leading to critical protein classes being synthesized abnormally and creating a damaging feedback loop.

This revelation could pave the path for innovative approaches to addressing cognitive decline in aging; Alessandro Cellerino from the Leibniz Institute on Aging in Germany states, “Our focus is more on enhancing cognitive function and preventing cognitive impairment, rather than merely extending life span.”

Within cells, the templates for protein synthesis are encoded in DNA. When proteins are required, these instructions are transcribed into mRNA molecules.

This mRNA is then processed and transported to ribosomes, the cellular factories responsible for protein assembly. Ribosomes attach to and traverse mRNA strands, interpreting the three-letter codons and translating them into amino acid sequences, ultimately forming proteins.

Typically, a greater quantity of mRNA leads to increased protein synthesis. However, numerous studies indicate that this relationship falters in aging human cells, suggesting that protein output may diminish even if mRNA levels remain unchanged.

Through their investigation of aging ribosomes in the brains of Killifish, Cellerino and his team may have identified the cause of this phenomenon. Employing advanced imaging techniques, the researchers captured dynamic movements of ribosomes on constrained mRNA.

The findings revealed that, as the Killifish brain aged, an unexpected buildup of ribosomes occurred, particularly at codons for the amino acids arginine and lysine, leading to stalled ribosome activity and incomplete protein synthesis.

Arginine and lysine are crucial for numerous biomolecules associated with DNA and RNA, and their charged nature suggests that these stallings could significantly disrupt RNA and DNA-binding proteins.

These protein malfunctions pose a serious issue, as they are integral to crucial cellular processes such as RNA synthesis, splicing, and DNA repair.

“Aging is associated with increased DNA damage, reduced RNA production, decreased splicing efficiency, and diminished protein synthesis,” explains Cellerino. “We propose that this ribosome stalling binds these diverse senescence phenomena together.”

Moreover, Cellerino notes that ribosomes themselves harbor RNA-binding proteins, creating a detrimental cycle of stalling that further reduces ribosome availability and, accordingly, protein production.

The pressing question remains whether ribosomal stalling is also present in the human brain. Recent work by Jean Yeo at UC San Diego indicates that RNA-binding proteins diminish in aging human neurons, echoing Cellerino’s findings, although the underlying causes are still uncertain. “This change in RNA-binding proteins could explain their declining levels,” Yeo states.

If these observations hold true for humans, it could herald new strategies for treating age-associated cognitive disorders. Additionally, in Killifish, ribosomal stalling triggers stress signals that instigate inflammatory responses. “The persistent activation of this pathway leads to chronic inflammation,” warns Cellerino. “Chronic inflammation is a significant factor in brain aging.”

Experimental drugs that may mitigate this condition by blocking the associated signaling pathways are on the horizon, according to Cellerino.

“However, it is premature to draw definitive conclusions regarding their potential impact on longevity,” he cautions. This uncertainty arises from the lack of understanding regarding the initiation of ribosomal stalling at specific amino acids, as well as whether the same stalling mechanism exists across all organs.