Aging Rewrites the Brain’s Protein Code – and Scientists Just Found the Switch

Age-related changes in protein tagging and degradation may help explain how the brain declines over time and why diet can still influence these processes.

As people grow older, the proteins that keep the brain running gradually change in both structure and function. These shifts can shape how well the brain works later in life, influencing memory, reaction speed, and vulnerability to neurodegenerative disease.

A new study led by Dr. Alessandro Ori at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena shows that a chemical process called ubiquitylation plays a central role in this transition. Ubiquitylation helps decide which proteins stay active and which are broken down and removed. The results of the international research effort appear in Nature Communications.

How aging alters brain proteins

Proteins carry out many of the brain’s essential jobs. They regulate metabolism, enable communication between nerve cells, and help maintain the energy balance within brain tissue. To keep these processes running smoothly, proteins must be continually replaced, adjusted, or dismantled when they are damaged or no longer needed. Ubiquitylation is one of the key chemical modifications involved. By attaching a small molecule called ubiquitin to a protein, the cell can fine-tune that protein’s activity or mark it for destruction.

“Our analyses have shown that aging leads to fundamental changes in how the proteins in the brain are chemically labelled,” explains Dr. Alessandro Ori, former research group leader at the FLI. “The ubiquitylation process acts like a molecular switch—it determines whether a protein remains active, changes its function, or is degraded. In the aging brains of mice, we observed that this finely tuned system becomes increasingly unbalanced: many labels accumulate, and some are even lost, regardless of how much of a particular protein is present.”

The “recycling system” of the cell loses its power

The study also points to a decline in the brain’s internal waste disposal system as animals get older. Central to this process is the proteasome, a complex molecular machine that breaks down proteins that are damaged or no longer useful. With age, the proteasome becomes less efficient. Proteins that have been tagged with ubiquitin for removal begin to accumulate instead of being cleared away, signaling that the cell’s normal maintenance system is struggling.

The researchers estimate that about one-third of the age-related changes seen in protein ubiquitylation in the brain can be directly traced to reduced proteasome activity. This slowdown may help explain why aging brains are more vulnerable to protein buildup and the functional decline that often follows.

“Our data shows that the reduced ability of cells to completely eliminate damaged proteins is a central mechanism of the aging brain,” summarize Dr. Antonio Marino and Dr. Domenico Di Fraia, both first authors of the study. “The sensitive balance between protein synthesis and degradation shifts—a typical feature of cellular aging. In the long term, this can also impair the function of nerve cells in the brain.”

Diet as a modulator—a hopeful sign

In a further step, the researchers investigated whether the ubiquitylation patterns found could be influenced by changes in diet. To this end, older mice were fed a moderate diet (calorie restriction) for four weeks before being returned to a normal diet. The surprising result was that the short-term change in diet significantly altered the ubiquitylation pattern in the mice—in some proteins, it even reverted to the previous, youthful state.

“Our results show that even in old age, diet can still have an important influence on molecular processes in the brain,” emphasizes Dr. Ori. “However, diet does not affect all aging processes in the brain equally: some are slowed down, while others hardly change or even increase.”

The study thus provides new insights into the molecular mechanisms of brain aging. It suggests that ubiquitylation is a sensitive biomarker of the aging processes—and potentially a starting point for slowing down age-related damage to nerve cells. In the long term, the study of these processes could help to better understand the connection between nutrition, protein balance, and neurodegenerative diseases such as Alzheimer’s disease.

Reference: “Aging and diet alter the protein ubiquitylation landscape in the mouse brain” by Antonio Marino, Domenico Di Fraia, Diana Panfilova, Amit Kumar Sahu, Alberto Minetti, Omid Omrani, Emilio Cirri and Alessandro Ori, 6 June 2025, Nature Communications.
DOI: 10.1038/s41467-025-60542-6

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