A new study is shedding further light on the link between aging and neurodegenerative disease, after researchers found that protein turnover occurs about 20% slower in the brains of older mice compared with younger mice, affecting distinct pathways linked to these diseases.

Moreover, aging-related changes in turnover rates varied from protein to protein, with some neuroprotective proteins carrying a high metabolic cost to replace with a slower turnover rate in older mouse brains.

"The most important finding of our work is that in the aging brain there is a change in the lifetime of many proteins linked to neurodegeneration. This indicates that those proteins have something in common that makes them more sensitive to the aging process," Eugenio Fornasiero, co-study author and group leader at the University of Gottingen, Germany, told BioWorld Science.

Published in the May 20, 2022 edition of Science Advances, the study findings suggest that future therapeutics could address these metabolic adaptations to delay the onset of neurodegenerative disorders.

The molecular mechanisms that make aging brains particularly susceptible to neurodegenerative diseases have been unclear. While scientists have flagged protein turnover as a possible culprit, previous studies have shown little to no overall change in protein turnover for older animals compared with younger animals.

The main motivation behind the study was to understand the link between neurodegeneration and physiological normal aging, Fornasiero said.

"We know that aging is a major risk factor for neurodegenerative diseases, and we suppose that with the passing of time there are more chances that molecular errors accumulate within cells. At the same time, we don't know exactly why specific pathways and proteins are preferentially affected, such as in the case of the amyloid precursor protein in Alzheimer's disease or alpha synuclein in Parkinson's disease," he said.

Several thousands of protein types coexist within each single cell, and to better understand changes in biological systems, scientists often measure protein abundance, which is useful, he said, but "changes in the aging brain are very small and difficult to measure precisely."

He said that measuring protein turnover, which is a sort of expiration date written on each protein, could be as important as protein abundance for understanding these changes.

"By studying protein turnover in the aging brain and comparing it to protein turnover in normal younger brains [we could learn] which proteins might change their expiration date due to the aging process and teach us something about brain aging.

"Surprisingly, many of the proteins that change their turnover are actually linked to neurodegenerative diseases," he said, suggesting that even in the absence of a clear neuropathology, there are proteins that are preferentially disposed to accumulate problems during the aging process, and these proteins are those connected to neurodegenerative diseases.

Link between physiological aging and neurodegenerative diseases

To explore the link between physiological aging and neurodegenerative diseases, researchers explored protein turnover by feeding aged mice and young mice a complete diet in which one essential amino acid was replaced with a stable isotope to enable metabolic labeling. After 14 or 21 days, they dissected the mice's brains and compared the lifetimes of synaptic and nonsynaptic proteins in the cortex and cerebellum.

On average, proteins in the older mice's brains had longer lifetimes than those in the young mice's brains -- a trait that could lead to the accumulation of damaged proteins.

Using bioinformatics, study authors found that the proteins whose lifetime increased the most in aged mice were those that carry a high metabolic cost to replace.

Furthermore, they observed that histones, extracellular matrix proteins, and myelin components are among the longest-lived proteins in the aged mice cortex, while transcription factors and proteins involved in mRNA processing and translation are short-lived.

"Our study shows that protein lifetimes in general are increased in aged mouse brains with some proteins being relatively longer and others relatively shorter lived. Interestingly, the relatively longer-lived proteins belong to disordered proteins, and those with higher bioenergetic costs," researcher and co-study author Anja Schneider, Department of Neurodegenerative Diseases and Geriatric Psychiatry, at the University of Bonn, Germany, told BioWorld Science.

"For me, the most interesting aspect is the relative increase in lifetimes of many proteins related to neurodegenerative diseases, as a slower protein turnover could facilitate protein aggregation. This is an important finding, as this may explain why aging is one of the most relevant risk factors in many neurodegenerative diseases," she said.

"One of the surprises," Fornasiero said, "was to observe that in general the proteins in the aged brain tend to live about 20% longer than in younger brains. This might indicate that in the aging brain the mechanisms for the degradation of proteins are slowed down.

"By replacing proteins in a slower manner, they might accumulate higher molecular damage and thus suggest why brain function declines with age."

Next steps will be to leverage these learnings to "actually interfere with the aging process and possibly revert some of the effects that we observe during brain aging, delaying the occurrence of neurodegenerative diseases," he said, adding that the most important aim of the research is to ameliorate the life quality during aging.

And, since aging research takes a long time, researchers will collaborate with other groups to use fast-aging animals to dig deeper into the research to better understand the molecular mechanisms at play.

Since food is also a medicine, and the group found that some of the effects are due to a metabolic shift that prioritizes the more expensive amino acids compared to others, there might be a therapeutic diet that contrasts the deregulation of protein turnover, he suggested.

Future studies might show which tweaks in the diet have therapeutic potential. Moreover, there are several FDA-approved drugs that interfere with protein and amino acid metabolism, and experiments measuring protein turnover in the aged animals following treatment with these drugs might provide further answers.