Brain Aging Insights from Individuals Without Neurodegeneration

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A healthy brain continuously produces new proteins to support synaptic plasticity, maintain neuronal health, facilitate signaling pathways, produce neurotransmitters, enable neuroplasticity and adaptation, and meet its metabolic demands. These processes are essential for normal brain function, learning, memory, and overall cognitive abilities. Researchers believe that the dysregulation of proteins is at the core of brain aging. However, the exact recipe for protein dysregulation that leads to accelerated brain aging and neurodegenerative disorders has yet to be brought to light. 

Previous brain proteostasis (referring to the maintenance of protein homeostasis in brain cells) studies in individuals with Alzheimer’s disease (AD) pathology and age-related neuropathological changes have shown protein dysregulation leading to a buildup of amyloid plaques and neurofibrillary tangles. While these studies have greatly enhanced our knowledge of brain aging, gaps in our understanding remain. What proteomic characteristics do healthy brain aging individuals—without neurodegenerative disorders—have in common?

“To our knowledge, whole phosphoproteomes centered on the human brain aging without AD pathology are unavailable.”

In a new study, researchers Pol Andrés-Benito, Ignacio Íñigo-Marco, Marta Brullas, Margarita Carmona, José Antonio del Rio, Joaquín Fernández-Irigoyen, Enrique Santamaría, Mónica Povedano, and Isidro Ferrer from Bellvitge Institute for Biomedical Research, Universidad Pública de Navarra, Barcelona Institute for Science and Technology, and University of Barcelona aimed to shed light on the mechanisms underlying brain aging in the absence of AD pathology and age-related neuropathological changes. Their research paper was published on May 13, 2023, in Aging’s Volume 15, Issue 9, and entitled, “Proteostatic modulation in brain aging without associated Alzheimer’s disease-and age-related neuropathological changes.”

The Study

The production of new proteins is crucial for maintaining protein homeostasis in the brain. A post-translational modification used to maintain this homeostasis is protein phosphorylation. In this study, the researchers conducted proteomic and phosphoproteomic analyses of frontal cortex samples from the donor brains of deceased individuals between the ages of 30 and 85. These individuals had passed away due to non-neurological complications and were reported to have had full cognitive function. Individuals were divided into four groups: young group one (30–44), middle-aged group two (45-52), early-elderly group three (64–70), and late-elderly group four (75–85).

“​​We chose the FC [frontal cortex] because of its role in cognition and emotion and the abundant molecular information that permits comparison with other studies.”

Conventional label-free- and SWATH- (sequential window acquisition of all theoretical fragment ion spectra) mass spectrometry were used to assess the (phospho)proteomes of the frontal cortices from individuals in all four age groups. Immunohistochemistry and/or western blotting was/were also used to validate a subgroup of proteins. The researchers categorized deregulated proteins and phosphoproteins into eight clusters based on their age-dependent expression similarity (see paper for clusters). Interestingly, protein and phosphoprotein levels of the larger hierarchical clusters were stable until the age of 70 years. After 70, the late-elderly group showed significant decreased or increased expression of protein clusters one and seven, and major phosphorylation modifications occurred in clusters four and eight.


The team then used multi-comparative analyses to categorize altered proteins and phosphoproteins as neuronal, astroglial, oligodendroglial, microglial, and endothelial. They observed a similar pattern among proteomic and phosphoproteomic alterations: major changes were related to neuronal cell populations across all four groups—and these changes were more pronounced with age. Cytoskeletal and membrane proteins accounted for the largest number of differentially-expressed proteins and phosphoproteins.

“Furthermore, main alterations in the proteome are associated with proteins specific to neuronal populations, rather than those found in other cell types in the brain.”

Their findings also revealed a decline in the expression of P20S α + β with aging, while the expression of P19S and immunoproteasome subunits LMP2 and LMP7 remained preserved. Notably, the expression levels of an autophagy component, ATG5, remained unchanged with age. Some mitochondrial membrane proteins showed altered levels at advanced ages, but key markers of mitochondrial function were preserved. These findings suggest a potential preservation of these pathways in advanced aging, contrasting with observations in neurodegenerative disorders. Additionally, reduced levels of GSK3α/β were observed, and the researchers point out that this decrease in GSK3α/β with age may be understood as protective against different age-related brain diseases.

Summary & Conclusion

“Therefore, our results fill the gap between brain ageing without ADNC [AD neuropathological changes], and cases with early and advanced stages of AD pathology.”

The researchers are forthcoming about limitations of this study. Given it is rare for old-aged individuals not to have neurological deficits, AD or other neuropathological changes, their main limitation was that each of the four groups included merely four individuals (N = 16). Despite limitations, these findings contribute to our understanding of brain aging in the absence of AD pathology and age-related neuropathological changes. 

The study revealed that major changes in protein expression were primarily associated with neuronal cell populations and became more pronounced with age. The preservation of specific protein pathways, proteasome components, autophagy-related components, and mitochondrial markers in advanced aging individuals without neurodegenerative disorders suggests the presence of resilience mechanisms that protect against protein dysregulation and neurodegeneration. Overall, this research provides valuable insights into the proteomic characteristics of healthy brain aging and highlights potential targets for therapeutic interventions aimed at promoting healthy brain aging and preventing age-related neurodegenerative diseases. Further studies are necessary to elucidate the specific mechanisms underlying these proteomic alterations and their functional implications in brain aging.

“The present observations identify proteostatic changes, including different changes in the phosphoproteome in the human FC in brain aging in the rare subpopulation of old-aged individuals without neurological deficits, and not having ADNC and other neuropathological change in any region of the telencephalon.”

Click here to read the full research paper published by Aging.

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