PROTEOMIC SIGNATURES IN A RAT MODEL OF SUCCESSFUL BRAIN AGING

Preserving cognitive function during aging remains a major biological challenge. The LOU/c/Jall rat represents one of the few preclinical models of successful aging. In contrast to the Wistar strain from which it is derived, LOU rats exhibit remarkable metabolic stability, preserved cognitive performance into advanced age, and extended lifespan. To identify early molecular adaptations that may underlie this exceptional aging trajectory, we compared hippocampal and cortical proteomic profiles between the two strains. High-resolution mass spectrometry enabled the identification of nearly 8,000 proteins, of which 513 were differentially expressed in the hippocampus. Expression changes reveal a clear cell-type shift: downregulated genes cluster in oligodendrocytes, while upregulated genes are enriched in neurons. Functional enrichment analyses revealed a strong overrepresentation of pathways related to mitochondrial bioenergetics, oxidative phosphorylation, aminoacyl-tRNA biosynthesis, and vesicular trafficking. Notably, LOU rats displayed increased expression of multiple mitochondrial complex I subunits and aminoacyl-tRNA synthetases, consistent with enhanced energetic efficiency and translational fidelity. Conversely, proteins involved in oxidative stress responses and detoxification, including quinone oxidoreductase 2 (NQO2), were significantly downregulated. In contrast to the hippocampus, cortical changes were more modest and did not yield a clear cell-type enrichment signature. Collectively, these findings indicate that the LOU hippocampus harbors an intrinsic proteomic signature early in life that favors mitochondrial integrity, redox homeostasis, and synaptic maintenance. Such a molecular profile may contribute to sustained cognitive function during aging and highlights potential targets for promoting healthy cognitive longevity.