Unveiling proteomic and peptide-level modifications in cerebrospinal fluid and plasma in normal cognitive aging

Normal cognitive aging is accompanied by molecular changes in the brain and periphery, but the specific proteomic and peptide-level alterations remain poorly defined. This study aimed to characterize age-related protein and peptide modifications by analyzing matched cerebrospinal fluid (CSF) and plasma samples from cognitively normal individuals. Mass spectrometry was used to profile the proteome and peptide-level data of CSF and plasma samples from young (n = 52; mean age 29 ± 5.9 years; 4% male) and older (n = 40; mean age 69 ± 6.3 years; 48% male) adults. Differential abundance analysis, gene set enrichment, and weighted correlation network analyses were performed to identify age-associated pathways. Protein cleavage, alternative splicing, and phosphorylation events were examined to capture post-translational modifications linked to aging. In CSF, aging is associated with significant upregulation of extracellular matrix (ECM) components, coagulation, and inflammatory pathways. In plasma, the insulin-like growth factor-1 (IGF-1) signaling pathway is notably downregulated. Peptide-level analysis reveals novel alternative cleavage and phosphorylation patterns in key proteins involved in lipid metabolism, ECM structure, axonogenesis, and synaptic activity, including APP, APOE, COL4A2, NRXN1, and NRCAM. These findings highlight distinct and compartment-specific molecular changes that occur with aging. This study provides a comprehensive proteomic and peptide-level landscape of normal cognitive aging, identifying both protein-level shifts and novel age-associated cleavage and phosphorylation events. As people age, their bodies and brains undergo gradual molecular changes, even in the absence of disease. In this study, we analyzed blood and cerebrospinal fluid (the fluid surrounding the brain and spinal cord) from healthy younger and older adults to understand how the proteins in these fluids change with normal aging. To do this, we used advanced mass spectrometry (MS), a powerful analytical method that measures the mass of molecules with extremely high precision. Our study found age-related changes in proteins involved in brain structure, inflammation, and metabolism. Notably, we also discovered subtle modifications in key proteins that may influence how cells communicate and maintain brain health over time. These findings provide new insights into the biology of healthy aging and may help researchers distinguish normal aging from the early stages of neurodegenerative diseases in the future. Kamalian et al. presents a deep proteomic and peptide-level analysis of matched cerebrospinal fluid and plasma from cognitively normal adults (From 18- to 83-year-olds). This study reveals distinct molecular signatures of normal aging and uncovers age-associated cleavage and phosphorylation events in key proteins such as APP, APOE, and NRXN1.