The study compared brain fluid and blood proteins of young and older adults and found that, as people age, the blood shows a clear drop in the activity of the IGF‑1 signaling pathway, while the brain fluid shows more inflammation and changes in the extracellular matrix. It also uncovered new ways that certain proteins are cut and phosphorylated with age.

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.