Resilient protein co-expression network in male orbitofrontal cortex layer 2/3 during human aging

Abstract

The orbitofrontal cortex (OFC) is vulnerable to normal and pathological aging. Currently, layer resolution large-scale proteomic studies describing “normal” age-related alterations at OFC are not available. Here, we performed a large-scale exploratory high-throughput mass spectrometry-based protein analysis on OFC layer 2/3 from 15 “young” (15–43 years) and 18 “old” (62–88 years) human male subjects. We detected 4,193 proteins and identified 127 differently expressed proteins (DE) (p-value ≤0.05; effect size >20%), including 65 up- and 62 down-regulated proteins (e.g., GFAP, CALB1). Using a previously-described categorization of biological aging based on somatic tissues, i.e., peripheral “hallmarks of aging”, and considering overlap in protein function, we show highest representation of altered cell-cell communication (54%), deregulated nutrient sensing (39%) and loss of proteostasis (35%) in the set of OFC layer 2/3 DE proteins. DE proteins also showed a significant association with several neurological disorders, e.g., Alzheimer’s disease and schizophrenia. Notably, despite age-related changes in individual protein levels, protein co-expression modules were remarkably conserved across age groups, suggesting robust functional homeostasis. Collectively, these results provide biological insight into aging and associated homeostatic mechanisms that maintain normal brain function with advancing age.

Temporal proteomic profiling of postnatal human cortical development

“…Mass spectrometry-based proteomics provides a comprehensive and complimentary perspective to transcriptomic changes and can serve as an indicator for functional and network levels of aging. Although human proteome research has predominately focused on defining a disease signature within a specific developmental period, there has been some progress in understanding the developmental proteome 23 – 25 . For example, a recent study profiled the orbitofrontal cortex and identified 127 proteins implicated in cellular growth and proliferation that were differentially expressed between young or old human male individuals 23 .…”

Temporal proteomic profiling of postnatal human cortical development

“…Mass spectrometry-based proteomics provides a comprehensive and complimentary perspective to transcriptomic changes and can serve as an indicator for functional and network levels of aging. Although human proteome research has predominately focused on defining a disease signature within a specific developmental period, there has been some progress in understanding the developmental proteome [23][24][25] . For example, a recent study profiled the orbitofrontal cortex and identified 127 proteins implicated in cellular growth and proliferation that were differentially expressed between young or old human male individuals 23 .…”

“…Although human proteome research has predominately focused on defining a disease signature within a specific developmental period, there has been some progress in understanding the developmental proteome [23][24][25] . For example, a recent study profiled the orbitofrontal cortex and identified 127 proteins implicated in cellular growth and proliferation that were differentially expressed between young or old human male individuals 23 . A separate study profiled seven different brain regions across 11 developmentally distinct individuals and found substantial differences in protein abundance between brain regions, reflective of cytoarchitectural and functional variation 25 .…”

AgeGuess, a Methylomic Prediction Model for Human Ages

“…Both CALB1 (Loerch et al, 2008) and KLF14 (Small et al, 2011) were known age-related biomarkers. CALB1 demonstrated robustly down-regulated expression across rhesus monkeys and humans (Loerch et al, 2008;Pabba et al, 2017). While KLF14 served as a master regulator of many genes and its altered methylation patterns were associated with the aging process (Spolnicka et al, 2018).…”