Integrated Multi-Omics Analysis of Brain Aging in Female Nonhuman Primates Reveals Altered Signaling Pathways Relevant to Age-Related Disorders

Abstract

The prefrontal cortex (PFC) is central to working memory, temporal processing, decision making, flexibility, and goal-oriented behavior, and has been implicated as a key brain region responsible for age-related cognitive decline. Although studies in humans and multiple nonhuman primate (NHP) species have shown reduction of PFC activity associated with cognitive decline, little is known about aging-related molecular changes in PFC that may mediate these effects. To date, no studies have used untargeted discovery methods and integrated analyses to determine PFC molecular changes across the adult age span in healthy primates. The goal of this study was to quantify PFC molecular changes associated with healthy aging in female baboons (Papio), a NHP model of aging, by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. Our integrated omics approach using unbiased weighted gene co-expression network analysis (WGCNA) to integrate data, revealed 2 modules containing 587 transcripts and 13 proteins negatively correlated with age. In addition, we identified an additional 57 proteins and 20 metabolites associated with age using regression analyses. Pathway enrichment analysis revealed 25 overlapping, coordinated pathways negatively correlated with age. We identified pathways previously associated with PFC aging such as dopamine-DARPP32 feedback in cAMP signaling, and additional pathways not previously associated with aging-related PFC changes such as nitric oxide signaling. In addition, we found GABA associated with these signaling pathways, providing one potential biomarker to assess PFC changes with age. These highly coordinated pathway changes during aging may represent early steps for aging-related decline in PFC functions, such as learning and memory, and provide potential biomarkers to assess cognitive status in humans.

Mitigation of aging-related plasticity decline through taurine supplementation and environmental enrichment

“…The direction of E/I changes may vary depending on the brain area studied. In the prefrontal cortex, available experimental data support an increase in inhibition with age, correlating with memory de cits (Potier et al, 2006;Stanley et al, 2012;Bories et al, 2013;Bañuelos et al, 2014;Cox et al, 2023), while evidence of decreased inhibition was found in the sensory systems and hippocampus (Yu, Wang et al, 2006). In the rat parietal cortex, an imbalance of arousal/inhibition in favor of inhibition correlated with cognitive impairment (Wong et al, 2006).…”