Abstract
Despite ongoing research efforts, mechanisms of brain aging are still enigmatic and need to be elucidated for a better understanding of age-associated cognitive decline. The aim of this study is to investigate aging in the prefrontal cortex region of human brain in a meta-analysis of transcriptome datasets. We analyzed 591 gene expression datasets pertaining to female and male human prefrontal cortex biopsies of distinct ages. We used hierarchical clustering and principal component analysis (PCA) to determine the influence of sex and age on global transcriptome levels. In sex-specific analysis we identified genes correlating with age and differentially expressed between groups of young, middle-aged and aged. Pathways and gene ontologies (GOs) over-represented in the resulting gene sets were calculated. Potential causal relationships between genes and between GOs were explored employing the Granger test of gene expression time series over the range of ages. The most outstanding results were the age-related decline of synaptic transmission and activated expression of glial fibrillary acidic protein (GFAP) in both sexes. We found an antagonistic relationship between calcium/calmodulin dependent protein kinase IV (CAMK4) and GFAP which may include regulatory mechanisms involving cAMP responsive element binding protein (CREB) and mitogen-activated protein kinase (MAPK, alias ERK). Common to both sexes was a decline in synaptic transmission, neurogenesis and an increased base-level of inflammatory and immune-related processes. Furthermore, we detected differences in dendritic spine morphogenesis, catecholamine signaling and cellular responses to external stimuli, particularly to metal (Zinc and cadmium) ions which were higher in female brains.
Highlights
Mechanisms associated with time-dependent physical decline, i.e., aging are complex and despite its omnipresence in biological organisms our understanding of it is still not complete
Sex differences are more prominent than age differences in prefrontal cortex Five hundred ninety-one prefrontal cortex (PFC) biopsiesderived transcriptome datasets (Supplementary Table 1) from control donors without diagnosed disease were downloaded from National Center for Biotechnology information (NCBI) Gene Expression Omnibus (GEO)
Many synapsis-related terms appear in Table 5 such as cAMP, dendrite- and calcium-transport–related terms and aging-related oxidative-stress-mediated apoptosis. In this meta-analysis of transcriptomes derived from 591 prefrontal cortex biopsies, we found a gene set with significantly increasing and another with significantly decreasing expression during aging
Summary
Mechanisms associated with time-dependent physical decline, i.e., aging are complex and despite its omnipresence in biological organisms our understanding of it is still not complete. The level of neurogenesis in the adult brain is at a low level and the established conclusions that most of the cognitive tasks are controlled by synapsis dynamics still holds true. Synapse dynamics depend on three types of dendritic spines: stubby, thin and mushroom spines [25]. Mushroom spines are considered responsible for long-term memory while thin spines are considered to arrange synapses for flexible cognitive tasks [6]. Morrison et al reported that these thin spines were found to be reduced during aging and their density showed the highest correlation to performance on a cognitive task (DNMS: delayed nonmatching-to-sample) in non-human primates [39]. Dendritic spine density can be increased by estradiol [52], hormonal balance plays an important role in cognitive performance. The body of literature is much smaller for males but regulation of dendritic spine density by testosterone has been reported [20]
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