Transcriptomic landscape, gene signatures and regulatory profile of aging in the human brain

The molecular characteristics of aging that lead to increased disease susceptibility remain poorly understood. Here we present a transcriptomic profile of the human brain associated with age and aging, derived from a systematic integrative analysis of four independent cohorts of genome-wide expression data from 2202 brain samples (cortex, hippocampus and cerebellum) of individuals of different ages (from young infants, 5-10 years old, to elderly people, up to 100 years old) categorized in age stages by decades. The study provides a signature of 1148 genes detected in cortex, 874 genes in hippocampus and 657 genes in cerebellum, that present significant differential expression changes with age according to a robust gamma rank correlation profiling. The signatures show a significant large overlap of 258 genes between cortex and hippocampus, and 63 common genes between the three brain regions. Focusing on cortex, functional enrichment analysis and cell-type analysis provided biological insight about the aging signature. Response to stress and immune response were up-regulated functions. Synapse, neurotransmission and calcium signaling were down-regulated functions. Cell analysis, derived from single-cell data, disclosed an increase of neuronal activity in the young stages of life and a decline of such activity in the old stages. A regulatory analysis identified the transcription factors (TF) associated with the signature of 258 genes, common to cortex and hippocampus; revealing the role of MEF2(A,D), PDX1, FOSL(1,2) and RFX(5,1) as candidate regulators of the signature. Finally, a deep-learning neural network algorithm was used to build a biological age predictor based on the aging signature. This article is part of a Special Issue entitled: Transcriptional Profiles and Regulatory Gene Networks edited by Dr. Federico Manuel Giorgi and Dr. Shaun Mahony.