Molecular inflection points in the aging human brain

The onset of neurodegenerative diseases has been associated with age-dependent changes of gene expression in the brain. Research on age-dependent genes commonly assumes gradual linear relationships between gene expression and aging, failing to identify sudden changes in gene expression that may provide insight into the aging process and its role in neurodegenerative diseases. Here, a piecewise linear regression model is proposed to identify critical inflection points at which aging mechanisms may accelerate. Age-related gene expression data from tissue of four regions of the human brain (frontal cortex, hippocampus, putamen, substantia nigra) and human microglia were analyzed for inflection points. The best piecewise model represented stable expression during younger ages followed by an increase or decrease with age after the inflection point. In brain tissue, genes showing inflection points in expression pattern were enriched for gene ontology terms involved in neurodegenerative diseases. The hippocampus showed the highest proportion of genes with inflection points and the lowest variability in inflection points. These findings suggest that inflection points in gene expression may be used to characterize the aging process in the human brain and may help identify markers for the onset of neurodegenerative diseases.