Isoswitching drives the aging process in human brains

Abstract

Learning, reasoning, and working memory functions are attributed to the dorsolateral prefrontal cortex (DLPFC), a brain region that is highly evolved in primates and notably variable among individuals. Environmental and genetic factors likely contribute to this variability, but little is known about how they influence changes within an individual brain across the lifespan as different cognitive tasks and challenges arise. Most genetic studies focus on DNA mutations or changes in overall gene expression levels. However, genes can also alter the form in which they are expressed through alternative splicing. Using RNA-seq data from prenatal and postnatal human DLPFCs, we observed that many genes undergo a dramatic rewiring of their isoform usage around the time of birth. Further, thousands of genes continue to undergo gradual, temporally regulated shifts in their preferred isoforms, a phenomenon we term isoswitching. We present isoswitching as a major force in brain development and aging, capable of accurately predicting subject age from prenatal stages through adulthood and beyond eighty years of age. This study represents the first human brain age prediction based solely on RNA-seq data, establishing a molecular framework for understanding normative brain development and aging. We also report isoswitching in the brain of a closely related primate, the rhesus macaque.