Isoswitching drives the aging process in human brains

Learning, reasoning, and working memory functions are attributed to the dorsolateral prefrontal cortex (DLPFC), a distinctive region of the human brain that is highly evolved in primates and exhibits notable variability 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 sequencing data from prenatal and postnatal human DLPFCs, we observed that many genes undergo dramatic shifts in their isoform preferences around the time of birth. We further found that thousands of genes continue to undergo gradual, temporally regulated changes in their preferred isoforms, a phenomenon we term 'isoswitching'. In this study, we present isoswitching as a major force in brain development, capable of accurately predicting human brain age from prenatal stages through late adulthood and beyond eighty years of age. This represents the first demonstration of brain age prediction based solely on RNA sequencing data. We also report isoswitching in the brain of a closely related primate, the rhesus macaque.