Maintenance of a healthy proteome is essential for cellular homeostasis and loss of proteostasis is associated with tissue dysfunction and neurodegenerative disease. The mechanisms that support proteostasis in healthy cells and how they become defective during aging or in disease states are not fully understood. Here, we investigate the transcriptional programs that are essential for neural stem and progenitor cell (NSPC) function and uncover a program of autophagy genes under the control of the transcription factor FOXO3. Using genomic approaches, we observe that FOXO3 directly binds a network of target genes in adult NSPCs that are involved in autophagy, and find that FOXO3 functionally regulates induction of autophagy in these cells. Interestingly, in the absence of FOXO activity, aggregates accumulate in NSPCs, and this effect is reversed by TOR (target of rapamycin) inhibition. Surprisingly, enhancing FOXO3 causes nucleation of protein aggregates, but does not increase their degradation. The work presented here identifies a genomic network under the direct control of a key transcriptional regulator of aging that is critical for maintaining a healthy mammalian stem cell pool to support lifelong neurogenesis.

FOXP2, initially identified for its role in human speech, contains two nonsynonymous substitutions derived in the human lineage. Evidence for a recent selective sweep in Homo sapiens, however, is at odds with the presence of these substitutions in archaic hominins. Here, we comprehensively reanalyze FOXP2 in hundreds of globally distributed genomes to test for recent selection. We do not find evidence of recent positive or balancing selection at FOXP2. Instead, the original signal appears to have been due to sample composition. Our tests do identify an intronic region that is enriched for highly conserved sites that are polymorphic among humans, compatible with a loss of function in humans. This region is lowly expressed in relevant tissue types that were tested via RNA-seq in human prefrontal cortex and RT-PCR in immortalized human brain cells. Our results represent a substantial revision to the adaptive history of FOXP2, a gene regarded as vital to human evolution.

The maintenance of neural stem cell function is vital to ensure neurogenesis throughout adulthood. During aging, there is a significant reduction in adult neurogenesis that correlates with a decline in cognitive function. Although recent studies have revealed novel extrinsic and intrinsic mechanisms that regulate the adult neural stem cell (NSC) pool and lineage progression, the precise molecular mechanisms that drive dysregulation of adult neurogenesis in the context of aging are only beginning to emerge. Recent studies have shed light on mechanisms that regulate the earliest step of adult neurogenesis, the activation of quiescent NSCs. Interestingly, the ability of NSCs to enter the cell cycle in the aged brain significantly declines suggesting a deepend state of quiescence. Given the likely contribution of adult neurogenesis to supporting cognitive function in humans, enhancing neurogenesis may be a strategy to combat age-related cognitive decline. This review highlights the mechanisms that regulate the NSC pool throughout adulthood and discusses how dysregulation of these processes may contribute to the decline in neurogenesis and cognitive function throughout aging.