Increased LINE-1 expression is associated with neuronal gene network downregulation in the aged mouse prefrontal cortex

Aging is associated with epigenetic alterations, neuroinflammation, and progressive decline of neuronal function. Derepression of the retrotransposon LINE-1 (L1) has been implicated in aging and age-related diseases. However, the regional expression of L1 and its relationships with DNA methylation, genomic L1 copy number, and aging-related transcriptional changes in the normal aging brain remain incompletely understood.

We examined L1 expression in the prefrontal cortex (PFC), hippocampus, and nucleus accumbens of young (17-week-old, n = 10) and aged (101-week-old, n = 7) male C57BL/6J mice. L1 expression, DNA methylation, and genomic copy number were quantified by RT-qPCR, pyrosequencing, and genomic qPCR, respectively. Transcriptomic alterations in the PFC were analyzed by RNA-seq, followed by weighted gene co-expression network analysis (WGCNA).

L1 expression was significantly increased in the aged PFC across multiple active L1 subfamilies, whereas no significant changes were observed in the other brain regions. Despite elevated L1 expression, no detectable changes were observed in the DNA methylation of active L1 promoters or in genomic L1 copy number between age groups. WGCNA identified three major aging-associated modules. Among these, only the neuronal module showed a significant negative correlation with L1 expression and was enriched for genes involved in synaptic signaling, neuronal development, and neuronal projections.

L1 expression increased in the aged mouse PFC and is associated with coordinated downregulation of neuronal gene networks rather than other major aging-associated transcriptional programs. These findings further characterize the molecular context of increased L1 expression during normal brain aging.