Retrotransposon Protein L1 ORF1p Expression in Aging Central Nervous System

The long-interspersed elements (LINE-1; L1) represent the main active family of retrotransposons in the human organism, comprising approximately 17% of its content. L1 sequence codifies for the two proteins involved in its retrotransposition: ORF1p, an RNA binding protein, and ORF2p, endowed with endonuclease and reverse transcriptase activity. The vast majority of L1 copies are inactive, with only a small percentage retaining their retrotransposition capacity, posing a threat to the organism due to its mutagenic potential. To mitigate such risks, mammals have evolved intricate regulatory mechanisms, including heterochromatin formation and RNA degradation pathways. Age-related diminution in these regulatory pathways may be particularly important within the Central Nervous System (CNS), where cellular regeneration is limited, and genomic integrity is critical for lifelong function. Here, we describe an age-associated upregulation of ORF1p in the mouse brain, indicating a potential role of L1 activity in aging. We further demonstrate the presence of ORF1p across diverse CNS cell types, including neurons, oligodendrocytes and microglia. Notably, we observe a correlation between ORF1p presence and microglial activation, a hallmark of neuroinflammation, during aging. This study advances our understanding of L1 dynamics in the CNS and underscores the significance of L1 in age-related neurological changes.