LINE-1 / Retrotransposon activation

Long interspersed nuclear elements-1 (LINE-1, or L1) are autonomous retrotransposons that comprise roughly 17% of the human genome; they encode the proteins ORF1p and ORF2p, which mediate a copy-and-paste mechanism by which LINE-1 sequences can replicate via an RNA intermediate and insert new copies elsewhere in the genome. In somatic cells, LINE-1 elements are normally silenced through DNA methylation, H3K9me3 heterochromatin and the PIWI-piRNA system, but their repression weakens with age as heterochromatin erodes. Reactivated LINE-1 elements can trigger cGAS-STING innate immune sensing via cytosolic reverse-transcribed DNA, promote genomic instability through new insertions, and contribute to the inflammatory milieu of aged cells; reverse transcriptase inhibitors such as lamivudine have been shown in mouse models to suppress LINE-1-driven inflammation and extend healthspan in some settings.