SIRT1 Silences L1 Retrotransposons by Stabilizing Heterochromatin-Modifying Complexes

SIRT1, a sirtuin family member, has been extensively documented to be closely linked to aging and aging-related disease. Cellular senescence is a state of irreversible cell cycle arrest that functions as a key driver of aging. During cellular senescence, LINE-1 (L1) retrotransposable elements become transcriptionally activated and stimulate a type-I interferon (IFN-I) response. L1 activity has been strongly linked to aging and a variety of age-related disorders. However, whether SIRT1 influences cellular senescence through the transposable element L1 remains unknown. In this study, we discovered that SIRT1 significantly suppresses L1 retrotransposition. Under quiescent conditions, SIRT1 exhibits increased enrichment at the L1 5'-UTR region. This recruitment enhances its interaction with the heterochromatin-regulatory factors Lamin B1 and KAP1, subsequently elevating H3K9me3 levels. This repressive chromatin mark inhibits L1 transcription, thereby maintaining genomic stability and delaying cellular senescence. Consistent with these observations, SIRT1-deficient cell lines exhibited a marked reduction of the interaction of Lamin B1 and KAP1 and a reduced presence of these factors at the L1 5'-UTR. Consequently, the elevated L1 transcription resulting from SIRT1 deficiency activated the cGAS-STING pathway and ultimately triggered cellular senescence, an effect that was rescued by treatment with 3TC (a nucleoside reverse transcriptase inhibitor). In summary, our findings demonstrate that SIRT1 suppresses L1 retrotransposition by recruiting heterochromatin factors, thereby delaying cellular senescence and providing new insights with implications for delaying aging and mitigating age-related pathologies.