L1 drives IFN in senescent cells and promotes age-associated inflammation

Abstract

Retrotransposable elements (RTEs) are deleterious at multiple levels, and failure of host surveillance systems can thus have negative consequences. However, the contribution of RTE activity to aging and age-associated diseases is not known. Here we show that during cellular senescence LINE-1 elements (L1s) become transcriptionally derepressed and activate a type-I interferon (IFN-I) response. The IFN-I response is a novel phenotype of late senescence and contributes to the maintenance of the senescence associated secretory phenotype (SASP). The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by nucleoside reverse transcriptase inhibitors (NRTIs) that inhibit the L1 reverse transcriptase (RT). Treatment of aged mice with the NRTI lamivudine downregulated IFN-I activation and age-associated inflammation in several tissues. We propose that RTE activation is an important component of sterile inflammation that is a hallmark of aging, and that L1 RT is a relevant target for the treatment of age-associated disorders.

Proteomics of Long‐Lived Mammals

“…Beyond its ability to enhance DSB repair, a major role of SIRT6 is to repress the expression of ancient retroviral elements (LINE1 or L1) that account for a significant fraction of mammalian genomes . The importance of LINE1 elements in aging as well as in the context of SIRT6 as a promoter of overall genome integrity was bolstered by two recent reports showing that showed that L1 elements become transcriptionally derepressed during aging and that this derepression activates a type‐I interferon (IFN‐I) inflammatory response . The effect can be suppressed by reverse transcriptase (RT) inhibitors to block expansion/reintegration of L1s.…”

Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin

“…Using DAPI staining, we also observed micronuclei in ERCC1‐deficient fibroblasts. Although we have not tested this hypothesis directly, it is conceivable that the formation of micronuclei and possibly cytosolic DNA triggers the cGAS‐STING pathway, thereby activating NF‐κB and elevating type I IFN signaling, both of which were recently shown to occur in senescent cells (De Cecco et al, ). Indeed, Tilstra et al reported that NF‐κB activation was significantly enhanced in multiple tissues from Ercc1 –/Δ mice, including kidney, liver, pancreas, spleen and muscle (Tilstra et al, ).…”

Transposable Elements Cross Kingdom Boundaries and Contribute to Inflammation and Ageing

“…L1 elements replicate through an RNA transcript that is reverse transcribed, and are capable of re‐integration into the genome, allowing for expansion in their copy numbers if de‐repressed during ageing or genotoxic stress . Importantly, the insertion of additional L1 elements into the genome following their de‐repression induces DNA breaks, and this damage further drives the migration of transcriptional repressors, leading to further de‐repression of other endogenous TEs, initiating a “vicious cycle” that could drive ageing . Increased L1 activity results in the accumulation of L1 ‐derived cytosolic DNA from extrachromosomal copies that fail to integrate, which is detected by innate immune systems that recognize cytosolic DNA from invading viruses.…”

“…Increased L1 activity results in the accumulation of L1 ‐derived cytosolic DNA from extrachromosomal copies that fail to integrate, which is detected by innate immune systems that recognize cytosolic DNA from invading viruses. This promotes interferon production, contributing to a chronic state of low‐grade inflammation that plays a role in ageing . Somatic L1 activity has been implicated in age‐related pathologies, including neurodegeneration and cancer, and small molecule inhibition of L1 reverse transcriptase activity maintains genome stability .…”

“…This promotes interferon production, contributing to a chronic state of low‐grade inflammation that plays a role in ageing . Somatic L1 activity has been implicated in age‐related pathologies, including neurodegeneration and cancer, and small molecule inhibition of L1 reverse transcriptase activity maintains genome stability . Together, these data suggest that the ability to prevent or break this cycle of transposon activity could slow age‐related dysfunction.…”