LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation

Abstract

Graphical Abstract Highlights d SIRT6 KO mice accumulate L1 cDNA, triggering interferon response via cGAS pathway d Wild-type aged mice accumulate L1 cDNA and display type I interferon response d Reverse-transcriptase inhibitors rescue type I interferon response and DNA damage d Reverse-transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice SUMMARYMice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS.Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies. Context and SignificanceMammalian aging is complex and likely reflects accumulated damage to our genes/DNA. Retrotransposons are a special class of parasitic genetic elements that can replicate their DNA within our genes, at times amounting to up to 20% of human DNA. Retrotransposons, such as the commonly occurring L1, have been associated with aging, neurodegeneration, and cancer. University of Rochester scientists uncovered L1 retrotransposons as the culprit in many aspects of accelerated aging in mice, a model for human aging. They also linked these special gene elements to inflammation. Experimentally blocking retrotransposon amplification improved the health and lifespan of mice. Although there is a long road ahead, inhibiting retrotransposon activity, and the related inflammation, could eventually be a therapy for age-related diseases.

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.…”

“…The effect can be suppressed by reverse transcriptase (RT) inhibitors to block expansion/reintegration of L1s. Furthermore, loss of L1 suppression is a major contributor to aging in SIRT6 knockout mice that can be partially rescued by adding RT inhibitors . Upon the loss of SIRT6, the copy number of cytoplasmic L1 species accumulate triggering type‐I interferon response via cGAS/STING pathway.…”

Transposable Elements Cross Kingdom Boundaries and Contribute to Inflammation and 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. 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 .…”

“…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.…”

“…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.…”