Department of Biology, University of Rochester, Rochester, NY 14627, USA.
Department of Pathology, University of Rochester Medical Center, Rochester, NY 14627, USA.
Cell Metab. 2019 Apr 2;29(4):871-885.e5. doi: 10.1016/j.cmet.2019.02.014. Epub 2019 Mar 7.
Mice 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.
SIRT6 缺失的小鼠表现出寿命严重缩短、生长迟缓以及 LINE1（L1）活性显著升高。在这里，我们报告 SIRT6 缺失的细胞和组织积累了丰富的细胞质 L1 cDNA，通过 cGAS 的激活引发强烈的 I 型干扰素反应。值得注意的是，核苷逆转录酶抑制剂（NRTIs）抑制 L1 反转录，可显著改善 SIRT6 敲除小鼠的健康和寿命，并完全挽救 I 型干扰素反应。在组织培养中，用 siRNA 或 NRTIs 抑制 L1 除了显著减少 DNA 损伤标志物外，还会阻断 I 型干扰素反应。这些结果表明 L1 的激活导致了 SIRT6 敲除小鼠的病理变化。同样，野生型老年小鼠的 L1 转录、细胞质 cDNA 拷贝数和 I 型干扰素水平升高。由于无菌性炎症是衰老的标志，我们提出调节 L1 活性可能是减轻与年龄相关的病理的重要策略。
