Retrotransposable elements in senescent cells drive inflammaging

The activity of retrotransposable elements (RTEs) can be deleterious, and RTE activation increases with age. The only human RTE capable of autonomous retrotransposition is the long-interspersed element-1 (L1, also known as LINE-1). Here, John Sedivy and colleagues show in mice and human cells that during cellular senescence L1 elements become transcriptionally de-repressed and trigger a type-I interferon (IFN-I) response. The robust activation of an IFN-I response is a novel phenotype of senescent cells, that is shown to contributes significantly to the so-called senescence associated secretory phenotype. The IFN-I response is mediated by the IFN-stimulatory DNA pathway, and is antagonized by nucleoside reverse transcriptase inhibitors (NRTIs) that inhibit the synthesis of L1 cDNA. Remarkably, treatment of aged mice with NRTI effectively not only antagonizes the IFN-I response, but also reduces age-associated inflammation as well as age-related phenotypes, such as glomerulosclerosis of the kidney and skeletal muscle atrophy. Sterile inflammation, also known as inflammaging, is a hallmark of ageing and thought to contribute to various age-related disorders. The authors propose that the activation of L1 elements promotes inflammaging, and that L1 reverse transcriptase may be a target for the development of drugs to treat age-associated disorders.