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.

Age-related macular degeneration (AMD), a progressive condition that is untreatable in up to 90% of patients, is a leading cause of blindness in the elderly worldwide. The two forms of AMD, wet and dry, are classified based on the presence or absence of blood vessels that have disruptively invaded the retina, respectively. A detailed understanding of the molecular mechanisms underlying wet AMD has led to several robust FDA-approved therapies. In contrast, there are not any approved treatments for dry AMD. In this review, we provide insight into the critical effector pathways that mediate each form of disease. The interplay of immune and vascular systems for wet AMD, and the proliferating interest in hunting for gene variants to explain AMD pathogenesis, are placed in the context of the latest clinical and experimental data. Emerging models of dry AMD pathogenesis are presented, with a focus on DICER1 deficit and the toxic accumulation of retinal debris. A recurring theme that spans most aspects of AMD pathogenesis is defective immune modulation in the classically immune-privileged ocular haven. Interestingly, the latest advances in AMD research highlight common molecular disease pathways with other common neurodegenerations. Finally, the therapeutic potential of intervening at known mechanisms of AMD pathogenesis is discussed.

Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro-and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-a/b activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-c and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.Therapeutic application of long, double-stranded (ds)RNAmediated RNAi and sequence-specific gene silencing through RNAi by short synthetic RNA duplexes is challenging because mammalian cells do not uptake 'naked' siRNA (whether chemically modified or not) without cell-permeating entities [1][2][3][4] . To minimize systemic exposure, initial clinical trials of siRNA were launched using intraocular injection in patients with CNV. CNV, wherein the retina is invaded by choroidal vessels beneath the retinal pigmented epithelium (RPE), is a late stage of age-related macular degeneration that afflicts 30-50 million people globally. The preclinical bases for trials of naked VEGFA siRNA (Bevasiranib) or VEGFR1 siRNA (AGN211745/ siRNA-027) were single reports in mice 5,6 that such siRNAs suppressed laser-injury-induced CNV, a model predictive of efficacy in humans 7,8 . These findings were interpreted as anomalous examples of local delivery surmounting the impediment to intracellular entry 9-11 . Instead, we show in two animal models that suppression of neovascularization is a generic property of siRNAs independent of sequence, target and internalization.Sequence-independent angiogenesis suppression by siRNA Numerous synthetic non-targeted 21-nucleotide duplex siRNAs from multiple vendors, when injected into the vitreous humour of wild-type mice, uniformly and dose-dependently suppressed CNV (Fig. 1a, b and Supplementary Fig. 1). siRNAs targeting jellyfish green fluorescent ...