Project Summary Cell senescence is an irreversible proliferation arrest caused by a variety of stresses. It is characterized by the secretion of proinflammatory factors, the senescence associated secretory phenotype (SASP), which is believed to contribute to an important hallmark of aging, a chronic inflammatory state known as 'inflammaging' (1). The parent grant elucidated a novel mechanism which propagates cell senescence and its SASP and thus promotes inflammaging. This mechanism involves retrotransposable elements (RTEs), and in particular the long inter- spersed nuclear elements (LINE-1, or L1). These elements are activated in senescent cells and induce a type-I interferon (IFN-I) response, which in turn drives the SASP. The IFN-I response is triggered by innate immune system DNA sensors that detect cytoplasmic L1 cDNAs. The 4th and final aim of the parent grant was to explore possible strategies for therapeutic interventions. The class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs) were developed to treat HIV, and we found that several well-tolerated NRTI drugs potently inhibit the L1 reverse transcriptase (RT) enzyme. We have shown that treatment of senescent cells with NRTIs blocks the synthesis of L1 cDNA and induction of an IFN-I response (2, 3). More importantly, treatment of aged mice with NRTIs downregulated inflammaging in several tissues. Alzheimer's disease (AD) and AD-related dementias (ADRDs) are associated with neuroinflammation, which establishes an environment in the brain that is hostile for the function and survival of neurons. Many brain cell types, astrocytes and microglia in particular, can become senescent. The frequency of senescent cells increases in Alzheimer's and ADRDs (4-6), and removing senescent cells in mouse models of Alzheimer's reduces neuroinflammation, alleviates pathology and improves cognitive function (6, 7). While it is not yet clear if neuroinflammation is a cause of Alzheimer's, it is increasingly believed that alleviating neuroinflammatory processes might slow down Alzheimer's disease progression. On the basis of the research performed by the parent grant, as well as extensive evidence in the published literature, we believe that NRTI drugs should be investigated for repurposing to treat Alzheimer's and ADRDs. NRTIs have excellent bioavailability and blood brain barrier (BBB) permeability, and recent generations, such as Emtricitabine (FTC) show both high efficacy and safety. Based on the above premise, I applied, in collaboration with Stephen Salloway, MD, Director of the Memory and Aging Program at Butler Hospital (an affiliate of Brown Medical School), to the Alzheimer's Association of America to conduct a phase 1b clinical trial to establish the safety and tolerability of Emtricitabine in a geriatric population with mild cognitive impairment or early Alzheimer's. Our application was approved, see: · https://www.brown.edu/news/2019-12-10/alzgrant; · https://www.alz.org...