DESCRIPTION (provided by applicant): Chronic inflammation (CI) as defined by chronic elevation in serum inflammatory markers such as C-reactive protein (CRP) and Interleukin-6 (IL-6) is a known risk for the development of adverse health outcomes in older adults, including mortality, frailty, chronic disease, and mobility declines. Despite this, little is known about how best to measure CI. Because of the heterogeneity of CI in older adults, and complexity of etiology, few if any interventions have been developed that specifically target CI and downstream consequences such as mobility decline. Our overarching hypothesis states that decreasing inflammatory signaling over a period of several months will decrease serum levels of inflammatory markers and improve mobility. In order to adequately test this hypothesis in a definitive clinical trial, a great deal of information related in inflammation, mobility and anti- inflammatory interventions must be determined. We propose, through 4 specific aims, to develop the team and data necessary to ultimately design and implement a definitive, multi-site clinical trial in older adults with CI that aims to improve mobility through anti-inflammatory treatment strategies. We have established a highly experienced collaborative research team with expertise in clinical trials development, chronic inflammation biology, measurement, and analysis, mobility measurement and analysis, and recruitment of old adults into clinical studies. The PI, coordinating center, pharmacy analytical team, and recruitment site will be at Johns Hopkins University. Other recruitment sites will be at the University of Michigan, University of Nebraska Medical Center, and Duke University. These sites were chosen based on their recruitment experience, availability of aging research registry, and expertise of co-investigators in CI or mobility. The Biorepository and Measurement Core will be at the University of Vermont under the leadership of Russ Tracy, PhD. Dr. Tracy has long standing expertise in CI measurement in population studies of older adults. The first aim is to further develop and integrate this team and infrastructure necessary to develop a definitive multisite trial. Aim 2 is designed to inform a definitive clinical trial design on CI and mobility through the development and refinement of mobility and inflammatory measurements, compilation of an evidence base on which to design and target a large-scale CI intervention, and through the identification of safe and potentially effective anti-inflammatory agents. Aim 3 was designed to inform a definitive clinical trial design through a series of pilot trials of oral anti- inflammatory agents, including lactoferrin, zinc gluconate, and losartan. These pilot studies will help to develop the definitive trial infrastructure, formalize recruitment and measurement procedures, and identify safe and potentially effective interventions. Finally, Aim 4 articulates the group's road map towards a `shovel ready' definitive clinical trial that will be built on the data generated in aims 2 and 3 ad on the study team and infrastructure developed during the 3 year timeline. At the end of this 3 year study, the compiled research team full expects to have a definitive clinical trial of CI and mobility in older adults ready for implementation.

PUBLIC HEALTH RELEVANCE: Chronic inflammation is likely a cause of increased risk for declines in walking ability and chronic diseases. Investigators from around the country will gather and analyze information about how best to measure chronic inflammation and its impact on walking, and will test some nutrients and pharmaceutical agents to assess the feasibility and safety of performing a bigger study. We plan to take information gained from this grant and develop a large and more definitive study at several sites around the country.