PROJECT SUMMARY The All of Us New England Clinical Center (AoU-NE-CC) is a collaboration of New England–based research teams with the necessary expertise and resources in nutrition and clinical translational science to implement successfully all 3 modules of the NIH Common Fund’s Nutrition for Precision Health (NPH) Clinical Center program. The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University (Tufts- HNRCA) and Massachusetts General Hospital (MGH) will lead the AoU-NE-CC and partner with All of Us New England to ensure the diversity of participants and scientific rigor required to identify inter-individual variability of response to dietary patterns. The AoU-NE-CC is committed to All of Us core values and has implemented best practices of team science throughout its development. The AoU-NE-CC will serve as a key partner in the development of a rigorous NPH common protocol and examine habitual dietary intake (Module 1), measure physiological responses to a mixed-meal challenge (Modules 1-3), and identify responses to 3 intervention diets in both free-living (Module 2) and domiciled (Module 3) controlled feeding conditions. Coupled with standard All of Us data, the physiological responses collected through these modules will be used to develop predictive algorithms that inform precision nutrition approaches for long-term health. To attain maximum metabolic and microbiome response variability, we propose the following 14-day isocaloric diets for Modules 2 and 3, separated by 4-week washout periods: (1) a high-adherence Dietary Approaches to Stop Hypertension (DASH) diet; (2) a low-adherence DASH diet; and (3) a ketogenic diet. We also propose the use of the thoroughly tested mixed-meal challenge PhenFlex, which can be standardized across clinical centers to provide a multisystem assessment of metabolic flexibility. With its outstanding core facilities, including metabolic kitchens and domiciled feeding and nursing centers, as well as a rich legacy of conducting rigorous feeding studies, the AoU-NE-CC is uniquely skilled and positioned to serve as a clinical center for the NPH. Additional strengths of the AoU-NE-CC include extensive experience in recruiting clinical populations and biobanking, engaging volunteers through community outreach, active participation in global precision nutrition initiatives, and an outstanding track record of productive multisite collaborations in nutrition, omics, and precision health. Importantly, the Tufts-HNRCA and MGH teams are closely aligned with the All of Us New England team and its record of high participant recruitment and retention and its diverse cohort, which will support the NPH consortium goals. By partnering with NPH and All of Us in this novel modular discovery science study, the AoU-NE-CC and its experienced, forward-thinking, highly collaborative team will contribute to the development of precision nutrition approaches that support optimal health across the adult lifespan.

PROJECT NARRATIVE The New England–based clinical center will implement the NIH Common Fund’s Nutrition for Precision Health initiative, powered by the NIH All of Us Research Program. The clinical center has the capacity and expertise to fulfill the initiative’s objective of obtaining critical information on dietary, microbiome, physiological, metabolic, behavioral, cognitive, environmental, and contextual factors that are expected to contribute to inter- individual variability in responses to foods. These data will be integrated with All of Us–collected genomic, electronic health, and survey data to develop predictive algorithms to inform precision nutrition strategies, with a goal of supporting optimal health for individuals throughout the lifespan and retooling public health initiatives for reducing the risk of chronic disease.