Aina-Based Engagement and Social Epigenomic Pathways to Metabolic Health in Native Hawaiian Youth - PROJECT SUMMARY/ABSTRACT Native Hawaiians and other Pacific Islanders (NHPIs) experience among the highest rates of type 2 diabetes mellitus (DM) in the United States, with onset nearly a decade earlier than other groups. These disparities arise from historical, social, and environmental adversities that influence behavior, metabolism, and opportunity. Yet the biological mechanisms through which these social-environmental conditions become physiologically embedded remain poorly understood, particularly among Indigenous youth for whom early intervention could more effectively alter disease trajectories. This application responds to PAR-25-379: Intervention Research to Improve Native American Health by testing an innovative, community-anchored intervention that integrates Indigenous knowledge with multi-omic science. The MAʻO Organic Farms Youth Leadership Training (YLT) program, a Native Hawaiian-led ʻāina-based intervention, provides workforce training, higher education, and mentorship through organic farming grounded in the values of aloha ʻāina (care for the land) and kuleana (reciprocal responsibility). We hypothesize that participation in ʻāina-based practices improves glycemic control by reducing inflammation and decelerating immunoepigenetic (biological) aging, with the gut microbiome acting as a biological modifier of these effects. A 12-month longitudinal, mixed-methods cohort study (N=400) will compare YLT-engaged participants (n=200) with propensity-matched NHPI controls (n=200) drawn from the Waiʻanae community and/or our established Hawaiʻi Social Epigenomics of Early Diabetes (HI-SEED) cohort unaffiliated with MAʻO. Participants will complete behavioral, psychosocial, and clinical assessments, and provide fasting blood and stool specimens at baseline and 12 months for quantification of HbA1c, insulin resistance, cytokine profiles (e.g., IL-6, TNF-α, hsCRP), monocyte-based DNA methylation (Illumina MethylationEPIC v2 arrays), and gut microbial diversity and function (16S rRNA sequencing). A delayed-start subcohort of HI-SEED participants who later enroll in YLT will enable causal inference using difference-in- differences and marginal-structural modeling. Aim 1 evaluates the impact of the ʻāina-based intervention (the MAʻO-led YLT) on glycemic and behavioral outcomes; Aim 2 determines whether behavioral and psychosocial improvements mediate reductions in immunoepigenetic (biological) aging and inflammation; and Aim 3 defines the gut microbiome as a biological modifier linking social-behavioral change, immunoepigenetic regulation, biological aging, and glycemic health. Results of these aims will meet our goal of learning how an Indigenous, ʻāina-based intervention biologically embeds social experience to promote metabolic resilience and healthy aging. Findings will establish a scalable, community-governed model of precision health promotion that advances NIH and Native health priorities through rigorous, culturally grounded interventions by integrating Indigenous knowledge with cutting-edge multidisciplinary systems biology with the potential to enable meaningful prevention.
