PROJECT ABSTRACT/SUMMARY Growing evidence suggests the presence of dysregulated pain modulation in older adults, and affect which may heighten age-associated risk for chronic pain. Additionally, chronic pain and Alzheimer’s Disease and related dementias (AD/ADRD) are highly prevalent and comorbid in older adults, and research suggests that they may have overlapping etiologies and pathologies. Chronic pain may a predictor for the development of AD, and almost half of AD patients report having pain. Thus, understanding of the shared mechanisms underlying both is critical in order to develop effective treatment and prevention modalities. Recently, epigenetics has been implicated in both disease states, with many modifications of the epigenome that may go on to result in immune system dysfunction, of which is a hallmark of both chronic pain and AD. While there are many environmental factors that can influence the epigenome, nutrition status has been shown to be one of the most common and modifiable factors therein. Thus, it may be efficacious to understand dietary interactions with the epigenome to target epigenetic regulation of the development and maintenance of chronic pain and AD. Therefore, the overall goal for this mentored career development proposal (K99/R00) is to fill this knowledge gap and determine the influence of overall diet pattern as well as Vitamins A and D specifically on the epigenetic environment as it relates to chronic pain and AD/ADRD. Primary training goals for the current proposal are to: Increase knowledge and understanding of measurement techniques used to assess cognitive aging in humans, with a specific focus on mild cognitive impairment, and AD/ADRD; Further expand knowledge of nutri-epigenetics, and apply it to cognitive aging outcomes; Enhance clinical research skills related to the design, conduct and statistical analysis of multidisciplinary studies and rigorous translational research skills to function as an independent investigator. Study 1 (K99 Phase) will assess dietary differences and their associations with differences in epigenetic aging, pain, and cognition in individuals with and without chronic pain. Study 2 (R00 phase) will allow for the assessment of diet pattern as well as vitamin A and D status on DNA methylation patterns, gene and protein expression, pain and cognitive outcomes in older adults with and without mild cognitive impairment. This proposed career development plan extends from the PIs prior work in dietary and immune system modulation of pain, and will forge a path towards understanding and investigating side-effect free nutrigenomic targets that improve pain and AD/ADRD outcomes in older adults.