Geroprotective Precision Medicine Strategies in PWH that Use Alcohol - ABSTRACT People with HIV (PWH) suffer high rates of geriatric comorbidities and frailty syndromes due, in part, to unhealthy behaviors including harmful alcohol use. There is a paucity of evidence guiding treatment of geriatric comorbidity in PWH that use alcohol. This Project addresses the critical need to validate efficacious therapies for precocious aging in PWH with a significant history of alcohol use. Our group has identified microbiota characteristics linked to clinical frailty and senescent CD8+ T cells across distinctly different populations with different health behaviors. However, the specific relationships between the microbiota vary between studies, suggesting that personalized interventions are essential to prevent the development of clinical frailty. Precision medicine strategies incorporating host factors, the microbiota, and the exposome hold therapeutic promise. We have identified changes in the microbiota associated with alcohol use in humans that mediate the prevalence of senescent T cells in the circulation. In preclinical models, we have identified several alcohol-induced microbiota characteristics that mediate T cell function. Probiotics and antioxidant foods mitigate alcohol effects effectively in animal models but results in humans are inconsistent, likely due to inter-individual heterogeneity. Thus, there is a compelling rationale and necessity to develop personalized probiotic selection strategies as geroprotective interventions. The overall objective of this proposal is to identify personalized approaches to overcoming inconsistent responses to microbiota-targeted geroprotection and then validate the capacity of these precision medicine strategies to offset mechanisms of biological aging in PWH that consume alcohol. Our approach will test two Generally Recognized As Safe (GRAS) treatments, a Lactobacillus reuteri probiotic and a blueberry-based antioxidant mix, and their interactions with well-characterized human hosts to inform machine learning (ML) enabled predictive algorithms and to identify mechanisms contributing to treatment-specific effects. Our overarching hypothesis for this project is that an individual’s characteristics predict probiotic and blueberry supplement capacities to reduce senescent CD8+ T cells in PWH that use alcohol. The Specific Aims of our proposal are: Specific Aim 1: To derive and validate machine learning predictive algorithms that guide selection of probiotic and blueberry treatments to maximize the reduction of senescent CD8+ T cells in PWH that use alcohol. Specific Aim 2: To identify probiotic- and blueberry-specific effects on mechanisms contributing to senescent CD8+ T cell changes and aging biology characteristics in PWH that use alcohol. This project will provide [a] proof of concept of precision medicine geroprotective / senoprotective strategies, [b] mechanistic insights as to the impact of probiotic and antioxidant foods on aging mechanisms, and [c] a roadmap to optimize other treatments to maintain healthspan in aging PWH that use alcohol.
