Consumption of natural products claimed to have anti-aging properties is high in the US population. While some studies show an impact on age-related diseases such as cancer, heart disease and neurodegenerative disorders, there are large gaps in our knowledge about the mechanisms through which these CAM modulate aging. Our initial studies identified four botanicals (Rhodiola rosea, Rosa damascena, curcumin, and green tea extract) that attenuated aging without impacting known physiological confounds of aging such as depression in reproduction, caloric restriction, and reduced metabolic rate. We hypothesize that these botanicals extend life span and enhance health span by modulating one or more of the major pathways of aging: mitochondrial bioenergetics/oxidative stress, insulin signaling, sirtuins, and target of rapamycin (TOR). Using Drosophila melanogaster as our model system, we will use standardized botanical extracts to ask the following questions that test this hypothesis: 1) Do the botanicals that attenuate aging also improve health span?;2) Do these botanicals alter mitochondrial function, reduce free radicals, and/or protect against oxidative stress?;and 3) Do these botanicals act through the major pathways or proteins associated with aging? Our results will 1) elucidate the basic mechanism of action of these botanicals, 2) explore their potential role in diseases of aging since these pathways are tightly involved with many diseases of aging and 3) offer the opportunity to explore potential synergistic effects in the future, and to extend the results to mammals. Validation of our hypothesis will provide a platform for future mechanistic studies to understand anti-aging properties of these and other natural products. The proposed research addresses the major goal of this PA - elucidating basic mechanisms of CAM action - by studying the effects of CAM on aging. In addition, it has several novel aspects. Although some of these botanical are widely used, there are no reports of their impact on pathways of aging. While Drosophila is an established model system in aging research, there are no other studies using this model evaluating the impact of botanicals on these highly conserved aging pathways. We will also leverage the power of Drosophila genetics and use existing mutant fly lines to relate the effects of each botanical on particular gene products, which represent the major aging pathways. Our work is important because many natural products are promoted for "anti-aging" purposes without strong evidence to support lifespan and/or health span extension. The proposed research will produce experimental evidence supporting or refuting the anti-aging effects and close this important knowledge gap. PUBLIC HEALTH RELEVANCE: The intake of natural products with anti-aging claims is abundant among the US population and although many studies have evaluated their impact on age related diseases such as cancer, heart disease and neurodegenerative disorders, there are gaps in knowledge on the mechanisms through which botanicals modulate the aging process itself. Using fruit fly as the animal model, the current application will provide important new information on the impact of botanicals that extended the fly lifespan on the major pathways of aging. The identification of anti-aging natural products and pathways that they target offers the opportunity to explore potential synergistic effects in the future, and to extend the results to mammals.