Aging is a multi-faceted process influenced by both genetic and environmental factors. Many pharmaceuticals and nutraceuticals have been shown to have prolongevity effects from studies in model organisms. Nutraceuticals made from various plants and fruits are rich in phytochemicals and possess diverse bioactivities, including anti-aging effects. However, the mechanisms underlying how dietary nutrients influence the prolongevity effects of interventions for promoting healthy aging are not well understood. Moreover, how and when the interventions with nutraceuticals or pharmaceuticals remain elusive. These issues are critical for developing effective interventions for promoting healthy aging in human. To this end, based on our previous findings that cranberry supplementation can significantly increase lifespan in Drosophila, we have investigated the mechanisms underlying the lifespan extension induced by cranberry supplementation and also the critical timing of cranberry supplement for promoting longevity in Drosophila. We have found that cranberry supplementation can effectively promote longevity even when implemented in a relative short period time during any of health, transition and senescence life stage and this lifespan extension is likely through reducing oxidative damage. This line of work has been published in Experimental Gerontology 2014 and has been widely cited by a number of news outlets. This work provides a foundation for further investigating mechanistic studies on the effect of nutraceutical supplementation in delaying aging process and for designing cost effective and efficiency aging interventions in human. In our efforts to determine the general applicability of using cranberry as an effective aging intervention, we have investigated whether cranberry can promote longevity in other species. Through collaboration with Dr. Yuqing Dong at Clemson University, we have studied the prolongevity effect of cranberry and the underlying mechanisms in C. elegans. We have found that cranberry can promote longevity likely through at least two pathways, insulin-like signaling and osmotic response pathways, in C. elegans. Moreover, cranberry supplementation significantly improves worms resistance to heat shock stress and infection of V. cholera, a bacterium causing cholera. Furthermore, we have demonstrated that implementation of cranberry supplementation in the early life stage is more effective in promoting longevity than that in the late life stage. These findings have been published in AGE 2013 and Nutrients 2014. This line of research demonstrates the potential health benefits of cranberry supplementation in evolutionally divergent species. Many of the pathways critical for lifespan extension induced by cranberry, such as SOD2, osmotic response and insulin-like pathways, are conserved in human, which suggest that the likelihood of the similar beneficial effects in humans. These studies provide groundwork for developing effective interventions for promoting healthy aging in human using nature products, such as cranberry. In summary, we have investigated the prolongevity effects of a cranberry-containing nutraceutical in Drosophila and C. elegans. We have demonstrated the underlying mechanism of cranberry-induced lifespan extension and determined the optimal timing for inventions with cranberry. These findings provide the foundation for our future research directed towards understanding the molecular mechanisms underlying how nutraceuticals and pharmaceuticals promote and healthspan. These studies should provide valuable information for developing efficient interventions for promoting healthy aging in humans. This project should advance the objectives of the Translational Gerontology Branch and overall missions of the National Institute on Aging.