Project Summary This supplement proposes new studies to advance the goals of the parent R01 grant “Prebiotic Regulation of Longevity”. In our studies, we have discovered a pro-longevity compound, colanic acid (CA), produced and secreted from bacteria residing in the host, which regulates mitochondrial activities to exert its beneficial effects on the host. In the parent R01 grant, we proposed genetic and molecular studies in bacteria, Caenorhabditis elegans and mice to dissect the regulatory mechanisms underlying this novel longevity-promoting mechanism. In our recent studies, we also found that CA attenuates age-associated pathologies caused by toxic amyloid-b accumulation, and discovered a CA inducer, cephaloridine, that promotes the induction of CA from bacteria and lifespan extension in the host. Therefore, in this supplement, we propose to expand the parent award to add new studies on Alzheimer’s disease (AD). In the specific aim 1, we will determine the protective effect of CA and cephaloridine in C. elegans AD models; in the specific aim 2, we will determine the protective effect of cephaloridine in mouse AD models; in the specific aim 3, we will develop cephaloridine derivatives with enhanced CA induction activity. All the experiments are designed for the timeframe of one year. Successful accomplishment of these studies will significantly expand the scope and impact of the parent award by bridging aging biology, nutrition science and AD research. These studies will open a new avenue to apply nutraceutical approaches for the prevention and treatment of AD and will shed light on the extension and improvement of quality of life for AD patients in our current society and future generations.