POLYKETIDE-BASED ANTI-AGING THERAPEUTIC DEVELOPMENT VIA SYNTHETIC ENZYMOLOGY

Abstract

An intervention that extends life span is caloric restriction (CR), but its application in humans is not practical. A more feasible approach is to develop a CR mimetic that targets biochemical pathways affected by CR, and thus achieve life span extension. By establishing a combinatorial biosynthetic route in Escherichia coli and exploring the substrate promiscuity of a mutant polyketide synthase (PKS), many potential anti-aging polyketides and alkaloids can be biosynthesized. In this approach, novel acyl-CoA precursors generated by promiscuous acid-CoA ligases will be delivered to the mutant PKS, and the polyketides and alkaloids thus generated will be introduced to Caenorhabditis elegans when they feed on the engineered E. coli. Compound libraries can thus be screened in C. elegans-based life span assays. It was found that CR mimetics like resveratrol can also counter the age-associated decline in mitochondrial function. This study highlights the potential of synthetic enzymology in the development of anti-aging nutraceuticals.