Metabolic engineering has enabled the construction of efficient microbial cell factories, but cellular aging and the accumulation of toxic metabolites during prolonged fed-batch fermentation induce metabolic stress, which ultimately reduces cell productivity. Extending cellular lifespan represents an effective strategy to enhance biosynthetic capacity.

In a study published in PNAS, a team led by Prof. ZHOU Yongjin from the Dalian Institute of Chemical Physics of the Chinese Academy of Sciences demonstrated that combining lifespan engineering strategies with metabolic pathway optimization in Saccharomyces cerevisiae enables highly efficient sclareol biosynthesis, marking an advance in improving microbial production through lifespan engineering.

Sclareol is a valuable diterpene alcohol extracted from Salvia sclarea. It is widely used in pharmaceuticals and agrochemicals. Researchers systematically engineered cellular lifespan through four dimensions: nutrient sensing, mitophagy, protein stability, and genomic stability.

Using high-producing sclareol strain, they found that simultaneously weakening nutrient sensing and enhancing mitophagy, together with metabolic pathway optimization, resulted in a sclareol production of 25.9 g/L. 

Omics analysis showed that weakening nutrient sensing and enhancing mitophagy enhanced central metabolism and cellular robustness by extending chronological lifespan and regulating metabolic gene expression, thereby improving product synthesis in Saccharomyces cerevisiae during the later stages of cell growth.

In addition, researchers found that these lifespan engineering strategies improved the biosynthesis of other products such as sesquiterpenes and phenolic acids, which provides a generalizable approach for developing high-performance microbial cell factories.

"Our work not only establishes a clear connection between chronological lifespan and biosynthesis capacity for improving sclareol production, but also offers a feasible longevity engineering strategy that can be applied to diverse microbial cell factories for sustainable and economical biomanufacturing," said Prof. ZHOU.