Professor Nan Hao from UCSD and his research group published a paper titled Engineering longevity—design of a synthetic gene oscillator to slow cellular aging in Science on April 27, 2023. The research team used yeast cells as the subjects and employed synthetic biology techniques to design a gene oscillator that successfully prolonged the life span of yeast cells by 82%.

In 2020, Professor Nan Hao’s team identified two aging patterns associated with yeast cell death, mediated by the lysine deacetylase Sir2 and heme-activated protein (HAP), respectively. At the critical point where the yeast cell declines toward death, aging is not the result of the accumulation of the two patterns, but rather the yeast cell simply “chooses” one of the aging patterns to function until it dies. About half of cellular aging is caused by a gradual decrease in the stability of rDNA, while the other half by the functional damage of mitochondria.

After further identifying the characteristics and association of the two aging patterns, the researchers began to think about whether it is possible to influence the expression of the two proteins, Sir2 and HAP4, through gene editing or chemical interventions, and thus reprogram the cellular aging pattern to slow down yeast cell aging. Professor Nan Hao’s team conducted computational simulations of the biological mechanisms of yeast cell aging, tested the experimental design, and constructed and modified gene circuits in yeast cells.

The edited yeast cells switched back and forth between high levels of Sir2 and HAP, which the researchers call a “genetic oscillator. This “genetic oscillator” drives the cells to periodically switch between two different “senescence” states, slowing down cell degradation by avoiding prolonged development of one senescence process.

The team used microfluidics coupled with time-lapse microscopy to track dynamic changes throughout the life span of single cells. And the results of the experiments showed that the yeast cells with the gene oscillator increased their life span by 82% compared to the control group of WT yeast cells, setting a new record for life span extension through genetic and chemical interventions.

Unlike previous experiments that simply knocked out or overexpressed aging-related genes, Professor Nan Hao’s team set up a gene oscillator that effectively slowed down the progression of aging in yeast cells, and significantly increased the life span of the cells. This not only marks another critical step in studying the mechanism of aging, but also lays the foundation for the use of synthetic biology to extend the life span of complex organisms.

Read the paper on Science