Engineering longevity-design of a synthetic gene oscillator to slow cellular aging

• 成果类型: Article
• 署名作者: Zhou, Zhen; Liu, Yuting; Feng, Yushen; Klepin, Stephen; Tsimring, Lev S.; Pillus, Lorraine; Hasty, Jeff; Hao, Nan
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego; University of California System; University of California San Diego
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8235
• DOI: 10.1126/science.add7631
• 发表日期: 2023-04-28
• 页码: 376-381
• 关键词: replicative life-span; saccharomyces-cerevisiae; yeast hap2; complex; sir2; transcription; activators; chromatin; networks; pathways

摘要

Synthetic biology enables the design of gene networks to confer specific biological functions, yet it remains a challenge to rationally engineer a biological trait as complex as longevity. A naturally occurring toggle switch underlies fate decisions toward either nucleolar or mitochondrial decline during the aging of yeast cells. We rewired this endogenous toggle to engineer an autonomous genetic clock that generates sustained oscillations between the nucleolar and mitochondrial aging processes in individual cells. These oscillations increased cellular life span through the delay of the commitment to aging that resulted from either the loss of chromatin silencing or the depletion of heme. Our results establish a connection between gene network architecture and cellular longevity that could lead to rationally designed gene circuits that slow aging.