Partial Mechanisms For Drug Synergy Between Myriocin And Rapamycin-mediated Lifespan Extension In Yeast

Since ancient times,the pace of people's pursuit of healthy longevity has never stopped.Although modern medical technology has greatly prolonged human life,aging is still an inevi Table process of humankind.Aging itself is not a disease but accompanied aging-related diseases,such as cardiovascular diseases,neurodegenerative diseases,type II diabetes,and some cancers,destroy the body of the aged and increase the burden on families and social pressure.Aging has become an inevi Table trend in the development of modern human society.Simultaneously with the development of time,it will become an unavoidable social problem.So how to improve the healthy life of human beings,not just the ‘living'which plagued with age-related diseases,is the major issue and challenge that modern science and technology facing.With the efforts of many researchers,the aging model organisms such as yeast,Caenorhabditis elegans,and mice were established,and genetic disturbances,nutritional interventions,drug treatments were found to control aging.Among them,the research and development of anti-aging related active molecules is becoming a hot topic in the field of aging and age-related diseases because of its theoretical feasibility and clinically application.Combination of low dose of two or more sui Table drugs is able to reduce drug toxicity and cost while achieving greater efficacy,which is a feasible research method in the field of aging research.In this article,two anti-aging molecules have been selected: rapamycin and myriocin.Rapamycin is an immunosuppressive agent that has been proven in several studies to extend the lifespan of yeast and mice.Myriocin is a newly discovered immunosuppressant that specifically inhibits sphingolipid synthesis.Similar aging metabolism mechanism of Saccharomy cescerevisiae with that of human cells,let yeast now be widely applied to aging research.This study examined the effects of rapamycin and myriocin on the longevity of Saccharomy cescerevisiae and mechanisms for its regulating cell lifespan.This study first examined the effects of combination low-dose of rapamycin and myriocin on the growth of wild-type Saccharomy cescerevisiae DBY746 and found that compared to single drug treatment,the synergistic effect of the the two drugs was significantly inhibited the growth of Saccharomy cescerevisiae and greatly prolonged the lifespan.By examining the effects of rapamycin and myriocin on processes in budding yeast,it was found that the synergistic effect significantly enhanced the pressure resistance(hot press resistance,oxidative pressure resistance,acidic pressure resistance and salt ion resistance)of the Saccharomy cescerevisiae,and the level of reactive oxygen species(ROS)was significantly reduced.In order to elucidate the mechanism of this synergistic effect in inhibiting yeast growth,prolonging lifespan,increasing stress resistance,and reducing ROS levels,we analyzed the transcriptome of Saccharomy cescerevisiae after treatment with two drugs and found that a large number of genes were significantly differentially expressed,lifespan-related cellular processes or signaling pathways such as TCA cycle,glycolytic,oxidative phosphorylation,phagocytosis,and mitochondrial function are significantly altered.Thereafter,ADH5,GDH3,PYC1,and the aging-related gene TOR1 are quantitatively analyzed to verify transcription.The relative expression levels of ADH5,GDH3,PYC1,and TOR1 genes were consistent with the transcriptome data,indicating that ADH5,GDH3,PYC1 and TOR1 participate in the regulation of Saccharomy cescerevisiae aging.In addition,due to the growing maturity of meta-analysis in the field of psychiatric research,we hereby conducted a meta-analysis of the relationship between the SNP rs2391191 of the DAOA gene and mood disorder in Caucasians and Asians.Elaborated on data collection and analysis methods to expect meta-analysis can be applied to the study of aging and aging related diseases.The results showed that the change of risk gene A in rs2391191 was significantly associated with Caucasian mood disorder,but there was no correlation with Asian mood disorder.We'd like to take this as an example to provide a new method for the meta-analysis to apply to the study of aging and aging related diseases.