Mechanistic Study Of Mannose Extends Lifespan Of Caenorhabditis Elegans

Aging is the greatest risk factor for common chronic diseases in humans,which have placed medical health and social-economic severe challenges.Therefore,it is reasonable that aging research has been an important direction to develop interventions to prevent,cure or reverse a variety of age-related diseases.Recent studies have identified many drugs that promote longevity and anti-aging,such as rapamycin,metformin,and metabolic regulated compounds.Metabolism not only provides the energy,but also supplies various substances participated in biological responses.Cell metabolism,especially energy metabolism,is closely related to aging and longevity.Research in recent years has found that many metabolism-related genes or metabolites are involved in the regulation of biological processes such as epigenetic modifications,gene transcription and protein-protein interactions.Inhibiting or interfering energy metabolism has been proven to prevent premature aging and facilitate longevity.Mannose is a hexose that could be consumed in cells as the source for glycolysis.It was also involved the process of cellular glycosylation.It has been reported that mannose can suppress tumorigenesis by inhibiting the utilization of glucose in tumor cells.However,the effects of mannose on ageing and longevity has not been reported.Caenorhabditis elegans is one of the most commonly used animal model to study longevity due to its advantages of short generation time,short lifespan,ease of cultivation.By combining lifespan and heat stress assays with RNA-seq and metabolomics analysis,we found that mannose extends the lifespan of Caenorhabditis elegans and uncovered underlying mechanisms.The results are shown as follows:1.Previous research revealed that 5 m M mannose significantly extended the lifespan of the Caenorhabditis elegans,and enhanced the hallmarks of Caenorhabditis elegans health.Here,we found that mannose up-regulated the expression of heat shock protein genes and significantly improved the survival of Caenorhabditis elegans under heat stress environment through analysis of RNA-seq data.2.We knocked down the expression of hxk-1,mpi,pmm2 and gpi-1,which regulate mannose and glucose metabolism in Caenorhabditis elegans using RNA interference.Lifespan experiments revealed that mannose extends Caenorhabditis elegans longevity dependent on hxk-1 and mpi,as well as glucose metabolism.Similar effect was also observed in heat stress assay.3.Analysis of RNA-seq data showed that mannose activates the expression of genes regulating daf-16/Fox O signaling pathway.We found that mannose regulated nematode longevity through sir-2.1,daf-16 and hsf-1.However,the specific role of daf-2 which regulates daf-16 and hsf-1,was still unclear.4.Combining RNA-seq data with metabolomic analysis,we found that mannose metabolism inhibits the glycolysis of Caenorhabditis elegans to accumulate NAD~+.Interestingly,mannose had no effect on the accumulation of intermediate products in the TCA cycle and amino acids in Caenorhabditis elegans.5.Our preliminary results showed that mannose may have a therapeutic effect on Parkinson’s disease on nematode model of Parkinson’s disease.Taken together,our data showed that mannose inhibits glycolysis in Caenorhabditis elegans to enhance NAD~+accumulation,which then activates the NAD~+-Sir-2.1-daf-16 pathway to promote the expression of heat shock genes,extends lifespan and improves resistance to heat stress of Caenorhabditis elegans.Our study indicates that mannose may be used as a supplement to promote longevity and have a therapeutic effect on some age-related diseases.Nonetheless,we noted that the role of mannose-6-phosphate and phospho-mannose isomerase have not been revealed in this study.We will explore more in-depth molecular mechanisms.