Folic Acid Decreases The Sleep Deprivation Induced Oxidative Stress And Telomere Dysfunction

Sleep is a physiological state that is vital for the quality of life of an individual,but sleep deprivation（SD）or chronic sleep restriction has become a relevant health problem caused by social factors and leads to a number of aging-related diseases,including chronic inflammation,Alzheimer’s disease,cardiovascular disease,and even causes mortality when individuals are severely deprived of sleep.It’s important to put forward an effective strategy to decreased the harmful physical response.Folic acid is an essential compound involved in many important biochemical processes during periods of frequent cell division and growth.Previous evidences showed the folic acid function in the preventing of the disease including neural tube defects,cardiovascular disease,and stroke,which all related to oxidative stress.Objective:In our study,we proposed folic acid as an effective vitamin to counteract the sleep deprivation induced oxidative stress and telomere dysfunction,which could provide an appropriate guidance for the public health.Methods:（1）Animal experiment:To investigate the effect of sleep deprivation on oxidative stress response and telomere function in mice,sleep deprivation was performed using a multiple classical platform technique.These mice were fed with folic acid deficient or supplemented diet.The effects of sleep deprivation and folic acid on oxidative stress and aging related pathways in mice were investigated by detecting the expression of oxidative stress and aging related factors in mice.To evaluated the effects of sleep deprivation on the telomeres and aging related diseases,the telomere length and dysfunction in mice were detected by fluorescence in situ hybridization（FISH）and immunofluorescence（IF）technique.Next,RNA sequence was peformed and analysed to discovered the potential mechanism of the process.（2）Human research:We recruited human individuals to investigate the correlation in the sleep quality,folic acid and telomere length.All participants filled out the Pittsburgh Sleep Quality Inventory（PSQI）to assess their sleep quality in the preceding month to the start of the experiment.Results:（1）ELISA assay showed that sleep deprivation could induce oxidative stress response and significantly increase the secretion of IL-4,IL-6,TNF-α.The P16^INK4a-RB and P14^ARF-P53 pathways were activated,which eventually led to chronic inflammation and cell senescence.Folic acid could significantly reduce the level of ROS induced by sleep deprivation and enhance the activity of antioxidant enzyme SOD and improve the oxidative stress state of mice.In addition,folic acid could significantly decrease the expression of inflammatory factor and aging related factor in mice,and ameliorate cell senescence and damage.（2）Fluorescence in situ hybridization and immunofluorescence assay showed that the telomere length of bone marrow cells and testicular cells in mice was significantly shortened,and some telomere fluorescence signals were vanished.We supposed that it is directly or as an intermediate step to repair oxidative base modifications that over-elevated ROS leads to genomic DNA and telomere DNA fragmentation and damage.Folic acid supplementation can protect telomere to a certain extent,specifically reduce telomere DNA damage in testicular cells,and prevent telomere excessive shortening and dysfunction.Oxidative stress in testicular cells also led to abnormal spermatozoa production,resulting in a significant increase in sperm death arrest,and sperm motility was significantly improved after folic acid supplementation.（3）RNA sequencing showed that sleep deprivation mainly affected the gene expression of energy metabolism-related pathway,induced the oxidative phosphorylation and caused the production of ROS.Folic acid,as a cofactor and methyl group donor for DNA methylation may inhibit the expression of genes related to energy metabolism by enhancing the methylation,and improve the damage to genome or telomere caused by oxidative stress.（4）The further investigation in human revealed that poor sleep quality led to a severe telomere shortening which may contribute to aging and aging related diseases.Additionally,leukocyte telomere length of the population was significantly inversely associated to the age and triglyceride concentration and positively correlation with the blood folic acid,revealed that folic acid played a role in telomere protection in people with poor sleep quality.Conclusion:In mice,sleep deprivation could lead to oxidative stress,activate the RB-P16^INK4a and P53-P14^ARF pathway and induce the expression of inflammatory cytokines,resulting in an immune system disorder,as well as telomere length shortening and telomere dysfunction which could cause the occurrence of aging phenotypes.For human individuals,poor quality sleep can affect telomere length of peripheral blood leukocytes,which will promote the body’s aging process and lead to a series of aging or degenerative diseases.Our study implicated folic acid as an effective vitamin to counteract the oxidative stress and telomere dysfunction induced by sleep deprivation.This achievement could provide an appropriate guidance for the public health.However,the mechanism needs to be further clarified.