| Background:Recently,many researchers studied aging from different direction and generated different theory,which greatly enhanced the understanding of aging mechanism.However,those theory only grasped single point or reflected unilateral phenomena of aging and could not give a whole insight into aging progress.In fact, aging is the issue of system biology and aging progress is characterized by its systematic change.In some level of biological body,for example proteomics, metabolomics,transcriptomics,genomics etc,systematically mining time dynamic pattern,functional decline and association between tissues during aging progress could present a global and novel view of aging.In addition,aging almost involves all of body and the whole life cycle,which makes it difficult and unfeasible to study from all of system.Thus,it is necessary and feasible to research aging based on some foundation with abundant clinical practice of anti-aging action.The "shenxu" symptom in TCM is closely related to aging feature."Shenxu" symptom presents inner coherence with aging.The TCM drug Epimedium Flavonoids(EF) has experienced abundant clinical practice to be used to treat "shenxu" symptom and for anti-aging.So the diagnoses criteria of "shenxu" symptom can lead us to set about feasible and practical research for aging.In this study,we systematically investigate rat aging progress in level of genes expression of"shenxu" symptom related 7 tissues, including thalamencephalon,pituitary,adrenal gland,spleen lymphocyte,kidney,liver and bone.Illustrate time dynamic pattern of genes expression,genes expression behavior in different tissues and their relationship development during aging progress. Finally,we observe global action feature of anti-aging drug Epimedium Flavonoids(EF) in genes expression level and try to answer the inner disease mechanism of "shenxu" symptom.Content and Method:1.Time dynamic pattern of gene expression in different tissues during aging progress. We compared time points in succession to select differentially expressed genes during aging progress.Mine time dynamic pattern in different tissues by pattern score. Analyze the whole pattern feature of aging.Furthermore,find pattern genes enriched pathways to reveal the global change character of body biological function during aging.2.Time-space association in gene expression level during aging progress.Different tissues are related with one another and their association relationships experience dynamic development during the whole aging progress.Gene expression behaviors in different tissues present synchronism development,asynchronous development and specific development.Such feature of aging progress can be revealed by our method.We can score statistical significance of the genes association relationships in different tissues by hypergeometric distribution.And then,we can establish association network of tissues in different agi ng phase and reveal dynamic change of tissues association network with aging progress.Furthermore,we can establish stereo association network by time-space compare to reflect synchronism development,asynchronous development and specific development of gene expression in tissues with aging progress.3.The anti-aging effect of Epimedium Flavonoids(EF) in genes expression level. Study the anti-aging action effect of TCM drug- Epimedium Flavonoids(EF),observe it's adjustive action of thalamencephalon,pituitary,adrenal gland,spleen lymphocyte, renal,liver and bone in gene expression level.Select changed genes by EF action.By hypergeometric distribution,calculate statistical significance of association between genes adjusted by EF and aging related genes in 7 tissues to assess reverse effect of EF action of genes expression of aging rat.Finally,analyze function of genes adjusted by EF,systematically illustrate anti-aging action of EF in gene expression level to reveal inner mechanism of "shenxu" symptom.Results and Conclusion:1.Time dynamic pattern of genes expression in tissues during aging progress. Every particular pattern of genes expression during aging progress was scored,and the score ranged from -13 to +13,which can be further summarized as up-regulated pattern and down-regulated pattern.The patterns with score between -13 to -1 reflected down-regulated trend,that with score between 1 to 13 reflected up-regulated trend,that with zero score indicated no change of gene expression during all aging progress.The results showed that the mass of genes didn't present time dynamic pattern during aging progress(zero score pattern).Only few genes changed in expression and those changed genes were aging related genes.The number of genes in up-regulated pattern was approximately equal to that of down-regulated pattern.In those patterns,those with score -1,1,-3,3,-9 and 9 were majority of time dynamic patterns.1(-1) score pattern reflected up(down) regulation of genes expression from youth to middle age,3(-3) pattern reflected up(down) regulation of genes expression from middle age to middle old age,9(-9) pattern reflected up(down) regulation of genes expression from middle old age to old age.Especially,1 and -1 patterns contained more genes than others.These show that biological body successively opens or closes some genes in particular time and tissue space with aging progress and implies programmed senescence theory.By pathways analysis in 7 tissues,we found 46 statistically significant pathways containing genes with up-regulated trend and 46 statistically significant pathways containing genes with down-regulated trend.These pathways mainly involved cancer related pathways,stem cell signaling pathway,TGF-beta signaling pathway,cell adhesion and ECM-cell interaction signaling pathway,PPAR signaling pathway, metabolic pathway and old related disease as cancer,Alzheimer's disease,diabetes.2.Time-space association in gene expression level during aging progress.Gene expression behaviors in different tissues present synchronism development, asynchronous development and specific development.From youth,middle age, middle old age to old age,synchronism relationship between tissues gradually became weak,asynchronous relationship gradually appeared,specific relationship gradually became strong.As a whole,genes expression in different tissues behaved a progress from commonness to specificity,association relation between tissues gradually reduced.From youth to middle age,association relation between tissues mainly represented synchronism.From middle age to middle old age,association relation between tissues mainly represented asynchronous relationship.From middle old age to old age,association relation between tissues mainly represented specificity. By view of time-space association network,we found the differentially expressed genes of Adrenal gland(AR) from youth to middle age lied in hub point of synchronism relationship between tissues,the differentially expressed genes of thalamencephalon(H) and kidney(KR) from middle age to middle old age lied in hub point of asynchronous relationship between tissues.As a whole,the Adrenal glandAR),thalamencephalon(H) and kidney(KR) were closely related for jointly sharing changed genes during aging progress.3.The anti-aging effect of EF in genes expression level.We found the EF plays the important role in adjusting nerve,incretion,immunity and metabolism systems.EF increased the expression of many hormones,arginine vasopressin and hydroxysteroid 11-beta dehydrogenase 1,which indicated EF can improve function of HPA system.EF also increased the expression of procollagen typeⅹalpha 1,procollagen typeⅪalpha 1,cartilage oligomeric matrix protein, procollagen typeⅡalpha 1,procollagen typeⅨalpha 2(predicted),procollagen typeⅨalpha 1,and TGFβ,which indicated EF can improved cell-cell communication and association,rebuilt bone tissue and enhance bone function,which were consistent with previously clinical practice.From view of the whole,there were diverse effect to different extent for EF to adjust different tissues,which reflected action selection of EF to different tissues,also to genes in the same tissue.In addition,the results showed the differentially expressed genes of youth or middle age against old in Adrenal gland(AR) lied in hub point of EF action.The inner function mechanism of "shenxu" symptom represented in nerve, incretion,immunity and metabolism systems,which were closely related to Adrenal gland(AR),pituitary(P),thalamencephalon(H) and kidney(KR),the Adrenal gland (AR) played the core role. |
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