CN105259346A - Aging biomarker detection method - Google Patents
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- CN105259346A CN105259346A CN201510240753.4A CN201510240753A CN105259346A CN 105259346 A CN105259346 A CN 105259346A CN 201510240753 A CN201510240753 A CN 201510240753A CN 105259346 A CN105259346 A CN 105259346A
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Abstract
The invention relates to an aging biomarker detection method. The aging biomarker detection method comprises 1, collecting and treating a serum sample, 2, by a DNA sequenator-based fluorescence-assisted carbohydrate electrophoresis DSA-FACE technology, carrying out fluorescence labeling on an oligosaccharide chain of glycoprotein in the serum sample, 3, carrying out electrophoretic separation measurement on the sample to obtain fluorescently labeled oligosaccharide chain content and acquiring an oligosaccharide chain fingerprint, and 4, analyzing the oligosaccharide chain fingerprint. The aging biomarker detection method solves the problem of high difficulty of aging detection and realizes ageing degree quantitative evaluation detection.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to a kind of biological markers detection method of aging.
Background technology
As everyone knows, sugar, protein, nucleic acid relates to three class important biomolecule molecules of vital movement essence.In vital movement process, sugar as energy matter and structural material effect already be familiar with by people.Nearly 50% be glycosylated protein in all proteins in body.Along with the development of molecular biology and cell biology, other many biological functions of sugar are constantly found, are familiar with.Sugar chain has signal mark, participates in cellular immunity, composition blood group antigens, the water wettability improving albumen or lipid, protection modifying protein, as various functions such as malignant cell marks.In research aging process, find that oligosaccharide structure changed with the age, this change makes it to become potential aging mark.
Current result of study display, aging course is very complicated, relates to multiple metabolic pathway, and aging process mainly controls by heredity, and its aging course at molecular level is not yet clear.The elderly is the group of people at high risk of disease, if can detect the aging rate of aging, carries out ahead of time intervening slowing down aging progress, can play the effect of prevention and aging relevant disease.
Summary of the invention
The object of this invention is to provide a kind of biological markers detection method of quantitative detection aging.
The technical scheme realizing the object of the invention is a kind of biological markers detection method of aging, comprises the following steps: that (1) collects process blood serum sample; (2) by the oligonucleotide chain based on glycoprotein in the fluorescence assisted carbohydrate electrophoresis DSA-FACE technology fluorescence labeling blood serum sample of DNA sequencer; (3) electrophoretic separation is measured the content of fluorescently-labeled oligonucleotide chain in sample and is obtained oligonucleotide chain finger-print; (4) oligonucleotide chain finger-print is analyzed.
In preferred step (1) blood serum sample from 20,30,40,50,60 years old five age bracket totally 100 serum humans, each age bracket is made up of 10 male sex and 10 women, and blood serum sample is through sialidase digestion.
The corresponding N sugar chain of oligonucleotide chain fingerprint in preferred step (4), the N sugar chain concentration that blood serum sample is detected is shown as peak 1-9 with peak height, calculate by quantifying and determine the change of N sugar chain concentration along with age aging, 20,30, in 40 years old age bracket, the basic held stationary of peak value, from one's mid-40s, change is obviously, 50, in 60 years old age bracket, peak 1 and peak 6 along with the age old and feeble and change.
Measure sample in preferred step (3) and be divided into rheumatoid arthritis group, adult progeria group and human male control group, controlled condition is divided complete serum, immunoglobulin lgG serum and is not contained immunoglobulin lgG serum.
In preferred step (1), blood serum sample also comprises mice serum and rat blood serum, is all divided into go on a diet group and normal nursing group.
The corresponding N sugar chain of oligonucleotide chain fingerprint in preferred step (4), the N sugar chain concentration that blood serum sample is detected is shown as peak 1-10 with peak height, mice serum N sugar chain specific peak is expressed as m peak 2, m peak 4, m peak 8 and m peak 10, and rat blood serum N sugar chain specific peak is expressed as r peak 2, r peak 4, r peak 8 and r peak 10.
Preferred step (3) middle measurement sample is divided into phenixin group, phenixin adds IFN-γ group and control group.
The present invention has positive effect: by the quantitative analysis of glycoprotein glycan and physiological age relation in serum, oligosaccharide ingredient in serum in glycoprotein is relatively stable, its content is young and the middle age is relatively stable, and along with the increase at age, the content of some specific oligosaccharides changes.Oligonucleotide chain finger-print can make the index at quantitative forecast physiological aging age, carries out qualitative assessment detection to the degree of aging; Easy to operate, be applicable to all size analytical chemistry and biology laboratory, be also applicable to large flux and test on a large scale.
Accompanying drawing explanation
In order to make content of the present invention more easily be clearly understood, below according to specific embodiment also by reference to the accompanying drawings, the present invention is further detailed explanation, wherein
Fig. 1 is oligonucleotide chain fingerprint corresponding N sugar chain structure figure;
Fig. 2 is the evolution of mankind men and women blood serum sample N sugar chain peak 1-9 with transverse axis change of age, and Z-axis represents corresponding unit and fluorescence unit value;
Fig. 3 is the differentiation overview diagram of human serum sample N sugar chain peak with transverse axis change of age, the Z-axis of wherein scheming A represents the peak 1 unit and fluorescence unit value corresponding with the asialoglycoprotein galactosylation N sugar chain of 2, the Z-axis of figure B represents the corresponding unit and fluorescence unit value of the bisection N sugar chain at peak 2,4,7, the Z-axis of figure C represents the corresponding unit and fluorescence unit value of the core fucosylation N sugar chain at peak 1,2,6,7, and the Z-axis of figure D represents the corresponding unit and fluorescence unit value of peak 1-6 summation N sugar chain;
Fig. 4 top is the malto-oligosaccharide as reference, centre is not containing the electrophoresis of asialoglycoprotein N sugar chain in the serum of immunoglobulin lgG, bottom is the electrophoresis reference of asialoglycoprotein N sugar chain in the serum of immunoglobulin lgG, wherein transverse axis represents glucose unit value, and Z-axis represents corresponding unit and fluorescence unit value; Fig. 5 be the mankind containing the serum of immunoglobulin lgG and the serum N sugar chain peak 1-9 of the immunoglobulin lgG evolution with transverse axis change of age, Z-axis represents corresponding unit and fluorescence unit value;
Fig. 6 is rheumatoid arthritis group, adult progeria group, the evolution of serum N sugar chain peak 1-7 with transverse axis change of age not containing immunoglobulin lgG of human male control group, and Z-axis represents corresponding unit and fluorescence unit value;
Fig. 7 is rheumatoid arthritis group, adult progeria group, and the complete serum N sugar chain peak 1-9 of human male control group is with the evolution of transverse axis change of age, and Z-axis represents corresponding unit and fluorescence unit value;
Fig. 8 is rheumatoid arthritis group, adult progeria group, the N sugar chain analysis contrast at human male control group peak 5 and peak 6, the analysis of complete serum N sugar chain and receiver operating-characteristic curve are shown in lower left side, and the serum N sugar chain analysis of immunoglobulin lgG and receiver operating-characteristic curve are shown in lower right side;
Fig. 9 is top human serum sample N sugar chain peak 1-9, middle mice serum sample N sugar chain peak 1-10, and bottom is rat blood serum sample N sugar chain peak 1-10, and wherein transverse axis represents glucose unit value, and Z-axis represents corresponding unit and fluorescence unit value;
Figure 10 is go on a diet group and normal nursing group blood serum sample N sugar chain peak 1-9 of mouse is the evolution of monthly variation with transverse axis age unit, and Z-axis represents corresponding unit and fluorescence unit value;
Figure 11 is go on a diet group and normal nursing group blood serum sample N sugar chain peak 1-10 of rat is the evolution of monthly variation with transverse axis age unit, and Z-axis represents corresponding unit and fluorescence unit value;
Figure 12 is rat blood serum sample phenixin group, phenixin adds IFN-γ group and control group N sugar chain peak 1-6 is the evolution of Zhou Bianhua with transverse axis age unit, and Z-axis represents corresponding unit and fluorescence unit value;
Figure 13 is rat blood serum sample phenixin group, phenixin adds IFN-γ group and control group is every biochemical indicator evolution of Zhou Bianhua with transverse axis age unit.
Embodiment
The serum sugar spectrum of the mankind:
100 mankind's serum samples of five age groups (20,30,40,50,60) have been selected in research, and each age group is made up of 10 male sex and 10 women.N sugar chain albumen all purification process by analysis, serum sample all through sialidase digestion, different ages and gender group DSA-FACE technical Analysis N sugar spectrum.N sugar chain is quantized into the peak height (see Fig. 1) at 9 peaks respectively.9 peak value intermediate values of five groups of data and 4 score values carry out statistical study, and the size at peak represents the concentration of this structure oligosaccharides, do statistical test to seek the contact between N sugar chain and aging to peak value.As shown in Figure 2, P1 with P2 increased gradually with the age, and P6 increases with the age and reduces.These three variablees may be used as the old and feeble biomarker evaluating the general level of the health.In order to study by peak P1, the variable characteristics of P2, P6, P7 composition, we improve peak height, and P7 represents core fucose, P1 and P2 represents galactose, P2 and P7 represents binary N-Acetyl-D-glucosamine residue.The average level of two feeler galactosylation and binary N-Acetyl-D-glucosamine residue significantly rises, and core fucose average degree remains unchanged (see Fig. 3), and the two feeler risen and bisection glycosyl and 2,4, No. 7 peaks are consistent.
The N sugar spectrum of human antibodies:
Glycoprotein is immune key components, and the sugared structure be connected with immunoglobulin (Ig) is being synthesized, stable, identifies and controls to play important role in protein and many different interactions.In order to assess the change of N sugar chain concentration in aging course, we are to immunoglobulin lgG and do not detect containing the serum of immunoglobulin lgG, and antibody albumen agarose carries out purifying, and N sugar spectrum obtains being shown in Fig. 4 by DSA-FACE technology.Although N sugar spectrum has tissue specificity, 7 kinds of sugar chain structures are all found in serum and immunoglobulin lgG to be existed.The main sugared structure be connected with antibody is the two feeler galactose (P6) of fucosylation, but P3 is glycosyl (Fig. 1 and Fig. 4) the abundantest in serum.As shown in Figure 5, complete serum and containing immunoglobulin lgG serum in each peak value substantially not close.This has told that the sugared structure relative concentration in our serum and antibody have nothing to do.N sugar spectrum in antibody is similar with the reduction of P1, P2, P6 in complete serum.In addition, the content of P3 only has reduction in immunoglobulin lgG, complete serum and not containing not discovery in the serum of immunoglobulin lgG.
The N sugar spectrum of patient with rheumatoid arthritis:
Inflammation has the tissue of vital movement to machinery, chemistry, the response that immunologic mjury is made.Normal aging course can show as the excessive autoimmunity of articular cartilage and its hetero-organization usually.Rheumatoid arthritis is a kind of disease relevant with the age, the nearly patient group accounting for total population 1% of global range.Dysimmunity in body fluid and cell and the chronic inflammation of this disease are shown effect close association.Patient with rheumatoid arthritis grow louder and stronger to the cry that this disease is glycosylation imbalance.In order to provide new visual angle to rheumatoid arthritis pathogenesis, we are to 20 patient with rheumatoid arthritis N sugar analysis of spectrums, the sugar of they and normal donors is composed and contrasts.As shown in Figure 7, P5 and P6 glycosyl concentration change shows, and the former rises compared with Normal group, and the latter declines.The same age bracket of other peak values and Normal group similar.At antibody moiety, great changes have taken place for sugar group structural content, and P3, P4, P5 and P6 obviously reduce, and P7 rises.In rheumatoid arthritis the mean value of variable P5 and P6 and Normal group difference obvious, disclose the impact of rheumatoid arthritis on serum N sugar chain.These differences are assessed by receiver operating-characteristic curve.Curve shows the efficiency of classification, draws P5 content 0.086, P6 content 0.163 in antibody according to the region below curve, and in complete serum, P5 is 0.911, P6 is 0.160 (see Fig. 8).
Adult progeria patient N sugar spectrum:
Adult progeria is the hereditary disease that a kind of young man's appearance of normal age crosses presenility.The effect of adult progeria molecule aspect is also to be studied, and such as some effect may be consistent with common aging course.In order to assess contacting between adult progeria and aging, assess old and feeble mark, we study also an adult progeria patient N sugar spectrum and normal group contrasts.Carry out N sugar analysis of spectrum (Fig. 6 and Fig. 7) to immunoglobulin (Ig) and complete serum, in patient body, the concentration of glycosyl is compared with Normal group, and change is even also large than normal group more than 60 years old change.In complete serum, P1, P2, P4, P5 rise, and P3, P6 decline (Fig. 7).But immunoglobulin (Ig) and these peak values in complete serum show consistent changing pattern (Fig. 6 and Fig. 7).P4 with change contrary in complete serum, P5 does not change.The change at several the peaks observed in adult progeria is consistent with rheumatoid arthritis disease, imply that the value of N sugar chain as old and feeble biomarker.
Calorie restriction is on the impact of rat mice serum N sugar spectrum:
Much research all confirms that caloric restriction is life-extending, delays the most effectual way of the seizure of disease time relevant with the age, and in rodent experiment, we reduce the calorie of 30%-50% by food.Heat reduces fundamental mechanism that is life-extending and reduction disease susceptibility and does not also thoroughly understand.In order to test old and feeble mark, we are to normal nursing group and group N sugar chain analysis of going on a diet, and some sugar chain structures are different with the mankind is marked as specific peak (Fig. 9).This discovery sugared group of also demonstrate that N connects is the basic composition structure of each species.Figure 10 reflects that mouse is gone on a diet group N sugar analysis of spectrum result, and Figure 11 reflects that rat is gone on a diet group N sugar analysis of spectrum result, we have found several peaks and to go on a diet the difference of group and normal nursing group, and this concentration difference has species specificity.
Phenixin treatment is on the impact of rat blood serum N sugar spectrum:
Phenixin is usually used to reach cirrhosis and the fiberization that animal model carrys out simulating human.In order to assess the indicating effect of sugared mark for liver damage, we study rat and combine IFN-γ, control group N sugar spectrum at phenixin, consider that the N sugar spectrum in animal body is all special, a rat blood serum N sugar spectrum after asialoglycoprotein ferment treatment shows 10 main peaks (Fig. 9).Wherein P1, P3, P5, P6, P7, P9 and the mankind basically identical, but rP2, rP4, rP8, rP10 tetra-peaks are rat specificity N glycosyls.
As shown in figure 12,6 peaks show the peak change between two groups.IFN-γ group shows less rate of change compared with phenixin group, shows the protected effect to liver.
Phenixin group and control group N sugar spectrum showed different trends at the 9th week, and No. 4 peaks and No. 5 peaks be even just difference at the 6th week, but contrast Figure 13, biochemistry detection after experiment about 12 weeks phases time just show the damage that phenixin causes liver.This result shows N sugar spectrum and detects compared to biochemistry detection in cytotoxicity, and there is higher sensitivity liver lesion detection aspect.
Above-described specific embodiment; object of the present invention, technical scheme and beneficial effect are further described; be understood that; the foregoing is only specific embodiments of the invention; be not limited to the present invention; within the spirit and principles in the present invention all, any amendment made, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (7)
1. a biological markers detection method for aging, comprises the following steps: that (1) collects process blood serum sample; (2) by the oligonucleotide chain based on glycoprotein in the fluorescence assisted carbohydrate electrophoresis DSA-FACE technology fluorescence labeling blood serum sample of DNA sequencer; (3) electrophoretic separation is measured the content of fluorescently-labeled oligonucleotide chain in sample and is obtained oligonucleotide chain finger-print; (4) oligonucleotide chain finger-print is analyzed.
2. the biological markers detection method of aging according to claim 1, it is characterized in that: in step (1) blood serum sample from 20,30,40,50,60 years old five age bracket totally 100 serum humans, each age bracket is made up of 10 male sex and 10 women, and blood serum sample is through sialidase digestion.
3. the biological markers detection method of aging according to claim 2, it is characterized in that: the corresponding N sugar chain of oligonucleotide chain fingerprint in step (4), the N sugar chain concentration that blood serum sample is detected is shown as peak 1-9 with peak height, calculate by quantifying and determine the change of N sugar chain concentration along with age aging, 20,30, in 40 years old age bracket, the basic held stationary of peak value, from one's mid-40s, change obviously, 50, in 60 years old age bracket, peak 1 and peak 6 along with the age old and feeble and change.
4. the biological markers detection method of aging according to claim 3, it is characterized in that: measure sample in step (3) and be divided into rheumatoid arthritis group, adult progeria group and human male control group, controlled condition is divided complete serum, immunoglobulin lgG serum and is not contained immunoglobulin lgG serum.
5. the biological markers detection method of aging according to claim 2, is characterized in that: in step (1), blood serum sample also comprises mice serum and rat blood serum, is all divided into go on a diet group and normal nursing group.
6. the biological markers detection method of aging according to claim 5, it is characterized in that: the corresponding N sugar chain of oligonucleotide chain fingerprint in step (4), the N sugar chain concentration that blood serum sample is detected is shown as peak 1-10 with peak height, mice serum N sugar chain specific peak is expressed as m peak 2, m peak 4, m peak 8 and m peak 10, and rat blood serum N sugar chain specific peak is expressed as r peak 2, r peak 4, r peak 8 and r peak 10.
7. the biological markers detection method of aging according to claim 6, is characterized in that: step (3) middle measurement sample is divided into phenixin group, phenixin adds IFN-γ group and control group.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109596842A (en) * | 2018-12-29 | 2019-04-09 | 江苏先思达生物科技有限公司 | A kind of alzheimer's disease detection reagent and its application in alzheimer's disease detection |
| CN113651878A (en) * | 2021-04-27 | 2021-11-16 | 杨森 | Skin aging protein marker-1433T protein and non-invasive extraction method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2006058878A1 (en) * | 2004-12-01 | 2006-06-08 | Vib Vzw | Aging biomarker |
| CN103694342A (en) * | 2013-11-12 | 2014-04-02 | 北京理工大学 | Polypeptide marker for detecting human aging |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006058878A1 (en) * | 2004-12-01 | 2006-06-08 | Vib Vzw | Aging biomarker |
| CN103694342A (en) * | 2013-11-12 | 2014-04-02 | 北京理工大学 | Polypeptide marker for detecting human aging |
Non-Patent Citations (1)
| Title |
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| VALERIE VANHOOREN ET AL.: "N-Glycomic Changes in Serum Proteins During Human Aging", 《REJUVENATION RESEARCH》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109596842A (en) * | 2018-12-29 | 2019-04-09 | 江苏先思达生物科技有限公司 | A kind of alzheimer's disease detection reagent and its application in alzheimer's disease detection |
| CN109596842B (en) * | 2018-12-29 | 2022-02-22 | 江苏先思达生物科技有限公司 | Alzheimer disease detection reagent and application thereof in Alzheimer disease detection |
| CN113651878A (en) * | 2021-04-27 | 2021-11-16 | 杨森 | Skin aging protein marker-1433T protein and non-invasive extraction method thereof |
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