CN111380979A - Healthy aged diagnosis marker and application - Google Patents
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Abstract
The invention discloses a diagnosis marker for healthy old people and application thereof, wherein the marker comprises one or more of α -N-phenylacetyl-L-glutamine, 4-methylphenol, N6-methyladenosine, N1-methyl-2-pyridone-5-carboxamide, 3-phenyllactic acid, 5-hydroxyindoleacetic acid, dopamine, 4-hydroxyphenylpyruvic acid, propionylglycine, 4-aminomauric acid, indoxyl sulfate, 3, 4-dihydroxybutyric acid, O-acetylserine, N2, N2-dimethylguanosine, N-tegaseriglycine, threitol, methoxyacetic acid, indole-3-pyruvic acid, L-histidine, homoarginine and arachidonic acid.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to a healthy aged diagnosis marker and application thereof.
Background
The aging speed of the population in China is more than 2 times that of the western countries, wherein the aged of 65 years old is increased from 1.19 hundred million in 2010 to 3.6 hundred million in 2050 (accounting for 25.6 percent of the total population). The quality of life of Chinese people is seriously influenced by the aggravation of aging process and high incidence of senile diseases. Considering that the senile diseases are difficult to cure after the onset, it is necessary to discover key markers of healthy aging and further evaluate the healthy aging characteristics of the aging population.
At present, the internationally accepted research on known factors for health and aging mainly focuses on the discovery of longevity genes, such as longevity genes FOXO3 and APOE. However, the existing research shows that the contribution of the gene to the healthy old is only 15-25%, and more healthy old is the result of the interaction between the environment and the genetics, so that in addition to identifying the gene related to the healthy old, the genes are concerned with other factors which can indicate or evaluate the healthy old in real time, such as epigenetic factors, transcription characteristics, serum protein characteristics and endogenous metabolism micromolecule characteristics. At present, reports of the markers capable of indicating healthy aging in real time are not reported domestically and internationally.
The life of the centenarian as a natural model of healthy aging is far longer than that of the common people, and the trouble of serious diseases related to aging can be delayed and even avoided, so that a marker capable of indicating healthy aging in real time is needed.
Disclosure of Invention
In view of the above, the present invention provides a diagnostic marker for healthy aging and its application.
In order to solve the technical problems, the invention discloses a diagnosis marker for health aged, which comprises one or more of α -N-phenylacetyl-L-glutamine, 4-methylphenol, N6-methyladenosine, N1-methyl-2-pyridone-5-carboxamide, 3-phenyllactic acid, 5-hydroxyindoleacetic acid, dopamine, 4-hydroxyphenylpyruvic acid, propionylglycine, 4-aminomauric acid, indoxyl sulfate, 3, 4-dihydroxybutyric acid, O-acetylserine, N2, N2-dimethylguanosine, N-tegaserod, threitol, methoxyacetic acid, indole-3-pyruvic acid, L-histidine, homoarginine and arachidonic acid.
The invention also discloses application of the healthy aging diagnosis marker in preparing a healthy aging diagnosis product, wherein the diagnosis product comprises a reagent for detecting the one or more markers, and the reagent judges whether the testee has higher healthy aging possibility by detecting the concentration of the one or more markers in the body of the testee.
Optionally, in particular the concentration of one or more markers in the blood of the subject is detected.
Alternatively, the concentration of one or more of the markers α -N-phenylacetyl-L-glutamine, 4-methylphenol, N6-methyladenosine, N1-methyl-2-pyridone-5-carboxamide, 3-phenyllactic acid, 5-hydroxyindolacetic acid, dopamine, 4-hydroxyphenylpyruvic acid, propionylglycine, 4-aminomauric acid, indoxyl sulfate, 3, 4-dihydroxybutyric acid, O-acetylserine, N2, N2-dimethylguanosine, N-tegaserod, threitol, methoxyacetic acid, indole-3-pyruvic acid is significantly increased in healthy elderly people.
Optionally, the concentration of one or more of the markers L-histidine, homoarginine, arachidonic acid is significantly reduced in healthy elderly compared to normal.
The invention also discloses a health aged diagnosis composition, which comprises one or more of the health aged diagnosis markers.
Compared with the prior art, the invention can obtain the following technical effects:
the invention provides a new diagnosis marker for the healthy old blood, which has the characteristics of high accuracy and high sensitivity, and the predicted area AUC under the prediction line of a plurality of markers, such as α -N-phenylacetyl-L-glutamine, propionylglycine, 3-phenyllactic acid, dopamine and the like, reaches over 0.9, so that the diagnosis marker has higher accuracy and sensitivity, and can be directly used as an index for the healthy old blood.
Of course, it is not necessary for any one product to practice the invention to achieve all of the above-described technical results simultaneously.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention without limiting the invention to the best mode contemplated. In the drawings:
FIG. 1 is a ROC graph of the healthy aging marker α -N-phenylacetyl-L-glutamine of the present invention predicting healthy aging and the corresponding molecular formula, wherein A is the ROC graph of α -N-phenylacetyl-L-glutamine and B is the molecular formula of α -N-phenylacetyl-L-glutamine;
FIG. 2 is a ROC graph of 4-methylphenol, a marker for healthy aging, in accordance with the present invention, to predict healthy aging and the corresponding molecular formula; wherein A is ROC curve diagram of 4-methylphenol, and B is molecular formula of 4-methylphenol;
FIG. 3 is a ROC graph of the healthy aging marker N6-methyladenosine of the present invention predicting healthy aging and the corresponding molecular formula; wherein, A is ROC curve chart of N6-methyladenosine, B is molecular formula of N6-methyladenosine;
FIG. 4 is a ROC plot and corresponding molecular formula of the healthy aging marker N1-methyl-2-pyridone-5-carboxamide of the present invention predicting healthy aging; wherein A is ROC plot of N1-methyl-2-pyridone-5-carboxamide and B is the molecular formula of N1-methyl-2-pyridone-5-carboxamide;
FIG. 5 is a ROC plot and corresponding molecular formula for the healthy aging marker 3-phenyllactic acid of the present invention to predict healthy aging; wherein A is ROC curve diagram of 3-phenyllactic acid, B is molecular formula of 3-phenyllactic acid;
FIG. 6 is a ROC curve and corresponding molecular formula for the healthy aging marker 5-hydroxyindoleacetic acid of the present invention to predict healthy aging; wherein, A is ROC curve diagram of 5-hydroxy indoleacetic acid, B is molecular formula of 5-hydroxy indoleacetic acid;
FIG. 7 is a ROC graph of the healthy aging marker dopamine of the present invention predicting healthy aging and the corresponding molecular formula; wherein, A is an ROC curve chart of dopamine, and B is a molecular formula of the dopamine;
FIG. 8 is a ROC plot and corresponding molecular formula for the healthy aging marker 4-hydroxyphenylpyruvic acid of the present invention for predicting healthy aging; wherein A is ROC curve diagram of 4-hydroxyphenylpyruvic acid, and B is molecular formula of 4-hydroxyphenylpyruvic acid;
FIG. 9 is a ROC curve and corresponding molecular formula for predicting healthy aging using propionyl glycinamide as the marker of healthy aging; wherein, A is an ROC curve chart of propionyl glycine, and B is a molecular formula of propionyl glycine;
FIG. 10 is a ROC curve and corresponding molecular formula for the healthy aging marker 4-Aminohippuric acid of the present invention to predict healthy aging; wherein A is ROC curve diagram of 4-amino hippuric acid, B is molecular formula of 4-amino hippuric acid;
FIG. 11 is a ROC graph of the healthy aging marker indoxyl sulfate of the present invention predicting healthy aging and the corresponding molecular formula; wherein, A is ROC curve diagram of indoxyl sulfate, B is molecular formula of indoxyl sulfate;
FIG. 12 is a ROC curve and corresponding molecular formula for the healthy aging marker 3, 4-dihydroxybutyric acid of the present invention to predict healthy aging; wherein A is ROC curve diagram of 3, 4-dihydroxybutyric acid, and B is molecular formula of 3, 4-dihydroxybutyric acid;
FIG. 13 is a ROC curve and corresponding molecular formula for the healthy aging marker O-acetylserine of the present invention to predict healthy aging; wherein, A is ROC curve diagram of O-acetylserine, B is molecular formula of O-acetylserine;
FIG. 14 is a ROC plot and corresponding molecular formula of the healthy aging marker N2, N2-Dimethylguanosine predicted healthy aging according to the invention; wherein, A is ROC curve chart of N2, N2-dimethylguanosine, B is molecular formula of N2, N2-dimethylguanosine;
FIG. 15 is a ROC curve plot and corresponding molecular formula for the healthy aging marker N-tegaserod of the present invention to predict healthy aging; wherein A is an ROC curve diagram of N-tegaserod, and B is a molecular formula of the N-tegaserod;
FIG. 16 is a ROC graph and corresponding molecular formula for the healthy aging marker threitol of the present invention to predict healthy aging; wherein, A is an ROC curve chart of threitol, and B is a molecular formula of threitol;
FIG. 17 is a ROC plot and corresponding molecular formula for the healthy aging marker methoxyacetic acid of the present invention to predict healthy aging; wherein, A is ROC curve diagram of methoxyacetic acid amine, B is molecular formula of methoxyacetic acid;
FIG. 18 is a ROC curve and corresponding molecular formula for the healthy aging marker indole-3-pyruvic acid of the present invention predicting healthy aging; wherein, A is ROC curve diagram of indole-3-pyruvic acid, B is molecular formula of indole-3-pyruvic acid;
FIG. 19 is a ROC plot and corresponding molecular formula for the healthy aging marker L-histidine of the present invention for predicting healthy aging; wherein, A is an ROC curve chart of L-histidine, and B is a molecular formula of L-histidine;
FIG. 20 is a ROC plot and corresponding molecular formula for the healthy aging marker homoarginine predictive healthy aging of the present invention; wherein, A is ROC curve diagram of homoarginine, B is molecular formula of homoarginine;
FIG. 21 is a ROC plot and corresponding molecular formula of arachidonic acid as a marker of healthy aging to predict healthy aging in accordance with the present invention; wherein A is the ROC curve diagram of arachidonic acid, and B is the molecular formula of the arachidonic acid.
Detailed Description
The following embodiments are described in detail with reference to the accompanying drawings, so that how to implement the present invention by applying technical means to solve the technical problems and achieve the technical effects can be fully understood and implemented.
The healthy aging means that the world health organization defines healthy aging as: in the elderly stage, a series of functional abilities (including self-satisfying self-needs; learning and making decisions; acting, establishing and maintaining interpersonal relationships, and contributing to society) can be maintained, and a valuable life process can be brought to oneself (https:// www.who.int/serving/health-serving/en /).
To achieve healthy aging, it is essential that senile diseases (aged disease [ M ]. scientific press, 2011, 1/1) and serious diseases (defined in "standard for defining disease use for insurance of serious disease" started from 4/3/2007) be avoided during aging, and the elderly stage is progressed with little morbidity and extremely low hospitalization rate.
Example 1 diagnostic marker for healthy aging
A novel marker of blood health and aging can be used for evaluating whether an elderly person has characteristics of healthy aging or not by single or combination of two or more of α -N-Phenylacetyl-L-glutamine (Alpha-N-Phenylacetyl-L-glutamine), 4-Methylphenol (4-Methylphenol), N6-methyladenosine (N6-methyladenosine), N1-Methyl-2-pyridone-5-carboxamide (N1-Methyl-2-pyridone-5-carboxamide), 3-Phenyllactic Acid (DL-3-Phenyllactic Acid), 5-hydroxyindolacetic Acid (5-hydroxyindolacetate), Dopamine (Dopamine), 4-hydroxyphenylpropionic Acid (4-Hydroxyphenylpyruvate), Propionylglycine (Propionine), 4-aminomaleic Acid (4-aminomaleic Acid), thiopropionic Acid (N-acetylsalicylic Acid), N-acetylsalicylic Acid-L-glutamine (N-methoxyindole-3-Acetyl-L-glutamic Acid), N-acetylsalicylic Acid-5-methoxyindole-5-thiopropionic Acid (N8678), N-acetylsalicylic Acid-L-methionine-Indole-3-Histidine (N-acetylsalicylic Acid), N-acetylsalicylic Acid-L-phenylalanine-Indole-5-Indole-Acetic Acid (N-methoxyindole-3-Acetic Acid), N-Indole-acide (N-thiopropionic Acid), N-4-methoxyindole-thiopropionic Acid, N-4-thiopropionic Acid, N-thiopropionic Acid (N-4-thiopropionic Acid, N-4-thiopropionic Acid, N-.
Among the 21 diagnostic markers for healthy and old people, there are α -N-Phenylacetyl-L-glutamine (Alpha-N-Phenylacetyl-L-glutamine), 4-Methylphenol (4-Methylphenol), N6-methyladenosine (N6-methyladenosine), N1-Methyl-2-pyridone-5-carboxamide (N1-Methyl-2-pyridone-5-carboxamide), 3-Phenyllactic acid (DL-3-phenylactic acid), 5-hydroxyindoleacetic acid (5-hydroxyindolacetate), Dopamine (Dopamine), 4-hydroxyphenylpyruvic acid (4-Hydroxyphenylpyruvate), Propionylglycine (Propionine), 4-aminomaleuric acid (aminomaleuric acid), 4-hydroxyphenylpyruvic acid (4-hydroxyphenylpyruvic acid), thionine (N-acetylbutyrine-L-glutamic acid), N-acetylsalicylic acid (N-methoxyindole-3-L-glutamic acid), N6-methylacetophenol (N-methoxyindole-3-Acetyl-L-glutamine), N1-2-pyridone-5-carboxamide, 3-Phenyllactic acid (DL-3-methoxyindole-Acetic acid), 4-dihydroindole-Acetic acid (Indole-Acetic acid), N-methoxyindole-acide (Indole-3-thionine, thionine (N-thionine, N-D-N-2-thionine, N-D-.
The 21 healthy aged diagnosis markers are remarkably reduced in healthy aged people: L-Histidine (L-Histidine), Homoarginine (homoarginin), and Arachidonic Acid (Arachidonic Acid) in total 3 species.
Through prospective study on 351 centuries (age range of 92-110 years, average age: 98.4 years) and 410 control groups (age range of 23-86 years, average age of 54.6 years) in many areas including 351 centuries in Hainan Chengmei and Wanning county (74 elderly people, 85 controls), Hainan Ling Shuixing county (111 elderly people, 207 controls) and Hubei Zhongxiang (166 elderly people, 118 controls) in China, the change of each marker in the elderly and the corresponding area AUC under the prediction line are shown in Table 1, and ROC curves of the 21 healthy aging markers for predicting healthy aging are shown in FIGS. 1A, 2A and 3A-21A; the molecular formulas of the 21 blood health aged diagnostic markers are shown in fig. 1B, 2B and 3B-fig. 21B, wherein AUC represents the accuracy and sensitivity of prediction, and AUC ═ 1 represents that the accuracy and sensitivity of prediction are both 100%. The AUC of the markers in table 1 was all greater than 0.8, indicating that the given marker has higher accuracy and sensitivity.
TABLE 1 Change in each marker in centenarian and corresponding area under prediction AUC
Example 2
α -N-Phenylacetyl-L-glutamine (Alpha-N-Phenylacetyl-L-glutamine) is used as a single marker for diagnosing the old health, and the specific implementation method is as follows:
1. obtaining a sample of a subject, and carrying out pretreatment: collecting blood sample of a subject according to a standard and reasonable operation process, adding 100 mu L of blood into 350 mu L of methanol, performing vortex mixing, high-speed centrifugation, taking supernatant, performing concentration drying, adding 100 mu L of acetonitrile for redissolution, and performing liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-QTOFMS) test directly through a filter plug.
2. Data processing: and after the UHPLC-QTOFMS is tested, collecting UHPLC-QTOFMS data for analysis. The data processing uses XCMS program, and the parameter setting refers to software description. After XCMS program treatment, charge-to-mass ratios, retention times, peak areas and secondary mass spectrum indexes of all metabolites are obtained.
3.α concentration determination of N-phenylacetyl-L-glutamine by comparison of secondary mass spectra databases based on mass to charge ratio and mass spectral secondary fragments α concentration of N-phenylacetyl-L-glutamine in blood was determined by the ratio of its peak area to the peak area of a standard, wherein metabolite concentration determination was done by the Hippocampus biomedical science and technology Limited.
4. Diagnosis of healthy aging α -N-phenylacetyl-L-glutamine concentration in the blood of the subject measured as described above is compared with the threshold value of the general population (410 control groups). if the value exceeds the threshold value of the general population (410 control groups), the subject has a higher possibility of healthy aging, wherein α -N-phenylacetyl-L-glutamine has a threshold value of 3.34umol/L in the blood of the general population, the result shows that the area under the characteristic curve line is 0.918, and the concentration of α -N-phenylacetyl-L-glutamine in the blood of the subject is 10.70umol/L, which is higher than the threshold value of the general population (3.34umol/L), indicating that the subject has a better characteristic of healthy aging and should maintain the present state.
Example 3 diagnosis of healthy aging with N6-methyladenosine as a single marker:
the subject N6-methyladenosine was determined in steps 1-3 of example 2. The measured concentration of 5-hydroxyindoleacetic acid in the subject's blood is compared to a threshold value for the general population (410 control groups), and if the value exceeds the threshold value for the general population, then the subject has a higher likelihood of being healthy for the elderly. Wherein the blood concentration threshold value of the N6-methyladenosine in the general population is 0.11 umol/L; the results show that the area under the characteristic curve line is 0.905, the concentration of N6-methyladenosine in the blood of the subject is 0.18umol/L, and the value is higher than the threshold value (0.11umol/L) of the general population, which indicates that the individual has better healthy aging characteristics and should keep the current state.
Example 4
The diagnosis is carried out by combining α -N-phenylacetyl-L-glutamine and N6-methyladenosine metabolites, the concentration of α -N-phenylacetyl-L-glutamine in the blood of the subject is measured to be 9.45umol/L (greater than 3.34umol/L of a normal threshold value), the concentration of N6-methyladenosine is measured to be 0.15umol/L (greater than 0.11umol/L of the normal threshold value), and the two metabolites are increased in healthy and old people through a table look-up 2.
While the foregoing description shows and describes several preferred embodiments of the invention, it is to be understood, as noted above, that the invention is not limited to the forms disclosed herein, but is not to be construed as excluding other embodiments and is capable of use in various other combinations, modifications, and environments and is capable of changes within the scope of the inventive concept as expressed herein, commensurate with the above teachings, or the skill or knowledge of the relevant art. And that modifications and variations may be effected by those skilled in the art without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (6)
1. A diagnostic marker for the aged health, which comprises one or more of α -N-phenylacetyl-L-glutamine, 4-methylphenol, N6-methyladenosine, N1-methyl-2-pyridone-5-carboxamide, 3-phenyllactic acid, 5-hydroxyindolacetic acid, dopamine, 4-hydroxyphenylpyruvic acid, propionylglycine, 4-aminomauric acid, indoxyl sulfate, 3, 4-dihydroxybutyric acid, O-acetylserine, N2, N2-dimethylguanosine, N-tegaserod, threitol, methoxyacetic acid, indole-3-pyruvic acid, L-histidine, homoarginine and arachidonic acid.
2. Use of a healthy aging diagnostic marker according to claim 1 in the manufacture of a healthy aging diagnostic product comprising a reagent for detecting the one or more markers, wherein the reagent determines whether a subject has a higher likelihood of healthy aging by detecting the concentration of the one or more markers in the subject.
3. Use according to claim 2, in particular to detect the concentration of one or more markers in the blood of a subject.
4. The use according to claim 2, wherein the concentration of one or more of marker α -N-phenylacetyl-L-glutamine, 4-methylphenol, N6-methyladenosine, N1-methyl-2-pyridone-5-carboxamide, 3-phenyllactic acid, 5-hydroxyindolacetic acid, dopamine, 4-hydroxyphenylpyruvic acid, propionylglycine, 4-aminomauric acid, indoxyl sulfate, 3, 4-dihydroxybutyric acid, O-acetylserine, N2, N2-dimethylguanosine, N-tegaserod, threitol, methoxyacetic acid, indole-3-pyruvic acid is significantly increased in healthy elderly people.
5. Use according to claim 2, wherein the concentration of one or more of the markers L-histidine, homoarginine, arachidonic acid is significantly reduced in healthy elderly compared to normal.
6. A diagnostic composition for healthy aging comprising one or more of the diagnostic markers for healthy aging according to claim 1.
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Application publication date: 20200707 |