CN111398456A - 指征健康老龄关键通路的内源性代谢小分子标志物及应用 - Google Patents
指征健康老龄关键通路的内源性代谢小分子标志物及应用 Download PDFInfo
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- CN111398456A CN111398456A CN202010247801.3A CN202010247801A CN111398456A CN 111398456 A CN111398456 A CN 111398456A CN 202010247801 A CN202010247801 A CN 202010247801A CN 111398456 A CN111398456 A CN 111398456A
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Abstract
本发明公开了一种指征健康老龄关键通路的内源性代谢小分子标志物及应用，该内源性代谢小分子共有155个，该关键通路共有30个，本发明首次提出了新的指征血液健康老龄关键通路的内源性小分子标志物，通过测定这些小分子的变化，能综合评价人体内与健康老龄相关通路的变化，进而为后续干预与应对提供支撑。
Description
技术领域
本发明属于生物医学技术领域，具体地说，涉及一种指征健康老龄关键通路的内源性代谢小分子标志物及应用。
背景技术
我国人口的老龄化速度是西方国家的2倍以上，其中65岁以上的老人将从2010年1.19亿增加到2050年3.6亿(占总人口25.6％)。老龄化进程的加剧及老年疾病的高发严重影响了国人生活质量，加重家庭、社会负担。但如果老人健康每年比上一年相对改善1％，那么我国2050年家庭照料总成本将节省22,100亿元。如加上医疗费用，健康老龄化所可能节省的开支将更加惊人。考虑到老年病发生后往往难以治愈，且治疗过程中仍会消耗大量社会资源和成本。
健康老龄是一个复杂的多因素的生物学过程，除了长寿基因FOXO3及APOE等的知识外，还发现了大量能促进健康老龄的关键通路。这些通路包括：内分泌平衡，IGF通路,mTOR信号通路，DNA损伤修复,核糖体(Ribosome)，选择性剪接，蛋白酶体，蛋白泛素化，高尔基体功能，自噬通路(Genome Res,2018)，线粒体功能，能量代谢，脂代谢，免疫平衡(免疫本身及病毒感染应对)，衰老细胞表型等。以目前技术手段，评估每一个通路变化的技术手段都非常复杂，涉及到大量精确的实验手段，无法进行产业化和流程化运行。而目前尚没有同时评估一个或多个健康老龄相关的关键通路的技术手段。
而作为健康老龄的天然模型的百岁老人，其寿命不但远长于普通人群，还能延缓甚至规避衰老相关重大疾病的困扰，因此，有必要提供一种新的指征促进健康老龄的关键通路的标志物及关键通路。
发明内容
有鉴于此，本发明针对上述的问题，提供了一种指征健康老龄关键通路的内源性代谢小分子标志物及应用。
为了解决上述技术问题，本发明公开了一种基于内源性代谢小分子标志物的健康老龄的关键通路，包括：
a)、激素平衡6个通路：生长激素的合成，分泌作用，胰岛素分泌，GnRH信号通路，内分泌抵抗，甲状腺激素信号通路；
b)、信号传导平衡3个通路：mTOR信号通路，磷酸肌醇代谢，PPAR信号通路；
c)、DNA损伤修复2个通路：错配修复通路，碱基切除修复通路；
d)、蛋白质合成与质量控制6个通路：核糖体通路，真核生物的核糖体生物合成通路，泛素介导的蛋白水解通路，剪接体通路，内质网中的蛋白加工通路，蛋白酶体通路；
e)、自噬2个通路：溶酶体通路，动物线粒体自噬通路；
f)、能量代谢2个通路：氧化磷酸化通路，柠檬酸循环通路；
g)、糖代谢紊乱1个通路：II型糖尿病相关通路；
h)、脂肪酸代谢4个通路：脂肪酸代谢通路，脂肪酸降解通路，醚类脂代谢通路，过氧化物酶体通路；
i)NAD+代谢1个通路：烟酸和烟酰胺代谢通路；
j)免疫平衡3个通路：单纯疱疹病毒1感染通路，Th17细胞分化通路，Th1和Th2细胞分化通路。
本发明还公开了一种指征上述的健康老龄关键通路的内源性小分子标志物，包括1-甲基腺，20-羟基-(5Z,8Z,11Z,14Z)-二十碳四烯酸，2-脱氧tetron酸，2-乙基-2-羟基丁酸，2-羟基-3-甲基丁酸，2-甲基-3-羟基丁酸，2-羟吲哚，3,5-二羟基苯甲酸，3,6-脱水-D-半乳糖，3-乙酰基-11-酮-β-乳香酸，3-羟基十二烷酸，3-羟基异戊酸，3-羟基丙酮酸，3-吲哚硫酸盐，3-巯基-2-丁酮，3-甲基-2-氧戊酸，3-甲基组氨酸，3-苯基丙酸，4-吡啶氧酸，5-氨基-4-氨基甲酰咪唑，5-氨基戊酸，5-羟基吲哚乙酸酯，9-癸烯-1-醇，ACar 18：0，甲氧基乙酸，乙酰胆碱，别嘌呤核糖核苷，α-N-苯基乙酰基-L-谷氨酰胺，β-甘露糖酸甘油酯2：3，胆红素，Biliverdin，辛酸，肉碱(16：1)，Cellobiotol，鹅去氧胆酸盐，胆固醇3-硫酸盐，胆酸，柠檬酸盐，柠檬酸，皮质醇，肌酸，Dantron，D-阿拉伯糖醇，癸酰基肉碱，脱氧胆酸，DL-2-(乙酰基氨基)-3-苯基丙酸，DL-3-苯基乳酸，DL-乳酸，D-甘露糖，多巴胺，D-脯氨酸，肠抑素人，芥酸酰胺，丙二酸氢乙酯，γ-谷氨酰酪氨酸，戊二醛，乙醇酸去氧胆酸盐，乙醇酸，乙醇酸胆甾醇酸，十七烷酸，己酰基肉碱，庚酸，Ile-Val，吲哚，吲哚-3-丙烯酸，吲哚-3-丙酮酸，吲哚丙烯酸，吲哚硫酸盐，异亮氨酸，L-(+)-瓜氨酸，L-胱氨酸，L-谷氨酸，L-谷氨酰胺，L-组氨酸，L-高半胱氨酸，亚油酸，L-Kynurenine，L-亮氨酰-L-脯氨酸，L-薄荷醇，L-正亮氨酸，L-山梨糖，L-色氨酸，Lyxose，麦芽糖，单油酸甘油酯，肌醇，N(ε)-三甲基赖氨酸，N1-甲基-2-吡啶酮-5-羧酰胺，N6-甲基腺苷，N-苄氧羰基甘氨酸，N-甲基-L-谷氨酸，N-Tigloyl甘氨酸，O-乙酰基-L-丝氨酸，鸟氨酸，PA(16:0/0:0)，PA(16:1/0:0)，PA(18:1/0:0)，PA(18:2/0:0)，PC(14:0/0:0)，PC(16:0/0:0)，PC(16:1/0:0)，PC(17:0/0:0)，PC(18:0/0:0)，PC(18:1/0:0)，PC(18:2/0:0)，PC(18:3/0:0)，PC(20:1/0:0)，PC(20:4/0:0)，PC(20:5/0:0)，PC(22:5/0:0)，PC(22:6/0:0)，PC(O-16:0/0:0)，PC(O-16:1/0:0)，PC(P-16:0/2:0)，p-甲酚(p-cresol)，PE(16:1/0:0)，PE(16:1/16:0)，PE(18:0/0:0)，PE(18:1/0:0)，PE(18:2/0:0)，PE(18:3/0:0)，PE(20:3/0:0)，PE(20:4/0:0)，PE(20:5/0:0)，PE(P-16:0/0:0)，PE(P-18:0/0:0)，PE(P-18:0/22:6)，全氟辛酸，PG(18:2/18:2)，苯乳酸(Phenyllactic acid)，苯丙氨酸-色氨酸二肽，磷酸胆碱，磷酸胆碱，PI(16:0/18:1)，PI(16:1/0:0)，庚二酸，脯氨酸，丙酰甘氨酸，PS(20:4/0:0)，邻苯二酚，水杨酸，硫酸胆固醇，槐糖，山梨糖醇，角鲨烯，硬脂酰肉碱，蔗糖，四氢可的松，茶碱，苏糖醇：2，松糖，酪胺，缬氨酸-天冬酰胺二肽，香草酸。
本发明还公开了一种上述的健康老龄关键通路的内源性小分子标志物在制备人类健康老龄预测产品中的应用，所述预测产品包含一种或多种内源性小分子的试剂，所述试剂通过检测受试者体内的一种或多种内源性小分子的浓度，预测评估受试者是否是健康老龄。
可选地，具体是检测受试者血液中的一种或多种标志物的浓度。
与现有技术相比，本发明可以获得包括以下技术效果：
1)本发明通过比较分析百岁老人内源性代谢小分子特征，发掘能指征健康老龄关键通路的变化的内源性小分子，本发明可直接应用于指征普通老龄人当前状态下健康老龄相关通路变化的变化，从机制上评价健康老龄状态。
2)目前没有针对能指征健康老龄关键通路的小分子，本发明首次提出了新的指征血液健康老龄关键通路的内源性小分子标志物，通过测定这些小分子的变化，能综合评价人体内与健康老龄相关通路的变化，进而为后续干预与应对提供支撑。
当然，实施本发明的任一产品并不一定需要同时达到以上所述的所有技术效果。
具体实施方式
以下将配合实施例来详细说明本发明的实施方式，藉此对本发明如何应用技术手段来解决技术问题并达成技术功效的实现过程能充分理解并据以实施。
实施例1基于内源性代谢小分子标志物的健康老龄的关键通路
其中，世界卫生组织将健康衰老定义为：在老年阶段，能够维持一系列功能能力(包括可自我满足自身需求；可以学习并作出决定；可以活动、建立和维持人际关系，能够对社会有所贡献)而使自身得到有价值的生活的过程(https://www.who.int/ageing/healthy-ageing/en/)。
要达到健康衰老，最基本的是在衰老过程中，能够规避老年性疾病(老年疾病[M].科学出版社，2011年1月1日)以及重大疾病(2007年4月3日起开始实施的《重大疾病保险的疾病定义使用规范》中所定义的)，以很少患病、住院率极低的状态度过老年阶段。
健康老龄的关键通路包括11大类30个代谢通路：
a)、激素平衡6个通路：生长激素的合成(Growth hormone synthesis),分泌作用(secretion and action)，胰岛素分泌(Insulin secretion)，GnRH信号通路(GnRHsignaling pathway)，内分泌抵抗(Endocrine resistance)，甲状腺激素信号通路(Thyroid hormone signaling pathway)。
b)、信号传导平衡3个通路：mTOR信号通路(mTOR signaling pathway)，磷酸肌醇代谢(Inositol phosphate metabolism)，PPAR信号通路(PPAR signaling pathway)。
c)、DNA损伤修复2个通路：错配修复通路(Mismatch repair)，碱基切除修复通路(Base excision repair)。
d)、蛋白质合成与质量控制6个通路：核糖体(Ribosome)，真核生物的核糖体生物合成(Ribosome biogenesis in eukaryotes)，泛素介导的蛋白水解(Ubiquitin mediatedproteolysis)，剪接体(Spliceosome)，内质网中的蛋白加工(Protein processing inendoplasmic reticulum)，蛋白酶体(Proteasome)。
e)、自噬2个通路：溶酶体(Lysosome)，动物线粒体自噬通路(Mitophagy -animal)。
f)、能量代谢2个通路：氧化磷酸化(Oxidative phosphorylation)，柠檬酸循环(Citrate cycle)。
g)、糖代谢紊乱1个通路：II型糖尿病相关通路(Type II diabetes mellitus)。
h)、脂肪酸代谢4个通路：脂肪酸代谢(Fatty acid metabolism)，脂肪酸降解(Fatty acid degradation)，醚类脂代谢(Ether lipid metabolism)，过氧化物酶体(Peroxisome)。
i)NAD+代谢1个通路：烟酸和烟酰胺代谢(Nicotinate and nicotinamidemetabolism)。
j)免疫平衡3个通路：单纯疱疹病毒1感染(Herpes simplex virus 1infection)，Th17细胞分化(Th17 cell differentiation),Th1和Th2细胞分化(Th1 and Th2 celldifferentiation)。
通过分析我国目前长寿老人转录组数据，上述31个健康老龄相关关键通路在健康老龄人群中的方向如表1所示。
表1 31个与健康老龄相关的关键信号通路及变化方向
实施例2指征实施例1中的健康老龄关键通路的内源性小分子标志物
本发明还提供了一类全新的指征健康老龄关键通路的血液诊断小分子标志物，这类标志物可以单独或两种或两种以上的组合来评估健康老龄关键通路的变化情况，共155个，包括1-甲基腺苷(1-Methyladenosine)，20-羟基-(5Z,8Z,11Z,14Z)-二十碳四烯酸(20-Hydroxy-(5Z,8Z,11Z,14Z)-eicosatetraenoic acid)，2-脱氧tetron酸(2-Deoxytetronicacid)，2-乙基-2-羟基丁酸(2-Ethyl-2-Hydroxybutyric acid)，2-羟基-3-甲基丁酸(2-Hydroxy-3-methylbutyric acid)，2-甲基-3-羟基丁酸(2-Methyl-3-hydroxybutyricacid)，2-羟吲哚(2-Oxindole)，3,5-二羟基苯甲酸(3,5-Dihydroxybenzoic acid)，3,6-脱水-D-半乳糖(3,6-Anhydro-D-galactose)，3-乙酰基-11-酮-β-乳香酸(3-Acetyl-11-keto-.beta.-boswellic acid)，3-羟基十二烷酸(3-Hydroxydodecanoic acid)，3-羟基异戊酸(3-Hydroxyisovaleric acid)，3-羟基丙酮酸(3-hydroxypyruvate)，3-吲哚硫酸盐(3-Indoxyl sulphate)，3-巯基-2-丁酮(3-Mercapto-2-butanone)，3-甲基-2-氧戊酸(3-Methyl-2-oxopentanoate)，3-甲基组氨酸(3-Methylhistidine)，3-苯基丙酸(3-Phenylpropanoic acid)，4-吡啶氧酸(4-Pyridoxic acid)，5-氨基-4-氨基甲酰咪唑(AICA)(5-Amino-4-carbamoylimidazole(AICA))，5-氨基戊酸(5-Aminovaleric acid)，5-羟基吲哚乙酸酯(5-Hydroxyindoleacetate)，9-癸烯-1-醇(9-Decen-1-ol)，ACar 18：0(ACar 18:0)，甲氧基乙酸(Acetic acid,methoxy-)，乙酰胆碱(Acetylcholine)，别嘌呤核糖核苷(Allopurinol riboside)，α-N-苯基乙酰基-L-谷氨酰胺(Alpha-N-Phenylacetyl-L-glutamine)，β-甘露糖酸甘油酯2：3(beta-Mannosylglycerate 2:3)，胆红素(Bilirubin)，Biliverdin(Biliverdin)，辛酸(Caprylic acid)，肉碱(16：1)(carnitine(16:1))，Cellobiotol(Cellobiotol)，鹅去氧胆酸盐(Chenodeoxycholate)，胆固醇3-硫酸盐(Cholesterol 3-sulfate)，胆酸(Cholic acid)，柠檬酸盐(Citrate)，柠檬酸(citricacid)，皮质醇(Cortisol)，肌酸(creatine)，Dantron(Dantron)，D-阿拉伯糖醇(D-Arabitol)，癸酰基肉碱(Decanoylcarnitine)，脱氧胆酸(Deoxycholic acid)，DL-2-(乙酰基氨基)-3-苯基丙酸(DL-2-(acetylamino)-3-phenylpropanoic acid)，DL-3-苯基乳酸(DL-3-Phenyllactic acid)，DL-乳酸(DL-lactate)，D-甘露糖(D-Mannose)，多巴胺(Dopamine)，D-脯氨酸(D-Proline)，肠抑素人(Enterostatin human)，芥酸酰胺(Erucamide)，丙二酸氢乙酯(Ethyl hydrogen malonate)，γ-谷氨酰酪氨酸(gamma-Glutamyltyrosine)，戊二醛(Glutaraldehyde)，乙醇酸去氧胆酸盐(Glycochenodeoxycholate)，乙醇酸(Glycocholic acid)，乙醇酸胆甾醇酸(Glycolithocholic acid)，十七烷酸(Heptadecanoic acid)，己酰基肉碱(Hexanoylcarnitine)，庚酸(Hippuric acid)，Ile-Val(Ile-Val)，吲哚(Indole)，吲哚-3-丙烯酸(Indole-3-acrylic acid)，吲哚-3-丙酮酸(Indole-3-pyruvic acid)，吲哚丙烯酸(Indoleacrylic acid)，吲哚硫酸盐(Indoxyl sulfate)，异亮氨酸(Isoleucine)，L-(+)-瓜氨酸(L-(+)-Citrulline)，L-胱氨酸(L-Cystine)，L-谷氨酸(L-Glutamic acid)，L-谷氨酰胺(L-Glutamine)，L-组氨酸(L-Histidine)，L-高半胱氨酸(L-homocysteic acid)，亚油酸(linoleic acid)，L-Kynurenine(L-Kynurenine)，L-亮氨酰-L-脯氨酸(L-leucyl-L-proline)，L-薄荷醇(L-Menthol)，L-正亮氨酸(L-Norleucine)，L-山梨糖(L-Sorbose)，L-色氨酸(L-Tryptophan)，Lyxose(Lyxose)，麦芽糖(maltose)，单油酸甘油酯(Monoolein)，肌醇(myo-inositol)，N(ε)-三甲基赖氨酸(N(epsilon)-Trimethyllysine)，N1-甲基-2-吡啶酮-5-羧酰胺(N1-Methyl-2-pyridone-5-carboxamide)，N6-甲基腺苷(N6-methyladenosine)，N-苄氧羰基甘氨酸(N-Benzyloxycarbonylglycine)，N-甲基-L-谷氨酸(N-Methyl-L-glutamic acid)，N-Tigloyl甘氨酸(N-Tigloylglycine)，O-乙酰基-L-丝氨酸(O-Acetyl-L-serine)，鸟氨酸(Ornithine)，PA(16:0/0:0)，PA(16:1/0:0)，PA(18:1/0:0)，PA(18:2/0:0)，PC(14:0/0:0)，PC(16:0/0:0)，PC(16:1/0:0)，PC(17:0/0:0)，PC(18:0/0:0)，PC(18:1/0:0)，PC(18:2/0:0)，PC(18:3/0:0)，PC(20:1/0:0)，PC(20:4/0:0)，PC(20:5/0:0)，PC(22:5/0:0)，PC(22:6/0:0)，PC(O-16:0/0:0)，PC(O-16:1/0:0)，PC(P-16:0/2:0)，p-甲酚(p-cresol)，PE(16:1/0:0)，PE(16:1/16:0)，PE(18:0/0:0)，PE(18:1/0:0)，PE(18:2/0:0)，PE(18:3/0:0)，PE(20:3/0:0)，PE(20:4/0:0)，PE(20:5/0:0)，PE(P-16:0/0:0)，PE(P-18:0/0:0)，PE(P-18:0/22:6)，全氟辛酸(PFOA)(Perfluorooctanoic acid(PFOA))，PG(18:2/18:2)，苯乳酸(Phenyllactic acid)，苯丙氨酸-色氨酸二肽(Phe-Trp，Phloretin)，磷酸胆碱(Phosphocholine)，磷酸胆碱(Phosphorylcholine)，PI(16:0/18:1)，PI(16:1/0:0)，庚二酸(Pimelic acid)，脯氨酸(proline)，丙酰甘氨酸(Propionylglycine)，PS(20:4/0:0)，邻苯二酚(Pyrocatechol)，水杨酸(Salicyluricacid)，硫酸胆固醇(Sholesteryl sulfate)，槐糖(Sophorose)，山梨糖醇(sorbitol)，角鲨烯(Squalene)，硬脂酰肉碱(Stearoylcarnitine)，蔗糖(Sucrose)，四氢可的松(Tetrahydrocortisone)，茶碱(Theophylline)，苏糖醇：2(Threitol:2)，松糖(Turanose)，酪胺(Tyramine)，缬氨酸-天冬酰胺二肽(Val-Asn)，香草酸(Vanillic acid)，其分子式见表2。通过对我国海南澄迈和万宁县(74个长寿老人，85个对照)，海南陵水县(111个长寿老人，207个对照)和湖北钟祥(166个长寿老人，118个对照)多地共351个百岁老人(年龄范围在93岁-111岁，平均年龄：98.3岁)及410个对照组(年龄范围在23岁-86岁，平均年龄为54.4岁)的前瞻性研究，每个代谢小分子指征的健康老龄的关键通路及对应方向及显著性见表3，其中同一个代谢小分子可以指征多个健康老龄的关键通路。
表2 155个指征健康老龄关键通路的小分子的名称、pubchem编号以及smile分子式
其中，其中pubchem编号是国际通用的用于确定目前已知化合物小分子的识别号，一个pubchem编号唯一对应一个目前已知的化合物小分子。smile分子式是国际通用的存储化合物的结构的一种方式，通过smile分子式可以唯一确定一个分子的结构。
表3各标志物以及对不同健康老龄关键通路的影响、方向及显著性
其中，由于本发明中我们进行了多重的统计检验，因此，需要采用矫正后的p值来避免假阳性结果的出现。本发明中的所有p值的矫正采用的是R语言包里面的"Falsepositive rate"的方法。
实施例3以α-N-苯基乙酰基-L-谷氨酰胺(Alpha-N-Phenylacetyl-L-glutamine)为单标志物对健康老龄关键通路进行评价。
具体实施方法如下：
1、获取受试者样品，并进行前处理：依据规范、合理的操作流程采集受试者血液样品后，取100μL血液加入350μL甲醇中，进行涡旋混匀，高速离心，取上清液，进行浓缩干燥，加入100μL乙腈进行复溶，经过滤塞，可直接进行液相色谱-四极杆-飞行时间质谱技术(UHPLC-QTOFMS)测试。
2、数据处理：UHPLC-QTOFMS测试后，收集UHPLC-QTOFMS数据进行分析。数据处理使用XCMS程序，参数设置参照软件说明。XCMS程序处理后，获得所有代谢物的荷质比、保留时间、峰面积和二级质谱指标。
3、α-N-苯基乙酰基-L-谷氨酰胺的浓度确定：根据质荷质比和质谱二级片段通过比对二级质谱数据库来确定。α-N-苯基乙酰基-L-谷氨酰胺在血液中的浓度通过其峰面积和标准品的峰面积的比值来确定,其中代谢物浓度测定由上海百趣生物医学科技有限公司完成。
4、健康老龄关键通路评价：将上述测得的受试者血液中的α-N-苯基乙酰基-L-谷氨酰胺浓度和一般人群(410个对照组)的阈值(3.34umol/L)作比较。测得受试者样本血液中α-N-苯基乙酰基-L-谷氨酰胺的浓度为10.70umol/L，该值高于一般人群的阈值(3.34umol/L)，通过查询表3数据可知该受试者具有较高的健康老龄的关键通路自噬(Lysosome)信号增强，核糖体功能(Ribosome)降低，HSV1病毒感染(Herpes simplex virus1infection)可能性降低。而通过表1查询可以知道，自噬溶酶体(Lysosome)增强，核糖体功能(Ribosome)降低，以及HSV1病毒感染率降低是健康老龄的信号，基于此可以评价该受试者在自噬溶酶体(Lysosome)，核糖体功能(Ribosome)降低及HSV1病毒感染(Herpessimplex virus 1infection)这三个健康老龄的关键信号通路上具有较好的特征，应维持当前状态。
实施例4谷氨酰胺(L-Glutamine)为单标志物进行健康老龄关键通路进行诊断：
受试者谷氨酰胺浓度的确定同实施例3中的1-5步。将上述测得的受试者血液中的谷氨酰胺浓度和一般人群(410个对照组)的阈值(>300umol/L)作比较。测得受试者样本血液中样本中谷氨酰胺浓度为180umol/L,小于一般人群阈值下限，通过查询表3得到该受试者的自噬溶酶体(Lysosome)信号降低，内质网蛋白质组装(Protein processing inendoplasmic reticulum)降低，HSV1病毒感染(Herpes simplex virus 1infection)可能性增加。而通过表1查询可知上述三个通路的变化方向与对应健康老龄的变化方向相反，因此可以判断该受试者在这三个健康老龄关键信号通路上具有较差的特征，应该提前预警，需针对这三个关键通路进行针对性的干预。
实施例5以表3的多种代谢物质联合进行健康老龄关键通路的诊断：
以α-N-苯基乙酰基-L-谷氨酰胺和N6-甲基腺苷两种代谢物联合进行诊断，测得受试者样本中α-N-苯基乙酰基-L-谷氨酰胺的浓度为9.45umol/L(大于正常阈值3.34umol/L)，N6-甲基腺苷的浓度为0.15umol/L(大于正常阈值0.11umol/L)，通通过查询表3数据可知这两个标志物指征该受试者具有较高的健康老龄的关键通路自噬(Lysosome)信号增强，内质网中的蛋白加工(Protein processing in endoplasmic reticulum)，核糖体功能(Ribosome)降低，HSV1病毒感染(Herpes simplex virus 1infection)可能性降低。而通过表1查询可以知道，自噬溶酶体(Lysosome)增强，内质网中的蛋白加工(Proteinprocessing in endoplasmic reticulum)增加，核糖体功能(Ribosome)降低，以及HSV1病毒感染率降低是健康老龄的信号，基于此可以评价该受试者在自噬溶酶体(Lysosome)，内质网中的蛋白加工(Protein processing in endoplasmic reticulum)，核糖体功能(Ribosome)降低及HSV1病毒感染(Herpes simplex virus 1infection)这四个健康老龄的关键信号通路上具有较好的特征，应维持当前状态。
上述说明示出并描述了发明的若干优选实施例，但如前所述，应当理解发明并非局限于本文所披露的形式，不应看作是对其他实施例的排除，而可用于各种其他组合、修改和环境，并能够在本文所述发明构想范围内，通过上述教导或相关领域的技术或知识进行改动。而本领域人员所进行的改动和变化不脱离发明的精神和范围，则都应在发明所附权利要求的保护范围内。
Claims (4)
1.基于内源性代谢小分子标志物的健康老龄的关键通路，其特征在于，包括：
a)、激素平衡6个通路：生长激素的合成，分泌作用，胰岛素分泌，GnRH信号通路，内分泌抵抗，甲状腺激素信号通路；
b)、信号传导平衡3个通路：mTOR信号通路，磷酸肌醇代谢，PPAR信号通路；
c)、DNA损伤修复2个通路：错配修复通路，碱基切除修复通路；
d)、蛋白质合成与质量控制6个通路：核糖体通路，真核生物的核糖体生物合成通路，泛素介导的蛋白水解通路，剪接体通路，内质网中的蛋白加工通路，蛋白酶体通路；
e)、自噬2个通路：溶酶体通路，动物线粒体自噬通路；
f)、能量代谢2个通路：氧化磷酸化通路，柠檬酸循环通路；
g)、糖代谢紊乱1个通路：II型糖尿病相关通路；
h)、脂肪酸代谢4个通路：脂肪酸代谢通路，脂肪酸降解通路，醚类脂代谢通路，过氧化物酶体通路；
i)NAD+代谢1个通路：烟酸和烟酰胺代谢通路；
j)免疫平衡3个通路：单纯疱疹病毒1感染通路，Th17细胞分化通路，Th1和Th2细胞分化通路。
2.指征权利要求1所述的健康老龄关键通路的内源性小分子标志物，其特征在于，包括1-甲基腺，20-羟基-(5Z,8Z,11Z,14Z)-二十碳四烯酸，2-脱氧tetron酸，2-乙基-2-羟基丁酸，2-羟基-3-甲基丁酸，2-甲基-3-羟基丁酸，2-羟吲哚，3,5-二羟基苯甲酸，3,6-脱水-D-半乳糖，3-乙酰基-11-酮-β-乳香酸，3-羟基十二烷酸，3-羟基异戊酸，3-羟基丙酮酸，3-吲哚硫酸盐，3-巯基-2-丁酮，3-甲基-2-氧戊酸，3-甲基组氨酸，3-苯基丙酸，4-吡啶氧酸，5-氨基-4-氨基甲酰咪唑，5-氨基戊酸，5-羟基吲哚乙酸酯，9-癸烯-1-醇，ACar 18：0，甲氧基乙酸，乙酰胆碱，别嘌呤核糖核苷，α-N-苯基乙酰基-L-谷氨酰胺，β-甘露糖酸甘油酯2：3，胆红素，Biliverdin，辛酸，肉碱(16：1)，Cellobiotol，鹅去氧胆酸盐，胆固醇3-硫酸盐，胆酸，柠檬酸盐，柠檬酸，皮质醇，肌酸，Dantron，D-阿拉伯糖醇，癸酰基肉碱，脱氧胆酸，DL-2-(乙酰基氨基)-3-苯基丙酸，DL-3-苯基乳酸，DL-乳酸，D-甘露糖，多巴胺，D-脯氨酸，肠抑素人，芥酸酰胺，丙二酸氢乙酯，γ-谷氨酰酪氨酸，戊二醛，乙醇酸去氧胆酸盐，乙醇酸，乙醇酸胆甾醇酸，十七烷酸，己酰基肉碱，庚酸，Ile-Val，吲哚，吲哚-3-丙烯酸，吲哚-3-丙酮酸，吲哚丙烯酸，吲哚硫酸盐，异亮氨酸，L-(+)-瓜氨酸，L-胱氨酸，L-谷氨酸，L-谷氨酰胺，L-组氨酸，L-高半胱氨酸，亚油酸，L-Kynurenine，L-亮氨酰-L-脯氨酸，L-薄荷醇，L-正亮氨酸，L-山梨糖，L-色氨酸，Lyxose，麦芽糖，单油酸甘油酯，肌醇，N(ε)-三甲基赖氨酸，N1-甲基-2-吡啶酮-5-羧酰胺，N6-甲基腺苷，N-苄氧羰基甘氨酸，N-甲基-L-谷氨酸，N-Tigloyl甘氨酸，O-乙酰基-L-丝氨酸，鸟氨酸，PA(16:0/0:0)，PA(16:1/0:0)，PA(18:1/0:0)，PA(18:2/0:0)，PC(14:0/0:0)，PC(16:0/0:0)，PC(16:1/0:0)，PC(17:0/0:0)，PC(18:0/0:0)，PC(18:1/0:0)，PC(18:2/0:0)，PC(18:3/0:0)，PC(20:1/0:0)，PC(20:4/0:0)，PC(20:5/0:0)，PC(22:5/0:0)，PC(22:6/0:0)，PC(O-16:0/0:0)，PC(O-16:1/0:0)，PC(P-16:0/2:0)，p-甲酚(p-cresol)，PE(16:1/0:0)，PE(16:1/16:0)，PE(18:0/0:0)，PE(18:1/0:0)，PE(18:2/0:0)，PE(18:3/0:0)，PE(20:3/0:0)，PE(20:4/0:0)，PE(20:5/0:0)，PE(P-16:0/0:0)，PE(P-18:0/0:0)，PE(P-18:0/22:6)，全氟辛酸，PG(18:2/18:2)，苯乳酸(Phenyllactic acid)，苯丙氨酸-色氨酸二肽，磷酸胆碱，磷酸胆碱，PI(16:0/18:1)，PI(16:1/0:0)，庚二酸，脯氨酸，丙酰甘氨酸，PS(20:4/0:0)，邻苯二酚，水杨酸，硫酸胆固醇，槐糖，山梨糖醇，角鲨烯，硬脂酰肉碱，蔗糖，四氢可的松，茶碱，苏糖醇：2，松糖，酪胺，缬氨酸-天冬酰胺二肽，香草酸。
3.权利要求2所述的健康老龄关键通路的内源性小分子标志物在制备人类健康老龄预测产品中的应用，其特征在于，所述预测产品包含一种或多种内源性小分子的试剂，所述试剂通过检测受试者体内的一种或多种内源性小分子的浓度，预测评估受试者是否是健康老龄。
4.根据权利要求3所述的应用，其特征在于，具体是检测受试者血液中的一种或多种标志物的浓度。
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