基于多组学的老年衰弱人群生物标志物研究

doi:10.12114/j.issn.1007-9572.2022.0743

摘要/Abstract

摘要： 衰弱是指老年人以肌少症为基本特征的全身多系统的稳态受损，导致生理储备下降、抗疾病能力减退及应激后恢复能力下降的非特异性状态，衰弱的早期诊断对于帮助老年人恢复健康具有重要价值。近年来，随着组学研究的技术进步，为发现早期衰弱潜在的特异性强及稳定可靠的相关生物标志物提供了新的途径。本文整理分析相关研究后，从基因组学、转录组学、蛋白质组学、代谢组学的角度整理衰弱生物标志物的研究进展，有助于评估衰弱风险，探索衰弱的潜在机制，制订针对性的干预措施，助力老年人健康。

关键词: 衰弱, 早期衰弱, 老年人, 多组学, 生物标志物, 综述

Abstract:

Early diagnosis of frailty is of great value in helping the elderly to regain their health, as it is a non-specific state of reduced physiological reserve, resistance to disease and ability to recover from stress caused by the impairment in homeostasis maintained by multiple systems with sarcopenia as the basic characteristic. Recent developments in multiomic techniques provide new approaches to the detection of potentially specific, stable and reliable biomarkers of pre-frailty. We collected and reviewed recent advances in multiomic techniques for identifying frailty biomarkers, involving genomics, transcriptomics, proteomics and metabolomics, which can assist in assessing the risk of frailty, exploring potential mechanisms of frailty and developing targeted interventions to support healthy aging.

Key words: Frailty, Pre-frailty, Aged, Multi-omics, Biomarkers, Review

徐婷,季明辉,陈一萌,等. 基于多组学的老年衰弱人群生物标志物研究[J]. 中国全科医学, 2023, 26(23): 2871-2876. DOI: 10.12114/j.issn.1007-9572.2022.0743.
XU Ting,JI Minghui,CHEN Yimeng, et al. Advances in Multiomic Analyses of Frailty Biomarkers in the Elderly[J]. Chinese General Practice, 2023, 26(23): 2871-2876. DOI: 10.12114/j.issn.1007-9572.2022.0743.

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参考文献 46

[1]	O'CAOIMH R, SEZGIN D, O'DONOVAN M R, et al. Prevalence of frailty in 62 countries across the world：a systematic review and meta-analysis of population-level studies[J]. Age Ageing，2021，50(1):96-104. DOI：10.1093/ageing/afaa219.
[2]	RATTRAY N J W, TRIVEDI D K, XU Y, et al. Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty[J]. Nat Commun，2019，10(1):5027. DOI：10.1038/s41467-019-12716-2.
[3]	STERNBERG S A, WERSHOF SCHWARTZ A, KARUNANANTHAN S, et al. The identification of frailty：a systematic literature review[J]. J Am Geriatr Soc，2011，59(11):2129-2138. DOI：10.1111/j.1532-5415.2011.03597.x.
[4]	LOOMAN W M, FABBRICOTTI I N, BLOM J W, et al. The frail older person does not exist：development of frailty profiles with latent class analysis[J]. BMC Geriatr，2018，18(1):84. DOI：10.1186/s12877-018-0776-5.
[5]	ERUSALIMSKY J D, GRILLARI J, GRUNE T, et al. In search of 'omics'-based biomarkers to predict risk of frailty and its consequences in older individuals：the FRAILOMIC initiative[J]. Gerontology，2016，62(2):182-190. DOI：10.1159/000435853.
[6]	VIÑA J, TARAZONA-SANTABALBINA F J, PÉREZ-ROS P, et al. Biology of frailty：modulation of ageing genes and its importance to prevent age-associated loss of function[J]. Mol Aspects Med，2016，50:88-108. DOI：10.1016/j.mam.2016.04.005.
[7]	MACAULEY A, LADIGES W C. Approaches to determine clinical significance of genetic variants[J]. Mutat Res，2005，573(1/2):205-220. DOI：10.1016/j.mrfmmm.2005.01.009.
[8]	INGLES M, MAS-BARGUES C, GIMENO-MALLENCH L, et al. Relation between genetic factors and frailty in older adults [J]. J Am Med Dir Assoc，2019，20(11):1451-1457. DOI：10.1016/j.jamda.2019.03.011.
[9]	GALE C R, MARIONI R E, HARRIS S E, et al. DNA methylation and the epigenetic clock in relation to physical frailty in older people：the Lothian Birth Cohort 1936 [J]. Clin Epigenetics，2018，10(1):101. DOI：10.1186/s13148-018-0538-4.
[10]	GENSOUS N, BACALINI M G, PIRAZZINI C, et al. The epigenetic landscape of age-related diseases：the geroscience perspective[J]. Biogerontology，2017，18(4):549-559. DOI：10.1007/s10522-017-9695-7.
[11]	COLLERTON J, GAUTREY H E, VAN OTTERDIJK S D, et al. Acquisition of aberrant DNA methylation is associated with frailty in the very old：findings from the Newcastle 85+ Study[J]. Biogerontology，2014，15(4):317-328. DOI：10.1007/s10522-014-9500-9.
[12]	MCCRORY C, FIORITO G, HERNANDEZ B, et al. GrimAge outperforms other epigenetic clocks in the prediction of age-related clinical phenotypes and all-cause mortality[J]. J Gerontol A Biol Sci Med Sci，2021，76(5):741-749. DOI：10.1093/gerona/glaa286.
[13]	LEVINE M E, LU A T, QUACH A, et al. An epigenetic biomarker of aging for lifespan and healthspan[J]. Aging：Albany NY，2018，10(4):573-591. DOI：10.18632/aging.101414.
[14]	BELL C G, LOWE R, ADAMS P D, et al. DNA methylation aging clocks：challenges and recommendations[J]. Genome Biol，2019，20(1):249. DOI：10.1186/s13059-019-1824-y.
[15]	IPSON B R, FLETCHER M B, ESPINOZA S E, et al. Identifying exosome-derived microRNAs as candidate biomarkers of frailty[J]. J Frailty Aging，2018，7(2):100-103. DOI：10.14283/jfa.2017.45.
[16]	RUSANOVA I, FERNANDEZ-MARTINEZ J, FERNANDEZ-ORTIZ M, et al. Involvement of plasma miRNAs，muscle miRNAs and mitochondrial miRNAs in the pathophysiology of frailty [J]. Exp Gerontol，2019，124:110637. DOI：10.1016/j.exger.2019.110637.
[17]	KENNETH R, HOWLETT SUSAN E. Fifteen years of progress in understanding frailty and health in aging[J]. BMC Med，2018，16(1):220.
[18]	LI C W, WANG W H, CHEN B S. Investigating the specific core genetic-and-epigenetic networks of cellular mechanisms involved in human aging in peripheral blood mononuclear cells[J]. Oncotarget，2016，7(8):8556-8579. DOI：10.18632/oncotarget.7388.
[19]	CAPRI M, MORSIANI C, SANTORO A, et al. Recovery from 6-month spaceflight at the International Space Station：muscle-related stress into a proinflammatory setting[J]. FASEB J，2019，33(4):5168-5180. DOI：10.1096/fj.201801625r.
[20]	ELSHARAWY A, KELLER A, FLACHSBART F, et al. Genome-wide miRNA signatures of human longevity[J]. Aging Cell，2012，11(4):607-616. DOI：10.1111/j.1474-9726.2012.00824.x.
[21]	HOLMBERG J, ALAJBEGOVIC A, GAWLIK K I, et al. Laminin α2 chain-deficiency is associated with microRNA deregulation in skeletal muscle and plasma[J]. Front Aging Neurosci，2014，6:155. DOI：10.3389/fnagi.2014.00155.
[22]	COPPE J P, PATIL C K, RODIER F, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor[J]. PLoS Biol，2008，6(12):2853-2868. DOI：10.1371/journal.pbio.0060301.
[23]	DI FILIPPO E S, MANCINELLI R, PIETRANGELO T, et al. Myomir dysregulation and reactive oxygen species in aged human satellite cells[J]. Biochem Biophys Res Commun，2016，473(2):462-470. DOI：10.1016/j.bbrc.2016.03.030.
[24]	ZHENG Y, KONG J, LI Q, et al. Role of miRNAs in skeletal muscle aging[J]. Clin Interv Aging，2018，13:2407-2419. DOI：10.2147/cia.s169202.
[25]	SZEWCZYK-GOLEC K, CZUCZEJKO J, TYLZANOWSKI P, et al. Strategies for modulating oxidative stress under diverse physiological and pathological conditions[J]. Oxid Med Cell Longev，2018，2018:3987941. DOI：10.1155/2018/3987941.
[26]	PRINCE C S, NOREN HOOTEN N, MODE N A, et al. Frailty in middle age is associated with frailty status and race-specific changes to the transcriptome[J]. Aging：Albany NY，2019，11(15):5518-5534. DOI：10.18632/aging.102135.
[27]	ZHANG Y, CHATZISTAMOU I, KIARIS H. Identification of frailty-associated genes by coordination analysis of gene expression[J]. Aging：Albany NY，2020，12(5):4222-4229. DOI：10.18632/aging.102875.
[28]	CARDOSO A L, FERNANDES A, AGUILAR-PIMENTEL J A, et al. Towards frailty biomarkers：candidates from genes and pathways regulated in aging and age-related diseases[J]. Ageing Res Rev，2018，47:214-277. DOI：10.1016/j.arr.2018.07.004.
[29]	DANESE E, MONTAGNANA M, LIPPI G. Proteomics and frailty：a clinical overview[J]. Expert Rev Proteomics，2018，15(8):657-664. DOI：10.1080/14789450.2018.1505511.
[30]	UBAIDA-MOHIEN C, LYASHKOV A, GONZALEZ-FREIRE M, et al. Discovery proteomics in aging human skeletal muscle finds change in spliceosome，immunity，proteostasis and mitochondria[J]. Elife，2019，8:e49874. DOI：10.7554/elife.49874.
[31]	MICHAUD M, BALARDY L, MOULIS G, et al. Proinflammatory cytokines，aging，and age-related diseases[J]. J Am Med Dir Assoc，2013，14(12):877-882. DOI：10.1016/j.jamda.2013.05.009.
[32]	CHEW J, TAY L, LIM J P, et al. Serum myostatin and IGF-1 as gender-specific biomarkers of frailty and low muscle mass in community-dwelling older adults[J]. J Nutr Health Aging，2019，23(10):979-986. DOI：10.1007/s12603-019-1255-1.
[33]	LIN C H, LIAO C C, HUANG C H, et al. Proteomics analysis to identify and characterize the biomarkers and physical activities of non-frail and frail older adults[J]. Int J Med Sci，2017，14(3):231-239. DOI：10.7150/ijms.17627.
[34]	FRIED L P, TANGEN C M, WALSTON J, et al. Frailty in older adults：evidence for a phenotype[J]. J Gerontol A Biol Sci Med Sci，2001，56(3):M146-157. DOI：10.1093/gerona/56.3.M146.
[35]	WESTBROOK R, ZHANG C, YANG H L, et al. Metabolomics-based identification of metabolic dysfunction in frailty[J]. J Gerontol A Biol Sci Med Sci，2022，77(12):2367-2372. DOI：10.1093/gerona/glab315.
[36]	RAMÍREZ-VÉLEZ R, MARTÍNEZ-VELILLA N, CORREA-RODRÍGUEZ M, et al. Lipidomic signatures from physically frail and robust older adults at hospital admission[J]. Geroscience，2022，44(3):1677-1688. DOI：10.1007/s11357-021-00511-1.
[37]	MOADDEL R, FABBRI E, KHADEER M A, et al. Plasma biomarkers of poor muscle quality in older men and women from the Baltimore longitudinal study of aging[J]. J Gerontol A Biol Sci Med Sci，2016，71(10):1266-1272. DOI：10.1093/gerona/glw046.
[38]	FERRUCCI L, ZAMPINO M. A mitochondrial root to accelerated ageing and frailty[J]. Nat Rev Endocrinol，2020，16(3):133-134. DOI：10.1038/s41574-020-0319-y.
[39]	CALVANI R, PICCA A, MARINI F, et al. The "BIOmarkers associated with Sarcopenia and PHysical frailty in EldeRly pErsons" （BIOSPHERE）study：rationale，design and methods[J]. Eur J Intern Med，2018，56:19-25. DOI：10.1016/j.ejim.2018.05.001.
[40]	HSU B, CUMMING R G, HANDELSMAN D J. Testosterone，frailty and physical function in older men[J]. Expert Rev Endocrinol Metab，2018，13(3):159-165. DOI：10.1080/17446651.2018.1475227.
[41]	SRINIVAS-SHANKAR U, ROBERTS S A, CONNOLLY M J, et al. Effects of testosterone on muscle strength，physical function，body composition，and quality of life in intermediate-frail and frail elderly men：a randomized，double-blind，placebo-controlled study[J]. J Clin Endocrinol Metab，2010，95(2):639-650. DOI：10.1210/jc.2009-1251.
[42]	KENNY A M, BOXER R S, KLEPPINGER A, et al. Dehydroepiandrosterone combined with exercise improves muscle strength and physical function in frail older women[J]. J Am Geriatr Soc，2010，58(9):1707-1714. DOI：10.1111/j.1532-5415.2010.03019.x.
[43]	CARCAILLON L, GARCIA-GARCIA F J, TRESGUERRES J A, et al. Higher levels of endogenous estradiol are associated with frailty in postmenopausal women from the Toledo study for healthy aging[J]. J Clin Endocrinol Metab，2012，97(8):2898-2906. DOI：10.1210/jc.2012-1271.
[44]	PAN Y, LI Y, MA L. Metabolites as frailty biomarkers in older adults[J]. Proc Natl Acad Sci USA，2021，118(1):e2016187118. DOI：10.1073/pnas.2016187118.
[45]	MENG L, SHI H, WANG D G, et al. Specific metabolites involved in antioxidation and mitochondrial function are correlated with frailty in elderly men [J]. Front Med（Lausanne），2022，9:816045. DOI：10.3389/fmed.2022.816045.
[46]	LIU C K, LYASS A, LARSON M G, et al. Biomarkers of oxidative stress are associated with frailty：the Framingham Offspring Study[J]. Age：Dordr，2016，38(1):1. DOI：10.1007/s11357-015-9864-z.

第一作者	来源组织	miRNA	变化情况
IPSON^[15]	血浆	miRNA-10a-3p，miRNA-92a-3p，miRNA-185-3p，miRNA-194-5p，miRNA-326，miRNA-532-5p，miRNA-576-5p，miRNA-760	升高
RUSANOVA^[16]	血浆	miRNA-1，miRNA-21，miRNA-34a，miRNA-146a，miRNA-185和miRNA-206，miRNA-223	升高
ROCKWOOD^[17]	血浆	miRNA-21	升高
LI^[18]	外周血单核细胞	miRNA-130a，miRNA-223	升高
CAPRI^[19]	肌肉	miRNA-206	升高
ELSHARAWY^[20]	全血	miRNA-320b，miRNA-423-5p，miRNA-106b-5p，miRNA-20a-3p	升高
		miRNA-301a，miRNA-374a	降低
HOLMBERG^[21]	血清	miRNA-151a-5p，miRNA-181a-5p，miRNA-1248	降低
COPPE^[22]	肌肉	miRNA-146a，miRNA-185，miRNA-206，miRNA-215，miRNA-223	升高
		miRNA-148a，miRNA-434	降低
DI FILIPPO^[23]	股外侧肌卫星细胞	miRNA-1，miRNA-133b	升高
ZHENG^[24]	骨骼肌	has-miRNA-34a，has-miRNA-449b	升高

第一作者	来源组织	miRNA	变化情况
IPSON^[15]	血浆	miRNA-10a-3p，miRNA-92a-3p，miRNA-185-3p，miRNA-194-5p，miRNA-326，miRNA-532-5p，miRNA-576-5p，miRNA-760	升高
RUSANOVA^[16]	血浆	miRNA-1，miRNA-21，miRNA-34a，miRNA-146a，miRNA-185和miRNA-206，miRNA-223	升高
ROCKWOOD^[17]	血浆	miRNA-21	升高
LI^[18]	外周血单核细胞	miRNA-130a，miRNA-223	升高
CAPRI^[19]	肌肉	miRNA-206	升高
ELSHARAWY^[20]	全血	miRNA-320b，miRNA-423-5p，miRNA-106b-5p，miRNA-20a-3p	升高
		miRNA-301a，miRNA-374a	降低
HOLMBERG^[21]	血清	miRNA-151a-5p，miRNA-181a-5p，miRNA-1248	降低
COPPE^[22]	肌肉	miRNA-146a，miRNA-185，miRNA-206，miRNA-215，miRNA-223	升高
		miRNA-148a，miRNA-434	降低
DI FILIPPO^[23]	股外侧肌卫星细胞	miRNA-1，miRNA-133b	升高
ZHENG^[24]	骨骼肌	has-miRNA-34a，has-miRNA-449b	升高