{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T22:31:04Z","timestamp":1788474664475,"version":"build-2803163510"},"reference-count":115,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T00:00:00Z","timestamp":1707782400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Physical weakness and cardiovascular risk increase significantly with age, but the underlying biological mechanisms remain largely unknown. This study aims to reveal the causal effect of circulating metabolites on frailty, sarcopenia and vascular aging related traits and diseases through a two-sample Mendelian Randomization (MR) analysis.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Exposures were 486 metabolites analyzed in a genome-wide association study (GWAS), while outcomes included frailty, sarcopenia, arterial stiffness, atherosclerosis, peripheral vascular disease (PAD) and aortic aneurysm. Primary causal estimates were calculated using the inverse-variance weighted (IVW) method. Methods including MR Egger, weighted median, Q-test, and leave-one-out analysis were used for the sensitive analysis.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> A total of 125 suggestive causative associations between metabolites and outcomes were identified. Seven strong causal links were ultimately identified between six metabolites (kynurenine, pentadecanoate (15:0), 1-arachidonoylglycerophosphocholine, androsterone sulfate, glycine and mannose) and three diseases (sarcopenia, PAD and atherosclerosis). Besides, metabolic pathway analysis identified 13 significant metabolic pathways in 6 age-related diseases. Furthermore, the metabolite-gene interaction networks were constructed.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Our research suggested new evidence of the relationship between identified metabolites and 6 age-related diseases, which may hold promise as valuable biomarkers.<\/jats:p>","DOI":"10.3389\/fgene.2024.1353908","type":"journal-article","created":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T04:31:46Z","timestamp":1707798706000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Metabolic clues to aging: exploring the role of circulating metabolites in frailty, sarcopenia and vascular aging related traits and diseases"],"prefix":"10.3389","volume":"15","author":[{"given":"Zonghao","family":"Qian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzhen","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ni","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziwei","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuntai","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11786469221096643","DOI":"10.1177\/11786469221096643","article-title":"The footprint of kynurenine pathway in cardiovascular diseases","volume":"15","author":"Ala","year":"2022","journal-title":"Int. J. Tryptophan Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"111359","DOI":"10.1016\/j.exger.2021.111359","article-title":"Beta 2 microglobulin correlates with oxidative stress in elderly","volume":"150","author":"Althubiti","year":"2021","journal-title":"Exp. Gerontol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"111260","DOI":"10.1016\/j.exger.2021.111260","article-title":"Vascular endothelial dysfunction may be an early predictor of physical frailty and sarcopenia: a meta-analysis of available data from observational studies","volume":"148","author":"Amarasekera","year":"2021","journal-title":"Exp. Gerontol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"709396","DOI":"10.3389\/fcvm.2021.709396","article-title":"Aortic stiffness: epidemiology, risk factors, and relevant biomarkers","volume":"8","author":"Angoff","year":"2021","journal-title":"Front. Cardiovasc Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.freeradbiomed.2020.01.007","article-title":"Older adults with frailty syndrome present an altered platelet function and an increased level of circulating oxidative stress and mitochondrial dysfunction biomarker GDF-15","volume":"149","author":"Arauna","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e13459","DOI":"10.1111\/acel.13459","article-title":"A genome-wide association study of the frailty index highlights brain pathways in ageing","volume":"20","author":"Atkins","year":"2021","journal-title":"Aging Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e0125967","DOI":"10.1371\/journal.pone.0125967","article-title":"Strategies to rescue the consequences of inducible arginase-1 deficiency in mice","volume":"10","author":"Ballantyne","year":"2015","journal-title":"PLoS One"},{"key":"B8","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1007\/s11427-023-2305-0","article-title":"Biomarkers of aging","volume":"66","author":"Bao","year":"2023","journal-title":"Sci. China Life Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"154148","DOI":"10.1016\/j.cyto.2017.09.004","article-title":"The interplay between cytokines and the Kynurenine pathway in inflammation and atherosclerosis","volume":"122","author":"Baumgartner","year":"2019","journal-title":"Cytokine"},{"key":"B10","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1016\/S0140-6736(15)00516-4","article-title":"The World report on ageing and health: a policy framework for healthy ageing","volume":"387","author":"Beard","year":"2016","journal-title":"Lancet"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e0169548","DOI":"10.1371\/journal.pone.0169548","article-title":"Health outcomes of sarcopenia: a systematic review and meta-analysis","volume":"12","author":"Beaudart","year":"2017","journal-title":"PLoS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1161\/ATVBAHA.119.312142","article-title":"Evidence-based medical management of peripheral artery disease","volume":"40","author":"Bevan","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1186\/s12967-022-03648-5","article-title":"Assessing the causal association between human blood metabolites and the risk of epilepsy","volume":"20","author":"Cai","year":"2022","journal-title":"J. Transl. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1186\/s12964-022-00993-2","article-title":"How vascular smooth muscle cell phenotype switching contributes to vascular disease","volume":"20","author":"Cao","year":"2022","journal-title":"Cell Commun. Signal"},{"key":"B15","doi-asserted-by":"publisher","first-page":"106586","DOI":"10.1016\/j.phrs.2022.106586","article-title":"Gut microbiome and metabolites, the future direction of diagnosis and treatment of atherosclerosis?","volume":"187","author":"Cao","year":"2023","journal-title":"Pharmacol. Res."},{"key":"B16","first-page":"5064","article-title":"Intramuscular accumulation of pentadecanoic acid activates AKT1 to phosphorylate NCOR1 and triggers FOXM1-mediated apoptosis in the pathogenesis of sarcopenia","volume":"12","author":"Chen","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1161\/CIRCRESAHA.116.308895","article-title":"Age-associated sirtuin 1 reduction in vascular smooth muscle links vascular senescence and inflammation to abdominal aortic aneurysm","volume":"119","author":"Chen","year":"2016","journal-title":"Circ. Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"104709","DOI":"10.1016\/j.archger.2022.104709","article-title":"Urbanization and population aging: converging trends of demographic transitions in modern world","volume":"101","author":"Chen","year":"2022","journal-title":"Arch. Gerontol. Geriatr."},{"key":"B19","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1016\/j.gendis.2021.12.023","article-title":"Cysteine dioxygenase type 1 (CDO1): its functional role in physiological and pathophysiological processes","volume":"10","author":"Chen","year":"","journal-title":"Genes Dis."},{"key":"B20","doi-asserted-by":"publisher","first-page":"e13899","DOI":"10.1111\/acel.13899","article-title":"Mendelian randomization supports causality between overweight status and accelerated aging","volume":"22","author":"Chen","year":"","journal-title":"Aging Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/s12881-014-0101-x","article-title":"Identification of genes with altered expression in male and female Schlager hypertensive mice","volume":"15","author":"Chiu","year":"2014","journal-title":"BMC Med. Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1016\/j.jamda.2023.06.015","article-title":"Consumption of coffee, tea, and caffeine at midlife, and the risk of physical frailty in late life","volume":"24","author":"Chua","year":"2023","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1093\/lifemedi\/lnad033","article-title":"A framework of biomarkers for vascular aging: a consensus statement by the Aging Biomarker Consortium","volume":"2","author":"Consortium","year":"2023","journal-title":"Life Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/s41580-020-00313-x","article-title":"NAD(+) metabolism and its roles in cellular processes during ageing","volume":"22","author":"Covarrubias","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2636","DOI":"10.1016\/S0140-6736(19)31138-9","article-title":"Sarcopenia","volume":"393","author":"Cruz-Jentoft","year":"2019","journal-title":"Lancet"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.exger.2016.09.007","article-title":"Biomarkers in sarcopenia: a multifactorial approach","volume":"85","author":"Curcio","year":"2016","journal-title":"Exp. Gerontol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1161\/CIRCULATIONAHA.123.064071","article-title":"Sarcopenia and cardiovascular diseases","volume":"147","author":"Damluji","year":"2023","journal-title":"Circulation"},{"key":"B28","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1111\/jnc.13496","article-title":"Central kynurenine pathway shift with age in women","volume":"136","author":"De Bie","year":"2016","journal-title":"J. Neurochem."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.ejim.2016.03.007","article-title":"Frailty measurement in research and clinical practice: a review","volume":"31","author":"Dent","year":"2016","journal-title":"Eur. J. Intern Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1016\/S0140-6736(19)31785-4","article-title":"Management of frailty: opportunities, challenges, and future directions","volume":"394","author":"Dent","year":"2019","journal-title":"Lancet"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.nut.2015.02.011","article-title":"The aromatic amino acid tryptophan stimulates skeletal muscle IGF1\/p70s6k\/mTor signaling in vivo and the expression of myogenic genes in vitro","volume":"31","author":"Dukes","year":"2015","journal-title":"Nutrition"},{"key":"B32","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1016\/j.ijcard.2021.11.038","article-title":"Mannose as a biomarker of coronary artery disease: angiographic evidence and clinical significance","volume":"346","author":"Ferrannini","year":"2022","journal-title":"Int. J. Cardiol."},{"key":"B33","first-page":"362","article-title":"Lower extremity peripheral artery disease: diagnosis and treatment","volume":"99","author":"Firnhaber","year":"2019","journal-title":"Am. Fam. Physician"},{"key":"B34","doi-asserted-by":"publisher","first-page":"9143","DOI":"10.1038\/s41598-019-45703-0","article-title":"Genome-wide association study identifies loci for arterial stiffness index in 127,121 UK Biobank participants","volume":"9","author":"Fung","year":"2019","journal-title":"Sci. Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/j.cell.2023.01.021","article-title":"\u03b22-microglobulin functions as an endogenous NMDAR antagonist to impair synaptic function","volume":"186","author":"Gao","year":"2023","journal-title":"Cell"},{"key":"B36","doi-asserted-by":"publisher","first-page":"173442","DOI":"10.1016\/j.ejphar.2020.173442","article-title":"Arginase inhibition by (-)-Epicatechin reverses endothelial cell aging","volume":"885","author":"Garate-Carrillo","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"768560","DOI":"10.3389\/fimmu.2021.768560","article-title":"Kynurenine pathway metabolites as potential clinical biomarkers in coronary artery disease","volume":"12","author":"G\u00e1sp\u00e1r","year":"2021","journal-title":"Front. Immunol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"5552","DOI":"10.3390\/jcm10235552","article-title":"Sarcopenia: diagnosis and management, state of the art and contribution of ultrasound","volume":"10","author":"Giovannini","year":"2021","journal-title":"J. Clin. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1236430","DOI":"10.3389\/fphys.2023.1236430","article-title":"Relationship between the structure, function and endothelial damage, and vascular ageing and the biopsychological situation in adults diagnosed with persistent COVID (BioICOPER study). A research protocol of a cross-sectional study","volume":"14","author":"G\u00f3mez-S\u00e1nchez","year":"2023","journal-title":"Front. Physiol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1007\/s00018-013-1539-2","article-title":"Regulation of pyruvate metabolism and human disease","volume":"71","author":"Gray","year":"2014","journal-title":"Cell Mol. Life Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1093\/eurheartj\/ehab644","article-title":"Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism","volume":"43","author":"Haghikia","year":"2022","journal-title":"Eur. Heart J."},{"key":"B42","doi-asserted-by":"publisher","first-page":"E970","DOI":"10.1152\/ajpendo.00468.2015","article-title":"Glycine restores the anabolic response to leucine in a mouse model of acute inflammation","volume":"310","author":"Ham","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"B43","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.clnu.2013.06.013","article-title":"Glycine administration attenuates skeletal muscle wasting in a mouse model of cancer cachexia","volume":"33","author":"Ham","year":"2014","journal-title":"Clin. Nutr."},{"key":"B44","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/s0378-1119(01)00691-6","article-title":"Murine cysteine dioxygenase gene: structural organization, tissue-specific expression and promoter identification","volume":"277","author":"Hirschberger","year":"2001","journal-title":"Gene"},{"key":"B45","doi-asserted-by":"publisher","first-page":"101706","DOI":"10.1016\/j.arr.2022.101706","article-title":"Short-chain fatty acid metabolism and multiple effects on cardiovascular diseases","volume":"81","author":"Hu","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"B46","doi-asserted-by":"publisher","first-page":"S15","DOI":"10.1016\/j.amjmed.2008.10.014","article-title":"Diagnosis of atherosclerosis by imaging","volume":"122","author":"Iba\u00f1ez","year":"2009","journal-title":"Am. J. Med."},{"key":"B47","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1002\/jcsm.13166","article-title":"Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1-Arih2 axis","volume":"14","author":"Jiang","year":"2023","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"B48","doi-asserted-by":"publisher","first-page":"15302","DOI":"10.18632\/aging.103456","article-title":"Associations between serum metabolites and subclinical atherosclerosis in a Chinese population: the Taizhou Imaging Study","volume":"12","author":"Jiang","year":"2020","journal-title":"Aging (Albany NY)"},{"key":"B49","doi-asserted-by":"publisher","first-page":"654","DOI":"10.1038\/s41467-021-20918-w","article-title":"Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women","volume":"12","author":"Jones","year":"2021","journal-title":"Nat. Commun."},{"key":"B50","doi-asserted-by":"publisher","first-page":"9483","DOI":"10.1073\/pnas.1920795117","article-title":"Frailty markers comprise blood metabolites involved in antioxidation, cognition, and mobility","volume":"117","author":"Kameda","year":"2020","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B51","doi-asserted-by":"publisher","first-page":"D587","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for taxonomy-based analysis of pathways and genomes","volume":"51","author":"Kanehisa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"B52","doi-asserted-by":"publisher","first-page":"D109","DOI":"10.1093\/nar\/gkr988","article-title":"KEGG for integration and interpretation of large-scale molecular data sets","volume":"40","author":"Kanehisa","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1038\/s41371-020-00434-y","article-title":"Associations between circulating metabolites and arterial stiffness","volume":"35","author":"Kauko","year":"2021","journal-title":"J. Hum. Hypertens."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e83","DOI":"10.1111\/jgs.14733","article-title":"Association between serum \u03b22 -microglobulin levels and prevalent and incident physical frailty in community-dwelling older women","volume":"65","author":"Kim","year":"2017","journal-title":"J. Am. Geriatr. Soc."},{"key":"B55","doi-asserted-by":"publisher","first-page":"153","DOI":"10.4093\/dmj.2022.0305","article-title":"The link between mitochondrial dysfunction and sarcopenia: an update focusing on the role of pyruvate dehydrogenase kinase 4","volume":"47","author":"Kim","year":"2023","journal-title":"Diabetes Metab. J."},{"key":"B56","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.freeradbiomed.2021.07.036","article-title":"Carnosine dipeptidase II (CNDP2) protects cells under cysteine insufficiency by hydrolyzing glutathione-related peptides","volume":"174","author":"Kobayashi","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"B57","doi-asserted-by":"publisher","first-page":"2229","DOI":"10.3390\/jcm9072229","article-title":"Impact of galectin-3 circulating levels on frailty in elderly patients with systolic Heart failure","volume":"9","author":"Komici","year":"2020","journal-title":"J. Clin. Med."},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1111\/ggi.14684","article-title":"Metabolites in aging and aging-relevant diseases: frailty, sarcopenia and cognitive decline","author":"Kondoh","year":"2023","journal-title":"Geriatr. Gerontol. Int"},{"key":"B59","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1097\/MCO.0000000000000383","article-title":"Glycine metabolism in skeletal muscle: implications for metabolic homeostasis","volume":"20","author":"Koopman","year":"2017","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"B60","doi-asserted-by":"publisher","first-page":"e372","DOI":"10.1002\/ctm2.372","article-title":"Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: results of a pilot clinical trial","volume":"11","author":"Kumar","year":"2021","journal-title":"Clin. Transl. Med."},{"key":"B61","doi-asserted-by":"publisher","first-page":"102148","DOI":"10.1016\/j.arr.2023.102148","article-title":"Blood biomarkers for sarcopenia: a systematic review and meta-analysis of diagnostic test accuracy studies","volume":"93","author":"Lian","year":"2023","journal-title":"Ageing Res. Rev."},{"key":"B62","doi-asserted-by":"publisher","first-page":"555","DOI":"10.3390\/metabo11080555","article-title":"Metabolomic profile of abdominal aortic aneurysm","volume":"11","author":"Lieberg","year":"2021","journal-title":"Metabolites"},{"key":"B63","doi-asserted-by":"publisher","first-page":"975647","DOI":"10.3389\/fendo.2022.975647","article-title":"Osteoporosis and sarcopenia-related traits: a bi-directional Mendelian randomization study","volume":"13","author":"Liu","year":"2022","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B64","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11357-015-9864-z","article-title":"Biomarkers of oxidative stress are associated with frailty: the Framingham Offspring Study","volume":"38","author":"Liu","year":"2016","journal-title":"Age (Dordr)"},{"key":"B65","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1186\/s12933-023-01974-6","article-title":"Causal associations between type 1 diabetes mellitus and cardiovascular diseases: a Mendelian randomization study","volume":"22","author":"Liu","year":"2023","journal-title":"Cardiovasc Diabetol."},{"key":"B66","doi-asserted-by":"publisher","first-page":"837490","DOI":"10.3389\/fcvm.2022.837490","article-title":"Association between plasma fibulin-1 and brachial-ankle pulse wave velocity in arterial stiffness","volume":"9","author":"Luo","year":"2022","journal-title":"Front. Cardiovasc Med."},{"key":"B67","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/35025203","article-title":"Atherosclerosis","volume":"407","author":"Lusis","year":"2000","journal-title":"Nature"},{"key":"B68","doi-asserted-by":"publisher","first-page":"5681","DOI":"10.18632\/aging.204145","article-title":"A bi-directional Mendelian randomization study of the sarcopenia-related traits and osteoporosis","volume":"14","author":"Ma","year":"2022","journal-title":"Aging (Albany NY)"},{"key":"B69","doi-asserted-by":"publisher","first-page":"e13868","DOI":"10.1111\/acel.13868","article-title":"Unraveling the metabolic underpinnings of frailty using multicohort observational and Mendelian randomization analyses","volume":"22","author":"Mak","year":"2023","journal-title":"Aging Cell"},{"key":"B70","doi-asserted-by":"publisher","first-page":"e029466","DOI":"10.1161\/JAHA.122.029466","article-title":"Arterial age and early vascular aging, but not chronological age, are associated with faster thoracic aortic aneurysm growth","volume":"12","author":"Mian","year":"2023","journal-title":"J. Am. Heart Assoc."},{"key":"B71","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1161\/HYPERTENSIONAHA.123.21638","article-title":"Vascular age assessed from an uncalibrated, noninvasive pressure waveform by using a deep learning approach: the AI-VascularAge model","volume":"81","author":"Mitchell","year":"2023","journal-title":"Hypertension"},{"key":"B72","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1100\/tsw.2001.58","article-title":"Accumulation of deficits as a proxy measure of aging","volume":"1","author":"Mitnitski","year":"2001","journal-title":"ScientificWorldJournal"},{"key":"B73","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.cpcardiol.2010.08.004","article-title":"Diagnosis and monitoring of abdominal aortic aneurysm: current status and future prospects","volume":"35","author":"Moxon","year":"2010","journal-title":"Curr. Probl. Cardiol."},{"key":"B74","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.3390\/life12101464","article-title":"The correlation of short-chain fatty acids with peripheral arterial disease in diabetes mellitus patients","volume":"12","author":"Muradi","year":"2022","journal-title":"Life (Basel)"},{"key":"B75","doi-asserted-by":"publisher","first-page":"2110","DOI":"10.1161\/CIRCULATIONAHA.120.047689","article-title":"Comprehensive metabolic phenotyping refines cardiovascular risk in young adults","volume":"142","author":"Murthy","year":"2020","journal-title":"Circulation"},{"key":"B76","doi-asserted-by":"publisher","first-page":"370","DOI":"10.3390\/metabo12050370","article-title":"Metabolomics of arterial stiffness","volume":"12","author":"Paapstel","year":"2022","journal-title":"Metabolites"},{"key":"B77","doi-asserted-by":"publisher","first-page":"830723","DOI":"10.3389\/fmed.2021.830723","article-title":"Metabolomics-based frailty biomarkers in older Chinese adults","volume":"8","author":"Pan","year":"2021","journal-title":"Front. Med. (Lausanne)"},{"key":"B78","doi-asserted-by":"publisher","first-page":"1704650","DOI":"10.1155\/2019\/1704650","article-title":"Age-Dependent oxidative stress elevates arginase 1 and uncoupled nitric oxide synthesis in skeletal muscle of aged mice","volume":"2019","author":"Pandya","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"B79","doi-asserted-by":"publisher","first-page":"1075817","DOI":"10.3389\/fnut.2023.1075817","article-title":"Association between coffee intake and frailty among older American adults: a population-based cross-sectional study","volume":"10","author":"Pang","year":"2023","journal-title":"Front. Nutr."},{"key":"B80","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/bs.acc.2022.03.003","article-title":"Cysteine and related aminothiols in cardiovascular disease, obesity and insulin resistance","volume":"109","author":"Pav\u00e3o","year":"2022","journal-title":"Adv. Clin. Chem."},{"key":"B81","doi-asserted-by":"publisher","first-page":"608","DOI":"10.1038\/s42003-020-01334-0","article-title":"The genetic architecture of appendicular lean mass characterized by association analysis in the UK Biobank study","volume":"3","author":"Pei","year":"2020","journal-title":"Commun. Biol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.ymgme.2019.01.015","article-title":"Regulation and tissue-specific expression of \u03b4-aminolevulinic acid synthases in non-syndromic sideroblastic anemias and porphyrias","volume":"128","author":"Peoc'h","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"B83","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1002\/ana.410180411","article-title":"Hallervorden-Spatz disease: cysteine accumulation and cysteine dioxygenase deficiency in the globus pallidus","volume":"18","author":"Perry","year":"1985","journal-title":"Ann. Neurol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.mad.2006.01.020","article-title":"Indoleamine 2,3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality","volume":"127","author":"Pertovaara","year":"2006","journal-title":"Mech. Ageing Dev."},{"key":"B85","doi-asserted-by":"publisher","first-page":"101530","DOI":"10.1016\/j.arr.2021.101530","article-title":"Biomarkers shared by frailty and sarcopenia in older adults: a systematic review and meta-analysis","volume":"73","author":"Picca","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1152\/physiolgenomics.00054.2015","article-title":"Gene transcripts associated with muscle strength: a CHARGE meta-analysis of 7,781 persons","volume":"48","author":"Pilling","year":"2016","journal-title":"Physiol. Genomics"},{"key":"B87","doi-asserted-by":"publisher","first-page":"1903","DOI":"10.3389\/fphys.2018.01903","article-title":"Identification of pre-frailty sub-phenotypes in elderly using metabolomics","volume":"9","author":"Pujos-Guillot","year":"2018","journal-title":"Front. Physiol."},{"key":"B88","first-page":"1127","article-title":"Exploring schizophrenia drug-gene interactions through molecular network and pathway modeling","volume":"2011","author":"Putnam","year":"2011","journal-title":"AMIA Annu. Symp. Proc."},{"key":"B89","doi-asserted-by":"publisher","first-page":"2182","DOI":"10.1002\/jbmr.3224","article-title":"Kynurenine, a tryptophan metabolite that accumulates with age, induces bone loss","volume":"32","author":"Refaey","year":"2017","journal-title":"J. Bone Min. Res."},{"key":"B90","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1097\/MOL.0000000000000381","article-title":"Milk fat biomarkers and cardiometabolic disease","volume":"28","author":"Ris\u00e9rus","year":"2017","journal-title":"Curr. Opin. Lipidol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00109-020-01988-7","article-title":"Increased immunosuppression impairs tissue homeostasis with aging and age-related diseases","volume":"99","author":"Salminen","year":"2021","journal-title":"J. Mol. Med. Berl."},{"key":"B92","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.3390\/ph16081067","article-title":"Overview of caffeine effects on human health and emerging delivery strategies","volume":"16","author":"Saraiva","year":"2023","journal-title":"Pharm. (Basel)"},{"key":"B93","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1016\/j.jacc.2014.12.040","article-title":"Pre-frailty and risk of cardiovascular disease in elderly men and women: the Pro.V.A. study","volume":"65","author":"Sergi","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"3964","DOI":"10.3390\/nu15183964","article-title":"Genetically predicted levels of serum metabolites and risk of sarcopenia: a mendelian randomization study","volume":"15","author":"Sha","year":"2023","journal-title":"Nutrients"},{"key":"B95","doi-asserted-by":"publisher","first-page":"e14079","DOI":"10.1111\/eci.14079","article-title":"Human blood metabolites and risk of severe COVID-19: a Mendelian randomization study","volume":"53","author":"Shang","year":"2023","journal-title":"Eur. J. Clin. Invest."},{"key":"B96","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1038\/ng.2982","article-title":"An atlas of genetic influences on human blood metabolites","volume":"46","author":"Shin","year":"2014","journal-title":"Nat. Genet."},{"key":"B97","doi-asserted-by":"publisher","first-page":"25","DOI":"10.2302\/kjm.2015-0015-IR","article-title":"Cardiac senescence, Heart failure, and frailty: a triangle in elderly people","volume":"65","author":"Shinmura","year":"2016","journal-title":"Keio J. Med."},{"key":"B98","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1038\/nm.3898","article-title":"\u03b22-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis","volume":"21","author":"Smith","year":"2015","journal-title":"Nat. Med."},{"key":"B99","doi-asserted-by":"publisher","first-page":"99","DOI":"10.2174\/0929867328666210714153649","article-title":"Tryptophan metabolism in atherosclerosis and diabetes","volume":"29","author":"Sudar-Milovanovic","year":"2022","journal-title":"Curr. Med. Chem."},{"key":"B100","doi-asserted-by":"publisher","first-page":"1119782","DOI":"10.3389\/fendo.2023.1119782","article-title":"Metabolomics analysis reveals serum biomarkers in patients with diabetic sarcopenia","volume":"14","author":"Tan","year":"2023","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B101","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s10020-019-0070-9","article-title":"Molecular expression, characterization and mechanism of ALAS2 gain-of-function mutants","volume":"25","author":"Tchaikovskii","year":"2019","journal-title":"Mol. Med."},{"key":"B102","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/s41569-021-00607-3","article-title":"Epidemiology of cardiovascular disease in Europe","volume":"19","author":"Townsend","year":"2022","journal-title":"Nat. Rev. Cardiol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"112163","DOI":"10.1016\/j.exger.2023.112163","article-title":"Biomarkers of the ageing immune system and their association with frailty - a systematic review","volume":"176","author":"Tran Van Hoi","year":"2023","journal-title":"Exp. Gerontol."},{"key":"B104","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1016\/j.jacc.2019.11.061","article-title":"Mechanisms of vascular aging, A geroscience perspective: JACC focus seminar","volume":"75","author":"Ungvari","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.exger.2018.09.010","article-title":"Immunological alterations in frail older adults: a cross sectional study","volume":"112","author":"Valdiglesias","year":"2018","journal-title":"Exp. Gerontol."},{"key":"B106","doi-asserted-by":"publisher","first-page":"444","DOI":"10.3389\/fgene.2018.00444","article-title":"Editorial: arterial aging and age-associated arterial diseases","volume":"9","author":"Wang","year":"2018","journal-title":"Front. Genet."},{"key":"B107","doi-asserted-by":"publisher","first-page":"3869","DOI":"10.7150\/ijbs.85467","article-title":"Targeting metabolism in aortic aneurysm and dissection: from basic research to clinical applications","volume":"19","author":"Wang","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"B108","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cger.2010.08.009","article-title":"The frailty syndrome: definition and natural history","volume":"27","author":"Xue","year":"2011","journal-title":"Clin. Geriatr. Med."},{"key":"B109","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1016\/j.jacbts.2022.05.001","article-title":"Propionate alleviates abdominal aortic aneurysm by modulating colonic regulatory T-cell expansion and recirculation","volume":"7","author":"Yang","year":"2022","journal-title":"JACC Basic Transl. Sci."},{"key":"B110","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.cytogfr.2022.11.001","article-title":"Crosstalk between glucose metabolism, lactate production and immune response modulation","volume":"68","author":"Ye","year":"2022","journal-title":"Cytokine Growth Factor Rev."},{"key":"B111","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1016\/j.molcel.2013.01.019","article-title":"Nutrient sensing, metabolism, and cell growth control","volume":"49","author":"Yuan","year":"2013","journal-title":"Mol. Cell"},{"key":"B112","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1002\/agm2.12049","article-title":"Expert consensus on clinical assessment and intervention of vascular aging in China (2018)","volume":"1","author":"Zhang","year":"2018","journal-title":"Aging Med. Milt."},{"key":"B113","doi-asserted-by":"publisher","first-page":"212","DOI":"10.1186\/s12964-023-01219-9","article-title":"Short-chain fatty acids in diseases","volume":"21","author":"Zhang","year":"2023","journal-title":"Cell Commun. Signal"},{"key":"B114","doi-asserted-by":"publisher","first-page":"pbad010","DOI":"10.1093\/pcmedi\/pbad010","article-title":"Investigating association between gut microbiota and sarcopenia-related traits: a Mendelian randomization study","volume":"6","author":"Zhao","year":"2023","journal-title":"Precis. Clin. Med."},{"key":"B115","doi-asserted-by":"publisher","first-page":"11786388211053407","DOI":"10.1177\/11786388211053407","article-title":"NAD(+), senolytics, or pyruvate for healthy aging?","volume":"14","author":"Zhou","year":"2021","journal-title":"Nutr. Metab. Insights"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1353908\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,13]],"date-time":"2024-02-13T04:31:49Z","timestamp":1707798709000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2024.1353908\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,13]]},"references-count":115,"alternative-id":["10.3389\/fgene.2024.1353908"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2024.1353908","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,13]]},"article-number":"1353908"}}