{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:37:45Z","timestamp":1791520665695,"version":"4.3.4"},"reference-count":130,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T00:00:00Z","timestamp":1674259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Frailty is a clinical condition closely related to aging which is characterized by a multidimensional decline in biological reserves, a failure of physiological mechanisms and vulnerability to minor stressors. Chronic inflammation, the impairment of endothelial function, age-related endocrine system modifications and immunosenescence are important mechanisms in the pathophysiology of frailty. Endothelial progenitor cells (EPCs) are considered important contributors of the endothelium homeostasis and turn-over. In the elderly, EPCs are impaired in terms of function, number and survival. In addition, the modification of EPCs\u2019 level and function has been widely demonstrated in atherosclerosis, hypertension and diabetes mellitus, which are the most common age-related diseases. The purpose of this review is to illustrate the role of EPCs in frailty. Initially, we describe the endothelial dysfunction in frailty, the response of EPCs to the endothelial dysfunction associated with frailty and, finally, interventions which may restore the EPCs expression and function in frail people.<\/jats:p>","DOI":"10.3390\/ijms24032139","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T02:27:45Z","timestamp":1674440865000},"page":"2139","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Role of Endothelial Progenitor Cells in Frailty"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9419-2426","authenticated-orcid":false,"given":"Klara","family":"Komici","sequence":"first","affiliation":[{"name":"Department of Medicine and Health Sciences, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7853-9159","authenticated-orcid":false,"given":"Angelica","family":"Perna","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4342-962X","authenticated-orcid":false,"given":"Germano","family":"Guerra","sequence":"additional","affiliation":[{"name":"Department of Medicine and Health Sciences, University of Molise, 86100 Campobasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,21]]},"reference":[{"key":"ref_1","unstructured":"United Nations Department of Economic and Social Affairs Population Division (2020). World Population Ageing 2020 Highlights: Living Arrangements of Older Persons, United Nations. (ST\/ESA\/SER.A\/451)."},{"key":"ref_2","unstructured":"United Nations Department of Economic and Social Affairs Population Division (2019). World Population Ageing 2019: Highlights, United Nations. (ST\/ESA\/SER.A\/430)."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/S0140-6736(12)62167-9","article-title":"Frailty in elderly people","volume":"381","author":"Clegg","year":"2013","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.chest.2018.03.041","article-title":"Frailty: Is This a New Vital Sign?","volume":"154","author":"Cicutto","year":"2018","journal-title":"Chest"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"638e7","DOI":"10.1016\/j.jamda.2017.04.011","article-title":"Frailty and Risk of Adverse Outcomes in Hospitalized Older Adults: A Comparison of Different Frailty Measures","volume":"18","author":"Chong","year":"2017","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"197","DOI":"10.23736\/S1973-9087.20.05970-5","article-title":"Psychophysical health of elderly inpatients in cardiac rehabilitation: A retrospective cohort study","volume":"56","author":"Balestroni","year":"2020","journal-title":"Eur. J. Phys. Rehabil. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"M146","DOI":"10.1093\/gerona\/56.3.M146","article-title":"Frailty in older adults: Evidence for a phenotype","volume":"56","author":"Fried","year":"2001","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.chest.2022.02.027","article-title":"Frailty in Patients With Lung Cancer: A Systematic Review and Meta-Analysis","volume":"162","author":"Komici","year":"2022","journal-title":"Chest"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/S0140-6736(19)31786-6","article-title":"Frailty: Implications for clinical practice and public health","volume":"394","author":"Hoogendijk","year":"2019","journal-title":"Lancet"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1111\/j.1532-5415.2007.01186.x","article-title":"Inflammation and frailty in older women","volume":"55","author":"Leng","year":"2007","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1111\/j.1582-4934.2009.00733.x","article-title":"Inflammation and frailty measures in older people","volume":"13","author":"Hubbard","year":"2009","journal-title":"J. Cell Mol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1001\/archinte.167.7.635","article-title":"Insulin resistance and inflammation as precursors of frailty: The Cardiovascular Health Study","volume":"167","author":"Barzilay","year":"2007","journal-title":"Arch. Intern. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1126\/science.273.5271.70","article-title":"The aging immune system: Primer and prospectus","volume":"273","author":"Miller","year":"1996","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1161\/CIRCRESAHA.115.306301","article-title":"Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis","volume":"118","author":"Gimbrone","year":"2016","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.mad.2016.03.005","article-title":"Cellular and molecular basis of the imbalance between vascular damage and repair in ageing and age-related diseases: As biomarkers and targets for new treatments","volume":"159","author":"Madonna","year":"2016","journal-title":"Mech. Ageing Dev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1093\/ageing\/afaa237","article-title":"Does vascular endothelial dysfunction play a role in physical frailty and sarcopenia? A systematic review","volume":"50","author":"Amarasekera","year":"2021","journal-title":"Age Ageing"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1177\/0963689718779345","article-title":"Endothelial progenitor cells in age-related vascular remodeling","volume":"27","author":"Yang","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_18","first-page":"6","article-title":"Circulating CD34-Positive Cells Are Associated with Handgrip Strength in Japanese Older Men: The Nagasaki Islands Study","volume":"6","author":"Yamanashi","year":"2017","journal-title":"J. Frailty Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1002\/agm2.12041","article-title":"Endothelial progenitor cells in cardiovascular diseases","volume":"1","author":"Qiu","year":"2018","journal-title":"Aging Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Perrotta, F., Perna, A., Komici, K., Nigro, E., Mollica, M., D\u2019Agnano, V., De Luca, A., and Guerra, G. (2020). The State of Art of Regenerative Therapy in Cardiovascular Ischemic Disease: Biology, Signaling Pathways, and Epigenetics of Endothelial Progenitor Cells. Cells, 9.","DOI":"10.3390\/cells9081886"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"752","DOI":"10.14740\/jocmr3581w","article-title":"Dysfunction and Therapeutic Potential of Endothelial Progenitor Cells in Diabetes Mellitus","volume":"10","author":"Hu","year":"2018","journal-title":"J. Clin. Med. Res."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Komici, K., Perna, A., Rocca, A., Bencivenga, L., Rengo, G., and Guerra, G. (2021). Endothelial Progenitor Cells and Rheumatoid Arthritis: Response to Endothelial Dysfunction and Clinical Evidences. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222413675"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"811210","DOI":"10.3389\/fnagi.2021.811210","article-title":"Endothelial Progenitor Cells and Vascular Alterations in Alzheimer\u2019s Disease","volume":"13","author":"Custodia","year":"2021","journal-title":"Front Aging Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.phrs.2008.07.008","article-title":"Endothelial progenitor cells in vascular repair and remodeling","volume":"58","author":"Hristov","year":"2008","journal-title":"Pharmacol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1002\/stem.745","article-title":"Concise review: Circulating endothelial progenitor cells for vascular medicine","volume":"29","author":"Asahara","year":"2011","journal-title":"Stem Cells"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3964","DOI":"10.1093\/emboj\/18.14.3964","article-title":"VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells","volume":"18","author":"Asahara","year":"1999","journal-title":"EMBO J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1038\/nm948","article-title":"Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells","volume":"9","author":"Aicher","year":"2003","journal-title":"Nat. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1002\/sctm.16-0360","article-title":"Endothelial Progenitors: A Consensus Statement on Nomenclature","volume":"6","author":"Medina","year":"2017","journal-title":"Stem Cells Transl. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10137","DOI":"10.1073\/pnas.1405388111","article-title":"Human endothelial colony-forming cells serve as trophic mediators for mesenchymal stem cell engraftment via paracrine signaling","volume":"111","author":"Lin","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Moccia, F., Negri, S., Shekha, M., Faris, P., and Guerra, G. (2019). Endothelial Ca(2+) Signaling, Angiogenesis and Vasculogenesis: Just What It Takes to Make a Blood Vessel. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20163962"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1097\/FJC.0b013e31812564e4","article-title":"Therapeutic effects of autologous bone marrow cells and metabolic intervention in the ischemic hindlimb of spontaneously hypertensive rats involve reduced cell senescence and CXCR4\/Akt\/eNOS pathways","volume":"50","author":"Balestrieri","year":"2007","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3017","DOI":"10.1161\/01.CIR.0000018166.84319.55","article-title":"Statin therapy accelerates reendothelialization: A novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells","volume":"105","author":"Walter","year":"2002","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1161\/01.ATV.0000215001.92941.6c","article-title":"Intercellular adhesion molecule-1 is upregulated in ischemic muscle, which mediates trafficking of endothelial progenitor cells","volume":"26","author":"Yoon","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1186\/s13287-016-0430-0","article-title":"Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor","volume":"7","author":"Hookham","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1161\/01.CIR.0000058702.69484.A0","article-title":"Peripheral blood \u201eendothelial progenitor cells\u201d are derived from monocyte\/macrophages and secrete angiogenic growth factors","volume":"107","author":"Rehman","year":"2003","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1172\/JCI58789","article-title":"Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats","volume":"122","author":"Wang","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.yjmcc.2007.08.001","article-title":"Bone marrow subpopulations contain distinct types of endothelial progenitor cells and angiogenic cytokine-producing cells","volume":"43","author":"Miyamoto","year":"2007","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1161\/01.CIR.0000157144.24888.7E","article-title":"Endothelial progenitor cells are rapidly recruited to myocardium and mediate protective effect of ischemic preconditioning via \u201cimported\u201d nitric oxide synthase activity","volume":"111","author":"Ii","year":"2005","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"F897","DOI":"10.1152\/ajprenal.00643.2016","article-title":"Endothelial colony-forming cells ameliorate endothelial dysfunction via secreted factors following ischemia-reperfusion injury","volume":"312","author":"Collett","year":"2017","journal-title":"Am. J. Physiol. Renal. Physiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/emboj.2011.465","article-title":"Identification and characterization of a resident vascular stem\/progenitor cell population in preexisting blood vessels","volume":"31","author":"Naito","year":"2012","journal-title":"EMBO J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1007\/s10456-013-9354-9","article-title":"Human vasculogenic cells form functional blood vessels and mitigate adverse remodeling after ischemia reperfusion injury in rats","volume":"16","author":"Kang","year":"2013","journal-title":"Angiogenesis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.brainres.2016.03.045","article-title":"Bioluminescence imaging of transplanted human endothelial colony-forming cells in an ischemic mouse model","volume":"1642","author":"Ding","year":"2016","journal-title":"Brain Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41598-017-00809-1","article-title":"Endothelial colony forming cells and mesenchymal progenitor cells form blood vessels and increase blood flow in ischemic muscle","volume":"7","author":"Kang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1093\/cvr\/cvq224","article-title":"Role of myofibroblasts in vascular remodelling: Focus on restenosis and aneurysm","volume":"88","author":"Forte","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1016\/j.jacc.2003.07.025","article-title":"Age-dependent depression in circulating endothelial progenitor cells in patients undergoing coronary artery bypass grafting","volume":"42","author":"Scheubel","year":"2003","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2281870","DOI":"10.1155\/2022\/2281870","article-title":"Aging-Related Endothelial Progenitor Cell Dysfunction and Its Association with IL-17 and IL-23 in HFmrEF Patients","volume":"2022","author":"Zeng","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"687590","DOI":"10.3389\/fcvm.2021.687590","article-title":"Hypofunction of Circulating Endothelial Progenitor Cells and Aggravated Severity in Elderly Male Patients With Non-ST Segment Elevation Myocardial Infarction: Its Association With Systemic Inflammation","volume":"8","author":"Zeng","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1111\/j.1582-4934.2010.01231.x","article-title":"Defective CXCR4 expression in aged bone marrow cells impairs vascular regeneration","volume":"15","author":"Shao","year":"2011","journal-title":"J. Cell Mol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.atherosclerosis.2011.07.118","article-title":"Impaired CXCR4 expression and cell engraftment of bone marrow-derived cells from aged atherogenic mice","volume":"219","author":"Xu","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1111\/j.1474-9726.2011.00758.x","article-title":"Physical exercise attenuates age-associated reduction in endothelium-reparative capacity of endothelial progenitor cells by increasing CXCR4\/JAK-2 signaling in healthy men","volume":"11","author":"Xia","year":"2012","journal-title":"Aging Cell"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1161\/ATVBAHA.107.155960","article-title":"Assessing identity, phenotype, and fate of endothelial progenitor cells","volume":"28","author":"Hirschi","year":"2008","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"6603","DOI":"10.1007\/s13277-015-3823-2","article-title":"Endothelial progenitor cells support tumour growth and metastatisation: Implications for the resistance to anti-angiogenic therapy","volume":"36","author":"Moccia","year":"2015","journal-title":"Tumour. Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/cyto.b.20040","article-title":"Detection of circulating endothelial cells and endothelial progenitor cells by flow cytometry","volume":"64","author":"Khan","year":"2005","journal-title":"Cytometry B Clin. Cytom."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1182\/blood.V95.3.952.003k27_952_958","article-title":"Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors","volume":"95","author":"Peichev","year":"2000","journal-title":"Blood"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3106","DOI":"10.1182\/blood.V95.10.3106","article-title":"In vitro differentiation of endothelial cells from AC133-positive progenitor cells","volume":"95","author":"Gehling","year":"2000","journal-title":"Blood"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.exphem.2007.04.002","article-title":"Human CD34+AC133+VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors","volume":"35","author":"Case","year":"2007","journal-title":"Exp. Hematol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1161\/ATVBAHA.107.144972","article-title":"Endothelial outgrowth cells are not derived from CD133+ cells or CD45+ hematopoietic precursors","volume":"27","author":"Timmermans","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1126\/science.275.5302.964","article-title":"Isolation of putative progenitor endothelial cells for angiogenesis","volume":"275","author":"Asahara","year":"1997","journal-title":"Science"},{"key":"ref_59","first-page":"5875","article-title":"Endothelial progenitor cells as putative targets for angiostatin","volume":"59","author":"Ito","year":"1999","journal-title":"Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1056\/NEJMoa022287","article-title":"Circulating endothelial progenitor cells, vascular function, and cardiovascular risk","volume":"348","author":"Hill","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1182\/blood-2006-08-043471","article-title":"Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem\/progenitor cell principals","volume":"109","author":"Yoder","year":"2007","journal-title":"Blood"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1634\/stemcells.2005-0072","article-title":"Blood monocytes mimic endothelial progenitor cells","volume":"24","author":"Rohde","year":"2006","journal-title":"Stem Cells"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3422","DOI":"10.1073\/pnas.97.7.3422","article-title":"Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization","volume":"97","author":"Kalka","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1172\/JCI8071","article-title":"Origins of circulating endothelial cells and endothelial outgrowth from blood","volume":"105","author":"Lin","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1111\/j.1532-5415.2008.02008.x","article-title":"Prognostic significance of potential frailty criteria","volume":"56","author":"Rothman","year":"2008","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_66","doi-asserted-by":"crossref","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":"Sci. World J."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1111\/j.1532-5415.2006.00738.x","article-title":"Long-term risks of death and institutionalization of elderly people in relation to deficit accumulation at age 70","volume":"54","author":"Rockwood","year":"2006","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/j.1532-5415.2010.02764.x","article-title":"Prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation","volume":"58","author":"Song","year":"2010","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Sutton, J.L., Gould, R.L., Daley, S., Coulson, M.C., Ward, E.V., Butler, A.M., Nunn, S.P., and Howard, R.J. (2016). Psychometric properties of multicomponent tools designed to assess frailty in older adults: A systematic review. BMC Geriatr., 16.","DOI":"10.1186\/s12877-016-0225-2"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/BF03327413","article-title":"Evaluation of a frailty index based on a comprehensive geriatric assessment in a population based study of elderly Canadians","volume":"17","author":"Jones","year":"2005","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e1751","DOI":"10.1002\/onco.13894","article-title":"A 10-Item Frailty Index Based on a Comprehensive Geriatric Assessment (FI-CGA-10) in Older Adults with Cancer: Development and Construct Validation","volume":"26","author":"Nishijima","year":"2021","journal-title":"Oncologist"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Komici, K., Cappuccio, M., Scacchi, A., Vaschetti, R., Delli Carpini, G., Picerno, V., Avella, P., Brunese, M.C., Rengo, G., and Guerra, G. (2022). The Prevalence and the Impact of Frailty in Hepato-Biliary Pancreatic Cancers: A Systematic Review and Meta-Analysis. J. Clin. Med., 11.","DOI":"10.3390\/jcm11041116"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1111\/j.1532-5415.2009.02137.x","article-title":"A comparison of frailty indexes for the prediction of falls, disability, fractures, and mortality in older men","volume":"57","author":"Ensrud","year":"2009","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Metzelthin, S.F., Daniels, R., van Rossum, E., de Witte, L., van den Heuvel, W.J., and Kempen, G.I. (2010). The psychometric properties of three self-report screening instruments for identifying frail older people in the community. BMC Public Health, 10.","DOI":"10.1186\/1471-2458-10-176"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1093\/ageing\/afaa219","article-title":"Prevalence of frailty in 62 countries across the world: A systematic review and meta-analysis of population-level studies","volume":"50","author":"Sezgin","year":"2021","journal-title":"Age Ageing"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Feng, Z., Lugtenberg, M., Franse, C., Fang, X., Hu, S., Jin, C., and Raat, H. (2017). Risk factors and protective factors associated with incident or increase of frailty among community-dwelling older adults: A systematic review of longitudinal studies. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178383"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"M158","DOI":"10.1093\/gerona\/56.3.M158","article-title":"Associations of subclinical cardiovascular disease with frailty","volume":"56","author":"Newman","year":"2001","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1007\/s11357-013-9576-1","article-title":"Association between endothelial dysfunction and frailty: The Toledo Study for Healthy Aging","volume":"36","author":"Carcaillon","year":"2014","journal-title":"Age"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1111\/j.1474-9726.2009.00466.x","article-title":"Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammation","volume":"8","author":"Vallejo","year":"2009","journal-title":"Aging Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1002\/jbmr.2773","article-title":"Association of Serum Asymmetric Dimethylarginine With Muscle Strength and Gait Speed: A Cross-Sectional Study of the HEIJO-KYO Cohort","volume":"31","author":"Obayashi","year":"2016","journal-title":"J. Bone Miner Res."},{"key":"ref_81","doi-asserted-by":"crossref","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":"ref_82","doi-asserted-by":"crossref","first-page":"386387","DOI":"10.1155\/2012\/386387","article-title":"Systemic vascular function is associated with muscular power in older adults","volume":"2012","author":"Heffernan","year":"2012","journal-title":"J. Aging Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.atherosclerosis.2017.01.005","article-title":"Sarcopenia, but not excess weight or increased caloric intake, is associated with coronary subclinical atherosclerosis in the very elderly","volume":"258","author":"Campos","year":"2017","journal-title":"Atherosclerosis"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1111\/ggi.13312","article-title":"Association between atherosclerosis and handgrip strength in non-hypertensive populations in India and Japan","volume":"18","author":"Yamanashi","year":"2018","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"92","DOI":"10.4103\/2455-3069.198368","article-title":"Frailty and flow-mediated dilation: A pilot study in hospitalized elderly","volume":"2","author":"Santillo","year":"2016","journal-title":"J. Curr. Res. Sci. Med."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Mansur, H.N., Lovisi, J.C., Colugnati, F.A., Raposo, N.R., Fernandes, N.M., and Bastos, M.G. (2015). Association of frailty with endothelial dysfunction and its possible impact on negative outcomes in Brazilian predialysis patients with chronic kidney disease. BMC Nephrol., 16.","DOI":"10.1186\/s12882-015-0150-1"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s12603-011-0134-1","article-title":"Physical frailty in older adults is associated with metabolic and atherosclerotic risk factors and cognitive impairment independent of muscle mass","volume":"15","author":"Lee","year":"2011","journal-title":"J. Nutr. Health Aging"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.ijcard.2015.09.039","article-title":"The association of frailty with abnormal ankle-brachial index determinations is related to age: Results from the Atahualpa Project","volume":"202","author":"Mera","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"McKechnie, D.G.J., Patel, M., Papacosta, A.O., Lennon, L.T., Ellins, E.A., Halcox, J.P.J., Ramsay, S.E., Whincup, P.H., and Wannamethee, S.G. (2022). Associations between inflammation, coagulation, cardiac strain and injury, and subclinical vascular disease with frailty in older men: A cross-sectional study. BMC Geriatr., 22.","DOI":"10.1186\/s12877-022-03106-3"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1093\/gerona\/glab317","article-title":"Sex Differences in the Relation between Frailty and Endothelial Dysfunction in Old Mice","volume":"77","author":"Cole","year":"2022","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1093\/gerona\/glt136","article-title":"A clinical frailty index in aging mice: Comparisons with frailty index data in humans","volume":"69","author":"Whitehead","year":"2014","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1016\/j.jacc.2005.04.066","article-title":"Suppression of endothelial progenitor cells in human coronary artery disease by the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine","volume":"46","author":"Thum","year":"2005","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.ijcard.2009.02.020","article-title":"The effects of G-CSF-induced mobilization of progenitor cells are limited by ADMA","volume":"143","author":"Goette","year":"2010","journal-title":"Int. J. Cardiol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1093\/ndt\/gfp439","article-title":"Synergistic effects of asymmetrical dimethyl-L-arginine accumulation and endothelial progenitor cell deficiency on renal function decline during a 2-year follow-up in stable angina","volume":"25","author":"Surdacki","year":"2010","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"21","DOI":"10.5414\/CN107318","article-title":"Decrease in endothelial progenitor cells associated with inflammation, but not with endothelial dysfunction in chronic hemodialysis patients","volume":"79","author":"Ozkok","year":"2013","journal-title":"Clin. Nephrol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1016\/j.bbrc.2015.02.050","article-title":"Accelerated onset of senescence of endothelial progenitor cells in patients with type 2 diabetes mellitus: Role of dimethylarginine dimethylaminohydrolase 2 and asymmetric dimethylarginine","volume":"458","author":"Yuan","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"6395601","DOI":"10.1155\/2017\/6395601","article-title":"Asymmetric Dimethylarginine Induced Apoptosis and Dysfunction of Endothelial Progenitor Cells: Role of Endoplasmic Reticulum Stress Pathway","volume":"2017","author":"Ye","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.12659\/MSM.904718","article-title":"Regulation of c-Jun N-Terminal Protein Kinase (JNK) Pathway in Apoptosis of Endothelial Outgrowth Cells Induced by Asymmetric Dimethylarginine","volume":"23","author":"Zhang","year":"2017","journal-title":"Med. Sci. Monit."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1161\/ATVBAHA.110.211581","article-title":"Nitric oxide synthase expression and functional response to nitric oxide are both important modulators of circulating angiogenic cell response to angiogenic stimuli","volume":"30","author":"Heiss","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"H1760","DOI":"10.1152\/ajpheart.01408.2006","article-title":"Endothelial nitric oxide synthase is dynamically expressed during bone marrow stem cell differentiation into endothelial cells","volume":"293","author":"Liu","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1177\/002215540305100902","article-title":"Impaired angiogenesis in aging is associated with alterations in vessel density, matrix composition, inflammatory response, and growth factor expression","volume":"51","author":"Sadoun","year":"2003","journal-title":"J. Histochem. Cytochem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1186\/s13287-017-0684-1","article-title":"VEGF promotes endothelial progenitor cell differentiation and vascular repair through connexin 43","volume":"8","author":"Li","year":"2017","journal-title":"Stem Cell Res. Ther."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"8479","DOI":"10.1126\/science.abc8479","article-title":"Counteracting age-related VEGF signaling insufficiency promotes healthy aging and extends life span","volume":"373","author":"Grunewald","year":"2021","journal-title":"Science"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3707","DOI":"10.1182\/blood-2008-12-195750","article-title":"Enhancement of vascular progenitor potential by protein kinase A through dual induction of Flk-1 and Neuropilin-1","volume":"114","author":"Yamamizu","year":"2009","journal-title":"Blood"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1093\/gerona\/glt067","article-title":"Lower levels of circulating progenitor cells are associated with low physical function and performance in elderly men with impaired glucose tolerance: A pilot substudy from the VA Enhanced Fitness trial","volume":"68","author":"Povsic","year":"2013","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1093\/gerona\/glv180","article-title":"Endothelial Progenitor Cell Levels Predict Future Physical Function: An Exploratory Analysis From the VA Enhanced Fitness Study","volume":"71","author":"Povsic","year":"2016","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3233\/JAD-170587","article-title":"Circulating Progenitor Cells Correlate with Memory, Posterior Cortical Thickness, and Hippocampal Perfusion","volume":"61","author":"Nation","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1007\/s40520-016-0535-4","article-title":"Biomarkers of vascular dysfunction and cognitive decline in patients with Alzheimer\u2019s disease: No evidence for association in elderly subjects","volume":"28","author":"Breining","year":"2016","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"659","DOI":"10.3233\/JAD-191063","article-title":"Circulating Progenitor Cells and Cognitive Impairment in Men and Women with Coronary Artery Disease","volume":"74","author":"Moazzami","year":"2020","journal-title":"J. Alzheimers Dis."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s11010-011-1157-y","article-title":"Human endothelial progenitor cells isolated from COPD patients are dysfunctional","volume":"363","author":"Liu","year":"2012","journal-title":"Mol. Cell Biochem."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1183\/09031936.06.00120604","article-title":"Circulating haemopoietic and endothelial progenitor cells are decreased in COPD","volume":"27","author":"Palange","year":"2006","journal-title":"Eur. Respir. J."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.exger.2017.06.004","article-title":"Age, gender, and percentage of circulating osteoprogenitor (COP) cells: The COP Study","volume":"96","author":"Gunawardene","year":"2017","journal-title":"Exp. Gerontol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1093\/gerona\/glac034","article-title":"DNA Damage in Circulating Hematopoietic Progenitor Stem Cells as Promising Biological Sensor of Frailty","volume":"77","author":"Grasselli","year":"2022","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e13545","DOI":"10.1111\/acel.13545","article-title":"Hematopoietic progenitor cell liabilities and alarmins S100A8\/A9-related inflammaging associate with frailty and predict poor cardiovascular outcomes in older adults","volume":"21","author":"Bonora","year":"2022","journal-title":"Aging Cell"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1111\/jgs.17941","article-title":"Effect of a physical activity intervention and frailty on frailty trajectory and major mobility disability","volume":"70","author":"Quach","year":"2022","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1016\/j.apmr.2021.06.017","article-title":"Effect of 12-Month Supervised, Home-Based Physical Exercise on Functioning among Persons with Signs of Frailty: A Randomized Controlled Trial","volume":"102","author":"Suikkanen","year":"2021","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Kao, C.H., Chiang, S.L., Chou, L.W., Lin, C.H., Lu, Y.H., Lu, L.H., Wang, X.M., and Lin, C.H. (2022). Validation of Vibration Exercises on Enhancing Muscle Strength and Upper Limb Functionality among Pre-Frail Community-Dwelling Older Adults. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph192114509"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s12603-022-1745-4","article-title":"The Effects of an Integrated Exercise Intervention on the Attenuation of Frailty in Elderly Nursing Homes: A Cluster Randomized Controlled Trial","volume":"26","author":"Liu","year":"2022","journal-title":"J. Nutr. Health Aging"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Beigiene, A., Petruseviciene, D., Barasaite, V., Kubilius, R., and Macijauskiene, J. (2021). Frailty and Different Exercise Interventions to Improve Gait Speed in Older Adults after Acute Coronary Syndrome. Medicina, 57.","DOI":"10.3390\/medicina57121344"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1717e9","DOI":"10.1016\/j.jamda.2022.07.010","article-title":"Changes in the Severity of Frailty among Older Adults after 12 Months of Supervised Home-Based Physical Exercise: A Randomized Clinical Trial","volume":"23","author":"Suikkanen","year":"2022","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Chen, J., Gu, S., Song, Y., Ji, X., Zeng, W., Wang, X., Wang, Y., and Feng, Q. (2021). The impact of cardiomotor rehabilitation on endothelial function in elderly patients with chronic heart failure. BMC Cardiovasc. Disord., 21.","DOI":"10.1186\/s12872-021-02327-5"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1016\/j.biocel.2013.05.035","article-title":"Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: Potential therapeutic targets for cardiac cachexia","volume":"45","author":"Yoshida","year":"2013","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1016\/S0140-6736(02)08024-8","article-title":"Relation between use of angiotensin-converting enzyme inhibitors and muscle strength and physical function in older women: An observational study","volume":"359","author":"Onder","year":"2002","journal-title":"Lancet"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s00228-011-1029-0","article-title":"Effects of ACE inhibition on circulating endothelial progenitor cells, vascular damage, and oxidative stress in hypertensive patients","volume":"67","author":"Cacciatore","year":"2011","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1215.e2","DOI":"10.1016\/j.jamda.2020.07.012","article-title":"Effect of Angiotensin System Inhibitors on Physical Performance in Older People\u2014A Systematic Review and Meta-Analysis","volume":"22","author":"Caulfield","year":"2021","journal-title":"J. Am. Med. Dir. Assoc."},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"LACE Study Group, Achison, M., Adamson, S., Akpan, A., Aspray, T., Avenell, A., Band, M.M., Bashir, T., Burton, L.A., and Cvoro, V. (2022). Effect of perindopril or leucine on physical performance in older people with sarcopenia: The LACE randomized controlled trial. J. Cachexia Sarcopenia Muscle, 13, 858\u2013871.","DOI":"10.1002\/jcsm.12934"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1161\/CIRCULATIONAHA.122.061754","article-title":"Efficacy and Safety of Dapagliflozin According to Frailty in Patients with Heart Failure: A Prespecified Analysis of the DELIVER Trial","volume":"146","author":"Butt","year":"2022","journal-title":"Circulation"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"3773","DOI":"10.1210\/jc.2018-00824","article-title":"Effects of SGLT2 Inhibitors on Circulating Stem and Progenitor Cells in Patients With Type 2 Diabetes","volume":"103","author":"Bonora","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1186\/s12933-021-01235-4","article-title":"Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes","volume":"20","author":"Nandula","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1161\/HYPERTENSIONAHA.122.19586","article-title":"SGLT2 Inhibition via Empagliflozin Improves Endothelial Function and Reduces Mitochondrial Oxidative Stress: Insights from Frail Hypertensive and Diabetic Patients","volume":"79","author":"Mone","year":"2022","journal-title":"Hypertension"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2139\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:12:43Z","timestamp":1760119963000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,21]]},"references-count":130,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032139"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032139","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,21]]}}}