cardioКардиологияKardiologiia0022-90402412-5660Kardiomag10.18087/cardio.2022.6.n2033cardio-2033Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИRESEARCH ARTICLESВзаимосвязь жесткости магистральных сосудов и биомаркеров накопления сенесцентных клеток у пожилых пациентовCorrelations between vessel stiffness and biomarkers of senescent cell in elderly patientshttps://orcid.org/0000-0003-2310-936XСорокинаА. Г.SorokinaA. G.

научный сотрудник отдела возраст-ассоциированных заболеваний

Москва, Россия

MD,  Researcher at the Department of  Age-associated diseases, Medical Scientific and Educational Center of Lomonosov Moscow State University

Moscow, Russia

drsorokinaag@gmail.comhttps://orcid.org/0000-0002-0696-1369ЕфименкоА. Ю.EfimenkoA. Yu.

кандидат медицинских наук, заведующий лабораторией репарации и регенерации тканей, доцент кафедры биохимии и молекулярной медицины

Москва, Россия

PhD, Head of laboratory of tissue repair and regeneration, Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University; 

Moscow, Russia

efimenkoan@gmail.comhttps://orcid.org/0000-0003-2954-2420ГригорьеваО. А.GrigorievaO. A.

кандидат биологических наук, младший научный сотрудник лаборатории репарации и регенерации тканей Института регенеративной медицины

Москва, Россия

PhD., researcher at the laboratory of tissue repair and regeneration, Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University; 

Moscow, Russia

go.grigorievaolga@gmail.comhttps://orcid.org/0000-0002-0922-9157НовоселецкаяЕ. С.NovoseletskayaE. S.

лаборант-исследователь лаборатории репарации и регенерации тканей Института регенеративной медицины, аспирант кафедры биохимии и молекулярной медицины

Москва, Россия

PhD., researcher at the laboratory of tissue repair and regeneration, Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University; 

Moscow, Russia

kuznecova2793@mail.ruhttps://orcid.org/0000-0002-2597-8879БасаловаН. А.BasalovaN. A.

лаборант-исследователь лаборатории репарации и регенерации тканей Института регенеративной медицины, аспирант кафедры биохимии и молекулярной медицины

Москва, Россия

 

PhD., researcher at the laboratory of tissue repair and regeneration, Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University; 

Moscow, Russia

natalia_ba@mail.ruhttps://orcid.org/0000-0003-4946-7843АлександрушкинаН. А.AleksandrushkinaN. A.

лаборант-исследователь лаборатории генно-клеточной терапии Института регенеративной медицины, аспирант кафедры биохимии и молекулярной медицины

Москва, Россия

PhD., researcher at the laboratory of tissue repair and regeneration, Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University;

Moscow, Russia

n.alexandrushkina@gmail.comhttps://orcid.org/0000-0003-2103-8158ВиговскийМ. А.VigovskiyM. A.

лаборант-исследователь лаборатории репарации и регенерации тканей Института регенеративной медицины, аспирант кафедры биохимии и молекулярной медицины

Москва, Россия

PhD student of  Faculty of Fundamental Medicine; Moscow, Russia and researcher at the laboratory of tissue repair and regeneration, Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University; 

Moscow, Russia

vigovskiy_m.a@mail.ruhttps://orcid.org/0000-0002-0873-7387КирилловаК. И.KirillovaK. I.

научный сотрудник отдела лабораторной диагностики

Москва, Россия

MD, Researcher at Medical Laboratory Department, Medical Scientific and Educational Center of Lomonosov Moscow State University.

Moscow, Russia

dkkirillova@gmail.comhttps://orcid.org/0000-0002-3657-0676СтражескоИ. Д.StrazheskoI. D.

доктор медицинских наук, профессор, заместитель директора по трансляционной медицине

Москва, Россия

MD, PhD, Deputy Director of translational medicine, Russian Gerontology Research Center of Pirogov Russian National Research Medical University, Leading Researcher at the Department of Age-related diseases, Medical Scientific and Educational Center of Lomonosov Moscow State University.

Moscow, Russia

istrazhesko@gmail.comhttps://orcid.org/0000-0003-1290-0113ОрловА. В.OrlovA. V.

младший научный сотрудник лаборатории физиологии кардиореспираторной системы и баромедицины отдела физиологии и биомеханики кардиореспираторной системы

Москва, Россия

 

Researcher

Moscow, Russia

Orlovartem@mail.ruhttps://orcid.org/0000-0002-6694-2231БалацкийА. В.BalatskiyA. V.

кандидат медицинских наук, старший научный сотрудник отдела лабораторной диагностики

Москва, Россия

 Researcher  at Medical Laboratory Department, Medical Scientific and Educational Center of Lomonosov Moscow State University.

Moscow, Russia

balatsky@fbm.msu.ruhttps://orcid.org/0000-0001-6734-3989СамоходскаяЛ. М.SamokhodskayaL. М.

кандидат медицинских наук, доцент, заведующий отделом лабораторной диагностики, старший научный сотрудник Евразийского центра по продовольственной безопасности (Аграрный центр), доцент факультета

Москва, Россия

MD, PhD, Associate Professor, Head of Medical Laboratory Department, Medical Scientific and Educational Center of Lomonosov Moscow State University.

Moscow, Russia

slm61@mail.ruhttps://orcid.org/0000-0001-7848-6707ДаниловаН. В.DanilovaN. V.

кандидат медицинских наук, старший научный сотрудник отдела клинической патологии, ассистент кафедры физиологии и общей патологии

Москва, Россия

PhD, Senior Researcher at Clinical Pathology Department,  Medical Scientific and Educational Center of Lomonosov Moscow State University.

Moscow, Russia

natalyadanilova@gmail.comhttps://orcid.org/0000-0002-6119-8976ДьячковаУ. Д.DychkovaU. D.

студент

Москва, Россия

student of Faculty of Fundamental Medicine; Moscow, Russia and Laboratory of tissue repair and regeneration, Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University;

Moscow, Russia

dyachkovauliana@gmail.comhttps://orcid.org/0000-0002-2362-9798АкопянА. А.AkopyanA. A.

стажер по совместительству, отдел возраст-ассоциированных заболеваний

Москва, Россия

MD, Research intern at the Department of  Age-associated diseases, Medical Scientific and Educational Center of Lomonosov Moscow State University

Moscow, Russia

a.alexandrova18@gmail.comhttps://orcid.org/0000-0003-0352-2317КакоткинВ. В.KakotkinV. V.

аспирант кафедры общей и специализированной хирургии

Москва, Россия

MD,  Researcher at Surgical Dept, Medical Scientific and Educational Center of Lomonosov Moscow State University

Moscow, Russia

axtroz4894@gmail.comhttps://orcid.org/0000-0002-1975-9872АсратянД. А.AsratyanD. A.

кандидат медицинских наук, руководитель отделения

Москва, Россия

MD,

Moscow, Russia

d.asratyan@gmail.comhttps://orcid.org/0000-0002-0989-7825АкопянЖ. А.AkopyanZ. A.

кандидат медицинских наук, зам. директора, заведующий кафедрой клинического моделирования и мануальных навыков

Москва, Россия

MD,  PhD, Deputy Head for Research, Medical Scientific and Educational Center of Lomonosov Moscow State University

Moscow, Russia

zhanna.fbm@gmail.comhttps://orcid.org/0000-0002-8160-5612ОрловаЯ. А.OrlovaYa. A.

доктор медицинских наук, заведующий отделом возраст-ассоциированных заболеваний, заведующий кафедрой терапии

Москва, Россия

MD, PhD, Professor, Head of the Department of Age-associated diseases, Medical Scientific and Educational Center of Lomonosov Moscow State University.  Head of the Department of Therapy, Faculty of Basic Medicine

Moscow, Russia

5163002@bk.ruМедицинский научно-образовательный центр МГУ им. М.В.Ломоносова; Факультет фундаментальной медицины, МГУ имени М. В. ЛомоносоваРоссияMedical Research and Educational Center, Lomonosov Moscow State University; Faculty of Fundamental Medicine, Lomonosov Moscow State UniversityRussian FederationМедицинский научно-образовательный центр МГУ им. М.В.ЛомоносоваРоссияMedical Research and Educational Center, Lomonosov Moscow State UniversityRussian Federation«Российский геронтологический научно-клинический центр», ФГАОУ ВО «РНИМУ им. Н. И. Пирогова» Минздрава РФРоссияRussian Gerontology Research Center of Pirogov Russian National Research Medical UniversityRussian FederationГосударственный научный центр Российской Федерации, Институт медико-биологических проблем РАНРоссияInstitute of Biomedical Problems of the Russian Academy of SciencesRussian FederationФакультет фундаментальной медицины, МГУ имени М. В. ЛомоносоваРоссияFaculty of Fundamental Medicine, Lomonosov Moscow State UniversityRussian Federation2022300620226261522Copyright © Kardiomag, 20222022KardiomagKardiomaghttps://cardio.elpub.ru/jour/about/submissions#copyrightNoticehttps://cardio.elpub.ru/jour/article/view/2033

Цель    Изучить связь между жесткостью сосудистой стенки и известными маркерами накопления сенесцентных клеток в крови, клетках и тканях у пожилых пациентов.Материал и методы    В исследование включали пациентов мужского и женского пола в возрасте 65 лет и старше, направленных на плановое оперативное вмешательство, предполагающее проведение хирургического разреза в области передней брюшной стенки или крупных суставов, и отвечающих критериям включения и исключения. Всем пациентам проводилась оценка традиционных факторов риска сердечно-сосудистых заболеваний (ССЗ), жесткости артериальной стенки (по скорости пульсовой волны (СПВ)), а также во время оперативного вмешательства осуществлялся забор биоматериалов (периферическая кровь, кожа, подкожная жировая клетчатка), из которых затем выделяли несколько типов клеток и проводили гистологический анализ с целью оценки различных маркеров сенесцентных клеток.Результаты    В исследование было включено 80 пациентов в возрасте от 65 до 90 лет. С помощью корреляционного анализа выделены наиболее значимые показатели, отражающие накопление сенесцентных клеток на системном, тканевом и клеточном уровнях (r>0,3, при р<0,05), демонстрировавшие положительные и отрицательные корреляции с СПВ. В качестве изучаемых маркеров старения были отобраны следующие показатели в плазме крови: инсулиноподобный фактор роста 1 (IGF-1), фактор роста фибробластов 21 (FGF-21), молекула адгезии сосудистого эндотелия 1 (VCAM-1); при этом выявлена значимая отрицательная корреляционная связь между СПВ и уровнем IGF-1. Среди тканевых маркеров ожидаемо продемонстрировал положительную корреляционную связь ключевой маркер накопления сенесцентных клеток в тканях – P16INK: r=0,394 (p<0,05). Средней силы корреляция выявлена с параметрами прироста мезенхимных стромальных клеток и фибробластов за 96 часов, а также слабая корреляция с IL-6, как элементом SASP (специфический секреторный фенотип, ассоциированный со старением). Результаты многофакторного линейного регрессионного анализа показали, что маркер плазмы крови VCAM-1 и клеточный маркер прирост фибробластов за 96 ч связаны с СПВ независимо от возраста.Заключение    Жесткость магистральных артерий, измеренная с помощью СПВ, значимо связана с рядом плазменных, тканевых и клеточных маркеров накопления сенесцентных клеток. Этот факт позволяет рассматривать СПВ в качестве претендента на включение в панель параметров для оценки и мониторирования биологического возраста организма при проведении сенолитической терапии.

Aim    To study the association between vascular wall stiffness and known markers for accumulation of senescent cells in blood, cells, and tissues of old patients.Material and methods    This study included male and female patients aged 65 years and older who were referred to an elective surgical intervention, that included a surgical incision in the area of the anterior abdominal wall or large joints and met the inclusion and exclusion criteria. For all patients, traditional cardiovascular (CV) risk factors and arterial wall stiffness (pulse wave velocity, PWV) were evaluated. Also, biomaterials (peripheral blood, skin, subcutaneous adipose tissue) were collected during the surgery and were used for isolation of several cell types and subsequent histological analysis to determine various markers of senescent cells.Results    The study included 80 patients aged 65 to 90 years. The correlation analysis identified the most significant indexes that reflected the accumulation of senescent cells at the systemic, tissue, and cellular levels (r>0.3, р<0.05) and showed positive and negative correlations with PWV. The following blood plasma factors were selected as the markers of ageing: insulin-like growth factor 1 (IGF-1), fibroblast growth factor 21 (FGF-21), and vascular endothelium adhesion molecule 1 (VCAM-1). A significant negative correlation between PWV and IGF-1 concentration was found. Among the tissue markers, P16INK, the key marker for tissue accumulation of senescent cells, predictably showed a positive correlation (r=0.394, p<0.05). A medium-strength correlation with parameters of the 96-h increment of mesenchymal stromal cells and fibroblasts and a weak correlation with IL-6 as a SASP (specific senescent-associated secretory phenotype) were noted. Results of the multifactorial linear regression analysis showed that the blood plasma marker, VCAM-1, and the cell marker, 96-h increment of fibroblasts, were associated with PWV regardless of the patient’s age.Conclusion    Stiffness of great arteries as measured by PWV significantly correlates with a number of plasma, tissue, and cellular markers for accumulation of senescent cells. This fact suggests PWV as a candidate for inclusion in the panel of parameters for evaluation and monitoring of the biological age during the senolytic therapy.

 

Скорость пульсовой волнысенесцентные клеткистарениебиомаркер р16INK4aмезенхимальная стромальная клеткаинсулиноподобный фактор роста 1фактор роста фибробластов 21молекула адгезии сосудистого эндотелия 1Pulse wave velocitysenescent cellsageingbiomarker р16INK4amesenchymal stromal cellinsulin-like growth factor 1fibroblast growth factor 21vascular endothelium adhesion molecule 1Исследование выполнено в рамках Государственного задания МНОЦ МГУ имени М. В. Ломоносова и Междисциплинарной научно-образовательной школы «Молекулярные технологии живых систем и синтетическая биология» МГУ имени М. В. Ломоносова.No conflict of interest is reported.ReferencesSt Sauver JL, Boyd CM, Grossardt BR, Bobo WV, Finney Rutten LJ, Roger VL et al. Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity. BMJ Open. 2015;5(2):e006413. DOI: 10.1136/bmjopen-2014-006413St Sauver JL, Boyd CM, Grossardt BR, Bobo WV, Finney Rutten LJ, Roger VL et al. Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity. BMJ Open. 2015;5(2):e006413. DOI: 10.1136/bmjopen-2014-006413Kirkland JL. Translating the Science of Aging into Therapeutic Interventions. Cold Spring Harbor Perspectives in Medicine. 2016;6(3):a025908. DOI: 10.1101/cshperspect.a025908Kirkland JL. Translating the Science of Aging into Therapeutic Interventions. Cold Spring Harbor Perspectives in Medicine. 2016;6(3):a025908. DOI: 10.1101/cshperspect.a025908Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. Journal of Internal Medicine. 2020;288(5):518–36. DOI: 10.1111/joim.13141Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. Journal of Internal Medicine. 2020;288(5):518–36. DOI: 10.1111/joim.13141World Health Organization. A global brief of hypertension. Silent killer, global public health crisis: World Health Day 2013. 2013. [Av. at: https://www.who.int/publications/i/item/a-global-brief-on-hypertension-silent-killer-global-public-health-crisis-world-health-day-2013]World Health Organization. A global brief of hypertension. Silent killer, global public health crisis: World Health Day 2013. 2013. [Av. at: https://www.who.int/publications/i/item/a-global-brief-on-hypertension-silent-killer-global-public-health-crisis-world-health-day-2013]Özcan S, Alessio N, Acar MB, Mert E, Omerli F, Peluso G et al. Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging. 2016;8(7):1316–29. DOI: 10.18632/aging.100971Özcan S, Alessio N, Acar MB, Mert E, Omerli F, Peluso G et al. Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging. 2016;8(7):1316–29. DOI: 10.18632/aging.100971Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184–9. DOI: 10.1038/nature16932Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184–9. DOI: 10.1038/nature16932Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017;21:21–8. DOI: 10.1016/j.ebiom.2017.04.013Kirkland JL, Tchkonia T. Cellular Senescence: A Translational Perspective. EBioMedicine. 2017;21:21–8. DOI: 10.1016/j.ebiom.2017.04.013Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG et al. Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell. 2009;8(4):439–48. DOI: 10.1111/j.1474-9726.2009.00489.xLiu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG et al. Expression of p16INK4a in peripheral blood T-cells is a biomarker of human aging. Aging Cell. 2009;8(4):439–48. DOI: 10.1111/j.1474-9726.2009.00489.xSpazzafumo L, Mensà E, Matacchione G, Galeazzi T, Zampini L, Recchioni R et al. Age-related modulation of plasmatic beta-Galactosidase activity in healthy subjects and in patients affected by T2DM. Oncotarget. 2017;8(55):93338–48. DOI: 10.18632/oncotarget.21848Spazzafumo L, Mensà E, Matacchione G, Galeazzi T, Zampini L, Recchioni R et al. Age-related modulation of plasmatic beta-Galactosidase activity in healthy subjects and in patients affected by T2DM. Oncotarget. 2017;8(55):93338–48. DOI: 10.18632/oncotarget.21848Moslehi J, DePinho RA, Sahin E. Telomeres and Mitochondria in the Aging Heart. Circulation Research. 2012;110(9):1226–37. DOI: 10.1161/CIRCRESAHA.111.246868Moslehi J, DePinho RA, Sahin E. Telomeres and Mitochondria in the Aging Heart. Circulation Research. 2012;110(9):1226–37. DOI: 10.1161/CIRCRESAHA.111.246868Salminen A, Kaarniranta K, Kauppinen A. Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases. Inflammation Research. 2021;70(10–12):1043–61. DOI: 10.1007/s00011-021-01498-3Salminen A, Kaarniranta K, Kauppinen A. Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases. Inflammation Research. 2021;70(10–12):1043–61. DOI: 10.1007/s00011-021-01498-3Vitale G, Pellegrino G, Vollery M, Hofland LJ. ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights from a Centenarians’ Perspective. Frontiers in Endocrinology. 2019; 10:27. DOI: 10.3389/fendo.2019.00027Vitale G, Pellegrino G, Vollery M, Hofland LJ. ROLE of IGF-1 System in the Modulation of Longevity: Controversies and New Insights from a Centenarians’ Perspective. Frontiers in Endocrinology. 2019; 10:27. DOI: 10.3389/fendo.2019.00027Matjusaitis M, Chin G, Sarnoski EA, Stolzing A. Biomarkers to identify and isolate senescent cells. Ageing Research Reviews. 2016;29:1–12. DOI: 10.1016/j.arr.2016.05.003Matjusaitis M, Chin G, Sarnoski EA, Stolzing A. Biomarkers to identify and isolate senescent cells. Ageing Research Reviews. 2016;29:1–12. DOI: 10.1016/j.arr.2016.05.003Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes & Development. 2020;34(23–24):1565–76. DOI: 10.1101/gad.343129.120Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes & Development. 2020;34(23–24):1565–76. DOI: 10.1101/gad.343129.120Mikael L de R, Paiva AMG de, Gomes MM, Sousa ALL, Jardim PCBV, Vitorino PV de O et al. Vascular Aging and Arterial Stiffness. Arquivos Brasileiros de Cardiologia. 2017;109(3):253–8. DOI: 10.5935/abc.20170091Mikael L de R, Paiva AMG de, Gomes MM, Sousa ALL, Jardim PCBV, Vitorino PV de O et al. Vascular Aging and Arterial Stiffness. Arquivos Brasileiros de Cardiologia. 2017;109(3):253–8. DOI: 10.5935/abc.20170091Кобалава Ж.Д., Конради А.О., Недогода С.В., Шляхто Е.В., Арутюнов Г.П., Баранова Е.И. и др. Артериальная гипертензия у взрослых. Клинические рекомендации 2020. Российский кардиологический журнал. 2020;25(3):149-218. DOI: 10.15829/1560-4071-2020-3-3786Kobalava Zh.D., Konradi A.O., Nedogoda S.V., Shlyakhto E.V., Arutyunov G.P., Baranova E.I. et al. Arterial hypertension in adults. Clinical guidelines 2020. Russian Journal of Cardiology. 2020;25(3):149–218. DOI: 10.15829/1560-4071-2020-3-3786Vlachopoulos C, Terentes-Printzios D, Laurent S, Nilsson PM, Protogerou AD, Aznaouridis K et al. Association of Estimated Pulse Wave Velocity with Survival: A Secondary Analysis of SPRINT. JAMA Network Open. 2019;2(10):e1912831. DOI: 10.1001/jamanetworkopen.2019.12831Vlachopoulos C, Terentes-Printzios D, Laurent S, Nilsson PM, Protogerou AD, Aznaouridis K et al. Association of Estimated Pulse Wave Velocity with Survival: A Secondary Analysis of SPRINT. JAMA Network Open. 2019;2(10):e1912831. DOI: 10.1001/jamanetworkopen.2019.12831Ткаченко Ю.В., Стражеско И.Д., Борисов Е.Н., Плисюк А.Г., Орлова Я.А. Адаптация методики измерения скорости пульсовой волны для скрининговых обследований в амбулаторной практике. Клиническая практика. 2019;10(1):48–56. DOI: 10.17816/clinpract10148-56Tkachenko Yu.V., Strazhesko I.D., Borisov E.N., Plisiuk A.G., Orlova Ya.A. Adaptation of the method of pulse wave velocity measurement for screening examinations in outpatient practice. Journal of Clinical Practice. 2019;10(1):48–56. DOI: 10.17816/clinpract10148-56Сорокина А.Г., Орлова Я.А., Григорьева О.А., Новоселецкая Е.С., Басалова Н.А., Александрушкина Н.А. и др. Создание коллекции биологических образцов разного типа, полученных от пожилых пациентов, для изучения взаимосвязей клинических, системных, тканевых и клеточных биомаркеров накопления сенесцентных клеток при старении. Кардиоваскулярная терапия и профилактика. 2021;20(8):164-75. DOI: 10.15829/1728-8800-2021-3051Sorokina A.G., Orlova Ya.A., Grigorieva O.A., Novoseletskaya E.S., Basalova N.A., Alexandrushkina N.A. et al. Creation of a collection of different biological sample types from elderly patients to study the relationship of clinical, systemic, tissue and cellular biomarkers of accumulation of senescent cells during aging. Cardiovascular Therapy and Prevention. 2021;20(8):164–75. DOI: 10.15829/1728-8800-2021-3051Avolio AP, Kuznetsova T, Heyndrickx GR, Kerkhof PLM, Li JK-J. Arterial Flow, Pulse Pressure and Pulse Wave Velocity in Men and Women at Various Ages. Advances in Experimental Medicine and Biology. 2018;1065:153–68. DOI: 10.1007/978-3-319-77932-4_10Avolio AP, Kuznetsova T, Heyndrickx GR, Kerkhof PLM, Li JK-J. Arterial Flow, Pulse Pressure and Pulse Wave Velocity in Men and Women at Various Ages. Advances in Experimental Medicine and Biology. 2018;1065:153–68. DOI: 10.1007/978-3-319-77932-4_10Battistoni A, Michielon A, Marino G, Savoia C. Vascular Aging and Central Aortic Blood Pressure: From Pathophysiology to Treatment. High Blood Pressure & Cardiovascular Prevention. 2020;27(4):299–308. DOI: 10.1007/s40292-020-00395-wBattistoni A, Michielon A, Marino G, Savoia C. Vascular Aging and Central Aortic Blood Pressure: From Pathophysiology to Treatment. High Blood Pressure & Cardiovascular Prevention. 2020;27(4):299–308. DOI: 10.1007/s40292-020-00395-wJohnson SC. Nutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease. Subcell Biochemistry. 2018;90:49–97. DOI: 10.1007/978-981-13-2835-0_3Johnson SC. Nutrient Sensing, Signaling and Ageing: The Role of IGF-1 and mTOR in Ageing and Age-Related Disease. Subcell Biochemistry. 2018;90:49–97. DOI: 10.1007/978-981-13-2835-0_3Chisalita SI, Johansson GS, Liefvendahl E, Bäck K, Arnqvist HJ. Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2. Journal of Molecular Endocrinology. 2009;43(6):231–9. DOI: 10.1677/JME-09-0021Chisalita SI, Johansson GS, Liefvendahl E, Bäck K, Arnqvist HJ. Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2. Journal of Molecular Endocrinology. 2009;43(6):231–9. DOI: 10.1677/JME-09-0021Planavila A, Redondo-Angulo I, Villarroya F. FGF21 and Cardiac Physiopathology. Frontiers in Endocrinology. 2015;6:133. DOI: 10.3389/fendo.2015.00133Planavila A, Redondo-Angulo I, Villarroya F. FGF21 and Cardiac Physiopathology. Frontiers in Endocrinology. 2015;6:133. DOI: 10.3389/fendo.2015.00133Planavila A, Redondo-Angulo I, Ribas F, Garrabou G, Casademont J, Giralt M et al. Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovascular Research. 2015;106(1):19–31. DOI: 10.1093/cvr/cvu263Planavila A, Redondo-Angulo I, Ribas F, Garrabou G, Casademont J, Giralt M et al. Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovascular Research. 2015;106(1):19–31. DOI: 10.1093/cvr/cvu263Joki Y, Ohashi K, Yuasa D, Shibata R, Ito M, Matsuo K et al. FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochemical and Biophysical Research Communications. 2015;459(1):124–30. DOI: 10.1016/j.bbrc.2015.02.081Joki Y, Ohashi K, Yuasa D, Shibata R, Ito M, Matsuo K et al. FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism. Biochemical and Biophysical Research Communications. 2015;459(1):124–30. DOI: 10.1016/j.bbrc.2015.02.081Rupérez C, Lerin C, Ferrer-Curriu G, Cairo M, Mas-Stachurska A, Sitges M et al. Autophagic control of cardiac steatosis through FGF21 in obesity-associated cardiomyopathy. International Journal of Cardiology. 2018;260:163–70. DOI: 10.1016/j.ijcard.2018.02.109Rupérez C, Lerin C, Ferrer-Curriu G, Cairo M, Mas-Stachurska A, Sitges M et al. Autophagic control of cardiac steatosis through FGF21 in obesity-associated cardiomyopathy. International Journal of Cardiology. 2018;260:163–70. DOI: 10.1016/j.ijcard.2018.02.109Cardoso AL, Fernandes A, Aguilar-Pimentel JA, de Angelis MH, Guedes JR, Brito MA et al. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases. Ageing Research Reviews. 2018;47:214–77. DOI: 10.1016/j.arr.2018.07.004Cardoso AL, Fernandes A, Aguilar-Pimentel JA, de Angelis MH, Guedes JR, Brito MA et al. Towards frailty biomarkers: Candidates from genes and pathways regulated in aging and age-related diseases. Ageing Research Reviews. 2018;47:214–77. DOI: 10.1016/j.arr.2018.07.004Tezze C, Romanello V, Sandri M. FGF21 as Modulator of Metabolism in Health and Disease. Frontiers in Physiology. 2019;10:419. DOI: 10.3389/fphys.2019.00419Tezze C, Romanello V, Sandri M. FGF21 as Modulator of Metabolism in Health and Disease. Frontiers in Physiology. 2019;10:419. DOI: 10.3389/fphys.2019.00419Chen W, Tian B, Liang J, Yu S, Zhou Y, Li S. Matrix stiffness regulates the interactions between endothelial cells and monocytes. Biomaterials. 2019;221:119362. DOI: 10.1016/j.biomaterials.2019.119362Chen W, Tian B, Liang J, Yu S, Zhou Y, Li S. Matrix stiffness regulates the interactions between endothelial cells and monocytes. Biomaterials. 2019;221:119362. DOI: 10.1016/j.biomaterials.2019.119362Srivastava P, Badhwar S, Chandran DS, Jaryal AK, Jyotsna VP, Deepak KK. Imbalance between Angiotensin II - Angiotensin (1- 7) system is associated with vascular endothelial dysfunction and inflammation in type 2 diabetes with newly diagnosed hypertension. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2019;13(3):2061–8. DOI: 10.1016/j.dsx.2019.04.042Srivastava P, Badhwar S, Chandran DS, Jaryal AK, Jyotsna VP, Deepak KK. Imbalance between Angiotensin II - Angiotensin (1- 7) system is associated with vascular endothelial dysfunction and inflammation in type 2 diabetes with newly diagnosed hypertension. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2019;13(3):2061–8. DOI: 10.1016/j.dsx.2019.04.042Stanifer JW, Landerman L, Pieper CF, Huffman KM, Kraus WE. Relations of established aging biomarkers (IL-6, D-dimer, s-VCAM) to glomerular filtration rate and mortality in community-dwelling elderly adults. Clinical Kidney Journal. 2018;11(3):377–82. DOI:10.1093/ckj/sfx097Stanifer JW, Landerman L, Pieper CF, Huffman KM, Kraus WE. Relations of established aging biomarkers (IL-6, D-dimer, s-VCAM) to glomerular filtration rate and mortality in community-dwelling elderly adults. Clinical Kidney Journal. 2018;11(3):377–82. DOI:10.1093/ckj/sfx097Villarroya J, Gallego-Escuredo JM, Delgado-Anglés A, Cairó M, Moure R, Gracia Mateo M et al. Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue. Aging Cell. 2018;17(5):e12822. DOI: 10.1111/acel.12822Villarroya J, Gallego-Escuredo JM, Delgado-Anglés A, Cairó M, Moure R, Gracia Mateo M et al. Aging is associated with increased FGF21 levels but unaltered FGF21 responsiveness in adipose tissue. Aging Cell. 2018;17(5):e12822. DOI: 10.1111/acel.12822Richter V, Rassoul F, Purschwitz K, Hentschel B, Reuter W, Kuntze T. Circulating Vascular Cell Adhesion Molecules VCAM-1, ICAM-1 and E-Selectin in Dependence on Aging. Gerontology. 2003;49(5):293–300. DOI: 10.1159/000071710Richter V, Rassoul F, Purschwitz K, Hentschel B, Reuter W, Kuntze T. Circulating Vascular Cell Adhesion Molecules VCAM-1, ICAM-1 and E-Selectin in Dependence on Aging. Gerontology. 2003;49(5):293–300. DOI: 10.1159/000071710Jia G, Aroor AR, Jia C, Sowers JR. Endothelial cell senescence in aging-related vascular dysfunction. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2019;1865(7):1802–9. DOI: 10.1016/j.bbadis.2018.08.008Jia G, Aroor AR, Jia C, Sowers JR. Endothelial cell senescence in aging-related vascular dysfunction. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2019;1865(7):1802–9. DOI: 10.1016/j.bbadis.2018.08.008Shimizu I, Minamino T. Cellular senescence in cardiac diseases. Journal of Cardiology. 2019;74(4):313–9. DOI: 10.1016/j.jjcc.2019.05.002Shimizu I, Minamino T. Cellular senescence in cardiac diseases. Journal of Cardiology. 2019;74(4):313–9. DOI: 10.1016/j.jjcc.2019.05.002Bruder SP, Jaiswal N, Haynesworth SE. Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. Journal of Cellular Biochemistry. 1997;64(2):278–94. DOI: 10.1002/(SICI)1097-4644(199702)64:2<278::AID-JCB11>3.0.CO;2-FBruder SP, Jaiswal N, Haynesworth SE. Growth kinetics, self-renewal, and the osteogenic potential of purified human mesenchymal stem cells during extensive subcultivation and following cryopreservation. Journal of Cellular Biochemistry. 1997;64(2):278–94. DOI: 10.1002/(SICI)1097-4644(199702)64:2<278::AID-JCB11>3.0.CO;2-FDodig S, Čepelak I, Pavić I. Hallmarks of senescence and aging. Biochemia medica. 2019;29(3):483–97. DOI: 10.11613/BM.2019.030501Dodig S, Čepelak I, Pavić I. Hallmarks of senescence and aging. Biochemia medica. 2019;29(3):483–97. DOI: 10.11613/BM.2019.030501

The authors declare that there are no conflicts of interest present.