perinatologyРоссийский вестник перинатологии и педиатрииRossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics)1027-40652500-2228Ltd. “The National Academy of Pediatric Science and Innovation”10.21508/1027-4065-2019-64-4-11-18perinatology-922Research ArticleОБЗОР ЛИТЕРАТУРЫREVIEWSБиомаркеры раннего сердечно-сосудистого старенияBiomarkers of early cardiovascular aginghttps://orcid.org/0000-0002-7511-3240ГрозноваО. С.GroznovaO. S.

д.м.н., вед. науч. сотр. отдела детской кардиологии и аритмологии,

Москва

Moscow

ogroznova@gmail.comhttps://orcid.org/0000-0001-8635-6216МиклашевичИ. М.MiklashevichI. M.

к.м.н., зав. детским кардиологическим отделением,

Москва

Moscow

https://orcid.org/0000-0001-8491-0228ВоиноваВ. Ю.VoinovaV. Yu.

д.м.н., гл. науч. сотр. отдела клинической генетики,

Москва

Moscow

https://orcid.org/0000-0001-7115-0186ШкольниковаМ. А.ShkolnikovaM. A.

д.м.н., проф., науч. рук.,

Москва

Moscow

ТкачеваО. Н.TkachevaO. N.

д.м.н., проф., директор, 

Москва

Moscow

ДудинскаяЕ. Н.DudinskayaE. N.

к.м.н., зав. лабораторией возрастных метаболических эндокринных нарушений,

129226, Москва, 1-ая Леонова ул., д. 16

Moscow

https://orcid.org/0000-0001-8491-0228КовалевИ. А.KovalevI. A.

д.м.н., проф., зав. отделом детской кардиологии и аритмологии,

125412 г. Москва, Талдомская ул., д. 2

Moscow

ОСП «Научно-исследовательский клинический институт педиатрии им. академика Ю.Е. Вельтищева» ФГБОУ ВО РНИМУ им. Н.И. Пирогова Минздрава РоссииРоссияVeltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical UniversityRussian FederationОСП «Российский геронтологический научно-клинический центр» ФГБОУ ВО РНИМУ им. Н.И. Пирогова Минздрава РоссииРоссияRussian Clinical and Research Center of Gerontology of the Pirogov Russian National Research Medical UniversityRussian Federation2019120920196441118Copyright © Ltd. “The National Academy of Pediatric Science and Innovation”, 20192019Ltd. “The National Academy of Pediatric Science and Innovation”Ltd. “The National Academy of Pediatric Science and Innovation”https://www.ped-perinatology.ru/jour/about/submissions#copyrightNoticehttps://www.ped-perinatology.ru/jour/article/view/922

Интенсивность и скорость старения организма (если не рассматривать токсические воздействия) в наибольшей мере регулируются генетическими аспектами, негативная роль которых зависит от  патогенности мутации. При  легком варианте генетического «дефекта» отсутствуют клинические признаки, по которым можно бы было причислить индивидуума к числу лиц с определенным известным генетическим синдромом, но выявляются биохимические, иммунологические, сосудистые и прочие аномалии, предрасполагающие к патологическому старению. В самом тяжелом случае, например при прогерии, патологическое старение – основной фенотипический признак, проявляющймся уже в детском возрасте. Весь спектр промежуточных состояний и составляет предмет исследования при патологическом старении. В обзоре наибольшее внимание уделено старению у лиц, не имеющих валидизируемых признаков заболеваний: ишемической болезни сердца, артериальной гипертензии, сахарного диабета или  гипергликемии натощак, гиперлипидемии и  прочих; представлены основные направления поиска биомаркеров старения (размер и  скорость укорочения теломер, разрывы их концевых петель; экспрессия белков воспаления, белков синаптических взаимодействий и  нейротрофических процессов; биогенез митохондрий; дисфункция эндотелия; активность метилирования ДНК).

Genetic aspects regulate the intensity and rate of aging (no toxic effects considered), their negative role depends on the pathogenicity of the mutation. The light variant of the genetic “defect” has no clinical signs which feature a certain known genetic syndrome, but it has the biochemical, immunological, vascular and other abnormalities leading to pathological aging. In the most severe case, e.g. progeria, pathological aging is the main phenotypic symptom that manifests already in childhood. The subject of the pathological aging research covers the whole range of intermediate states. The review focuses on aging in individuals without validated signs of disease: coronary heart disease, hypertension, diabetes or fasting hyperglycemia, hyperlipidemia, and others. The authors present the main searching directions of aging biomarkers (size and speed of telomere shortening, breaks in their terminal loops; expression of inflammatory proteins, synaptic interactions proteins and neurotrophic processes; mitochondrial biogenesis; endothelial dysfunction; DNA methylation activity).

детисердечно-сосудистое старениебиомаркеры старениядисфункция эндотелияchildrencardiovascular agingaging biomarkersendothelial dysfunctionReferencesWang C., Oshima M., Sashida G., Tomioka T., Hasegawa N., Mochizuki-Kashio M. et al. Non-Lethal Ionizing Radiation Promotes Aging-Like Phenotypic Changes of Human Hematopoietic Stem and Progenitor Cells in Humanized Mice. PLoS One 2015; 10(7): e0132041. DOI: 10.1371/journal.pone.0132041Wang C., Oshima M., Sashida G., Tomioka T., Hasegawa N., Mochizuki-Kashio M. et al. Non-Lethal Ionizing Radiation Promotes Aging-Like Phenotypic Changes of Human Hematopoietic Stem and Progenitor Cells in Humanized Mice. PLoS One 2015; 10(7): e0132041. DOI: 10.1371/journal.pone.0132041Кругликова А.С., Стражеско И.Д., Ткачева О.Н., Акашева Д.У., Плохова Е.В., Пыхтина В.С. и др. Взаимосвязь факторов сердечно-сосудистого риска и биологии теломер с признаками сосудистого старения. Кардиоваскулярная терапия и профилактика 2014; 13(3): 11–17.Kruglikova A.S., Strajesko I.D., Tkacheva O.N., Akasheva D.U., Plokhova E.V., Pykhtina V.S. et al. Interrelation between cardiovascular risk factors and telomere biology with the signs of vascular aging. Kardiovaskulyarnaya terapiya i profilaktika (Cardiovascular Therapy and Prevention) 2014; 13(3): 11–17. (in Russ.).Василенко Н.Ю. Социальная геронтология. Владивосток: Изд-во Дальневост. ун-та 2003; 140.Vasylenko N.Yu. Social gerontology. Vladivostok: Publishing house of the Far East University 2003; 140. (in Russ.).Гичев Ю.П. Экологическая обусловленность преждевременного старения и сокращения продолжительности жизни населения России. Гигиена и санитария 2002; 6: 48–51.Gichev Yu.P. Environmental conditionality of premature growth and shortening of the life expectancy of the population of Russia. Gigiyena i sanitariya (Hygiene and sanitation) 2002; 6: 48–51. (in Russ.).Тодоров И.Н., Тодоров Г.И. Стресс, старение и их биохимическая коррекция. М.: Наука, 2003; 479.Todorov I.N., Todorov G.I. Stress, aging and their biochemical correction. Moscow: Nauka, 2003; 479. (in Russ.).Кобалава Ж.Д., Котовская Ю.В., Семагина И.М. Маркеры сердечно-сосудистого старения: эффекты многокомпонентной терапии. Клиническая фармакология и терапия 2016; 25(3): 46–52.Kobalava Zh.D., Kotovskaya Yu.V., Semagina I.M. Markers of cardiovascular aging: effects of multicomponent therapy. Klinicheskaya farmakologiya i terapiya (Clinical Pharmacology and Therapy) 2016; 25(3): 46–52. (in Russ.).Пристром М.С., Пристром С.Л., Семененков И.И. Старение физиологическое и преждевременное. Современный взгляд на проблему. Медицинские новости 2015; 2(245): 36–45.Pristrom M.S., Pristrom S.L., Semenenkov I.I. Physiological and early aging. Modern view of the problem. Meditsinskie novosti 2015; 2(245): 36–45. (in Russ.).Хаммад Е.В., Медзиновский Ю.Ф., Плотникова А.А. Современный взгляд на молекулярные биомаркеры старения, определяемые в крови. Современные проблемы науки и образования 2017; 5: 97.Hammad E.V., Medzinovskiy Yu.F., Plotnikova A.A. Modern view on molecular biomarkers of aging identified in the blood. Sovremennye problemy nauki i obrazovaniya 2017; 5: 97. (in Russ.).Москалев А.А. Молекулярные биомаркеры старения для превентивной медицины. Вестник восстановительной медицины 2017; 1(77): 18–29.Moskalev A.A. Molecular biomarkers of aging for preventive medicine. Vestnik vosstanovitel’noj mediciny (Journal of Restorative Medicine & Rehabilitation) 2017; 1(77): 18–29. (in Russ.).Frenzel M., Ricoul M., Benadjaoud M.A., Bellamy M., Lenain A., Haddy N. et al. Retrospective cohort study and biobanking of patients treated for hemangioma in childhood – telomeres as biomarker of aging and radiation exposure. Int J Radiat Biol 2017; 93(10): 1040–1053. DOI: 10.1080/09553002.2017.1337278Frenzel M., Ricoul M., Benadjaoud M.A., Bellamy M., Lenain A., Haddy N. et al. Retrospective cohort study and biobanking of patients treated for hemangioma in childhood – telomeres as biomarker of aging and radiation exposure. Int J Radiat Biol 2017; 93(10): 1040–1053. DOI: 10.1080/09553002.2017.1337278Skilton M.R., Nakhla S., Ayer J.G., Harmer J.A., Toelle B.G., Leeder S.R. et al. Telomere length in early childhood: Early life risk factors and association with carotid intima–media thickness in later childhood. Eur J Prev Cardiol 2016; 23(10): 1086–92. DOI: 10.1177/2047487315607075Skilton M.R., Nakhla S., Ayer J.G., Harmer J.A., Toelle B.G., Leeder S.R. et al. Telomere length in early childhood: Early life risk factors and association with carotid intima–media thickness in later childhood. Eur J Prev Cardiol 2016; 23(10): 1086–92. DOI: 10.1177/2047487315607075Gruszecka A., Kopczyński P., Cudziło D., Lipińska N., Romaniuk A., Barczak W. et al. Telomere shortening in Down syndrome patients--when does it start? DNA Cell Biol 2015; 34(6): 412–417. DOI: 10.1089/dna.2014Gruszecka A., Kopczyński P., Cudziło D., Lipińska N., Romaniuk A., Barczak W. et al. Telomere shortening in Down syndrome patients--when does it start? DNA Cell Biol 2015; 34(6): 412–417. DOI: 10.1089/dna.2014Morgan R.G., Donato A.J., Walker A.E. Telomere uncapping and vascular aging. Am J Physiol Heart Circ Physiol 2018; 315(1): H1–H5. DOI: 10.1152/ajpheart.00008.2018Morgan R.G., Donato A.J., Walker A.E. Telomere uncapping and vascular aging. Am J Physiol Heart Circ Physiol 2018; 315(1): H1–H5. DOI: 10.1152/ajpheart.00008.2018Rotar O., Moguchaia E., Boyarinova M., Kolesova E., Khromova N., Freylikhman O. et al. Seventy years after the siege of Leningrad: does early life famine still affect cardiovascular risk and aging? J Hypertens 2015; 33(9): 1772–1779; discussion 1779. DOI: 10.1097/HJH.0000000000000640Rotar O., Moguchaia E., Boyarinova M., Kolesova E., Khromova N., Freylikhman O. et al. Seventy years after the siege of Leningrad: does early life famine still affect cardiovascular risk and aging? J Hypertens 2015; 33(9): 1772–1779; discussion 1779. DOI: 10.1097/HJH.0000000000000640Tyrka A.R., Parade S.H., Price L.H., Kao H.T., Porton B., Philip N.S. et al. Alterations of Mitochondrial DNA Copy Number and Telomere Length With Early Adversity and Psychopathology. Biol Psychiatry 2016; 79(2): 78–86. DOI: 10.1016/j.biopsych.2014.12.025Tyrka A.R., Parade S.H., Price L.H., Kao H.T., Porton B., Philip N.S. et al. Alterations of Mitochondrial DNA Copy Number and Telomere Length With Early Adversity and Psychopathology. Biol Psychiatry 2016; 79(2): 78–86. DOI: 10.1016/j.biopsych.2014.12.025Carrillo J., Calvete O., Pintado-Berninches L., Manguan-García C., Sevilla Navarro J., Arias-Salgado E.G. et al. Mutations in XLF/NHEJ1/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening. Hum Mol Genet 2017; 26(10): 1900–1914. DOI: 10.1093/hmg/ddx098Carrillo J., Calvete O., Pintado-Berninches L., Manguan-García C., Sevilla Navarro J., Arias-Salgado E.G. et al. Mutations in XLF/NHEJ1/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening. Hum Mol Genet 2017; 26(10): 1900–1914. DOI: 10.1093/hmg/ddx098Oja S., Komulainen P., Penttilä A., Nystedt J., Korhonen M. Automated image analysis detects aging in clinical-grade mesenchymal stromal cell cultures. Stem Cell Res Ther 2018; 9(1): 6. DOI: 10.1186/s13287-017-0740-xOja S., Komulainen P., Penttilä A., Nystedt J., Korhonen M. Automated image analysis detects aging in clinical-grade mesenchymal stromal cell cultures. Stem Cell Res Ther 2018; 9(1): 6. DOI: 10.1186/s13287-017-0740-xCasciaro M., Di Salvo E., Pace E., Ventura-Spagnolo E., Navarra M., Gangemi S. Chlorinative stress in age-related diseases: a literature review. Immun Ageing 2017; 14: 21. DOI: 10.1186/s12979-017-0104-5Casciaro M., Di Salvo E., Pace E., Ventura-Spagnolo E., Navarra M., Gangemi S. Chlorinative stress in age-related diseases: a literature review. Immun Ageing 2017; 14: 21. DOI: 10.1186/s12979-017-0104-5Calabrese V., Dattilo S., Petralia A., Parenti R., Pennisi M., Koverech G. et al. Analytical approaches to the diagnosis and treatment of aging and aging-related disease: redox status and proteomics. Free Radic Res 2015; 49(5): 511–524. DOI: 10.3109/10715762.2015.1020799Calabrese V., Dattilo S., Petralia A., Parenti R., Pennisi M., Koverech G. et al. Analytical approaches to the diagnosis and treatment of aging and aging-related disease: redox status and proteomics. Free Radic Res 2015; 49(5): 511–524. DOI: 10.3109/10715762.2015.1020799Primiani C.T., Ryan V.H., Rao J.S., Cam M.C., Ahn K., Modi H.R., Rapoport S.I. Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging. PLoS One 2014; 9(10): e110972. DOI: 10.1371/journal.pone.0110972Primiani C.T., Ryan V.H., Rao J.S., Cam M.C., Ahn K., Modi H.R., Rapoport S.I. Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging. PLoS One 2014; 9(10): e110972. DOI: 10.1371/journal.pone.0110972Zheng Y., Rao Y.Q., Li J.K., Huang Y., Zhao P., Li J. Agerelated pro-inflammatory and pro-angiogenic changes in human aqueous humor. Int J Ophthalmol 2018; 11(2): 196–200. DOI: 10.18240/ijo.2018.02.03Zheng Y., Rao Y.Q., Li J.K., Huang Y., Zhao P., Li J. Agerelated pro-inflammatory and pro-angiogenic changes in human aqueous humor. Int J Ophthalmol 2018; 11(2): 196–200. DOI: 10.18240/ijo.2018.02.03Minciullo P.L., Catalano A., Mandraffino G., Casciaro M., Crucitti A., Maltese G. et al. Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity. Arch Immunol Ther Exp (Warsz) 2016; 64(2): 111–126. DOI: 10.1007/s00005-015-0377-3Minciullo P.L., Catalano A., Mandraffino G., Casciaro M., Crucitti A., Maltese G. et al. Inflammaging and Anti-Inflammaging: The Role of Cytokines in Extreme Longevity. Arch Immunol Ther Exp (Warsz) 2016; 64(2): 111–126. DOI: 10.1007/s00005-015-0377-3Marosi K., Bori Z., Hart N., Sárga L., Koltai E., Radák Z., Nyakas C. Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience 2012; 226: 21–28. DOI: 10.1016/j.neuroscience.2012.09.001Marosi K., Bori Z., Hart N., Sárga L., Koltai E., Radák Z., Nyakas C. Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats. Neuroscience 2012; 226: 21–28. DOI: 10.1016/j.neuroscience.2012.09.001Villa F., Carrizzo A., Spinelli C.C., Ferrario A., Malovini A., Maci g A. et al. Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis. Circ Res 2015; 117(4): 333–345. DOI: 10.1161/CIRCRESAHA.117.305875Villa F., Carrizzo A., Spinelli C.C., Ferrario A., Malovini A., Maci g A. et al. Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis. Circ Res 2015; 117(4): 333–345. DOI: 10.1161/CIRCRESAHA.117.305875Balbi M., Ghosh M., Longden T.A., Jativa Vega M., Gesierich B., Hellal F. et al. Dysfunction of mouse cerebral arteries during early aging. J Cereb Blood Flow Metab 2015; 35(9): 1445–1453. DOI: 10.1038/jcbfm.2015.107Balbi M., Ghosh M., Longden T.A., Jativa Vega M., Gesierich B., Hellal F. et al. Dysfunction of mouse cerebral arteries during early aging. J Cereb Blood Flow Metab 2015; 35(9): 1445–1453. DOI: 10.1038/jcbfm.2015.107Ross M.D., Malone E.M., Simpson R., Cranston I., Ingram L., Wright G.P. et al. Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men. Am J Physiol Heart Circ Physiol 2018; 314(3): H392– H402. DOI: 10.1152/ajpheart.00592.2017Ross M.D., Malone E.M., Simpson R., Cranston I., Ingram L., Wright G.P. et al. Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men. Am J Physiol Heart Circ Physiol 2018; 314(3): H392– H402. DOI: 10.1152/ajpheart.00592.2017Sohn E.H., Flamme-Wiese M.J., Whitmore S.S., Wang K., Tucker B.A., Mullins R.F. Loss of CD34 expression in aging human choriocapillaris endothelial cells. PLoS One 2014; 9(1): e86538. DOI: 10.1371/journal.pone.0086538Sohn E.H., Flamme-Wiese M.J., Whitmore S.S., Wang K., Tucker B.A., Mullins R.F. Loss of CD34 expression in aging human choriocapillaris endothelial cells. PLoS One 2014; 9(1): e86538. DOI: 10.1371/journal.pone.0086538Picca A., Lezza A.M.S., Leeuwenburgh C., Pesce V., Calvani R., Bossola M. et al. Circulating Mitochondrial DNA at the Crossroads of Mitochondrial Dysfunction and Inflammation During Aging and Muscle Wasting Disorders. Rejuvenation Res 2018; 21(4): 351–359. DOI: 10.1089/rej.2017.1989Picca A., Lezza A.M.S., Leeuwenburgh C., Pesce V., Calvani R., Bossola M. et al. Circulating Mitochondrial DNA at the Crossroads of Mitochondrial Dysfunction and Inflammation During Aging and Muscle Wasting Disorders. Rejuvenation Res 2018; 21(4): 351–359. DOI: 10.1089/rej.2017.1989Gonzales-Ebsen A.C., Gregersen N., Olsen R.K. Linking telomere loss and mitochondrial dysfunction in chronic disease. Front Biosci (Landmark Ed) 2017; 22: 117–127.Gonzales-Ebsen A.C., Gregersen N., Olsen R.K. Linking telomere loss and mitochondrial dysfunction in chronic disease. Front Biosci (Landmark Ed) 2017; 22: 117–127.Khalifa A.R., Abdel-Rahman E.A., Mahmoud A.M., Ali M.H., Noureldin M., Saber S.H. et al. Sex-specific differences in mitochondria biogenesis, morphology, respiratory function, and ROS homeostasis in young mouse heart and brain. Physiol Rep 2017; 5(6): pii: e13125. DOI: 10.14814/phy2.13125Khalifa A.R., Abdel-Rahman E.A., Mahmoud A.M., Ali M.H., Noureldin M., Saber S.H. et al. Sex-specific differences in mitochondria biogenesis, morphology, respiratory function, and ROS homeostasis in young mouse heart and brain. Physiol Rep 2017; 5(6): pii: e13125. DOI: 10.14814/phy2.13125Joseph A.M., Nguyen L.M., Welter A.E., Dominguez J.M. 2nd, Behnke B.J., Adhihetty P.J. Mitochondrial adaptations evoked with exercise are associated with a reduction in age-induced testicular atrophy in Fischer-344 rats. Biogerontology 2014; 15(5): 517–534. DOI: 10.1007/s10522-014-9526-zJoseph A.M., Nguyen L.M., Welter A.E., Dominguez J.M. 2nd, Behnke B.J., Adhihetty P.J. Mitochondrial adaptations evoked with exercise are associated with a reduction in age-induced testicular atrophy in Fischer-344 rats. Biogerontology 2014; 15(5): 517–534. DOI: 10.1007/s10522-014-9526-zValero T., Moschopoulou G., Mayor-Lopez L., Kintzios S. Moderate superoxide production is an early promoter of mitochondrial biogenesis in differentiating N2a neuroblastoma cells. Neurochem Int 2012; 61(8): 1333–1343. DOI: 10.1016/j.neuint.2012.09.010Valero T., Moschopoulou G., Mayor-Lopez L., Kintzios S. Moderate superoxide production is an early promoter of mitochondrial biogenesis in differentiating N2a neuroblastoma cells. Neurochem Int 2012; 61(8): 1333–1343. DOI: 10.1016/j.neuint.2012.09.010Horvath S., Zhang Y., Langfelder P., Kahn R.S,. Boks M.P., van Eijk K. et al. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol 2012; 13(10): R97. DOI: 10.1186/gb-2012-13-10-r97Horvath S., Zhang Y., Langfelder P., Kahn R.S,. Boks M.P., van Eijk K. et al. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol 2012; 13(10): R97. DOI: 10.1186/gb-2012-13-10-r97Voskoboeva E., Semyachkina A., Yablonskaya M., Nikolaeva E. Homocystinuria due to cystathionine beta-synthase (CBS) deficiency in Russia: Molecular and clinical characterization. Molecular Genetics and Metabolism Reports 2018; 14: 47–54.Voskoboeva E., Semyachkina A., Yablonskaya M., Nikolaeva E. Homocystinuria due to cystathionine beta-synthase (CBS) deficiency in Russia: Molecular and clinical characterization. Molecular Genetics and Metabolism Reports 2018; 14: 47–54.Burla R, La Torre M, Merigliano C, Vernì F, Saggio I. Genomic instability and DNA replication defects in progeroid syndromes. Nucleus 2018; 23: 1–12. DOI: 10.1080/19491034.2018.1476793Burla R, La Torre M, Merigliano C, Vernì F, Saggio I. Genomic instability and DNA replication defects in progeroid syndromes. Nucleus 2018; 23: 1–12. DOI: 10.1080/19491034.2018.1476793

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