Инфламэйджинг (inflamaging): роль и значение в патогенезе заболеваний женской репродуктивной системы

DOI: https://doi.org/10.29296/24999490-2023-01-04

А.А. Штейман(3), Ю.С. Крылова(1, 2), М.А. Дохов(2, 4),
Т.С. Зубарева(2), Д.О. Леонтьева(2), А.В. Ботина(1), А.А. Тихомирова(4)
1-ФГБОУ ВО «Первый Санкт-Петербургский государственный
медицинский университет им. акад. И.П. Павлова» МЗ РФ,
Российская Федерация, 197022, Санкт-Петербург, ул. Льва Толстого, д. 6–8;
2-ФГБУ «Санкт-Петербургский научно-исследовательский
институт фтизиопульмонологии» МЗ РФ,
Российская Федерация, 191036, Санкт-Петербург, Лиговский пр., д. 2–4;
3-Санкт-Петербургский институт биорегуляции и геронтологии,
Российская Федеpация, 197110, Санкт-Петербург, пр. Динамо, д. 3;
4-ФГБОУ ВО «Санкт-Петербургский государственный
педиатрический медицинский университет» МЗ РФ,
Российская Федерация, 194100, Санкт-Петербург, ул. Литовская, 2

Актуальность. Обзор посвящен взаимосвязи молекулярных процессов старения с патологией репродуктивной системы Целью исследования было рассмотреть современные представления о старении, механизмы инфламейджинга и его роль в патологии таких заболеваний как эндометриоз, преждевременное истощение яичников и определить потенциальные мишени лечебного воздействия. Материал и методы: проведен анализ и систематизация литературы за последние 5 лет в базах данных PubMed, Scopus и Google Scholar. Результаты. В обзоре отражены основные механизмы, участвующие в старении репродуктивной системы, воздействие на которые как медикаментозными средствами, так и модификацией образа жизни и питания, позволит снизить число побочных эффектов при применении основного, гормонального, лечения.
Ключевые слова: 
старение, эндометриоз, репродуктивная система, таргетная терапия
Для цитирования: 
Штейман А.А., Крылова Ю.С., Дохов М.А., Зубарева Т.С., Леонтьева Д.О., Ботина А.В., Тихомирова А.А. Инфламэйджинг (inflamaging): роль и значение в патогенезе заболеваний женской репродуктивной системы. Молекулярная медицина, 2023; (1): 30-36https://doi.org/10.29296/24999490-2023-01-04
Список литературы: 
  1. Birch J., Gil J. Senescence and the SASP: many therapeutic avenues. Genes Dev. 2020; 34 (23–24): 1565–76. DOI: 10.1101/gad.343129.120.
  2. Gorgoulis V., Adams P.D., Alimonti A., Bennett D.C., Bischof O., Bishop C., Campisi J., Collado M., Evangelou K., Ferbeyre G., Gil J., Hara E., Krizhanovsky V., Jurk D., Maier A.B., Narita M., Niedernhofer L., Passos J.F., Robbins P.D., Schmitt C.A., Sedivy J., Vougas K., von Zglinicki T., Zhou D., Serrano M., Demaria M. Cellular Senescence: Defining a Path Forward. Cell. 2019; 179 (4): 813–27. DOI: 10.1016/j.cell.2019.10.005.
  3. McHugh D., Gil J. Senescence and aging: Causes, consequences, and therapeutic avenues. J. Cell. Biol. 2018; 217 (1): 65–77. DOI: 10.1083/jcb.201708092.
  4. Hoare M., Ito Y., Kang T.W., Weekes M.P., Matheson N.J., Patten D.A., Shetty S., Parry A.J., Menon S., Salama R., Antrobus R., Tomimatsu K., Howat W., Lehner P.J., Zender L., Narita M. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat Cell Biol. 2016; 18 (9): 979–92. DOI: 10.1038/ncb3397.
  5. Chuprin A., Gal H., Biron-Shental T., Biran A., Amiel A., Rozenblatt S., Krizhanovsky V. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 2013; 27 (21): 2356–66. DOI: 10.1101/gad.227512.113.
  6. Biran A., Zada L., Abou Karam P., Vadai E., Roitman L., Ovadya Y., Porat Z., Krizhanovsky V. Quantitative identification of senescent cells in aging and disease. Aging Cell. 2017; 16 (4): 661–71. DOI: 10.1111/acel.12592.
  7. Takasugi M., Okada R., Takahashi A., Virya Chen D., Watanabe S., Hara E. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat Commun. 2017; 8: 15729. DOI: 10.1038/ncomms15728.
  8. Franceschi C., Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol A Biol. Sci. Med Sci. 2014; 69 (1): 4–9. DOI: 10.1093/gerona/glu057.
  9. Daan N.M., Fauser B.C. Menopause prediction and potential implications. Maturitas. 2015; 82 (3): 257–65. DOI: 10.1016/j.maturitas.2015.07.019.
  10. Chow E.T., Mahalingaiah S. Cosmetics use and age at menopause: is there a connection? Fertil Steril. 2016; 106 (4): 978–90. DOI: 10.1016/j.fertnstert.2016.08.020.
  11. Moslehi N., Mirmiran P., Tehrani F.R., Azizi F. Current Evidence on Associations of Nutritional Factors with Ovarian Reserve and Timing of Menopause: A Systematic Review. Adv Nutr. 2017; 8 (4): 597–612. DOI: 10.3945/an.116.014647.
  12. Secomandi L., Borghesan M., Velarde M., Demaria M. The role of cellular senescence in female reproductive aging and the potential for senotherapeutic interventions. Hum Reprod Update. 2022; 28 (2): 172–89. DOI: 10.1093/humupd/dmab038.
  13. Lean S.C., Derricott H., Jones R.L., Heazell A.E.P. Advanced maternal age and adverse pregnancy outcomes: A systematic review and meta-analysis. PLoS One. 2017; 12 (10): e0186287. DOI: 10.1371/journal.pone.0186287.
  14. Frederiksen L.E., Ernst A., Brix N., Braskhøj Lauridsen L.L., Roos L., Ramlau-Hansen C.H., Ekelund C.K. Risk of Adverse Pregnancy Outcomes at Advanced Maternal Age. Obstet Gynecol. 2018; 131 (3): 457–63. DOI: 10.1097/AOG.0000000000002504.
  15. Pasquariello R., Ermisch A.F., Silva E., McCormick S., Logsdon D., Barfield J.P., Schoolcraft W.B., Krisher R.L. Alterations in oocyte mitochondrial number and function are related to spindle defects and occur with maternal aging in mice and humans†. Biol Reprod. 2019; 100 (4): 971–81. DOI: 10.1093/biolre/ioy248.
  16. Sultana Z., Maiti K., Dedman L., Smith R. Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction? Am. J. Obstet Gynecol. 2018; 218 (2S): 762–73. DOI: 10.1016/j.ajog.2017.11.567.
  17. Woods L., Perez-Garcia V., Kieckbusch J., Wang X., DeMayo F., Colucci F., Hemberger M. Decidualisation and placentation defects are a major cause of age-related reproductive decline. Nat Commun. 2017; 8 (1): 352. DOI: 10.1038/s41467-017-00308-x.
  18. Gargus E., Deans R., Anazodo A., Woodruff T.K. Management of Primary Ovarian Insufficiency Symptoms in Survivors of Childhood and Adolescent Cancer. J. Natl Compr Canc Netw. 2018; 16 (9): 1137–49. DOI: 10.6004/jnccn.2018.7023.
  19. Tsiligiannis S., Panay N., Stevenson J.C. Premature Ovarian Insufficiency and Long-Term Health Consequences. Curr Vasc Pharmacol. 2019; 17 (6): 604–9. DOI: 10.2174/1570161117666190122101611.
  20. Laven J.S.E. Early menopause results from instead of causes premature general ageing. Reprod Biomed Online. 2022; 45 (3): 421–4. DOI: 10.1016/j.rbmo.2022.02.027.
  21. Vilas Boas L., Bezerra Sobrinho C., Rahal D., Augusto Capellari C., Skare T., Nisihara R. Antinuclear antibodies in patients with endometriosis: A cross-sectional study in 94 patients. Hum Immunol. 2022; 83 (1): 70–3. DOI: 10.1016/j.humimm.2021.10.001.
  22. Pomatto L.C.D., Davies K.J.A. Adaptive homeostasis and the free radical theory of ageing. Free Radic Biol Med. 2018; 124: 420–30. DOI: 10.1016/j.freeradbiomed.2018.06.016.
  23. Scutiero G., Iannone P., Bernardi G., Bonaccorsi G., Spadaro S., Volta C.A., Greco P., Nappi L. Oxidative Stress and Endometriosis: A Systematic Review of the Literature. Oxid Med Cell Longev. 2017; 2017: 7265238. DOI: 10.1155/2017/7265238.
  24. Van Langendonckt A., Casanas-Roux F., Donnez J. Oxidative stress and peritoneal endometriosis. Fertil Steril. 2002; 77 (5): 861–70. DOI: 10.1016/s0015-0282(02)02959-x.
  25. Pertynska-Marczewska M., Diamanti-Kandarakis E. Aging ovary and the role for advanced glycation end products. Menopause. 2017; 24 (3): 345–51. DOI: 10.1097/GME.0000000000000755.
  26. Merhi Z., Du X.Q., Charron M.J. Postnatal weaning to different diets leads to different reproductive phenotypes in female offspring following perinatal exposure to high levels of dietary advanced glycation end products. F S Sci. 2022; 3 (1): 95–105. DOI: 10.1016/j.xfss.2021.12.001.
  27. Young J.M., McNeilly A.S. Theca: the forgotten cell of the ovarian follicle. Reproduction. 2010; 140 (4): 489–504. DOI: 10.1530/REP-10-0094.
  28. Pertynska-Marczewska M., Diamanti-Kandarakis E. Aging ovary and the role for advanced glycation end products. Menopause. 2017; 24 (3): 345–51. DOI: 10.1097/GME.0000000000000755.
  29. Laven J.S.E. Genetics of Menopause and Primary Ovarian Insufficiency: Time for a Paradigm Shift? Semin Reprod Med. 2020; 38 (4–05): 256–62. DOI: 10.1055/s-0040-1721796.
  30. Ruth K.S., Day F.R., Hussain J., Martinez-Marchal A., Aiken C.E., Azad A., Thompson D.J., Knoblochova L., Abe H., Tarry-Adkins J.L., Gonzalez J.M., Fontanillas P., Claringbould A., Bakker O.B., Sulem P., Walters R.G., Terao C., Turon S., Horikoshi M., Lin K., Onland-Moret N.C., Sankar A., Hertz E.P.T., Timshel P.N., Shukla V., Borup R., Olsen K.W., Aguilera P., Ferrer-Roda M., Huang Y., Stankovic S., Timmers P.R.H.J., Ahearn T.U., Alizadeh B.Z., Naderi E., Andrulis I.L., Arnold A.M., Aronson K.J., Augustinsson A., Bandinelli S., Barbieri C.M., Beaumont R.N., Becher H., Beckmann M.W., Benonisdottir S., Bergmann S., Bochud M., Boerwinkle E., Bojesen S.E., Bolla M.K., Boomsma D.I., Bowker N., Brody J.A., Broer L., Buring J.E., Campbell A., Campbell H., Castelao J.E., Catamo E., Chanock S.J., Chenevix-Trench G., Ciullo M., Corre T., Couch F.J., Cox A., Crisponi L., Cross S.S., Cucca F., Czene K., Smith G.D., de Geus EJCN, de Mutsert R., De Vivo I., Demerath E.W., Dennis J., Dunning A.M., Dwek M., Eriksson M., Esko T., Fasching P.A., Faul J.D., Ferrucci L., Franceschini N., Frayling T.M., Gago-Dominguez M., Mezzavilla M., Garcia-Closas M., Gieger C., Giles G.G., Grallert H., Gudbjartsson D.F., Gudnason V., Guénel P., Haiman C.A., Håkansson N., Hall P., Hayward C., He C., He W., Heiss G., Høffding M.K., Hopper J.L., Hottenga J.J., Hu F., Hunter D., Ikram M.A., Jackson R.D., Joaquim M.D.R., John E.M., Joshi P.K., Karasik D., Kardia S.L.R., Kartsonaki C., Karlsson R., Kitahara C.M., Kolcic I., Kooperberg C., Kraft P., Kurian A.W., Kutalik Z., La Bianca M., LaChance G., Langenberg C., Launer L.J., Laven J.S.E., Lawlor D.A., Le Marchand L., Li J., Lindblom A., Lindstrom S., Lindstrom T., Linet M., Liu Y., Liu S., Luan J., Mägi R., Magnusson P.K.E., Mangino M., Mannermaa A., Marco B., Marten J., Martin N.G., Mbarek H., McKnight B., Medland S.E., Meisinger C., Meitinger T., Menni C., Metspalu A., Milani L., Milne R.L., Montgomery G.W., Mook-Kanamori D.O., Mulas A., Mulligan A.M., Murray A., Nalls M.A., Newman A., Noordam R., Nutile T., Nyholt D.R., Olshan A.F., Olsson H., Painter J.N., Patel A.V., Pedersen N.L., Perjakova N., Peters A., Peters U., Pharoah P.D.P., Polasek O., Porcu E., Psaty B.M., Rahman I., Rennert G., Rennert H.S., Ridker P.M., Ring S.M., Robino A., Rose L.M., Rosendaal F.R., Rossouw J., Rudan I., Rueedi R., Ruggiero D., Sala C.F., Saloustros E., Sandler D.P., Sanna S., Sawyer E.J., Sarnowski C., Schlessinger D., Schmidt M.K., Schoemaker M.J., Schraut K.E., Scott C., Shekari S., Shrikhande A., Smith A.V., Smith B.H., Smith J.A., Sorice R., Southey M.C., Spector T.D., Spinelli J.J., Stampfer M., Stöckl D., van Meurs J.B.J., Strauch K., Styrkarsdottir U., Swerdlow A.J., Tanaka T., Teras L.R., Teumer A., Þorsteinsdottir U., Timpson N.J., Toniolo D., Traglia M., Troester M.A., Truong T., Tyrrell J., Uitterlinden A.G., Ulivi S., Vachon C.M., Vitart V., Völker U., Vollenweider P., Völzke H., Wang Q., Wareham N.J., Weinberg C.R., Weir D.R., Wilcox A.N., van Dijk K.W., Willemsen G., Wilson J.F., Wolffenbuttel B.H.R., Wolk A., Wood A.R., Zhao W., Zygmunt M. Biobank-based Integrative Omics Study (BIOS) Consortium; eQTLGen Consortium; Biobank Japan Project; China Kadoorie Biobank Collaborative Group; kConFab Investigators; LifeLines Cohort Study; InterAct consortium; 23andMe Research Team, Chen Z., Li L., Franke L., Burgess S., Deelen P., Pers T.H., Grøndahl M.L., Andersen C.Y., Pujol A., Lopez-Contreras A.J., Daniel J.A., Stefansson K., Chang-Claude J., van der Schouw Y.T., Lunetta K.L., Chasman D.I., Easton D.F., Visser J.A., Ozanne S.E., Namekawa S.H., Solc P., Murabito J.M., Ong K.K., Hoffmann E.R., Murray A., Roig I., Perry J.R.B. Genetic insights into biological mechanisms governing human ovarian ageing. Nature. 2021; 596 (7872): 393–7. DOI: 10.1038/s41586-021-03779-7.
  31. Denis-Laroque L., Drouet Y., Plotton I., Chopin N., Bonadona V., Lornage J., Salle B., Lasset C., Rousset-Jablonski C. Anti-müllerian hormone levels and antral follicle count in women with a BRCA1 or BRCA2 germline pathogenic variant: A retrospective cohort study. Breast. 2021; 59: 239–47. DOI: 10.1016/j.breast.2021.07.010.
  32. Chico-Sordo L., Córdova-Oriz I., Polonio A.M., S-Mellado L.S., Medrano M., Garcia-Velasco J.A., Varela E. Reproductive aging and telomeres: Are women and men equally affected? Mech Ageing Dev. 2021; 198: 111541. DOI: 10.1016/j.mad.2021.111541.
  33. Fernandes S.G., Dsouza R., Khattar E. External environmental agents influence telomere length and telomerase activity by modulating internal cellular processes: Implications in human aging. Environ Toxicol Pharmacol. 2021; 85: 103633. DOI: 10.1016/j.etap.2021.103633.
  34. Keefe D.L. Telomeres and genomic instability during early development. Eur. J. Med. Genet. 2020; 63 (2): 103638. DOI: 10.1016/j.ejmg.2019.03.002.
  35. Kosebent E.G., Uysal F., Ozturk S. The altered expression of telomerase components and telomere-linked proteins may associate with ovarian aging in mouse. Exp Gerontol. 2020; 138: 110975. DOI: 10.1016/j.exger.2020.110975.
  36. Sofiyeva N., Ekizoglu S., Gezer A., Yilmaz H., Kolomuc Gayretli T., Buyru N., Oral E. Does telomerase activity have an effect on infertility in patients with endometriosis? Eur. J. Obstet Gynecol Reprod Biol. 2017; 213: 116–22. DOI: 10.1016/j.ejogrb.2017.04.027.
  37. Chun Y., Kim J. Autophagy: An Essential Degradation Program for Cellular Homeostasis and Life. Cells. 2018; 7 (12): 278. DOI: 10.3390/cells7120278.
  38. Guo Z., Yu Q. Role of mTOR Signaling in Female Reproduction. Front Endocrinol (Lausanne). 2019; 10: 692. DOI: 10.3389/fendo.2019.00692.
  39. Li Q., Cai M., Wang J., Gao Q., Guo X., Jia X., Xu S., Zhu H. Decreased ovarian function and autophagy gene methylation in aging rats. J. Ovarian Res. 2020; 13 (1): 12. DOI: 10.1186/s13048-020-0615-0.
  40. Lagoumtzi S.M., Chondrogianni N. Senolytics and senomorphics: Natural and synthetic therapeutics in the treatment of aging and chronic diseases. Free Radic Biol Med. 2021; 171: 169–90. DOI: 10.1016/j.freeradbiomed.2021.05.003.
  41. Lin Y.H., Chen Y.H., Chang H.Y., Au H.K., Tzeng C.R., Huang Y.H. Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies. Int. J. Mol. Sci. 2018; 19 (8): 2385. DOI: 10.3390/ijms19082385.
  42. Anupa G., Poorasamy J., Bhat M.A., Sharma J.B., Sengupta J., Ghosh D. Endometrial stromal cell inflammatory phenotype during severe ovarian endometriosis as a cause of endometriosis-associated infertility. Reprod Biomed Online. 2020; 41 (4): 623–39. DOI: 10.1016/j.rbmo.2020.05.008.
  43. Habibi S., Ramazanali F., Favaedi R., Afsharian P., Amirchaghmaghi E., Shahhoseini M. Thymic stromal lymphopoietin (TSLP) is a potent pro-inflammatory mediator which is epigenetically deregulated in endometriosis. J. Reprod Immunol. 2022; 151: 103515. DOI: 10.1016/j.jri.2022.103515.
  44. Meldrum D.R., Casper R.F., Diez-Juan A., Simon C., Domar A.D., Frydman R. Aging and the environment affect gamete and embryo potential: can we intervene? Fertil Steril. 2016; 105 (3): 548–59. DOI: 10.1016/j.fertnstert.2016.01.013.
  45. Briley S.M., Jasti S., McCracken J.M., Hornick J.E., Fegley B., Pritchard M.T., Duncan F.E. Reproductive age-associated fibrosis in the stroma of the mammalian ovary. Reproduction. 2016; 152 (3): 245–60. DOI: 10.1530/REP-16-0129.
  46. Justice J.N., Nambiar A.M., Tchkonia T., LeBrasseur N.K., Pascual R., Hashmi S.K., Prata L., Masternak M.M., Kritchevsky S.B., Musi N., Kirkland J.L. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019; 40: 554–63. DOI: 10.1016/j.ebiom.2018.12.052.
  47. Pignolo R.J., Passos J.F., Khosla S., Tchkonia T., Kirkland J.L. Reducing Senescent Cell Burden in Aging and Disease. Trends Mol Med. 2020; 26 (7): 630–8. DOI: 10.1016/j.molmed.2020.03.005.
  48. Soto-Gamez A., Quax W.J., Demaria M. Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions. J. Mol. Biol. 2019; 431 (15): 2629–43. DOI: 10.1016/j.jmb.2019.05.036.
  49. Von Kobbe C. Targeting senescent cells: approaches, opportunities, challenges. Aging (Albany NY). 2019; 11 (24): 12844–61. DOI: 10.18632/aging.102557.
  50. Kim E.C., Kim J.R. Senotherapeutics: emerging strategy for healthy aging and age-related disease. BMB Rep. 2019; 52 (1): 47–55. DOI: 10.5483/BMBRep.2019.52.1.293.