Abstract

Age-related macular degeneration (AMD) is a significant problem in healthcare, because it is a leading cause of central vision loss in individuals over 50 years old in well-developed countries. Pathogenesis of AMD is multifactorial and still not completely understood. Proven risk factors include the following: natural senescence of retina, oxidative stress, complement activation, chronic subretinal inflammatory reaction, genetic and environmental factors. Data on links between autophagy and AMD development are being raised. Autophagy is a cellular process involving the degradation of long-lived proteins and damaged fragments and components of cells; it is responsible for the maintenance of dynamic intracellular homeostasis and it enables cell survival under stress conditions. Disturbances of autophagy mechanisms, i.e. its activation or inhibition, may lead to the development of many various pathologies. Thus, autophagy plays a dual role, as a mechanism responsible for protecting or killing cells. The paper describes autophagy mechanisms and their role in the natural process of retinal cells senescence and presents the autophagy impairment as a crucial cause of AMD development. We also describe the impact of intravitreal anti-VEGF therapy on retinal autophagy mechanisms and potential new therapeutic modalities for AMD based on autophagy modulation.

References

• 1. Abu-Amero K.K., Kondkar A.A., Chalam K.V.: Resveratrol andophthalmic diseases. Nutrients, 2016; 8: 200 2 Agarwal A., Rhoades W.R., Hanout M., Soliman M.K., Sarwar S.,Sadiq M.A., Sepah Y.J., Do D.V., Nguyen Q.D.: Management of neovascularage-related macular degeneration: Current state-of-the-artcare for optimizing visual outcomes and therapies in development.Clin. Ophthalmol., 2015; 9: 1001–1015
  Google Scholar
• 2. study: Micronutrients in the treatment of macular degeneration.Adv. Nutr., 2017; 8: 40–53
  Google Scholar
• 3. Ardeljan D., Tuo J., Chan C.C.: Carboxyethylpyrrole plasma biomarkersin age-related macular degeneration. Drugs Future, 2011;36: 712–718
  Google Scholar
• 4. Bellezza I.: Oxidative stress in age-related macular degeneration:Nrf2 as therapeutic target. Front. Pharmacol., 2018; 9: 1280
  Google Scholar
• 5. Bergmann M., Schütt F., Holz F.G., Kopitz J.: Inhibition of theATP-driven proton pump in RPE lysosomes by the major lipofuscinfluorophore A2-E may contribute to the pathogenesis of age-relatedmacular degeneration. FASEB J., 2004; 18: 562–564
  Google Scholar
• 6. Blasiak J., Pawlowska E., Szczepanska J., Kaarniranta K.: Interplaybetween autophagy and the ubiquitin-proteasome system and itsrole in the pathogenesis of age-related macular degeneration. Int.J. Mol. Sci., 2019; 20: 210
  Google Scholar
• 7. Blasiak J., Petrovski G., Veréb Z., Facskó A., Kaarniranta K.: Oxidativestress, hypoxia, and autophagy in the neovascular processes of age–related macular degeneration. Biomed. Res. Int., 2014; 2014: 768026
  Google Scholar
• 8. Blasiak J., Piechota M., Pawlowska E., Szatkowska M., Sikora E.,Kaarniranta K.: Cellular senescence in age-related macular degeneration:Can autophagy and DNA damage response play a role? Oxid.Med. Cell. Longev., 2017; 2017: 5293258
  Google Scholar
• 9. Bowes Rickman C., Farsiu S., Toth C.A., Klingeborn M.: Dry age–related macular degeneration: Mechanisms, therapeutic targets,and imaging. Invest. Ophthalmol. Vis. Sci., 2013; 54: ORSF68–ORSF80
  Google Scholar
• 10. Boya P., Esteban-Martínez L., Serrano-Puebla A., Gómez-SintesR., Villarejo-Zori B.: Autophagy in the eye: Development, degeneration,and aging. Prog. Retin. Eye Res., 2016; 55: 206–245
  Google Scholar
• 11. Cai J., Zhang H., Zhang Y.F., Zhou Z., Wu S.: MicroRNA-29 enhancesautophagy and cleanses exogenous mutant αB-crystallin inretinal pigment epithelial cells. Exp. Cell Res., 2019; 374: 231–248
  Google Scholar
• 12. Cerri S., Blandini F.: Role of autophagy in Parkinson’s disease.Curr. Med. Chem., 2019; 26: 3702–3718
  Google Scholar
• 13. Chai P., Ni H., Zhang H., Fan X.: The evolving functions of autophagyin ocular health: A double-edged sword. Int. J. Biol. Sci.,2016; 12: 1332–1340
  Google Scholar
• 14. Chen Y., Perusek L., Maeda A.: Autophagy in light-induced retinaldamage. Exp. Eye Res., 2016; 144: 64–72
  Google Scholar
• 15. Cheng Y.S., Linetsky M., Gu X., Ayyash N., Gardella A., SalomonR.G.: Light-induced generation and toxicity of docosahexaenoate–derived oxidation products in retinal pigmented epithelial cells.Exp. Eye Res., 2019; 181: 325–345
  Google Scholar
• 16. Cherra S.J. 3rd, Kulich S.M., Uechi G., Balasubramani M., MountzourisJ., Day B.W., Chu C.T.: Regulation of the autophagy protein LC3by phosphorylation. J. Cell Biol., 2010; 190: 533–539
  Google Scholar
• 17. Cheung C.M., Tai E.S., Kawasaki R., Tay W.T., Lee J.L., HamzahH., Wong T.Y.: Prevalence of and risk factors for age-related maculardegeneration in a multiethnic Asian cohort. Arch. Ophthalmol.2012; 130: 480–486
  Google Scholar
• 18. Cheung C.M., Wong T.Y.: Is age-related macular degenerationa manifestation of systemic disease? New prospects for early interventionand treatment. J. Intern. Med., 2014; 276: 140–153
  Google Scholar
• 19. Codogno P., Meijer A.J.: Autophagy and signaling: their role incell survival and cell death. Cell Death Differ., 2005; 12: 1509–1518
  Google Scholar
• 20. Cuervo A.M.: Chaperone-mediated autophagy: Selectivity paysoff. Trends Endocrinol. Metab., 2010; 21: 142–150
  Google Scholar
• 21. Dalal M., Jacobs-El N., Nicholson B., Tuo J., Chew E., Chan C.C.,Nussenblatt R., Ferris F., Meyerle C.: Subconjunctival Palomid 529in the treatment of neovascular age-related macular degeneration.Graefes Arch. Clin. Exp. Ophthalmol., 2013; 251: 2705–2709
  Google Scholar
• 22. DeAngelis M.M., Owen L.A., Morrison M.A., Morgan D.J., Li M.,Shakoor A., Vitale A., Iyengar S., Stambolian D., Kim I.K., Farrer L.A.:Genetics of age-related macular degeneration (AMD). Hum. Mol.Genet., 2017; 26: R45–R50
  Google Scholar
• 23. De Cillà S., Farruggio S., Vujosevic S., Raina G., Filippini D., GattiV., Clemente N., Mary D., Vezzola D., Casini G., Rossetti L., GrossiniE.: Anti-vascular endothelial growth factors protect retinal pigmentepithelium cells against oxidation by modulating nitric oxide releaseand autophagy. Cell Physiol. Biochem., 2017; 42: 1725–1738
  Google Scholar
• 24. De Duve S., Wattiaux R.: Functions of lysosomes. Annu. Rev.Physiol., 1966; 28: 435–492
  Google Scholar
• 25. Dokladny K., Myers O.B., Moseley P.L.: Heat shock response andautophagy – cooperation and control. Autophagy, 2015; 11: 200–213
  Google Scholar
• 26. Dokladny K., Zuhl M.N., Mandell M., Bhattacharya D., SchneiderS., Deretic V., Moseley P.L.: Regulatory coordination between twomajor intracellular homeostatic systems: Heat shock response andautophagy. J. Biol. Chem., 2013; 288: 14959–14972
  Google Scholar
• 27. Franceschi C., Bonafè M., Valensin S., Olivieri F., De Luca M., OttavianiE., De Benedictis G.: Inflamm-aging. An evolutionary perspectiveon immunosenescence. Ann. N.Y. Acad. Sci., 2000; 908: 244–254
  Google Scholar
• 28. Frost L.S., Mitchell C.H., Boesze-Battaglia K.: Autophagy in the eye:Implications for ocular cell health. Exp. Eye Res., 2014; 124: 56–66
  Google Scholar
• 29. Geerlings M.J., de Jong E.K., den Hollander A.I.: The complementsystem in age-related macular degeneration: A review of rare geneticvariants and implications for personalized treatment. Mol. Immunol.,2017; 84: 65–76
  Google Scholar
• 30. Glick D., Barth S., Macleod K.F.: Autophagy: Cellular and molecularmechanisms. J. Pathol., 2010; 221: 3–12
  Google Scholar
• 31. Golestaneh N., Chu Y., Xiao Y.Y., Stoleru G.L., Theos A.C.: Dysfunctionalautophagy in RPE, a contributing factor in age-related maculardegeneration. Cell Death Dis. 2017; 8: e2537
  Google Scholar
• 32. Gorusupudi A., Nelson K., Bernstein P.S.: The age-related eye disease
  Google Scholar
• 33. Gozuacik D., Kimchi A.: Autophagy and cell death. Curr. Topics Dev.Biol., 2007; 78: 217–245
  Google Scholar
• 34. Hyttinen J.M., Błasiak J., Niittykoski M., Kinnunen K., Kauppinen A.,Salminen A., Kaarniranta K.: DNA damage response and autophagy inthe degeneration of retinal pigment epithelial cells-implications for age–related macular degeneration (AMD). Ageing Res. Rev., 2017; 36: 64–77
  Google Scholar
• 35. Iwasaki M., Inomata H.: Lipofuscin granules in human photoreceptorcells. Invest. Ophthalmol. Vis. Sci., 1988; 29: 671–679
  Google Scholar
• 36. Jankowska-Lech I., Grabska-Liberek I., Krzyżewska-Niedziałek A., PietruszyńskaM.: Zwyrodnienie plamki związane z wiekiem (AMD) – chorobastarzejących się społeczeństw. Post. Nauk Med., 2013; 26: 868–873
  Google Scholar
• 37. Jarrett S.G., Boulton M.E.: Consequences of oxidative stress in agerelatedmacular degeneration. Mol. Aspects Med., 2012; 33: 399–417
  Google Scholar
• 38. Jarrett S.G., Lewin A.S., Boulton M.E.: The importance of mitochondriain age-related and inherited eye disorders. Ophthalmic Res.,2010; 44: 179–190
  Google Scholar
• 39. Jaul E., Barron J.: Age-related diseases and clinical and public healthimplications for the 85 years old and over population. Front. PublicHealth, 2017; 5: 335
  Google Scholar
• 40. Jiang P., Mizushima N.: Autophagy and human diseases. Cell Res.,2014: 24: 69–79
  Google Scholar
• 41. Jonas J.B., Cheung C.M., Panda-Jonas S.: Updates on the epidemiologyof age-related macular degeneration. Asia Pac. J. Ophthalmol.,2017; 6: 493–497
  Google Scholar
• 42. Kaarniranta A.: Autophagy a hot topic in AMD. Acta Ophthalmol.,2010; 88: 387–388
  Google Scholar
• 43. Kaarniranta K., Petrovski G., Kauppinen A.: The Nobel Prized cellulartarget autophagy in eye diseases. Acta Ophthalmol., 2017; 95: 335–336
  Google Scholar
• 44. Kaarniranta K., Sinha D., Blasiak J., Kauppinen A., Veréb Z., SalminenA., Boulton M.E., Petrovski G.: Autophagy and heterophagy dysregulationleads to retinal pigment epithelium dysfunction and developmentof age-related macular degeneration. Autophagy, 2013: 9: 973–984
  Google Scholar
• 45. Karlsson M., Frennesson C., Gustafsson T., Brunk U.T., Nilsson S.E.,Kurz T.: Autophagy of iron-binding proteins may contribute to the oxidativestress resistance of ARPE-19 cells. Exp. Eye Res., 2013: 116: 359–365
  Google Scholar
• 46. Kauppinen A., Paterno J.J., Blasiak J., Salminen A., Kaarniranta K.:Inflammation and its role in age-related macular degeneration. CellMol. Life Sci., 2016; 73: 1765–1786
  Google Scholar
• 47. Khan M., Agarwal K., Loutfi M., Kamal A.: Present and possibletherapies for age-related macular degeneration. ISRN Ophthalmol.,2014; 2014: 608390
  Google Scholar
• 48. Kivinen N.: The role of autophagy in age-related macular degeneration.Acta Ophthalmol., 2018; 96 (Suppl. A110): 1–50
  Google Scholar
• 49. Klettner A.K.: VEGF-A and its inhibitors in age-related macular degeneration– pharmacokinetic differences and their retinal and systemicimplications. J. Biochem. Pharmacol. Res., 2014; 2: 8–20
  Google Scholar
• 50. Klettner A., Möhle F., Roider J.: Intracellular bevacizumab reducesphagocytotic uptake in RPE cell. Graefes Arch. Clin. Exp. Ophthalmol.,2010; 248: 819–824
  Google Scholar
• 51. Klionsky D.J.: The molecular machinery of autophagy: Unansweredquestions. J. Cell Sci., 2005; 118: 7–18
  Google Scholar
• 52. Krohne T.U., Kaemmerer E., Holz F.G., Kopitz J.: Lipid peroxidationproducts reduce lysosomal protease activities in human retinal pigmentepithelial cells via two different mechanisms of action. Exp. EyeRes., 2010; 90: 261–266
  Google Scholar
• 53. Kunchithapautham K., Rohrer B.: Apoptosis and autophagy in photoreceptorsexposed to oxidative stress. Autophagy, 2007; 3: 433–441
  Google Scholar
• 54. Lei L., Tzekov R., Li H., McDowell J.H., Gao G., Smith W.C., Tang S.,Kaushal S.: Inhibition or stimulation of autophagy affects early formationof lipofuscin-like autofluorescence in the retinal pigment epitheliumcell. Int. J. Mol. Sci., 2017; 18: 728
  Google Scholar
• 55. Levine B., Klionsky D.J.: Autophagy wins the 2016 Nobel Prize inPhysiology or Medicine: Breakthroughs in baker’s yeast fuel advancesin biomedical research. Proc. Natl. Acad. Sci. USA, 2016; 114: 201–205
  Google Scholar
• 56. Levine B., Kroemer G.: Autophagy in the pathogenesis of disease.Cell, 2008; 132: 27–42
  Google Scholar
• 57. Li R., Wang L.Z., Du J.H., Zhao L., Yao Y.: Autophagy activation andthe mechanism of retinal microvascular endothelial cells in hypoxia.Int. J. Ophthalmol., 2018; 11: 567–574
  Google Scholar
• 58. Lin W., Xu G.: Autophagy: A role in the apoptosis, survival, inflammation,and development of the retina. Ophthalmic Res., 2019; 61: 65–72
  Google Scholar
• 59. Liu J., Copland D.A., Theodoropoulou S., Chiu H.A., Barba M.D., MakK.W., Mack M., Nicholson L.B., Dick A.D.: Impairing autophagy in retinalpigment epithelium leads to inflammasome activation and enhancedmacrophage-mediated angiogenesis. Sci. Rep., 2016; 6: 20639
  Google Scholar
• 60. Luthert P.J.: Pathogenesis of age-related macular degeneration.Diagn. Histopathol., 2011; 17: 10–16
  Google Scholar
• 61. Luthra S., Sharma A., Dong J., Neekhra A., Gramajo A.L., Seigel G.M.,Kenney M.C., Kuppermann B.D.: Effect of bevacizumab (AvastinTM) onmitochondrial function of in vitro retinal pigment epithelial, neurosensoryretinal and microvascular endothelial cells. Indian J. Ophthalmol.,2013; 61: 705–710
  Google Scholar
• 62. Mathenge W.: Age-related macular degeneration. Community EyeHealth. 2014; 27: 49–50
  Google Scholar
• 63. Mehrpour M., Esclatine A., Beau I., Codogno P.: Overview of macroautophagyregulation in mammalian cells. Cell Res., 2010; 20: 748–762
  Google Scholar
• 64. Miguel N.C. Matsuda M., Portes A.L., Allodi S., Mendez-Otero R.,Puntar T., Sholl-Franco A., Krempel P.G., Monteiro M.L.: In vitro effectsof bevacizumab treatment on newborn rat retinal cell proliferation, death,and differentiation. Invest. Ophthalmol. Vis. Sci. 2012; 53: 7904–7911
  Google Scholar
• 65. Mijaljica D., Prescott M., Devenish R.J.: Microautophagy in mammaliancells: Revisiting a 40-year-old conundrum. Autophagy, 2011;7: 673–682
  Google Scholar
• 66. Mitter S.K., Rao H.V., Qi X., Cai J., Sugrue A., Dunn W.A. Jr, Grant M.B.,Boulton M.E.: Autophagy in the retina: A potential role in age-relatedmacular degeneration. Adv. Exp. Med. Biol., 2012; 723: 83–90
  Google Scholar
• 67. Mizushima N.: The role of the Atg1/ULK1 complex in autophagyregulation. Curr. Opin. Cell Biol., 2010; 22: 132–139
  Google Scholar
• 68. Mizushima N., Komatsu M.: Autophagy: Renovation of cells andtissues. Cell, 2011; 147: 728–741
  Google Scholar
• 69. Moschos M.M, Nitoda E., Chatziralli I.P., Demopoulos C.A.: Age–related macular degeneration: Pathogenesis, genetic background,and the role of nutritional supplements. J. Chemistry., 2014; 2014:317536
  Google Scholar
• 70. Nita M., Grzybowski A., Ascaso F.J., Huerva V.: Age-related maculardegeneration in the aspect of chronic low-grade inflammation(pathophysiological parainflammation). Mediators Inflamm.,2014; 2014: 930671
  Google Scholar
• 71. Paimela T., Hyttinen J.M., Viiri J., Ryhänen T., Karjalainen R.O.,Salminend A., Kaarnirantaa K.: Celastrol regulates innate immunityresponse via NF-κB and Hsp70 in human retinal pigment epithelialcells. Pharmacol. Res., 2011; 64: 501–508
  Google Scholar
• 72. Park D., Jeong H., Lee M.N., Koh A., Kwon O., Yang Y.R., Noh J.,Suh P.G., Park H., Ryu S.H.: Resveratrol induces autophagy by directlyinhibiting mTOR through ATP competition. Sci. Rep., 2016; 6: 21772
  Google Scholar
• 73. Parzych K.R., Klionsky D.J.: An overview of autophagy: Morphology,mechanism, and regulation. Antioxid. Redox Signal., 2014;20: 460–473
  Google Scholar
• 74. Pennington K.L., DeAngelis M.M.: Epidemiology of age-relatedmacular degeneration (AMD): Associations with cardiovascular diseasephenotypes and lipid factors. Eye Vis., 2016; 3: 34
  Google Scholar
• 75. Perl A.: mTOR activation is a biomarker and a central pathwayto autoimmune disorders, cancer, obesity, and aging. Ann. N.Y. Acad.Sci., 2015; 1346: 33–44
  Google Scholar
• 76. Perusek L., Sahu B., Parmar T., Maeno H., Arai E., Le Y.Z., SubausteC.S., Chen Y., Palczewski K., Maeda A.: Di-retinoid-pyridiniumethanolamine(A2E) accumulation and the maintenance of the visualcycle are independent of Atg7-mediated autophagy in the retinalpigmented epithelium. J. Biol. Chem., 2015; 290: 29035–29044
  Google Scholar
• 77. Polewska J.: Autofagia – mechanizm molekularny, apoptozai nowotwory. Postępy Hig. Med. Dośw., 2012; 66: 921–936
  Google Scholar
• 78. Ravikumar B., Sarkar S., Davies J.E., Futter M., Garcia-ArencibiaM., Green-Thompson Z.W., Jimenez-Sanchez M., Korolchuk V.I.,Lichtenberg M., Luo S., Massey D.C., Menzies F.M., Moreau K., NarayananU., Renna M. i wsp.: Regulation of mammalian autophagyin physiology and pathophysiology. Physiol. Rev. 2010; 90:1383–1435
  Google Scholar
• 79. Remé C.E.: Autophagy in visual cells and pigment epithelium.Invest. Ophthalmol. Vis. Sci., 1977; 16: 807–814
  Google Scholar
• 80. Rinninella E., Mele M.C., Merendino N., Cintoni M., Anselmi G.,Caporossi A., Gasbarrini A., Minnella A.M.: The role of diet, micronutrientsand the gut microbiota in age-related macular degeneration:New perspectives from the gut-retina axis. Nutrients, 2018; 10: 1677
  Google Scholar
• 81. Ryhänen T., Hyttinen J.M., Kopitz J., Rilla K., Kuusisto E., MannermaaE., Viiri J., Holmberg C.I., Immonen I., Meri S., Parkkinen J.,Eskelinen E.L., Uusitalo H., Salminen A., Kaarniranta K.: Crosstalkbetween Hsp70 molecular chaperone, lysosomes and proteasomesin autophagy-mediated proteolysis in human retinal pigment epithelialcells. J. Cell Mol. Med., 2009; 13: 3616–3631
  Google Scholar
• 82. Schnichels S., Hagemann U., Januschowski K., Hofmann J., Bartz-Schmidt K.U., Szurman P., Spitzer M.S., Aisenbrey S.: Comparativetoxicity and proliferation testing of aflibercept, bevacizumab andranibizumab on different ocular cells. Br. J. Ophthalmol., 2013; 97:917–923
  Google Scholar
• 83. Sharifi M.N., Mowers E.E., Drake L.E., Macleod K.F.: Measuringautophagy in stressed cells. Methods Mol. Biol., 2015;1292:129–150
  Google Scholar
• 84. Szatmári-Tóth M., Kristóf E., Veréb Z., Akhtar S., Facskó A., FésüsL., Kauppinen A., Kaarniranta K., Petrovski G.: Clearance of autophagy-associated dying retinal pigment epithelial cells – a possiblesource for inflammation in age-related macular degeneration. CellDeath Dis., 2016; 7: e2367
  Google Scholar
• 85. Tanida I., Ueno T., Kominami E.: LC3 and autophagy. MethodsMol. Biol., 2008; 445: 77–88
  Google Scholar
• 86. Thapa R., Bajimaya S., Paudyal G., Khanal S., Tan S., Thapa S.S.,van Rens G.: Prevalence of and risk factors for age-related maculardegeneration in Nepal: The Bhaktapur Retina Study. Clin. Ophthalmol.,2017; 11: 963–972
  Google Scholar
• 87. Tomasiak M., Cichacz B., Pedrycz A.: Autofagia – adaptacyjnemechanizmy molekularne w warunkach głodu. Pol. Hyp. Res.,2015; 52: 71–75
  Google Scholar
• 88. Uddin M.S., Stachowiak A., Mamun A.A., Tzvetkov N.T., TakedaS., Atanasov A.G., Bergantin L.B., Abdel-Daim M.M., Stankiewicz A.M.:Autophagy and Alzheimer’s disease: From molecular mechanismsto therapeutic implications. Front. Aging Neurosci., 2018; 10: 04
  Google Scholar
• 89. van Deursen J.M.: The role of senescent cells in aging. Nature,2014; 509: 439–446
  Google Scholar
• 90. Velilla S., García-Medina J.J., García-Layana A., Dolz-Marco R.,Pons-Vázquez S., Pinazo-Durán M.D., Gómez-Ulla F., Arévalo J.F.,Díaz-Llopis M., Gallego-Pinazo R.: Smoking and age-related maculardegeneration: Review and update. J. Ophthalmol., 2013; 2013: 895147
  Google Scholar
• 91. Wang A.L., Lukas T.J., Yuan M., Du N., Tso M.O., Neufeld A.H.:Autophagy, exosomes and drusen formation in age-related maculardegeneration. Autophagy, 2009; 5: 563–564
  Google Scholar
• 92. Wang S., Wang X., Cheng Y., Ouyang W., Sang X., Liu J., Su Y.,Liu Y., Li C., Yang L., Jin L., Wang Z.: Autophagy dysfunction, cellularsenescence, and abnormal immune-inflammatory responses inAMD: From mechanisms to therapeutic potential. Oxid. Med. CellLongev., 2019; 2019: 3632169
  Google Scholar
• 93. Wang Z.V., Rothermel B.A., Hill J.A.: Autophagy in hypertensiveheart disease. J. Biol. Chem., 2010; 285: 8509–8514
  Google Scholar
• 94. Wirawan E., Vanden Berghe T., Lippens S., Agostinis P., VandenabeeleP.: Autophagy: For better or for worse. Cell Res., 2012; 22: 43–61
  Google Scholar
• 95. Wong W.L., Su X., Li X., Cheung C.M., Klein R., Cheng C.Y., WongT.Y.: Global prevalence of age-related macular degeneration and diseaseburden projection for 2020 and 2040: A systematic review andmeta-analysis. Lancet Glob. Health, 2014; 2: e106–e116
  Google Scholar
• 96. Xie W., Zhou J.: Aberrant regulation of autophagy in mammaliandiseases. Biol. Lett., 2018; 14: 20170540
  Google Scholar
• 97. Yagasaki R., Nakahara T., Ushikubo H., Mori A., Sakamoto K.,Ishii K.: Anti-angiogenic effects of mammalian target of rapamycininhibitors in a mouse model of oxygen-induced retinopathy. Biol.Pharm. Bull., 2014; 37: 1838–1842
  Google Scholar
• 98. Yang J.S., Lu C.C., Kuo S.C., Hsu Y.M., Tsai S.C., Chen S.Y., ChenY.T., Lin Y.J., Huang Y.C., Chen C.J., Lin W.D., Liao W.L., Lin W.Y., LiuY.H., Sheu J.C., Tsai F.J.: Autophagy and its link to type II diabetesmellitus. Biomedicine, 2017; 7: 8
  Google Scholar
• 99. Yang Y.P., Liang Z.Q., Gu Z.L., Qin Z.H.: Molecular mechanism andregulation of autophagy. Acta Pharmacol. Sin., 2005; 26: 1421–1434
  Google Scholar
• 100. Zarbin M.A.: Current concepts in the pathogenesis of age-relatedmacular degeneration. Arch. Ophthalmol., 2004; 122: 598–614
  Google Scholar
• 101. Zhang J., Bai Y., Huang L., Qi Y., Zhang Q., Li S., Wu Y., Li X.:Protective effect of autophagy on human retinal pigment epithelialcells against lipofuscin fluorophore A2E: Implications for age-relatedmacular degeneration. Cell Death Dis., 2015; 6: e1972
  Google Scholar
• 102. Zhang K., Zhang L., Weinreb R.N.: Ophthalmic drug discovery:Novel targets and mechanisms for retinal diseases and glaucoma.Nat. Rev. Drug Discov., 2012; 11: 541–559
  Google Scholar
• 103. Zhou H., Zhang H., Yu A., Xie J.: Association between sunlightexposure and risk of age-related macular degeneration: A meta–analysis. BMC Ophthalmol., 2018; 18: 331
  Google Scholar
• 104. Zhou Z., Doggett T.A., Sene A., Apte R.S., Ferguson T.A.: Autophagysupports survival and phototransduction protein levels in rodphotoreceptors. Cell Death Differ., 2015; 22: 488–498
  Google Scholar

Full text