Advertisement

GeroScience

pp 1–33 | Cite as

Microvascular contributions to age-related macular degeneration (AMD): from mechanisms of choriocapillaris aging to novel interventions

  • Agnes Lipecz
  • Lauren Miller
  • Illes Kovacs
  • Cecília Czakó
  • Tamas Csipo
  • Judit Baffi
  • Anna Csiszar
  • Stefano Tarantini
  • Zoltan Ungvari
  • Andriy Yabluchanskiy
  • Shannon ConleyEmail author
Review

Abstract

Aging of the microcirculatory network plays a central role in the pathogenesis of a wide range of age-related diseases, from heart failure to Alzheimer’s disease. In the eye, changes in the choroid and choroidal microcirculation (choriocapillaris) also occur with age, and these changes can play a critical role in the pathogenesis of age-related macular degeneration (AMD). In order to develop novel treatments for amelioration of choriocapillaris aging and prevention of AMD, it is essential to understand the cellular and functional changes that occur in the choroid and choriocapillaris during aging. In this review, recent advances in in vivo analysis of choroidal structure and function in AMD patients and patients at risk for AMD are discussed. The pathophysiological roles of fundamental cellular and molecular mechanisms of aging including oxidative stress, mitochondrial dysfunction, and impaired resistance to molecular stressors in the choriocapillaris are also considered in terms of their contribution to the pathogenesis of AMD. The pathogenic roles of cardiovascular risk factors that exacerbate microvascular aging processes, such as smoking, hypertension, and obesity as they relate to AMD and choroid and choriocapillaris changes in patients with these cardiovascular risk factors, are also discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay AMD by targeting fundamental cellular and molecular aging processes are presented.

Keywords

Retina SD-OCT OCTA Choroidal thickness Cardiovascular risk factors Smoking Hypertension 

Notes

Funding information

This work was supported by the National Institutes of Health (NIGMS 1 P20 GM12552801A1, SMC, AY), the Oklahoma Center for the Advancement of Science and Technology (HRP HR18-118, SMC), the Government of Hungary (EFOP-3.6.3-VEKOP-16-2017-00009 to CC), and the Presbyterian Health Foundation (SMC, LM).

References

  1. Aberami S, Nikhalashree S, Bharathselvi M, Biswas J, Sulochana KN, Coral K (2019) Elemental concentrations in choroid-RPE and retina of human eyes with age-related macular degeneration. Exp Eye Res 186:107718.  https://doi.org/10.1016/j.exer.2019.107718 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Addabbo F et al (2009) The Krebs cycle and mitochondrial mass are early victims of endothelial dysfunction: proteomic approach. Am J Pathol 174:34–43.  https://doi.org/10.2353/ajpath.2009.080650 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Adhi M, Lau M, Liang MC, Waheed NK, Duker JS (2014) Analysis of the thickness and vascular layers of the choroid in eyes with geographic atrophy using spectral-domain optical coherence tomography. Retina 34:306–312.  https://doi.org/10.1097/IAE.0b013e3182993e09 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Age-Related Eye Disease Study 2 Research G (2013) Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA 309:2005–2015.  https://doi.org/10.1001/jama.2013.4997 CrossRefGoogle Scholar
  5. Age-Related Eye Disease Study Research G (2000) Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-Related Eye Disease Study Report Number 3. Ophthalmology 107:2224–2232CrossRefGoogle Scholar
  6. Age-Related Eye Disease Study Research G (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 119:1417–1436.  https://doi.org/10.1001/archopht.119.10.1417 CrossRefGoogle Scholar
  7. Ahmad M, Kaszubski PA, Cobbs L, Reynolds H, Smith RT (2017) Choroidal thickness in patients with coronary artery disease. PLoS One 12:e0175691.  https://doi.org/10.1371/journal.pone.0175691 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Akahori T, Iwase T, Yamamoto K, Ra E, Terasaki H (2017) Changes in choroidal blood flow and morphology in response to increase in intraocular pressure. Invest Ophthalmol Vis Sci 58:5076–5085.  https://doi.org/10.1167/iovs.17-21745 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Akay F, Gundogan FC, Yolcu U, Toyran S, Uzun S (2016) Choroidal thickness in systemic arterial hypertension. Eur J Ophthalmol 26:152–157.  https://doi.org/10.5301/ejo.5000675 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Alagorie AR, Verma A, Nassisi M, Sadda SR (2019) Quantitative assessment of choriocapillaris flow deficits in eyes with advanced age-related macular degeneration versus healthy eyes. Am J Ophthalmol.  https://doi.org/10.1016/j.ajo.2019.04.037 PubMedCrossRefPubMedCentralGoogle Scholar
  11. Alder VA, Cringle SJ, Constable IJ (1983) The retinal oxygen profile in cats. Invest Ophthalmol Vis Sci 24:30–36PubMedPubMedCentralGoogle Scholar
  12. An JY et al (2017) Rapamycin treatment attenuates age-associated periodontitis in mice. Geroscience.  https://doi.org/10.1007/s11357-017-9994-6 PubMedPubMedCentralCrossRefGoogle Scholar
  13. An JY, Darveau R, Kaeberlein M (2018) Oral health in geroscience: animal models and the aging oral cavity. Geroscience 40:1–10.  https://doi.org/10.1007/s11357-017-0004-9 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Anderson B Jr (1968) Ocular effects of changes in oxygen and carbon dioxide tension. Trans Am Ophthalmol Soc 66:423–474PubMedPubMedCentralGoogle Scholar
  15. Arend N, Wertheimer C, Laubichler P, Wolf A, Kampik A, Kernt M (2015) Idebenone prevents oxidative stress, cell death and senescence of retinal pigment epithelium cells by stabilizing BAX/Bcl-2 ratio. Ophthalmologica 234:73–82.  https://doi.org/10.1159/000381726 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Aryan N, Betts-Obregon BS, Perry G, Tsin AT (2016) Oxidative Stress Induces Senescence in Cultured RPE. Cells Open Neurol J 10:83–87.  https://doi.org/10.2174/1874205X01610010083 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Atienzar-Aroca S et al (2016) Oxidative stress in retinal pigment epithelium cells increases exosome secretion and promotes angiogenesis in endothelial cells. J Cell Mol Med 20:1457–1466.  https://doi.org/10.1111/jcmm.12834 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Ayhan Z, Kaya M, Ozturk T, Karti O, Hakan Oner F (2017) Evaluation of macular perfusion in healthy smokers by using optical coherence tomography angiography. Ophthalmic Surg Lasers Imaging Retina 48:617–622.  https://doi.org/10.3928/23258160-20170802-03 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Bailey-Downs LC et al (2013) Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation. J Gerontol A Biol Sci Med Sci 68:780–792.  https://doi.org/10.1093/gerona/gls238 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Balaiya S, Khetpal V, Chalam KV (2012) Hypoxia initiates sirtuin1-mediated vascular endothelial growth factor activation in choroidal endothelial cells through hypoxia inducible factor-2alpha. Mol Vis 18:114–120PubMedPubMedCentralGoogle Scholar
  21. Balaiya S, Murthy RK, Chalam KV (2013) Resveratrol inhibits proliferation of hypoxic choroidal vascular endothelial cells. Mol Vis 19:2385–2392PubMedPubMedCentralGoogle Scholar
  22. Barreau E, Brossas JY, Courtois Y, Treton JA (1996) Accumulation of mitochondrial DNA deletions in human retina during aging. Invest Ophthalmol Vis Sci 37:384–391PubMedPubMedCentralGoogle Scholar
  23. Berenberg TL et al (2012) The association between drusen extent and foveolar choroidal blood flow in age-related macular degeneration. Retina 32:25–31.  https://doi.org/10.1097/IAE.0b013e3182150483 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Bhisitkul RB, Desai SJ, Boyer DS, Sadda SR, Zhang K (2016) Fellow eye comparisons for 7-year outcomes in ranibizumab-treated AMD subjects from ANCHOR, MARINA, and HORIZON (SEVEN-UP Study). Ophthalmology 123:1269–1277.  https://doi.org/10.1016/j.ophtha.2016.01.033 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Bhutto IA, Amemiya T (2002) Choroidal vasculature changes in spontaneously hypertensive rats—transmission electron microscopy and scanning electron microscopy with casts. Ophthalmic Res 34:54–62.  https://doi.org/10.1159/000048329 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Bhutto IA, Baba T, Merges C, Juriasinghani V, McLeod DS, Lutty GA (2011) C-reactive protein and complement factor H in aged human eyes and eyes with age-related macular degeneration. Br J Ophthalmol 95:1323–1330.  https://doi.org/10.1136/bjo.2010.199216 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Bhutto IA, McLeod DS, Jing T, Sunness JS, Seddon JM, Lutty GA (2016) Increased choroidal mast cells and their degranulation in age-related macular degeneration. Br J Ophthalmol 100:720–726.  https://doi.org/10.1136/bjophthalmol-2015-308290 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Biesemeier A, Taubitz T, Julien S, Yoeruek E, Schraermeyer U (2014) Choriocapillaris breakdown precedes retinal degeneration in age-related macular degeneration. Neurobiol Aging 35:2562–2573.  https://doi.org/10.1016/j.neurobiolaging.2014.05.003 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Blasiak J, Synowiec E, Salminen A, Kaarniranta K (2012) Genetic variability in DNA repair proteins in age-related macular degeneration. Int J Mol Sci 13:13378–13397.  https://doi.org/10.3390/ijms131013378 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Blasiak J, Piechota M, Pawlowska E, Szatkowska M, Sikora E, Kaarniranta K (2017) Cellular senescence in age-related macular degeneration: can autophagy and DNA damage response play a role? Oxidative Med Cell Longev 2017:5293258.  https://doi.org/10.1155/2017/5293258 CrossRefGoogle Scholar
  31. Bonilha VL et al (2017) Absence of DJ-1 causes age-related retinal abnormalities in association with increased oxidative stress. Free Radic Biol Med 104:226–237.  https://doi.org/10.1016/j.freeradbiomed.2017.01.018 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Bonyadi MHJ, Yaseri M, Bonyadi M, Soheilian M, Nikkhah H (2017) Association of combined cigarette smoking and ARMS2/LOC387715 A69S polymorphisms with age-related macular degeneration: a meta-analysis. Ophthalmic Genet 38:308–313.  https://doi.org/10.1080/13816810.2016.1237664 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Borrelli E, Sarraf D, Freund KB, Sadda SR (2018) OCT angiography and evaluation of the choroid and choroidal vascular disorders. Prog Retin Eye Res 67:30–55.  https://doi.org/10.1016/j.preteyeres.2018.07.002 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Bourne RR et al (2013) Causes of vision loss worldwide, 1990-2010: a systematic analysis. Lancet Glob Health 1:e339–e349.  https://doi.org/10.1016/S2214-109X(13)70113-X CrossRefPubMedPubMedCentralGoogle Scholar
  35. Bouteleux V et al (2019) Increased choroidal thickness: a new feature to monitor age-related macular degeneration recurrence. Graefes Arch Clin Exp Ophthalmol 257:699–707.  https://doi.org/10.1007/s00417-018-04216-8 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Brown DM et al (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432–1444.  https://doi.org/10.1056/NEJMoa062655 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Bulteau AL, Szweda LI, Friguet B (2002) Age-dependent declines in proteasome activity in the heart. Arch Biochem Biophys 397:298–304.  https://doi.org/10.1006/abbi.2001.2663 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Bulus AD, Can ME, Baytaroglu A, Can GD, Cakmak HB, Andiran N (2017) Choroidal thickness in childhood obesity. Ophthalmic Surg Lasers Imaging Retina 48:10–17.  https://doi.org/10.3928/23258160-20161219-02 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Cabrera AP, Bhaskaran A, Xu J, Yang X, Scott HA, Mohideen U, Ghosh K (2016) Senescence increases choroidal endothelial stiffness and susceptibility to complement injury: implications for choriocapillaris loss in AMD. Invest Ophthalmol Vis Sci 57:5910–5918.  https://doi.org/10.1167/iovs.16-19727 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Calzetti G et al (2018) Assessment of choroidal blood flow using laser speckle flowgraphy. Br J Ophthalmol 102:1679–1683.  https://doi.org/10.1136/bjophthalmol-2017-311750 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75:685–705.  https://doi.org/10.1146/annurev-physiol-030212-183653 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Campos MM, Abu-Asab MS (2017) Loss of endothelial planar cell polarity and cellular clearance mechanisms in age-related macular degeneration. Ultrastruct Pathol 41:312–319.  https://doi.org/10.1080/01913123.2017.1348418 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Cao J, McLeod S, Merges CA, Lutty GA (1998) Choriocapillaris degeneration and related pathologic changes in human diabetic eyes. Arch Ophthalmol 116:589–597PubMedCrossRefPubMedCentralGoogle Scholar
  44. Chakravarthy U et al (2007) Cigarette smoking and age-related macular degeneration in the EUREYE study. Ophthalmology 114:1157–1163.  https://doi.org/10.1016/j.ophtha.2006.09.022 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Chakravarthy U et al (2010) Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 10:31.  https://doi.org/10.1186/1471-2415-10-31 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Chakravarthy U et al (2013) Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet 382:1258–1267.  https://doi.org/10.1016/S0140-6736(13)61501-9 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Chang LY, Acosta ML, Black J (2019) Choroidal thinning and ocular electrophysiology in a case of vascular cognitive impairment after stroke. Clin Exp Optom 102:184–187.  https://doi.org/10.1111/cxo.12831 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Chen X et al (2014) Diabetes mellitus and risk of age-related macular degeneration: a systematic review and meta-analysis. PLoS One 9:e108196.  https://doi.org/10.1371/journal.pone.0108196 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Chen S, Zhou Y, Zhou L, Guan Y, Zhang Y, Han X (2018) Anti-neovascularization effects of DMBT in age-related macular degeneration by inhibition of VEGF secretion through ROS-dependent signaling pathway. Mol Cell Biochem 448:225–235.  https://doi.org/10.1007/s11010-018-3328-6 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Cheung CMG et al (2017) Characterization and differentiation of polypoidal choroidal vasculopathy using swept source optical coherence tomography angiography. Retina 37:1464–1474.  https://doi.org/10.1097/IAE.0000000000001391 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Cheung CMG et al (2019) Improved detection and diagnosis of polypoidal choroidal vasculopathy using a combination of optical coherence tomography and optical coherence tomography angiography. Retina 39:1655–1663.  https://doi.org/10.1097/IAE.0000000000002228 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Chinta SJ, Woods G, Rane A, Demaria M, Campisi J, Andersen JK (2014) Cellular senescence and the aging brain. Exp Gerontol.  https://doi.org/10.1016/j.exger.2014.09.018 PubMedCrossRefPubMedCentralGoogle Scholar
  53. Chinta SJ et al (2018) Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep 22:930–940.  https://doi.org/10.1016/j.celrep.2017.12.092 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Chirco KR, Tucker BA, Stone EM, Mullins RF (2016a) Selective accumulation of the complement membrane attack complex in aging choriocapillaris. Exp Eye Res 146:393–397.  https://doi.org/10.1016/j.exer.2015.09.003 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Chirco KR et al (2016b) Monomeric C-reactive protein and inflammation in age-related macular degeneration. J Pathol 240:173–183.  https://doi.org/10.1002/path.4766 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Chirco KR, Sohn EH, Stone EM, Tucker BA, Mullins RF (2017) Structural and molecular changes in the aging choroid: implications for age-related macular degeneration. Eye (Lond) 31:10–25.  https://doi.org/10.1038/eye.2016.216 CrossRefGoogle Scholar
  57. Chua J et al (2019) Impact of systemic vascular risk factors on the choriocapillaris using optical coherence tomography angiography in patients with systemic hypertension. Sci Rep 9:5819.  https://doi.org/10.1038/s41598-019-41917-4 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Chung SE, Kang SW, Lee JH, Kim YT (2011) Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology 118:840–845.  https://doi.org/10.1016/j.ophtha.2010.09.012 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Ciulla TA et al (1999) Color Doppler imaging discloses reduced ocular blood flow velocities in nonexudative age-related macular degeneration. Am J Ophthalmol 128:75–80PubMedCrossRefPubMedCentralGoogle Scholar
  60. Coleman DJ, Lizzi FL (1979) In vivo choroidal thickness measurement. Am J Ophthalmol 88:369–375PubMedCrossRefPubMedCentralGoogle Scholar
  61. Comparison of Age-related Macular Degeneration Treatments Trials Research G et al (2012) Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 119:1388–1398.  https://doi.org/10.1016/j.ophtha.2012.03.053 CrossRefGoogle Scholar
  62. Connelly JJ et al (2013) Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis. Hum Mol Genet 22:5107–5120.  https://doi.org/10.1093/hmg/ddt365 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Csipo T et al (2018) Short-term weight loss reverses obesity-induced microvascular endothelial dysfunction. Geroscience.  https://doi.org/10.1007/s11357-018-0028-9 PubMedCentralCrossRefGoogle Scholar
  64. Csiszar A, Ungvari Z, Koller A, Edwards JG, Kaley G (2003) Aging-induced proinflammatory shift in cytokine expression profile in rat coronary arteries. FASEB J 17:1183–1185PubMedCrossRefPubMedCentralGoogle Scholar
  65. Csiszar A et al (2007) Vascular superoxide and hydrogen peroxide production and oxidative stress resistance in two closely related rodent species with disparate longevity. Aging Cell 6:783–797PubMedCrossRefPubMedCentralGoogle Scholar
  66. Csiszar A et al (2008a) Endothelial function and vascular oxidative stress in long-lived GH/IGF-deficient Ames dwarf mice. Am J Physiol Heart Circ Physiol 295:H1882–H1894.  https://doi.org/10.1152/ajpheart.412.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Csiszar A et al (2008b) Vasoprotective effects of resveratrol and SIRT1: attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. Am J Physiol Heart Circ Physiol 294:H2721–H2735PubMedPubMedCentralCrossRefGoogle Scholar
  68. Csiszar A et al (2009a) Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol.  https://doi.org/10.1152/ajpheart.00368.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  69. Csiszar A, Podlutsky A, Wolin MS, Losonczy G, Pacher P, Ungvari Z (2009b) Oxidative stress and accelerated vascular aging: implications for cigarette smoking. Front Biosci 14:3128–3144PubMedCentralCrossRefGoogle Scholar
  70. Csiszar A, Sosnowska D, Wang M, Lakatta EG, Sonntag WE, Ungvari Z (2012) Age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate Macaca mulatta: reversal by resveratrol treatment. J Gerontol A Biol Sci Med Sci 67:811-820 doi: https://doi.org/10.1093/gerona/glr228 glr228 [pii]
  71. Csiszar A et al (2014) Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. Am J Physiol Heart Circ Physiol 307:H292–H306.  https://doi.org/10.1152/ajpheart.00307.2014 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Csiszar A et al (2019) Role of endothelial NAD+ deficiency in age-related vascular dysfunction. Am J Physiol Heart Circ Physiol:in press.  https://doi.org/10.1152/ajpheart.00039.2019 PubMedCrossRefPubMedCentralGoogle Scholar
  73. Datta S, Cano M, Ebrahimi K, Wang L, Handa JT (2017) The impact of oxidative stress and inflammation on RPE degeneration in non-neovascular AMD. Prog Retin Eye Res 60:201–218.  https://doi.org/10.1016/j.preteyeres.2017.03.002 CrossRefPubMedPubMedCentralGoogle Scholar
  74. de Carlo TE et al (2015) Spectral-domain optical coherence tomography angiography of choroidal neovascularization. Ophthalmology 122:1228–1238.  https://doi.org/10.1016/j.ophtha.2015.01.029 CrossRefPubMedPubMedCentralGoogle Scholar
  75. Delcourt C et al (2010) Nutrition and age-related eye diseases: the Alienor (Antioxydants, Lipides Essentiels, Nutrition et maladies OculaiRes) Study. J Nutr Health Aging 14:854–861PubMedPubMedCentralCrossRefGoogle Scholar
  76. Dikalov SI, Ungvari Z (2013) Role of mitochondrial oxidative stress in hypertension. Am J Physiol Heart Circ Physiol 305:H1417–H1427.  https://doi.org/10.1152/ajpheart.00089.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  77. Ding X, Patel M, Chan CC (2009) Molecular pathology of age-related macular degeneration. Prog Retin Eye Res 28:1–18.  https://doi.org/10.1016/j.preteyeres.2008.10.001 CrossRefPubMedPubMedCentralGoogle Scholar
  78. Dogan B, Kazim Erol M, Dogan U, Habibi M, Bulbuller N, Turgut Coban D, Bulut M (2016) The retinal nerve fiber layer, choroidal thickness, and central macular thickness in morbid obesity: an evaluation using spectral-domain optical coherence tomography. Eur Rev Med Pharmacol Sci 20:886–891PubMedPubMedCentralGoogle Scholar
  79. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424.  https://doi.org/10.1126/science.1110189 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Eichler W, Reiche A, Yafai Y, Lange J, Wiedemann P (2008) Growth-related effects of oxidant-induced stress on cultured RPE and choroidal endothelial cells. Exp Eye Res 87:342–348.  https://doi.org/10.1016/j.exer.2008.06.017 CrossRefPubMedPubMedCentralGoogle Scholar
  81. Ersan I et al (2016) Noninvasive assessment of the retina and the choroid using enhanced-depth imaging optical coherence tomography shows microvascular impairments in childhood obesity. J AAPOS 20:58–62.  https://doi.org/10.1016/j.jaapos.2015.10.006 CrossRefPubMedPubMedCentralGoogle Scholar
  82. Espinosa-Heidmann DG, Suner IJ, Catanuto P, Hernandez EP, Marin-Castano ME, Cousins SW (2006) Cigarette smoke-related oxidants and the development of sub-RPE deposits in an experimental animal model of dry AMD. Invest Ophthalmol Vis Sci 47:729–737.  https://doi.org/10.1167/iovs.05-0719 CrossRefPubMedPubMedCentralGoogle Scholar
  83. Evans JR (2001) Risk factors for age-related macular degeneration. Prog Retin Eye Res 20:227–253PubMedCrossRefPubMedCentralGoogle Scholar
  84. Farazdaghi MK, Ebrahimi KB (2019) Role of the choroid in age-related macular degeneration: a current review. J Ophthalmic Vis Res 14:78–87.  https://doi.org/10.4103/jovr.jovr_125_18 CrossRefPubMedPubMedCentralGoogle Scholar
  85. Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C (2006) Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol Aging 27:983–993.  https://doi.org/10.1016/j.neurobiolaging.2005.05.012 CrossRefPubMedPubMedCentralGoogle Scholar
  86. Ferris FL 3rd et al (2013) Clinical classification of age-related macular degeneration. Ophthalmology 120:844–851.  https://doi.org/10.1016/j.ophtha.2012.10.036 CrossRefGoogle Scholar
  87. Fett AL, Hermann MM, Muether PS, Kirchhof B, Fauser S (2012) Immunohistochemical localization of complement regulatory proteins in the human retina. Histol Histopathol 27:357–364.  https://doi.org/10.14670/HH-27.357 CrossRefPubMedPubMedCentralGoogle Scholar
  88. Friedman E (1997) A hemodynamic model of the pathogenesis of age-related macular degeneration. Am J Ophthalmol 124:677–682.  https://doi.org/10.1016/s0002-9394(14)70906-7 CrossRefPubMedPubMedCentralGoogle Scholar
  89. Friedman E, Smith TR, Kuwabara T (1963) Senile choroidal vascular patterns and drusen. Arch Ophthalmol 69:220–230PubMedCrossRefPubMedCentralGoogle Scholar
  90. Fry JL et al (2016) Vascular smooth muscle sirtuin-1 protects against diet-induced aortic stiffness. Hypertension 68:775–784.  https://doi.org/10.1161/HYPERTENSIONAHA.116.07622 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Fryczkowski AW (1994) Anatomical and functional choroidal lobuli. Int Ophthalmol 18:131–141PubMedCrossRefPubMedCentralGoogle Scholar
  92. Fulop GA et al (2018) Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. Geroscience 40:513–521.  https://doi.org/10.1007/s11357-018-0047-6 CrossRefPubMedPubMedCentralGoogle Scholar
  93. Gattoussi S et al (2019) Choroidal thickness, vascular factors, and age-related macular degeneration: the ALIENOR Study. Retina 39:34–43.  https://doi.org/10.1097/IAE.0000000000002237 CrossRefPubMedPubMedCentralGoogle Scholar
  94. Gelfand BD, Ambati J (2016) A revised hemodynamic theory of age-related macular degeneration. Trends Mol Med 22:656–670.  https://doi.org/10.1016/j.molmed.2016.06.009 CrossRefPubMedPubMedCentralGoogle Scholar
  95. Gok M, Karabas VL, Emre E, Aksar AT, Aslan MS, Ural D (2015) Evaluation of choroidal thickness via enhanced depth-imaging optical coherence tomography in patients with systemic hypertension. Indian J Ophthalmol 63:239–243.  https://doi.org/10.4103/0301-4738.156928 CrossRefPubMedPubMedCentralGoogle Scholar
  96. Gorusupudi A, Nelson K, Bernstein PS (2017) The Age-Related Eye Disease 2 Study: micronutrients in the treatment of macular degeneration. Adv Nutr 8:40–53.  https://doi.org/10.3945/an.116.013177 CrossRefPubMedPubMedCentralGoogle Scholar
  97. Granstam E, Granstam SO, Fellstrom B, Lind L (1998) Endothelium-dependent vasodilation in the uvea of hypertensive and normotensive rats. Curr Eye Res 17:189–196PubMedCrossRefPubMedCentralGoogle Scholar
  98. Grebe R, Mughal I, Bryden W, McLeod S, Edwards M, Hageman GS, Lutty G (2019) Ultrastructural analysis of submacular choriocapillaris and its transport systems in AMD and aged control eyes. Exp Eye Res 181:252–262.  https://doi.org/10.1016/j.exer.2019.02.018 CrossRefPubMedPubMedCentralGoogle Scholar
  99. Grunwald JE, Hariprasad SM, DuPont J (1998a) Effect of aging on foveolar choroidal circulation. Arch Ophthalmol 116:150–154PubMedCrossRefPubMedCentralGoogle Scholar
  100. Grunwald JE et al (1998b) Foveolar choroidal blood flow in age-related macular degeneration. Invest Ophthalmol Vis Sci 39:385–390PubMedPubMedCentralGoogle Scholar
  101. Grunwald JE, Metelitsina TI, Dupont JC, Ying GS, Maguire MG (2005) Reduced foveolar choroidal blood flow in eyes with increasing AMD severity. Invest Ophthalmol Vis Sci 46:1033–1038.  https://doi.org/10.1167/iovs.04-1050 CrossRefPubMedPubMedCentralGoogle Scholar
  102. Grunwald JE et al (2014) Risk of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology 121:150–161.  https://doi.org/10.1016/j.ophtha.2013.08.015 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Grunwald JE, Pistilli M, Ying GS, Maguire MG, Daniel E, Martin DF, Comparison of Age-related Macular Degeneration Treatments Trials Research G (2015) Growth of geographic atrophy in the comparison of age-related macular degeneration treatments trials. Ophthalmology 122:809-816 doi: https://doi.org/10.1016/j.ophtha.2014.11.007 PubMedCrossRefPubMedCentralGoogle Scholar
  104. Gupta T, Saini N, Arora J, Sahni D (2017) Age-related changes in the chorioretinal junction: an immunohistochemical study. J Histochem Cytochem 65:567–577.  https://doi.org/10.1369/0022155417726507 CrossRefPubMedPubMedCentralGoogle Scholar
  105. Ha JM et al (2015) Platelet-derived growth factor regulates vascular smooth muscle phenotype via mammalian target of rapamycin complex 1. Biochem Biophys Res Commun 464:57–62.  https://doi.org/10.1016/j.bbrc.2015.05.097 CrossRefPubMedPubMedCentralGoogle Scholar
  106. Hageman GS et al (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102:7227–7232.  https://doi.org/10.1073/pnas.0501536102 CrossRefPubMedPubMedCentralGoogle Scholar
  107. Hahn P, Acquah K, Cousins SW, Lee PP, Sloan FA (2013) Ten-year incidence of age-related macular degeneration according to diabetic retinopathy classification among Medicare beneficiaries. Retina 33:911–919.  https://doi.org/10.1097/IAE.0b013e3182831248 CrossRefPubMedPubMedCentralGoogle Scholar
  108. Haines JL et al (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419–421.  https://doi.org/10.1126/science.1110359 CrossRefPubMedPubMedCentralGoogle Scholar
  109. Hashitani H, Windle A, Suzuki H (1998) Neuroeffector transmission in arterioles of the guinea-pig choroid. J Physiol 510(Pt 1):209–223PubMedPubMedCentralCrossRefGoogle Scholar
  110. Hikichi T, Agarie M (2019) Reduced vessel density of the choriocapillaris during anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 60:1088–1095.  https://doi.org/10.1167/iovs.18-24522 CrossRefPubMedPubMedCentralGoogle Scholar
  111. Ho AC, Scott IU, Kim SJ, Brown GC, Brown MM, Ip MS, Recchia FM (2012) Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: a report by the American Academy of Ophthalmology. Ophthalmology 119:2179–2188.  https://doi.org/10.1016/j.ophtha.2012.07.058 CrossRefPubMedGoogle Scholar
  112. Hogg RE et al (2008) Cardiovascular disease and hypertension are strong risk factors for choroidal neovascularization. Ophthalmology 115(1046-1052):e1042.  https://doi.org/10.1016/j.ophtha.2007.07.031 CrossRefGoogle Scholar
  113. Icel E, Imamoglu HI, Turk A, Icel A, Akyol N (2018) A comparison of the effects of perindopril arginine and amlodipine on choroidal thickness in patients with primary hypertension. Turk J Med Sci 48:1247–1254.  https://doi.org/10.3906/sag-1803-171 CrossRefPubMedGoogle Scholar
  114. Ida H, Ishibashi K, Reiser K, Hjelmeland LM, Handa JT (2004) Ultrastructural aging of the RPE-Bruch’s membrane-choriocapillaris complex in the D-galactose-treated mouse. Invest Ophthalmol Vis Sci 45:2348–2354.  https://doi.org/10.1167/iovs.03-1337 CrossRefPubMedGoogle Scholar
  115. Imamura Y et al (2006) Drusen, choroidal neovascularization, and retinal pigment epithelium dysfunction in SOD1-deficient mice: a model of age-related macular degeneration. Proc Natl Acad Sci U S A 103:11282–11287.  https://doi.org/10.1073/pnas.0602131103 CrossRefPubMedPubMedCentralGoogle Scholar
  116. Inan S, Baysal Z, Inan UU (2019) Long-term changes in submacular choroidal thickness after intravitreal ranibizumab therapy for neovascular age-related macular degeneration: 14-mo follow-up. Curr Eye Res:1–8.  https://doi.org/10.1080/02713683.2019.1600195 PubMedCrossRefGoogle Scholar
  117. Inoue M, Balaratnasingam C, Freund KB (2015) Optical coherence tomography angiography of polypoidal choroidal vasculopathy and polypoidal choroidal neovascularization. Retina 35:2265–2274.  https://doi.org/10.1097/IAE.0000000000000777 CrossRefPubMedPubMedCentralGoogle Scholar
  118. Invernizzi A et al (2018) Choroidal structural changes correlate with neovascular activity in neovascular age related macular degeneration. Invest Ophthalmol Vis Sci 59:3836–3841.  https://doi.org/10.1167/iovs.18-23960 CrossRefPubMedPubMedCentralGoogle Scholar
  119. Ivanescu AA et al (2015) Modifying choroidal neovascularization development with a nutritional supplement in mice. Nutrients 7:5423–5442.  https://doi.org/10.3390/nu7075229 CrossRefPubMedPubMedCentralGoogle Scholar
  120. Jia Y et al (2014) Quantitative optical coherence tomography angiography of choroidal neovascularization in age-related macular degeneration. Ophthalmology 121:1435–1444.  https://doi.org/10.1016/j.ophtha.2014.01.034 CrossRefPubMedPubMedCentralGoogle Scholar
  121. Jia Y et al (2015) Quantitative optical coherence tomography angiography of vascular abnormalities in the living human eye. Proc Natl Acad Sci U S A 112:E2395–E2402.  https://doi.org/10.1073/pnas.1500185112 CrossRefPubMedPubMedCentralGoogle Scholar
  122. Jiang H et al (2017) Serine racemase deficiency attenuates choroidal neovascularization and reduces nitric oxide and VEGF levels by retinal pigment epithelial cells. J Neurochem 143:375–388.  https://doi.org/10.1111/jnc.14214 CrossRefPubMedPubMedCentralGoogle Scholar
  123. Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH (2000) A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 70:441–449.  https://doi.org/10.1006/exer.1999.0798 CrossRefPubMedPubMedCentralGoogle Scholar
  124. Kanavi MR et al (2014) The sustained delivery of resveratrol or a defined grape powder inhibits new blood vessel formation in a mouse model of choroidal neovascularization. Molecules 19:17578–17603.  https://doi.org/10.3390/molecules191117578 CrossRefPubMedPubMedCentralGoogle Scholar
  125. Kantarci FA, Tatar MG, Colak HN, Uslu H, Yildirim A, Goker H, Gurler B (2016) A pilot study of choroidal thickness in long-term smokers. Retina 36:986–991.  https://doi.org/10.1097/IAE.0000000000000815 CrossRefPubMedPubMedCentralGoogle Scholar
  126. Keenan TD et al (2014) Age-dependent changes in heparan sulfate in human Bruch’s membrane: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci 55:5370–5379.  https://doi.org/10.1167/iovs.14-14126 CrossRefPubMedPubMedCentralGoogle Scholar
  127. Keenan TD et al (2018) Progression of geographic atrophy in age-related macular degeneration: AREDS2 report number 16. Ophthalmology 125:1913–1928.  https://doi.org/10.1016/j.ophtha.2018.05.028 CrossRefPubMedPubMedCentralGoogle Scholar
  128. Keir LS et al (2017) VEGF regulates local inhibitory complement proteins in the eye and kidney. J Clin Invest 127:199–214.  https://doi.org/10.1172/JCI86418 CrossRefPubMedPubMedCentralGoogle Scholar
  129. Kiel JW, Shepherd AP (1992) Autoregulation of choroidal blood flow in the rabbit. Invest Ophthalmol Vis Sci 33:2399–2410PubMedPubMedCentralGoogle Scholar
  130. Kim JT, Lee DH, Joe SG, Kim JG, Yoon YH (2013) Changes in choroidal thickness in relation to the severity of retinopathy and macular edema in type 2 diabetic patients. Invest Ophthalmol Vis Sci 54:3378–3384.  https://doi.org/10.1167/iovs.12-11503 CrossRefPubMedPubMedCentralGoogle Scholar
  131. Kim M, Ha MJ, Choi SY, Park YH (2018) Choroidal vascularity index in type-2 diabetes analyzed by swept-source optical coherence tomography. Sci Rep 8.  https://doi.org/10.1038/s41598-017-18511-7
  132. Kim J et al (2019) Tie2 activation promotes choriocapillary regeneration for alleviating neovascular age-related macular degeneration. Sci Adv 5:eaau6732.  https://doi.org/10.1126/sciadv.aau6732 CrossRefPubMedPubMedCentralGoogle Scholar
  133. Kiss T et al. (2019) Nicotinamide mononucleotide (NMN) treatment attenuates oxidative stress and rescues angiogenic capacity in aged cerebromicrovascular endothelial cells: a potential mechanism for prevention of vascular cognitive impairment. GeroScience:in pressGoogle Scholar
  134. Kivinen N et al (2016) Absence of collagen XVIII in mice causes age-related insufficiency in retinal pigment epithelium proteostasis. Biogerontology 17:749–761.  https://doi.org/10.1007/s10522-016-9647-7 CrossRefPubMedGoogle Scholar
  135. Klein BE, Klein R, Lee KE, Jensen SC (2001) Measures of obesity and age-related eye diseases. Ophthalmic Epidemiol 8:251–262PubMedCrossRefPubMedCentralGoogle Scholar
  136. Klein R, Peto T, Bird A, Vannewkirk MR (2004) The epidemiology of age-related macular degeneration. Am J Ophthalmol 137:486–495.  https://doi.org/10.1016/j.ajo.2003.11.069 CrossRefPubMedGoogle Scholar
  137. Klein RJ et al (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389.  https://doi.org/10.1126/science.1109557 CrossRefPubMedPubMedCentralGoogle Scholar
  138. Koh A et al (2012) EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina 32:1453–1464.  https://doi.org/10.1097/IAE.0b013e31824f91e8 CrossRefPubMedGoogle Scholar
  139. Koh AH et al (2013) Polypoidal choroidal vasculopathy: evidence-based guidelines for clinical diagnosis and treatment. Retina 33:686–716.  https://doi.org/10.1097/IAE.0b013e3182852446 CrossRefPubMedGoogle Scholar
  140. Koh A et al (2017a) Efficacy and safety of ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: a randomized clinical trial. JAMA Ophthalmol 135:1206–1213.  https://doi.org/10.1001/jamaophthalmol.2017.4030 CrossRefPubMedPubMedCentralGoogle Scholar
  141. Koh LHL, Agrawal R, Khandelwal N, Sai Charan L, Chhablani J (2017b) Choroidal vascular changes in age-related macular degeneration. Acta Ophthalmol 95:e597–e601.  https://doi.org/10.1111/aos.13399 CrossRefPubMedGoogle Scholar
  142. Kolosova NG, Muraleva NA, Zhdankina AA, Stefanova NA, Fursova AZ, Blagosklonny MV (2012) Prevention of age-related macular degeneration-like retinopathy by rapamycin in rats. Am J Pathol 181:472–477.  https://doi.org/10.1016/j.ajpath.2012.04.018 CrossRefPubMedGoogle Scholar
  143. Koss MC, Gherezghiher T (1993) Adrenoceptor subtypes involved in neurally evoked sympathetic vasoconstriction in the anterior choroid of cats. Exp Eye Res 57:441–447.  https://doi.org/10.1006/exer.1993.1146 CrossRefPubMedGoogle Scholar
  144. Kozhevnikova OS, Korbolina EE, Stefanova NA, Muraleva NA, Orlov YL, Kolosova NG (2013) Association of AMD-like retinopathy development with an Alzheimer’s disease metabolic pathway in OXYS rats. Biogerontology 14:753–762.  https://doi.org/10.1007/s10522-013-9439-2 CrossRefPubMedGoogle Scholar
  145. Kumase F, Morizane Y, Mohri S, Takasu I, Ohtsuka A, Ohtsuki H (2010) Glycocalyx degradation in retinal and choroidal capillary endothelium in rats with diabetes and hypertension. Acta Med Okayama 64:277–283.  https://doi.org/10.18926/AMO/40502 CrossRefPubMedGoogle Scholar
  146. Kur J, Newman EA, Chan-Ling T (2012) Cellular and physiological mechanisms underlying blood flow regulation in the retina and choroid in health and disease. Prog Retin Eye Res 31:377–406.  https://doi.org/10.1016/j.preteyeres.2012.04.004 CrossRefPubMedPubMedCentralGoogle Scholar
  147. Kurihara T, Westenskow PD, Bravo S, Aguilar E, Friedlander M (2012) Targeted deletion of Vegfa in adult mice induces vision loss. J Clin Invest 122:4213–4217.  https://doi.org/10.1172/JCI65157 CrossRefPubMedPubMedCentralGoogle Scholar
  148. Kurokawa K, Liu Z, Miller DT (2017) Adaptive optics optical coherence tomography angiography for morphometric analysis of choriocapillaris [Invited]. Biomed Opt Express 8:1803–1822.  https://doi.org/10.1364/BOE.8.001803 CrossRefPubMedPubMedCentralGoogle Scholar
  149. Labinskyy N et al (2009) Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus. Am J Physiol Heart Circ Physiol 296:H946–H956.  https://doi.org/10.1152/ajpheart.00693.2008 CrossRefPubMedPubMedCentralGoogle Scholar
  150. Lavinsky F, Lavinsky D (2016) Novel perspectives on swept-source optical coherence tomography. Int J Retina Vitreous 2:25.  https://doi.org/10.1186/s40942-016-0050-y CrossRefPubMedPubMedCentralGoogle Scholar
  151. Lee J et al (2014) Angiopoietin-1 suppresses choroidal neovascularization and vascular leakage. Invest Ophthalmol Vis Sci 55:2191–2199.  https://doi.org/10.1167/iovs.14-13897 CrossRefPubMedGoogle Scholar
  152. Lee MB et al (2017) A system to identify inhibitors of mTOR signaling using high-resolution growth analysis in Saccharomyces cerevisiae. Geroscience.  https://doi.org/10.1007/s11357-017-9988-4 PubMedPubMedCentralCrossRefGoogle Scholar
  153. Lee B, Ahn J, Yun C, Kim SW, Oh J (2018a) Variation of retinal and choroidal vasculatures in patients with age-related macular degeneration. Invest Ophthalmol Vis Sci 59:5246–5255.  https://doi.org/10.1167/iovs.17-23600 CrossRefPubMedPubMedCentralGoogle Scholar
  154. Lee HJ et al (2018b) Hydrogen sulfide ameliorates aging-associated changes in the kidney. Geroscience 40:163–176.  https://doi.org/10.1007/s11357-018-0018-y CrossRefPubMedPubMedCentralGoogle Scholar
  155. Leitgeb RA, Werkmeister RM, Blatter C, Schmetterer L (2014) Doppler optical coherence tomography. Prog Retin Eye Res 41:26–43.  https://doi.org/10.1016/j.preteyeres.2014.03.004 CrossRefPubMedPubMedCentralGoogle Scholar
  156. Lengyel I, Tufail A, Hosaini HA, Luthert P, Bird AC, Jeffery G (2004) Association of drusen deposition with choroidal intercapillary pillars in the aging human eye. Invest Ophthalmol Vis Sci 45:2886–2892.  https://doi.org/10.1167/iovs.03-1083 CrossRefPubMedPubMedCentralGoogle Scholar
  157. Lesniewski LA et al (2017) Dietary rapamycin supplementation reverses age-related vascular dysfunction and oxidative stress, while modulating nutrient-sensing, cell cycle, and senescence pathways. Aging Cell 16:17–26.  https://doi.org/10.1111/acel.12524 CrossRefPubMedPubMedCentralGoogle Scholar
  158. Li R, Du J, Chang Y (2016) Role of autophagy in hypoxia-induced angiogenesis of RF/6A cells in vitro. Curr Eye Res 41:1566–1570.  https://doi.org/10.3109/02713683.2016.1145234 CrossRefPubMedPubMedCentralGoogle Scholar
  159. Li J, Zhang R, Wang C, Wang X, Xu M, Ma J, Shang Q (2018) Activation of the small GTPase Rap1 inhibits choroidal neovascularization by regulating cell junctions and ROS generation in rats. Curr Eye Res 43:934–940.  https://doi.org/10.1080/02713683.2018.1454477 CrossRefPubMedPubMedCentralGoogle Scholar
  160. Lin H et al (2011) Mitochondrial DNA damage and repair in RPE associated with aging and age-related macular degeneration. Invest Ophthalmol Vis Sci 52:3521–3529.  https://doi.org/10.1167/iovs.10-6163 CrossRefPubMedPubMedCentralGoogle Scholar
  161. Lin AL et al (2013) Chronic rapamycin restores brain vascular integrity and function through NO synthase activation and improves memory in symptomatic mice modeling Alzheimer’s disease. J Cereb Blood Flow Metab 33:1412–1421.  https://doi.org/10.1038/jcbfm.2013.82 CrossRefPubMedPubMedCentralGoogle Scholar
  162. Lois N, McBain V, Abdelkader E, Scott NW, Kumari R (2013) Retinal pigment epithelial atrophy in patients with exudative age-related macular degeneration undergoing anti-vascular endothelial growth factor therapy. Retina 33:13–22.  https://doi.org/10.1097/IAE.0b013e3182657fff CrossRefPubMedPubMedCentralGoogle Scholar
  163. Lutjen-Drecoll E (2006) Choroidal innervation in primate eyes. Exp Eye Res 82:357–361.  https://doi.org/10.1016/j.exer.2005.09.015 CrossRefPubMedPubMedCentralGoogle Scholar
  164. Lutty G, Grunwald J, Majji AB, Uyama M, Yoneya S (1999) Changes in choriocapillaris and retinal pigment epithelium in age-related macular degeneration. Mol Vis 5:35PubMedPubMedCentralGoogle Scholar
  165. Majji AB, Cao J, Chang KY, Hayashi A, Aggarwal S, Grebe RR, De Juan E, Jr. (2000) Age-related retinal pigment epithelium and Bruch’s membrane degeneration in senescence-accelerated mouse. Invest Ophthalmol Vis Sci 41:3936–3942PubMedPubMedCentralGoogle Scholar
  166. Marazita MC, Dugour A, Marquioni-Ramella MD, Figueroa JM, Suburo AM (2016) Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: implications for age-related macular degeneration. Redox Biol 7:78–87.  https://doi.org/10.1016/j.redox.2015.11.011 CrossRefPubMedPubMedCentralGoogle Scholar
  167. Marfella R et al (2008) Effects of ubiquitin-proteasome system deregulation on the vascular senescence and atherosclerosis process in elderly patients. J Gerontol A Biol Sci Med Sci 63:200–203.  https://doi.org/10.1093/gerona/63.2.200 CrossRefPubMedPubMedCentralGoogle Scholar
  168. Markovets AM, Saprunova VB, Zhdankina AA, Fursova A, Bakeeva LE, Kolosova NG (2011) Alterations of retinal pigment epithelium cause AMD-like retinopathy in senescence-accelerated OXYS rats. Aging (Albany NY) 3:44–54.  https://doi.org/10.18632/aging.100243 CrossRefGoogle Scholar
  169. Mattison JA et al (2014) Resveratrol prevents high fat/sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metab 20:183–190.  https://doi.org/10.1016/j.cmet.2014.04.018 CrossRefPubMedPubMedCentralGoogle Scholar
  170. McHarg S, Clark SJ, Day AJ, Bishop PN (2015) Age-related macular degeneration and the role of the complement system. Mol Immunol 67:43–50.  https://doi.org/10.1016/j.molimm.2015.02.032 CrossRefPubMedPubMedCentralGoogle Scholar
  171. McLeod DS, Taomoto M, Otsuji T, Green WR, Sunness JS, Lutty GA (2002) Quantifying changes in RPE and choroidal vasculature in eyes with age-related macular degeneration. Invest Ophthalmol Vis Sci 43:1986–1993PubMedPubMedCentralGoogle Scholar
  172. McLeod DS, Grebe R, Bhutto I, Merges C, Baba T, Lutty GA (2009) Relationship between RPE and choriocapillaris in age-related macular degeneration. Invest Ophthalmol Vis Sci 50:4982–4991.  https://doi.org/10.1167/iovs.09-3639 CrossRefPubMedPubMedCentralGoogle Scholar
  173. Metelitsina TI, Grunwald JE, DuPont JC, Ying GS, Brucker AJ, Dunaief JL (2008) Foveolar choroidal circulation and choroidal neovascularization in age-related macular degeneration. Invest Ophthalmol Vis Sci 49:358–363.  https://doi.org/10.1167/iovs.07-0526 CrossRefPubMedPubMedCentralGoogle Scholar
  174. Minor RK et al (2011) SRT1720 improves survival and healthspan of obese mice. Sci Rep 1:70.  https://doi.org/10.1038/srep00070 CrossRefPubMedPubMedCentralGoogle Scholar
  175. Mitter SK et al (2014) Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD. Autophagy 10:1989–2005.  https://doi.org/10.4161/auto.36184 CrossRefPubMedPubMedCentralGoogle Scholar
  176. Moschos MM, Nitoda E, Laios K, Ladas DS, Chatziralli IP (2016) The impact of chronic tobacco smoking on retinal and choroidal thickness in Greek population. Oxidative Med Cell Longev 2016:2905789.  https://doi.org/10.1155/2016/2905789 CrossRefGoogle Scholar
  177. Mottet B et al (2018) Choroidal blood flow after the first intravitreal ranibizumab injection in neovascular age-related macular degeneration patients. Acta Ophthalmol 96:e783–e788.  https://doi.org/10.1111/aos.13763 CrossRefPubMedPubMedCentralGoogle Scholar
  178. Moult E et al (2014) Ultrahigh-speed swept-source OCT angiography in exudative AMD. Ophthalmic Surg Lasers Imaging Retina 45:496–505.  https://doi.org/10.3928/23258160-20141118-03 CrossRefPubMedPubMedCentralGoogle Scholar
  179. Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 14:835–846PubMedCrossRefPubMedCentralGoogle Scholar
  180. Mullins RF, Johnson MN, Faidley EA, Skeie JM, Huang J (2011) Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 52:1606–1612.  https://doi.org/10.1167/iovs.10-6476 CrossRefPubMedPubMedCentralGoogle Scholar
  181. Mullins RF et al (2014) The membrane attack complex in aging human choriocapillaris: relationship to macular degeneration and choroidal thinning. Am J Pathol 184:3142–3153.  https://doi.org/10.1016/j.ajpath.2014.07.017 CrossRefPubMedPubMedCentralGoogle Scholar
  182. Muraleva NA, Kozhevnikova OS, Zhdankina AA, Stefanova NA, Karamysheva TV, Fursova AZ, Kolosova NG (2014) The mitochondria-targeted antioxidant SkQ1 restores alphaB-crystallin expression and protects against AMD-like retinopathy in OXYS rats. Cell Cycle 13:3499–3505.  https://doi.org/10.4161/15384101.2014.958393 CrossRefPubMedPubMedCentralGoogle Scholar
  183. Nacarelli T, Azar A, Altinok O, Orynbayeva Z, Sell C (2018) Rapamycin increases oxidative metabolism and enhances metabolic flexibility in human cardiac fibroblasts. Geroscience.  https://doi.org/10.1007/s11357-018-0030-2 PubMedCentralCrossRefGoogle Scholar
  184. Nagai N, Kubota S, Tsubota K, Ozawa Y (2014) Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types. J Nutr Biochem 25:1218–1225.  https://doi.org/10.1016/j.jnutbio.2014.05.015 CrossRefPubMedPubMedCentralGoogle Scholar
  185. Nagaoka T et al (2004) Alteration of choroidal circulation in the foveal region in patients with type 2 diabetes. Br J Ophthalmol 88:1060–1063.  https://doi.org/10.1136/bjo.2003.035345 CrossRefPubMedPubMedCentralGoogle Scholar
  186. Nakamura S et al (2019) Nrf2 activator RS9 suppresses pathological ocular angiogenesis and hyperpermeability. Invest Ophthalmol Vis Sci 60:1943–1952.  https://doi.org/10.1167/iovs.18-25745 CrossRefPubMedPubMedCentralGoogle Scholar
  187. Nanoudis S, Pikilidou M, Yavropoulou M, Zebekakis P (2017) The role of microRNAs in arterial stiffness and arterial calcification. An update and review of the literature. Front Genet 8:209.  https://doi.org/10.3389/fgene.2017.00209 CrossRefPubMedPubMedCentralGoogle Scholar
  188. Nassisi M, Tepelus T, Nittala MG, Sadda SR (2019) Choriocapillaris flow impairment predicts the development and enlargement of drusen. Graefes Arch Clin Exp Ophthalmol.  https://doi.org/10.1007/s00417-019-04403-1 PubMedCrossRefPubMedCentralGoogle Scholar
  189. Nguyen A, Leblond F, Mamarbachi M, Geoffroy S, Thorin E (2016) Age-dependent demethylation of Sod2 promoter in the mouse femoral artery. Oxidative Med Cell Longev 2016:8627384.  https://doi.org/10.1155/2016/8627384 CrossRefGoogle Scholar
  190. Ninomiya H, Inomata T (2014) Functional microvascular anatomy of the horse eye: a scanning electron microscopic study of corrosion casts. Open Journal of Veterinary Medicine 04:91–101CrossRefGoogle Scholar
  191. Nita M, Grzybowski A (2017) Smoking and eye pathologies. a systemic review. Part II. Retina diseases, uveitis, optic neuropathies, thyroid-associated orbitopathy. Curr Pharm Des 23:639–654.  https://doi.org/10.2174/1381612823666170111095723 CrossRefPubMedPubMedCentralGoogle Scholar
  192. Oner RI, Karadag AS (2018) Evaluation of choroidal perfusion changes in obese patients: ocular effects of insulin resistance. Arq Bras Oftalmol 81:461–465.  https://doi.org/10.5935/0004-2749.20180088 CrossRefPubMedPubMedCentralGoogle Scholar
  193. Orosz Z et al (2007) Cigarette smoke-induced proinflammatory alterations in the endothelial phenotype: role of NAD(P)H oxidase activation. Am J Physiol 292:H130–H139Google Scholar
  194. Pandian S, Jeevanesan V, Ponnusamy C, Natesan S (2017) RES-loaded pegylated CS NPs: for efficient ocular delivery. IET Nanobiotechnol 11:32–39.  https://doi.org/10.1049/iet-nbt.2016.0069 CrossRefPubMedPubMedCentralGoogle Scholar
  195. Pauleikhoff D, Spital G, Radermacher M, Brumm GA, Lommatzsch A, Bird AC (1999) A fluorescein and indocyanine green angiographic study of choriocapillaris in age-related macular disease. Arch Ophthalmol 117:1353–1358PubMedCrossRefPubMedCentralGoogle Scholar
  196. Pawlowska E, Szczepanska J, Koskela A, Kaarniranta K, Blasiak J (2019) Dietary polyphenols in age-related macular degeneration: protection against oxidative stress and beyond. Oxidative Med Cell Longev 2019:9682318.  https://doi.org/10.1155/2019/9682318 CrossRefGoogle Scholar
  197. Paz AA et al (2019) Premature vascular aging in guinea pigs affected by fetal growth restriction. Int J Mol Sci:20.  https://doi.org/10.3390/ijms20143474 PubMedCentralCrossRefGoogle Scholar
  198. Peeters A, Magliano DJ, Stevens J, Duncan BB, Klein R, Wong TY (2008) Changes in abdominal obesity and age-related macular degeneration: the Atherosclerosis Risk in Communities Study. Arch Ophthalmol 126:1554–1560.  https://doi.org/10.1001/archopht.126.11.1554 CrossRefPubMedPubMedCentralGoogle Scholar
  199. Pemp B, Schmetterer L (2008) Ocular blood flow in diabetes and age-related macular degeneration. Can J Ophthalmol 43:295–301.  https://doi.org/10.3129/i08-049 CrossRefPubMedPubMedCentralGoogle Scholar
  200. Peters S et al (2007) Ultrastructural findings in the primate eye after intravitreal injection of bevacizumab. Am J Ophthalmol 143:995–1002.  https://doi.org/10.1016/j.ajo.2007.03.007 CrossRefPubMedPubMedCentralGoogle Scholar
  201. Pilotto E, Midena E, Longhin E, Parrozzani R, Frisina R, Frizziero L (2019) Muller cells and choriocapillaris in the pathogenesis of geographic atrophy secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol.  https://doi.org/10.1007/s00417-019-04289-z PubMedCrossRefPubMedCentralGoogle Scholar
  202. Polak K et al (2003) Choroidal blood flow and arterial blood pressure. Eye (Lond) 17:84–88.  https://doi.org/10.1038/sj.eye.6700246 CrossRefGoogle Scholar
  203. Polska E, Simader C, Weigert G, Doelemeyer A, Kolodjaschna J, Scharmann O, Schmetterer L (2007) Regulation of choroidal blood flow during combined changes in intraocular pressure and arterial blood pressure. Invest Ophthalmol Vis Sci 48:3768–3774.  https://doi.org/10.1167/iovs.07-0307 CrossRefPubMedPubMedCentralGoogle Scholar
  204. Possek E (1905) Ueber senile. Maculaveränderung bei Arteriosklerose Ophthalmologica 13(suppl 1):771–779.  https://doi.org/10.1159/000290375 CrossRefGoogle Scholar
  205. Querques G et al (2012) Enhanced depth imaging optical coherence tomography in type 2 diabetes. Invest Ophthalmol Vis Sci 53:6017–6024.  https://doi.org/10.1167/iovs.12-9692 CrossRefPubMedPubMedCentralGoogle Scholar
  206. Rahman W, Chen FK, Yeoh J, Patel P, Tufail A, Da Cruz L (2011) Repeatability of manual subfoveal choroidal thickness measurements in healthy subjects using the technique of enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci 52:2267–2271.  https://doi.org/10.1167/iovs.10-6024 CrossRefPubMedPubMedCentralGoogle Scholar
  207. Ramírez JM, Salazar JJ, de Hoz R, Rojas B, Gallego BI, Ramírez AI, Triviño A (2012) Choroidal vessel wall: hypercholesterolaemia-induced dysfunction and potential role of statins. In: Sugi H (ed) Current basic and pathological approaches to the function of muscle cells and tissues—from molecules to humans. Intech, Rijeka, Croatia, p 255Google Scholar
  208. Ramrattan RS, van der Schaft TL, Mooy CM, de Bruijn WC, Mulder PG, de Jong PT (1994) Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 35:2857–2864PubMedPubMedCentralGoogle Scholar
  209. Regatieri CV, Branchini L, Carmody J, Fujimoto JG, Duker JS (2012) Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 32:563–568.  https://doi.org/10.1097/IAE.0b013e31822f5678 CrossRefPubMedPubMedCentralGoogle Scholar
  210. Rezkallah A, Kodjikian L, Abukhashabah A, Denis P, Mathis T (2019) Hypertensive choroidopathy: multimodal imaging and the contribution of wide-field swept-source OCT-angiography. Am J Ophthalmol Case Rep 13:131–135.  https://doi.org/10.1016/j.ajoc.2019.01.001 CrossRefPubMedPubMedCentralGoogle Scholar
  211. Rispoli M, Savastano MC, Lumbroso B (2018) Quantitative vascular density changes in choriocapillaris around CNV after anti-VEGF treatment: dark halo. Ophthalmic Surg Lasers Imaging Retina 49:918–924.  https://doi.org/10.3928/23258160-20181203-02 CrossRefPubMedPubMedCentralGoogle Scholar
  212. Riva CE, Titze P, Hero M, Petrig BL (1997) Effect of acute decreases of perfusion pressure on choroidal blood flow in humans. Invest Ophthalmol Vis Sci 38:1752–1760PubMedPubMedCentralGoogle Scholar
  213. Riva CE, Geiser M, Petrig BL (2010) Ocular blood flow assessment using continuous laser Doppler flowmetry. Acta Ophthalmol 88:622–629.  https://doi.org/10.1111/j.1755-3768.2009.01621.x CrossRefPubMedPubMedCentralGoogle Scholar
  214. Rofagha S, Bhisitkul RB, Boyer DS, Sadda SR, Zhang K, Group S-US (2013) Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: a multicenter cohort study (SEVEN-UP). Ophthalmology 120:2292–2299.  https://doi.org/10.1016/j.ophtha.2013.03.046 CrossRefPubMedPubMedCentralGoogle Scholar
  215. Roos CM et al (2016) Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15:973–977.  https://doi.org/10.1111/acel.12458 CrossRefPubMedPubMedCentralGoogle Scholar
  216. Rossman MJ et al (2017) Endothelial cell senescence with aging in healthy humans: prevention by habitual exercise and relation to vascular endothelial function. Am J Physiol Heart Circ Physiol 313:H890–H895.  https://doi.org/10.1152/ajpheart.00416.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  217. Saito M, Ishibazawa A, Kinouchi R, Yoshida A (2018) Reperfusion of the choriocapillaris observed using optical coherence tomography angiography in hypertensive choroidopathy. Int Ophthalmol 38:2205–2210.  https://doi.org/10.1007/s10792-017-0705-1 CrossRefPubMedPubMedCentralGoogle Scholar
  218. Sariyeva Ismayilov A, Esen E, Sizmaz S, Demircan AN (2019) Aflibercept therapy in eyes with neovascular age-related macular degeneration and its effect on choroidal thickness. Clin Exp Optom.  https://doi.org/10.1111/cxo.12877 PubMedCrossRefPubMedCentralGoogle Scholar
  219. Sato T, Takeuchi M (2018) Pregnancy-induced hypertension-related chorioretinitis resembling uveal effusion syndrome: a case report. Medicine (Baltimore) 97:e11572.  https://doi.org/10.1097/MD.0000000000011572 CrossRefGoogle Scholar
  220. Saunier V et al (2018) Incidence of and risk factors associated with age-related macular degeneration: four-year follow-up from the ALIENOR study. JAMA Ophthalmol 136:473–481.  https://doi.org/10.1001/jamaophthalmol.2018.0504 CrossRefPubMedPubMedCentralGoogle Scholar
  221. Schuster AK et al (2019) Choroidal thickness is associated with cardiovascular risk factors and cardiac health: the Gutenberg Health Study. Clin Res Cardiol.  https://doi.org/10.1007/s00392-019-01498-8
  222. Seddon JM, Cote J, Davis N, Rosner B (2003) Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol 121:785–792.  https://doi.org/10.1001/archopht.121.6.785 CrossRefPubMedPubMedCentralGoogle Scholar
  223. Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N (2004) Association between C-reactive protein and age-related macular degeneration. JAMA 291:704–710.  https://doi.org/10.1001/jama.291.6.704 CrossRefPubMedPubMedCentralGoogle Scholar
  224. Seddon JM, George S, Rosner B, Rifai N (2005) Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers. Arch Ophthalmol 123:774–782.  https://doi.org/10.1001/archopht.123.6.774 CrossRefPubMedPubMedCentralGoogle Scholar
  225. Seddon JM et al (2016) Histopathological insights into choroidal vascular loss in clinically documented cases of age-related macular degeneration. JAMA Ophthalmol 134:1272–1280.  https://doi.org/10.1001/jamaophthalmol.2016.3519 CrossRefPubMedPubMedCentralGoogle Scholar
  226. Seth A, Cui J, To E, Kwee M, Matsubara J (2008) Complement-associated deposits in the human retina. Invest Ophthalmol Vis Sci 49:743–750.  https://doi.org/10.1167/iovs.07-1072 CrossRefPubMedPubMedCentralGoogle Scholar
  227. Shen ZJ, Yang XF, Xu J, She CY, Wei WW, Zhu WL, Liu NP (2017) Association of choroidal thickness with early stages of diabetic retinopathy in type 2 diabetes. Int J Ophthalmol 10:613–618.  https://doi.org/10.18240/ijo.2017.04.18 CrossRefPubMedPubMedCentralGoogle Scholar
  228. Shiragami C, Shiraga F, Matsuo T, Tsuchida Y, Ohtsuki H (2002) Risk factors for diabetic choroidopathy in patients with diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 240:436–442.  https://doi.org/10.1007/s00417-002-0451-5 CrossRefPubMedPubMedCentralGoogle Scholar
  229. Sigler EJ, Randolph JC, Calzada JI, Charles S (2014) Smoking and choroidal thickness in patients over 65 with early-atrophic age-related macular degeneration and normals. Eye (Lond) 28:838–846.  https://doi.org/10.1038/eye.2014.100 CrossRefGoogle Scholar
  230. Sizmaz S, Kucukerdonmez C, Pinarci EY, Karalezli A, Canan H, Yilmaz G (2013) The effect of smoking on choroidal thickness measured by optical coherence tomography. Br J Ophthalmol 97:601–604.  https://doi.org/10.1136/bjophthalmol-2012-302393 CrossRefPubMedGoogle Scholar
  231. Skeie JM, Fingert JH, Russell SR, Stone EM, Mullins RF (2010) Complement component C5a activates ICAM-1 expression on human choroidal endothelial cells. Invest Ophthalmol Vis Sci 51:5336–5342.  https://doi.org/10.1167/iovs.10-5322 CrossRefPubMedPubMedCentralGoogle Scholar
  232. Smit-McBride Z, Forward KI, Nguyen AT, Bordbari MH, Oltjen SL, Hjelmeland LM (2014) Age-dependent increase in miRNA-34a expression in the posterior pole of the mouse eye. Mol Vis 20:1569–1578PubMedPubMedCentralGoogle Scholar
  233. Sohn EH, Flamme-Wiese MJ, Whitmore SS, Wang K, Tucker BA, Mullins RF (2014) Loss of CD34 expression in aging human choriocapillaris endothelial cells. PLoS One 9:e86538.  https://doi.org/10.1371/journal.pone.0086538 CrossRefPubMedPubMedCentralGoogle Scholar
  234. Sohn EH et al (2019) Choriocapillaris degeneration in geographic atrophy. Am J Pathol.  https://doi.org/10.1016/j.ajpath.2019.04.005 PubMedCrossRefGoogle Scholar
  235. Spaide RF (2016) Choriocapillaris flow features follow a power law distribution: implications for characterization and mechanisms of disease progression. Am J Ophthalmol 170:58–67.  https://doi.org/10.1016/j.ajo.2016.07.023 CrossRefPubMedGoogle Scholar
  236. Spaide RF, Koizumi H, Pozzoni MC (2008) Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 146:496–500.  https://doi.org/10.1016/j.ajo.2008.05.032 CrossRefPubMedGoogle Scholar
  237. Spaide RF, Fujimoto JG, Waheed NK, Sadda SR, Staurenghi G (2018) Optical coherence tomography angiography. Prog Retin Eye Res 64:1–55.  https://doi.org/10.1016/j.preteyeres.2017.11.003 CrossRefPubMedGoogle Scholar
  238. Springo Z et al (2015) Aging exacerbates pressure-induced mitochondrial oxidative stress in mouse cerebral arteries. J Gerontol A Biol Sci Med Sci 70:1355–1359.  https://doi.org/10.1093/gerona/glu244 CrossRefPubMedPubMedCentralGoogle Scholar
  239. Srour M et al (2016) Optical coherence tomography angiography characteristics of polypoidal choroidal vasculopathy. Br J Ophthalmol 100:1489–1493.  https://doi.org/10.1136/bjophthalmol-2015-307892 CrossRefPubMedPubMedCentralGoogle Scholar
  240. Stalmans I et al (2011) Use of colour Doppler imaging in ocular blood flow research. Acta Ophthalmol 89:e609–e630.  https://doi.org/10.1111/j.1755-3768.2011.02178.x CrossRefPubMedGoogle Scholar
  241. Straubhaar M, Orgul S, Gugleta K, Schotzau A, Erb C, Flammer J (2000) Choroidal laser Doppler flowmetry in healthy subjects. Arch Ophthalmol 118:211–215PubMedCrossRefPubMedCentralGoogle Scholar
  242. Sugiyama T, Araie M, Riva CE, Schmetterer L, Orgul S (2010) Use of laser speckle flowgraphy in ocular blood flow research. Acta Ophthalmol 88:723–729.  https://doi.org/10.1111/j.1755-3768.2009.01586.x CrossRefPubMedPubMedCentralGoogle Scholar
  243. Sun L, Huang T, Xu W, Sun J, Lv Y, Wang Y (2017) Advanced glycation end products promote VEGF expression and thus choroidal neovascularization via Cyr61-PI3K/AKT signaling pathway. Sci Rep 7:14925.  https://doi.org/10.1038/s41598-017-14015-6 CrossRefPubMedPubMedCentralGoogle Scholar
  244. Supanji SM, Hasan MZ, Kawaichi M, Oka C (2013) HtrA1 is induced by oxidative stress and enhances cell senescence through p38 MAPK pathway. Exp Eye Res 112:79–92.  https://doi.org/10.1016/j.exer.2013.04.013 CrossRefPubMedPubMedCentralGoogle Scholar
  245. Synowiec E, Blasiak J, Zaras M, Szaflik J, Szaflik JP (2012) Association between polymorphisms of the DNA base excision repair genes MUTYH and hOGG1 and age-related macular degeneration. Exp Eye Res 98:58–66.  https://doi.org/10.1016/j.exer.2012.02.008 CrossRefPubMedPubMedCentralGoogle Scholar
  246. Tamaki Y, Araie M, Nagahara M, Tomita K, Matsubara M (2000) The acute effects of cigarette smoking on human optic nerve head and posterior fundus circulation in light smokers. Eye (Lond) 14(Pt 1):67–72.  https://doi.org/10.1038/eye.2000.15 CrossRefGoogle Scholar
  247. Tan KA, Laude A, Yip V, Loo E, Wong EP, Agrawal R (2016) Choroidal vascularity index—a novel optical coherence tomography parameter for disease monitoring in diabetes mellitus? Acta Ophthalmol 94:e612-e616 doi: https://doi.org/10.1111/aos.13044 PubMedCrossRefPubMedCentralGoogle Scholar
  248. Tarantini S et al (2017) Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging. Geroscience.  https://doi.org/10.1007/s11357-017-9980-z PubMedPubMedCentralCrossRefGoogle Scholar
  249. Tarantini S et al. (2018a) Nrf2 deficiency exacerbates obesity-induced oxidative stress, neurovascular dysfunction, blood brain barrier disruption, neuroinflammation, amyloidogenic gene expression and cognitive decline in mice, mimicking the aging phenotype. J Gerontol A Biol Sci Med Sci:in pressGoogle Scholar
  250. Tarantini S et al (2018b) Treatment with the mitochondrial-targeted antioxidant peptide SS-31 rescues neurovascular coupling responses and cerebrovascular endothelial function and improves cognition in aged mice. Aging Cell 17.  https://doi.org/10.1111/acel.12731 PubMedCentralCrossRefGoogle Scholar
  251. Tarantini S et al (2019) Nicotinamide mononucleotide (NMN) supplementation rescues cerebromicrovascular endothelial function and neurovascular coupling responses and improves cognitive function in aged mice. Redox Biol 24:101192.  https://doi.org/10.1016/j.redox.2019.101192 CrossRefPubMedPubMedCentralGoogle Scholar
  252. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL (2013) Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest 123:966–972.  https://doi.org/10.1172/JCI64098 CrossRefPubMedPubMedCentralGoogle Scholar
  253. Telegina DV, Korbolina EE, Ershov NI, Kolosova NG, Kozhevnikova OS (2015) Identification of functional networks associated with cell death in the retina of OXYS rats during the development of retinopathy. Cell Cycle 14:3544–3556.  https://doi.org/10.1080/15384101.2015.1080399 CrossRefPubMedPubMedCentralGoogle Scholar
  254. Thomas J, Mohammad S, Charnigo R, Baffi J, Abdel-Latif A, Ziada KM (2015) Age-related macular degeneration and coronary artery disease in a VA population. South Med J 108:502–506.  https://doi.org/10.14423/SMJ.0000000000000329 CrossRefPubMedPubMedCentralGoogle Scholar
  255. Thulliez M et al (2019) Correlations between choriocapillaris flow deficits around geographic atrophy and enlargement rates based on swept-source OCT. Imaging Ophthalmol Retina 3:478–488.  https://doi.org/10.1016/j.oret.2019.01.024 CrossRefPubMedGoogle Scholar
  256. Ting DS et al (2016) Choroidal thickness changes in age-related macular degeneration and polypoidal choroidal vasculopathy: a 12-month prospective study. Am J Ophthalmol 164(128-136):e121.  https://doi.org/10.1016/j.ajo.2015.12.024 CrossRefGoogle Scholar
  257. Tokarz P, Piastowska-Ciesielska AW, Kaarniranta K, Blasiak J (2016) All-trans retinoic acid modulates DNA damage response and the expression of the VEGF-A and MKI67 genes in ARPE-19 cells subjected to oxidative stress. Int J Mol Sci 17.  https://doi.org/10.3390/ijms17060898 PubMedCentralCrossRefPubMedGoogle Scholar
  258. Tomassoni D, Mancinelli G, Mignini F, Sabbatini M, Amenta F (2002) Quantitative image analysis of choroid and retinal vasculature in SHR: a model of cerebrovascular hypertensive changes? Clin Exp Hypertens 24:741–752PubMedCrossRefGoogle Scholar
  259. Topcu-Yilmaz P, Akyurek N, Erdogan E (2018) The effect of obesity and insulin resistance on macular choroidal thickness in a pediatric population as assessed by enhanced depth imaging optical coherence tomography. J Pediatr Endocrinol Metab 31:855–860.  https://doi.org/10.1515/jpem-2018-0079 CrossRefPubMedGoogle Scholar
  260. Toth P et al (2015) Aging exacerbates hypertension-induced cerebral microhemorrhages in mice: role of resveratrol treatment in vasoprotection. Aging Cell 14:400–408.  https://doi.org/10.1111/acel.12315 CrossRefPubMedPubMedCentralGoogle Scholar
  261. Treister AD, Nesper PL, Fayed AE, Gill MK, Mirza RG, Fawzi AA (2018) Prevalence of subclinical CNV and choriocapillaris nonperfusion in fellow eyes of unilateral exudative AMD on OCT angiography. Transl Vis Sci Technol 7:19.  https://doi.org/10.1167/tvst.7.5.19 CrossRefPubMedPubMedCentralGoogle Scholar
  262. Tucsek Z et al (2014a) Obesity in aging exacerbates blood brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 69:1212–1226PubMedCrossRefGoogle Scholar
  263. Tucsek Z et al. (2014b) Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol A Biol Sci Med Sci 69:1212-1226 doi: https://doi.org/10.1093/gerona/glt177 glt177 [pii]
  264. Tucsek Z et al (2014c) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69:1339–1352.  https://doi.org/10.1093/gerona/glu080 CrossRefPubMedPubMedCentralGoogle Scholar
  265. Tucsek Z et al (2017) Hypertension-induced synapse loss and impairment in synaptic plasticity in the mouse hippocampus mimics the aging phenotype: implications for the pathogenesis of vascular cognitive impairment. Geroscience.  https://doi.org/10.1007/s11357-017-9981-y PubMedPubMedCentralCrossRefGoogle Scholar
  266. Ulas F, Celik F, Dogan U, Celebi S (2014) Effect of smoking on choroidal thickness in healthy smokers. Curr Eye Res 39:504–511.  https://doi.org/10.3109/02713683.2013.850099 CrossRefPubMedGoogle Scholar
  267. Ungvari Z, Csiszar A, Kaminski PM, Wolin MS, Koller A (2004) Chronic high pressure-induced arterial oxidative stress: involvement of protein kinase C-dependent NAD(P)H oxidase and local renin-angiotensin system. Am J Pathol 165:219–226PubMedPubMedCentralCrossRefGoogle Scholar
  268. Ungvari Z, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith K, Csiszar A (2007a) Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293:H37–H47PubMedCrossRefGoogle Scholar
  269. Ungvari ZI, Orosz Z, Labinskyy N, Rivera A, Xiangmin Z, Smith KE, Csiszar A (2007b) Increased mitochondrial H2O2 production promotes endothelial NF-kB activation in aged rat arteries. Am J Physiol Heart Circ Physiol 293:H37–H47PubMedCrossRefGoogle Scholar
  270. Ungvari ZI, Labinskyy N, Gupte SA, Chander PN, Edwards JG, Csiszar A (2008) Dysregulation of mitochondrial biogenesis in vascular endothelial and smooth muscle cells of aged rats. Am J Physiol Heart Circ Physiol 294:H2121–H2128PubMedCrossRefGoogle Scholar
  271. Ungvari Z et al (2009) Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Am J Physiol Heart Circ Physiol 297:H1876–H1881.  https://doi.org/10.1152/ajpheart.00375.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  272. Ungvari Z et al (2011a) Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66:866–875.  https://doi.org/10.1093/gerona/glr092 CrossRefPubMedGoogle Scholar
  273. Ungvari Z et al (2011b) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301:H363–H372.  https://doi.org/10.1152/ajpheart.01134.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  274. Ungvari ZI et al (2011c) Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol 300:H1133–H1140.  https://doi.org/10.1152/ajpheart.00402.2010 CrossRefPubMedPubMedCentralGoogle Scholar
  275. Ungvari Z et al (2017a) Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence. Geroscience 39:33–42.  https://doi.org/10.1007/s11357-017-9964-z CrossRefPubMedPubMedCentralGoogle Scholar
  276. Ungvari Z, Tarantini S, Kirkpatrick AC, Csiszar A, Prodan CI (2017b) Cerebral microhemorrhages: mechanisms, consequences, and prevention. Am J Physiol Heart Circ Physiol 312:H1128–H1143.  https://doi.org/10.1152/ajpheart.00780.2016 CrossRefPubMedPubMedCentralGoogle Scholar
  277. Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A (2018) Mechanisms of vascular aging. Circ Res 123:849–867.  https://doi.org/10.1161/CIRCRESAHA.118.311378 CrossRefPubMedPubMedCentralGoogle Scholar
  278. Urfer SR, Kaeberlein TL, Mailheau S, Bergman PJ, Creevy KE, Promislow DE, Kaeberlein M (2017) A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 39:117–127.  https://doi.org/10.1007/s11357-017-9972-z CrossRefPubMedPubMedCentralGoogle Scholar
  279. Uryga AK, Bennett MR (2016) Ageing induced vascular smooth muscle cell senescence in atherosclerosis. J Physiol 594:2115–2124.  https://doi.org/10.1113/JP270923 CrossRefPubMedPubMedCentralGoogle Scholar
  280. Usui S, Ikuno Y, Akiba M, Maruko I, Sekiryu T, Nishida K, Iida T (2012) Circadian changes in subfoveal choroidal thickness and the relationship with circulatory factors in healthy subjects. Invest Ophthalmol Vis Sci 53:2300–2307.  https://doi.org/10.1167/iovs.11-8383 CrossRefPubMedPubMedCentralGoogle Scholar
  281. Valcarcel-Ares MN et al. (2012) Disruption of Nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging. J Gerontol A Biol Sci Med Sci 67:821-829 doi: https://doi.org/10.1093/gerona/glr229 glr229 [pii]
  282. Valcarcel-Ares MN et al (2018) Obesity in aging exacerbates neuroinflammation, dysregulating synaptic function-related genes and altering eicosanoid synthesis in the mouse hippocampus: potential role in impaired synaptic plasticity and cognitive decline. J Gerontol A Biol Sci Med Sci.  https://doi.org/10.1093/gerona/gly127 CrossRefGoogle Scholar
  283. Van Skike CE et al (2018) Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment. Am J Physiol Heart Circ Physiol 314:H693–H703.  https://doi.org/10.1152/ajpheart.00570.2017 CrossRefPubMedPubMedCentralGoogle Scholar
  284. van Stokkum IH, Lambrou GN, van den Berg TJ (1995) Hemodynamic parameter estimation from ocular fluorescein angiograms. Graefes Arch Clin Exp Ophthalmol 233:123–130PubMedCrossRefPubMedCentralGoogle Scholar
  285. Verstappen M, Draganova D, Judice L, Makhoul D, Papadaki M, Caspers L, Willermain F (2019) Hypertensive choroidopathy revealing malignant hypertension in a young patient. Retina 39:e12–e13.  https://doi.org/10.1097/IAE.0000000000002509 CrossRefPubMedPubMedCentralGoogle Scholar
  286. Viiri J et al (2013) Autophagy activation clears ELAVL1/HuR-mediated accumulation of SQSTM1/p62 during proteasomal inhibition in human retinal pigment epithelial cells. PLoS One 8:e69563.  https://doi.org/10.1371/journal.pone.0069563 CrossRefPubMedPubMedCentralGoogle Scholar
  287. Vujosevic S, Martini F, Cavarzeran F, Pilotto E, Midena E (2012) Macular and peripapillary choroidal thickness in diabetic patients. Retina 32:1781–1790.  https://doi.org/10.1097/IAE.0b013e31825db73d CrossRefPubMedPubMedCentralGoogle Scholar
  288. Vujosevic S et al (2019) Quantitative choriocapillaris evaluation in intermediate age-related macular degeneration by swept-source optical coherence tomography angiography. Acta Ophthalmol.  https://doi.org/10.1111/aos.14088
  289. Wakatsuki Y, Shinojima A, Kawamura A, Yuzawa M (2015) Correlation of aging and segmental choroidal thickness measurement using swept source optical coherence tomography in healthy eyes. PLoS One 10:e0144156.  https://doi.org/10.1371/journal.pone.0144156 CrossRefPubMedPubMedCentralGoogle Scholar
  290. Wang AL, Lukas TJ, Yuan M, Neufeld AH (2008) Increased mitochondrial DNA damage and down-regulation of DNA repair enzymes in aged rodent retinal pigment epithelium and choroid. Mol Vis 14:644–651PubMedPubMedCentralGoogle Scholar
  291. Wang AL, Lukas TJ, Yuan M, Du N, Handa JT, Neufeld AH (2009a) Changes in retinal pigment epithelium related to cigarette smoke: possible relevance to smoking as a risk factor for age-related macular degeneration. PLoS One 4:e5304.  https://doi.org/10.1371/journal.pone.0005304 CrossRefPubMedPubMedCentralGoogle Scholar
  292. Wang CY et al (2009b) Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR. Sci Signal 2:ra11.  https://doi.org/10.1126/scisignal.2000143 CrossRefPubMedPubMedCentralGoogle Scholar
  293. Wang L et al (2016) Pentraxin 3 recruits complement factor H to protect against oxidative stress-induced complement and inflammasome overactivation. J Pathol 240:495–506.  https://doi.org/10.1002/path.4811 CrossRefPubMedPubMedCentralGoogle Scholar
  294. Wang J, Jiang J, Zhang Y, Qian YW, Zhang JF, Wang ZL (2019) Retinal and choroidal vascular changes in coronary heart disease: an optical coherence tomography angiography study. Biomed Opt Express 10:1532–1544.  https://doi.org/10.1364/BOE.10.001532 CrossRefPubMedPubMedCentralGoogle Scholar
  295. Wei X, Kumar S, Ding J, Khandelwal N, Agarwal M, Agrawal R (2019) Choroidal structural changes in smokers measured using choroidal vascularity index. Invest Ophthalmol Vis Sci 60:1316–1320.  https://doi.org/10.1167/iovs.18-25764 CrossRefPubMedPubMedCentralGoogle Scholar
  296. Whitmore SS, Sohn EH, Chirco KR, Drack AV, Stone EM, Tucker BA, Mullins RF (2015) Complement activation and choriocapillaris loss in early AMD: implications for pathophysiology and therapy. Prog Retin Eye Res 45:1–29.  https://doi.org/10.1016/j.preteyeres.2014.11.005 CrossRefPubMedPubMedCentralGoogle Scholar
  297. Wong WL, Su X, Li X, Cheung CM, Klein R, Cheng CY, Wong TY (2014) Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health 2:e106–e116.  https://doi.org/10.1016/S2214-109X(13)70145-1 CrossRefPubMedPubMedCentralGoogle Scholar
  298. Yamazaki T, Koizumi H, Yamagishi T, Kinoshita S (2012) Subfoveal choroidal thickness after ranibizumab therapy for neovascular age-related macular degeneration: 12-month results. Ophthalmology 119:1621–1627.  https://doi.org/10.1016/j.ophtha.2012.02.022 CrossRefPubMedPubMedCentralGoogle Scholar
  299. Yang J et al (2019) Optical coherence tomography angiography analysis of the choriocapillary layer in treatment-naive diabetic eyes. Graefes Arch Clin Exp Ophthalmol 257:1393–1399.  https://doi.org/10.1007/s00417-019-04326-x CrossRefPubMedPubMedCentralGoogle Scholar
  300. Yannuzzi LA, Sorenson J, Spaide RF, Lipson B (1990) Idiopathic polypoidal choroidal vasculopathy (IPCV). Retina 10:1–8PubMedCrossRefPubMedCentralGoogle Scholar
  301. Yoshinaga N, Arimura N, Otsuka H, Kawahara K, Hashiguchi T, Maruyama I, Sakamoto T (2011) NSAIDs inhibit neovascularization of choroid through HO-1-dependent pathway. Lab Investig 91:1277–1290.  https://doi.org/10.1038/labinvest.2011.101 CrossRefPubMedPubMedCentralGoogle Scholar
  302. Yu DY, Cringle SJ (2001) Oxygen distribution and consumption within the retina in vascularised and avascular retinas and in animal models of retinal disease. Prog Retin Eye Res 20:175–208PubMedCrossRefPubMedCentralGoogle Scholar
  303. Zeng S et al (2016) Molecular response of chorioretinal endothelial cells to complement injury: implications for macular degeneration. J Pathol 238:446–456.  https://doi.org/10.1002/path.4669 CrossRefPubMedPubMedCentralGoogle Scholar
  304. Zhang W, Liu H, Al-Shabrawey M, Caldwell RW, Caldwell RB (2011) Inflammation and diabetic retinal microvascular complications. J Cardiovasc Dis Res 2:96–103.  https://doi.org/10.4103/0975-3583.83035 CrossRefPubMedPubMedCentralGoogle Scholar
  305. Zhang QY et al (2016) Overweight, obesity, and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci 57:1276–1283.  https://doi.org/10.1167/iovs.15-18637 CrossRefPubMedPubMedCentralGoogle Scholar
  306. Zhang Q et al (2018a) A novel strategy for quantifying choriocapillaris flow voids using swept-source OCT angiography. Invest Ophthalmol Vis Sci 59:203–211.  https://doi.org/10.1167/iovs.17-22953 CrossRefPubMedPubMedCentralGoogle Scholar
  307. Zhang Y, Liao J, Zhang L, Li S, Wu Y, Shi L (2018b) BKCa channel activity and vascular contractility alterations with hypertension and aging via beta1 subunit promoter methylation in mesenteric arteries. Hypertens Res 41:96–103.  https://doi.org/10.1038/hr.2017.96 CrossRefPubMedPubMedCentralGoogle Scholar
  308. Zhao Z, Chen Y, Wang J, Sternberg P, Freeman ML, Grossniklaus HE, Cai J (2011) Age-related retinopathy in NRF2-deficient mice. PLoS One 6:e19456.  https://doi.org/10.1371/journal.pone.0019456 CrossRefPubMedPubMedCentralGoogle Scholar
  309. Zhdankina AA, Fursova A, Logvinov SV, Kolosova NG (2008) Clinical and morphological characteristics of chorioretinal degeneration in early aging OXYS rats. Bull Exp Biol Med 146:455–458PubMedCrossRefPubMedCentralGoogle Scholar
  310. Zheng F et al (2019) Age-dependent changes in the macular choriocapillaris of normal eyes imaged with swept-source optical coherence tomography angiography. Am J Ophthalmol 200:110–122.  https://doi.org/10.1016/j.ajo.2018.12.025 CrossRefPubMedPubMedCentralGoogle Scholar
  311. Zhuang P, Shen Y, Lin BQ, Zhang WY, Chiou GC (2011) Effect of quercetin on formation of choroidal neovascularization (CNV) in age-related macular degeneration(AMD). Eye Sci 26:23–29.  https://doi.org/10.3969/j.issn.1000-4432.2011.01.006 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  • Agnes Lipecz
    • 1
    • 2
    • 3
    • 4
    • 5
  • Lauren Miller
    • 2
    • 6
  • Illes Kovacs
    • 2
    • 5
    • 7
  • Cecília Czakó
    • 5
  • Tamas Csipo
    • 1
    • 2
    • 4
    • 8
  • Judit Baffi
    • 2
  • Anna Csiszar
    • 1
    • 2
    • 4
    • 9
  • Stefano Tarantini
    • 1
    • 2
    • 4
    • 9
  • Zoltan Ungvari
    • 1
    • 2
    • 4
    • 9
    • 10
  • Andriy Yabluchanskiy
    • 1
    • 2
  • Shannon Conley
    • 2
    • 6
    Email author
  1. 1.Translational Geroscience Laboratory, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Vascular Cognitive Impairment and Neurodegeneration Program, Center for Geroscience and Healthy Brain Aging/Reynolds Oklahoma Center on Aging, Department of Biochemistry and Molecular BiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  3. 3.Department of OphthalmologyJosa Andras HospitalNyiregyhazaHungary
  4. 4.International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine/Department of Public HealthSemmelweis UniversityBudapestHungary
  5. 5.Department of OphthalmologySemmelweis UniversityBudapestHungary
  6. 6.Department of Cell BiologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  7. 7.Department of OphthalmologyWeill Cornell Medical CollegeNew York CityUSA
  8. 8.International Training Program in Geroscience, Division of Clinical Physiology, Department of Cardiology, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  9. 9.International Training Program in Geroscience, Theoretical Medicine Doctoral SchoolUniversity of SzegedSzegedHungary
  10. 10.Department of Health Promotion Sciences, College of Public HealthUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations