Autophagy Dysfunction, Cellular Senescence, and Abnormal Immune-Inflammatory Responses in AMD: From Mechanisms to Therapeutic Potential

Age-related macular degeneration (AMD) is a blinding disease caused by multiple factors and is the primary cause of vision loss in the elderly. The morbidity of AMD increases every year. Currently, there is no effective treatment option for AMD. Intravitreal injection of antivascular endothelial growth factor (anti-VEGF) is currently the most widely used therapy, but it only aims at neovascularization, which is an intermediate pathological phenomenon of wet AMD, not at the etiological treatment. Anti-VEGF therapy can only temporarily delay the degeneration process of wet AMD, and AMD is easy to relapse after drug withdrawal. Therefore, it is urgent to deepen our understanding of the pathophysiological processes underlying AMD and to identify integrated or new strategies for AMD prevention and treatment. Recent studies have found that autophagy dysfunction in retinal pigment epithelial (RPE) cells, cellular senescence, and abnormal immune-inflammatory responses play key roles in the pathogenesis of AMD. For many age-related diseases, the main focus is currently the clearing of senescent cells (SNCs) as an antiaging treatment, thereby delaying diseases. However, in AMD, there is no relevant antiaging application. This review will discuss the pathogenesis of AMD and how interactions among RPE autophagy dysfunction, cellular senescence, and abnormal immune-inflammatory responses are involved in AMD, and it will summarize the three antiaging strategies that have been developed, with the aim of providing important information for the integrated prevention and treatment of AMD and laying the ground work for the application of antiaging strategies in AMD treatment.

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Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

Journal of Neuroinflammation ◽

10.1186/s12974-021-02088-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Keng Siang Lee ◽

Shuxiao Lin ◽

David A. Copland ◽

Andrew D. Dick ◽

Jian Liu

Keyword(s):

Retinal Pigment Epithelium ◽

Macular Degeneration ◽

Cellular Senescence ◽

Vision Loss ◽

Inflammatory Responses ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The Elderly ◽

Age Related Macular Degeneration ◽

Age Related

AbstractAge-related macular degeneration (AMD), a degenerative disease in the central macula area of the neuroretina and the supporting retinal pigment epithelium, is the most common cause of vision loss in the elderly. Although advances have been made, treatment to prevent the progressive degeneration is lacking. Besides the association of innate immune pathway genes with AMD susceptibility, environmental stress- and cellular senescence-induced alterations in pathways such as metabolic functions and inflammatory responses are also implicated in the pathophysiology of AMD. Cellular senescence is an adaptive cell process in response to noxious stimuli in both mitotic and postmitotic cells, activated by tumor suppressor proteins and prosecuted via an inflammatory secretome. In addition to physiological roles in embryogenesis and tissue regeneration, cellular senescence is augmented with age and contributes to a variety of age-related chronic conditions. Accumulation of senescent cells accompanied by an impairment in the immune-mediated elimination mechanisms results in increased frequency of senescent cells, termed “chronic” senescence. Age-associated senescent cells exhibit abnormal metabolism, increased generation of reactive oxygen species, and a heightened senescence-associated secretory phenotype that nurture a proinflammatory milieu detrimental to neighboring cells. Senescent changes in various retinal and choroidal tissue cells including the retinal pigment epithelium, microglia, neurons, and endothelial cells, contemporaneous with systemic immune aging in both innate and adaptive cells, have emerged as important contributors to the onset and development of AMD. The repertoire of senotherapeutic strategies such as senolytics, senomorphics, cell cycle regulation, and restoring cell homeostasis targeted both at tissue and systemic levels is expanding with the potential to treat a spectrum of age-related diseases, including AMD.

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Autophagy Genes for Wet Age-Related Macular Degeneration in a Finnish Case-Control Study

Genes ◽

10.3390/genes11111318 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1318

Author(s):

Jussi J. Paterno ◽

Ali Koskela ◽

Juha M.T. Hyttinen ◽

Elina Vattulainen ◽

Ewelina Synowiec ◽

...

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Retinal Pigment ◽

Developed Countries ◽

Age Related Macular Degeneration ◽

Cumulative Number ◽

Sequestosome 1 ◽

Anti Vegf ◽

Age Related ◽

Wet Amd

Age-related macular degeneration is an eye disease that is the main cause of legal blindness in the elderly in developed countries. Despite this, its pathogenesis is not completely known, and many genetic, epigenetic, environmental and lifestyle factors may be involved. Vision loss in age-related macular degeneration (AMD) is usually consequence of the occurrence of its wet (neovascular) form that is targeted in the clinic by anti-VEGF (vascular endothelial growth factor) treatment. The wet form of AMD is associated with the accumulation of cellular waste in the retinal pigment epithelium, which is removed by autophagy and the proteosomal degradation system. In the present work, we searched for the association between genotypes and alleles of single nucleotide polymorphisms (SNPs) of autophagy-related genes and wet AMD occurrence in a cohort of Finnish patients undergoing anti-VEGF therapy and controls. Additionally, the correlation between treatment efficacy and genotypes was investigated. Overall, 225 wet AMD patients and 161 controls were enrolled in this study. Ten SNPs (rs2295080, rs11121704, rs1057079, rs1064261, rs573775, rs11246867, rs3088051, rs10902469, rs73105013, rs10277) in the mTOR (Mechanistic Target of Rapamycin), ATG5 (Autophagy Related 5), ULK1 (Unc-51-Like Autophagy Activating Kinase 1), MAP1LC3A (Microtubule Associated Protein 1 Light Chain 3 α), SQSTM1 (Sequestosome 1) were analyzed with RT-PCR-based genotyping. The genotype/alleles rs2295080-G, rs11121704-C, rs1057079-C and rs73105013-T associated with an increased, whereas rs2295080-TT, rs2295080-T, rs11121704-TT, rs1057079-TT, rs1057079-T, rs573775-AA and rs73105013-C with a decreased occurrence of wet AMD. In addition, the rs2295080-GG, rs2295080-GT, rs1057079-TT, rs11246867-AG, rs3088051-CC and rs10277-CC genotypes were a positively correlated cumulative number of anti-VEGF injections in 2 years. Therefore, variability in autophagy genes may have an impact on the risk of wet AMD occurrence and the efficacy of anti-VEGF treatment.

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PGC-1α Protects RPE Cells of the Aging Retina against Oxidative Stress-Induced Degeneration through the Regulation of Senescence and Mitochondrial Quality Control. The Significance for AMD Pathogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms19082317 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2317 ◽

Cited By ~ 32

Author(s):

Kai Kaarniranta ◽

Jakub Kajdanek ◽

Jan Morawiec ◽

Elzbieta Pawlowska ◽

Janusz Blasiak

Keyword(s):

Oxidative Stress ◽

Cellular Senescence ◽

Mitochondrial Biogenesis ◽

Vision Loss ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Sirtuin 1 ◽

Age Related Macular Degeneration ◽

Rpe Cells ◽

Age Related

PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha) is a transcriptional coactivator of many genes involved in energy management and mitochondrial biogenesis. PGC-1α expression is associated with cellular senescence, organismal aging, and many age-related diseases, including AMD (age-related macular degeneration), an important global issue concerning vision loss. We and others have developed a model of AMD pathogenesis, in which stress-induced senescence of retinal pigment epithelium (RPE) cells leads to AMD-related pathological changes. PGC-1α can decrease oxidative stress, a key factor of AMD pathogenesis related to senescence, through upregulation of antioxidant enzymes and DNA damage response. PGC-1α is an important regulator of VEGF (vascular endothelial growth factor), which is targeted in the therapy of wet AMD, the most devastating form of AMD. Dysfunction of mitochondria induces cellular senescence associated with AMD pathogenesis. PGC-1α can improve mitochondrial biogenesis and negatively regulate senescence, although this function of PGC-1α in AMD needs further studies. Post-translational modifications of PGC-1α by AMPK (AMP kinase) and SIRT1 (sirtuin 1) are crucial for its activation and important in AMD pathogenesis.

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Modulated anti-VEGF therapy under the influence of lipid metabolizing proteins in Age related macular degeneration: a pilot study

Scientific Reports ◽

10.1038/s41598-021-04269-6 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Kaushal Sharma ◽

Priya Battu ◽

Ramandeep Singh ◽

Suresh Kumar Sharma ◽

Akshay Anand

Keyword(s):

Visual Acuity ◽

Macular Degeneration ◽

Vision Loss ◽

Retinal Disease ◽

Age Related Macular Degeneration ◽

Clinical Images ◽

Anti Vegf ◽

Age Related ◽

Wet Amd ◽

Group 1

AbstractAge-related macular degeneration (AMD) is a devastating retinal disease that results in irreversible vision loss in the aged population. The complex genetic nature and degree of genetic penetrance require a redefinition of the current therapeutic strategy for AMD. We aimed to investigate the role of modifiers for current anti-VEGF therapy especially for non-responder AMD patients. We recruited 78 wet AMD cases (out of 278 AMD patients) with their socio-demographic and treatment regimen. Serum protein levels were estimated by ELISA in AMD patients. Data pertaining to the number of anti-VEGF injections given (in 1 year) along with clinical images (FFA and OCT) of AMD patients were also included. Visual acuity data (logMAR) for 46 wet AMD cases out of a total of 78 patients were also retrieved to examine the response of anti-VEGF injections in wet AMD cases. Lipid metabolizing genes (LIPC and APOE) have been identified as chief biomarkers for anti-VEGF response in AMD patients. Both genotypes ‘CC’ and ‘GC’ of LIPC have found to be associated with a number of anti-VEGF injections in AMD patients which could influence the expression of B3GALTL,HTRA1, IER3, LIPC and SLC16A8 proteins in patients bearing both genotypes as compared to reference genotype. Elevated levels of APOE were also observed in group 2 wet AMD patients as compared to group 1 suggesting the significance of APOE levels in anti-VEGF response. The genotype of B3GALTL has also been shown to have a significant association with the number of anti-VEGF injections. Moreover, visual acuity of group 1 (≤ 4 anti-VEGF injections/year) AMD patients was found significantly improved after 3 doses of anti-VEGF injections and maintained longitudinally as compared to groups 2 and 3. Lipid metabolising genes may impact the outcome of anti-VEGF AMD treatment.

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Association of Anti-VEGF Injections with Progression of Geographic Atrophy

Ophthalmology and Eye Diseases ◽

10.4137/oed.s38863 ◽

2016 ◽

Vol 8 ◽

pp. OED.S38863 ◽

Cited By ~ 15

Author(s):

Ryan Enslow ◽

Sai Bhuvanagiri ◽

Sravanthi Vegunta ◽

Benjamin Cutler ◽

Michael Neff ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Macular Degeneration ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Developed Countries ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Anti Vegf ◽

Age Related ◽

Wet Amd

Age-related macular degeneration (AMD) is one of the leading causes of blindness in developed countries in people over the age of 60 years. One of the forms of advanced AMD is wet AMD. Wet AMD is a result of leakage and bleeding from abnormal neovascularization. The principal treatment for wet AMD is intravitreal anti-VEGF injections. A second form of advanced AMD is geographic atrophy (GA). GA refers to large areas of retinal pigment epithelium loss. In the literature, there is some concern that anti-VEGF injections administered to treat wet AMD may be associated with progression of GA. This review discusses evidence suggesting the association of anti-VEGF injections with progression of GA.

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Unravelling the therapeutic potential of IL-33 for atrophic AMD

Eye ◽

10.1038/s41433-021-01725-5 ◽

2021 ◽

Author(s):

Alison J. Clare ◽

Jian Liu ◽

David A. Copland ◽

Sofia Theodoropoulou ◽

Andrew D. Dick

Keyword(s):

Vision Loss ◽

Therapeutic Potential ◽

Pigment Epithelium ◽

Retinal Pigment ◽

The Elderly ◽

Age Related Macular Degeneration ◽

Interleukin 33 ◽

Age Related ◽

Therapeutic Development ◽

Disease Pathways

AbstractAge-related macular degeneration (AMD), a degenerative disease affecting the retinal pigment epithelium (RPE) and photoreceptors in the macula, is the leading cause of central blindness in the elderly. AMD progresses to advanced stages of the disease, atrophic AMD (aAMD), or in 15% of cases “wet” or neovascular AMD (nAMD), associated with substantial vision loss. Whilst there has been advancement in therapies treating nAMD, to date, there are no licenced effective treatments for the 85% affected by aAMD, with disease managed by changes to diet, vitamin supplements, and regular monitoring. AMD has a complex pathogenesis, involving highly integrated and common age-related disease pathways, including dysregulated complement/inflammation, impaired autophagy, and oxidative stress. The intricacy of AMD pathogenesis makes therapeutic development challenging and identifying a target that combats the converging disease pathways is essential to provide a globally effective treatment. Interleukin-33 is a cytokine, classically known for the proinflammatory role it plays in allergic disease. Recent evidence across degenerative and inflammatory disease conditions reveals a diverse immune-modulatory role for IL-33, with promising therapeutic potential. Here, we will review IL-33 function in disease and discuss the future potential for this homeostatic cytokine in treating AMD.

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Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

BMJ Open Ophthalmology ◽

10.1136/bmjophth-2021-000774 ◽

2021 ◽

Vol 6 (1) ◽

pp. e000774

Author(s):

Minwei Wang ◽

Shiqi Su ◽

Shaoyun Jiang ◽

Xinghuai Sun ◽

Jiantao Wang

Keyword(s):

Mitochondrial Dysfunction ◽

Macular Degeneration ◽

Vision Loss ◽

Cell Structure ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Amyloid Β ◽

Age Related Macular Degeneration ◽

Amyloid Β Peptide ◽

Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

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Mingjing granule, a traditional Chinese medicine in the treatment of neovascular age-related macular degeneration: study protocol for a randomized controlled trial

Trials ◽

10.1186/s13063-021-05025-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yamin Li ◽

Lina Liang ◽

Torkel Snellingen ◽

Kai Xu ◽

Yun Gao ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Macular Degeneration ◽

Vision Loss ◽

Age Related Macular Degeneration ◽

Case Report Form ◽

Link Type ◽

Anti Vegf ◽

Age Related ◽

Function Test

Abstract Background Neovascular age-related macular degeneration (nAMD) is the most common cause of irreversible vision loss and blindness among the older people aged 50 and over. Although anti-vascular endothelial growth factor (anti-VEGF) therapies have resulted in improving patient outcomes, there are limitations associated with these treatments. In China, traditional Chinese medicine (TCM) has been used to treat eye diseases for more than 2000 years. Previous studies have shown that TCM may be beneficial for nAMD patients. However, explicit evidence has not been obtained. The purpose of the present trial is to examine the efficacy and safety of the Mingjing granule, a compound Chinese herbal medicine, for nAMD patients. Methods/design This is a double-blind, placebo-controlled, randomized trial of Mingjing granule as an add-on to intravitreous ranibizumab for nAMD. One hundred eighty nAMD patients from six hospitals in China will be enrolled according to the inclusion and exclusion criteria and randomly allocated into two groups, 90 in each. All participants will receive a 24-week treatment and then be followed up for another 24 weeks. The primary outcome is the mean change of best-corrected visual acuity at week 24 and 48 as compared to the baseline. The secondary outcomes include mean change in central retinal thickness, area of retinal hemorrhage and exudation, and TCM syndrome score, mean number of intravitreal ranibizumab injection, and total cost of the treatment. Indexes of safety include blood regular test, urine regular test, liver function test, renal function test, and electrocardiogram from baseline to weeks 24 and 48. Qualitative control and some standard operating processes will be formed throughout the trial. Any ocular or systemic adverse events will be treated suitably, and related data will be recorded accurately and completely in the case report form. Discussion Based on previous empirical and animal laboratory studies, this study will address the question of whether Mingjing granule could contribute to improving efficacy, safety, and efficiency with need for fewer intravitreal injections of anti-VEGF, improving compliance and visual outcomes in the management of persons with nAMD. Trial registration Chinese Clinical Trial Registry (http://www.chictr.org.cn), ChiCTR2000035990. Registered on 21 August 2020.

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A Systematic Review of Carotenoids in the Management of Diabetic Retinopathy

Nutrients ◽

10.3390/nu13072441 ◽

2021 ◽

Vol 13 (7) ◽

pp. 2441

Author(s):

Drake W. Lem ◽

Dennis L. Gierhart ◽

Pinakin Gunvant Davey

Keyword(s):

Diabetic Retinopathy ◽

Vision Loss ◽

Therapeutic Potential ◽

Microvascular Disease ◽

Age Related Macular Degeneration ◽

Cell Degeneration ◽

Neuroprotective Effects ◽

Age Related ◽

Induced Changes ◽

Dietary Carotenoid

Diabetic retinopathy, which was primarily regarded as a microvascular disease, is the leading cause of irreversible blindness worldwide. With obesity at epidemic proportions, diabetes-related ocular problems are exponentially increasing in the developed world. Oxidative stress due to hyperglycemic states and its associated inflammation is one of the pathological mechanisms which leads to depletion of endogenous antioxidants in retina in a diabetic patient. This contributes to a cascade of events that finally leads to retinal neurodegeneration and irreversible vision loss. The xanthophylls lutein and zeaxanthin are known to promote retinal health, improve visual function in retinal diseases such as age-related macular degeneration that has oxidative damage central in its etiopathogenesis. Thus, it can be hypothesized that dietary supplements with xanthophylls that are potent antioxidants may regenerate the compromised antioxidant capacity as a consequence of the diabetic state, therefore ultimately promoting retinal health and visual improvement. We performed a comprehensive literature review of the National Library of Medicine and Web of Science databases, resulting in 341 publications meeting search criteria, of which, 18 were found eligible for inclusion in this review. Lutein and zeaxanthin demonstrated significant protection against capillary cell degeneration and hyperglycemia-induced changes in retinal vasculature. Observational studies indicate that depletion of xanthophyll carotenoids in the macula may represent a novel feature of DR, specifically in patients with type 2 or poorly managed type 1 diabetes. Meanwhile, early interventional trials with dietary carotenoid supplementation show promise in improving their levels in serum and macular pigments concomitant with benefits in visual performance. These findings provide a strong molecular basis and a line of evidence that suggests carotenoid vitamin therapy may offer enhanced neuroprotective effects with therapeutic potential to function as an adjunct nutraceutical strategy for management of diabetic retinopathy.

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Pharmaceutical Induction of PGC-1α Promotes Retinal Pigment Epithelial Cell Metabolism and Protects against Oxidative Damage

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/9248640 ◽

2018 ◽

Vol 2018 ◽

pp. 1-9 ◽

Cited By ~ 13

Author(s):

Sangeeta Satish ◽

Hannah Philipose ◽

Mariana Aparecida Brunini Rosales ◽

Magali Saint-Geniez

Keyword(s):

Cell Death ◽

Antioxidant Enzymes ◽

Oxidative Damage ◽

Therapeutic Potential ◽

Retinal Pigment Epithelial Cell ◽

Cell Metabolism ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Age Related Macular Degeneration ◽

Age Related

Retinal pigment epithelium (RPE) dysfunction due to accumulation of reactive oxygen species and oxidative damage is a key event in the development of age-related macular degeneration (AMD). Here, we examine the therapeutic potential of ZLN005, a selective PGC-1α transcriptional regulator, in protecting RPE from cytotoxic oxidative damage. Gene expression analysis on ARPE-19 cells treated with ZLN005 shows robust upregulation of PGC-1α and its associated transcription factors, antioxidant enzymes, and mitochondrial genes. Energetic profiling shows that ZLN005 treatment enhances RPE mitochondrial function by increasing basal and maximal respiration rates, and spare respiratory capacity. In addition, ZLN005 robustly protects ARPE-19 cells from cell death caused by H2O2, ox-LDL, and NaIO3 without exhibiting any cytotoxicity under basal conditions. ZLN005 protection against H2O2-mediated cell death was lost in PGC-1α-silenced cells. Our data indicates that ZLN005 efficiently protects RPE cells from oxidative damage through selective induction of PGC-1α and its target antioxidant enzymes. ZLN005 may serve as a novel therapeutic agent for retinal diseases associated with RPE dystrophies.

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