Calpain and PARP Activation during Photoreceptor Cell Death in P23H and S334ter Rhodopsin Mutant Rats

Retinitis pigmentosa (RP) is a heterogeneous group of inherited neurodegenerative diseases affecting photoreceptors and causing blindness. Many human cases are caused by mutations in the rhodopsin gene. An important question regarding RP pathology is whether different genetic defects trigger the same or different cell death mechanisms. To answer this question, we analysed photoreceptor degeneration in P23H and S334ter transgenic rats carrying rhodopsin mutations that affect protein folding and sorting respectively. We found strong activation of calpain and poly(ADP-ribose) polymerase (PARP) in both mutants, concomitant with calpastatin down-regulation, increased oxidative DNA damage and accumulation of PAR polymers. These parameters were strictly correlated with the temporal progression of photoreceptor degeneration, mirroring earlier findings in the phosphodiesterase-6 mutant rd1 mouse, and suggesting execution of non-apoptotic cell death mechanisms. Interestingly, activation of caspases-3 and -9 and cytochrome c leakage—key events in apoptotic cell death—were observed only in the S334ter mutant, which also showed increased expression of PARP-1. The identification of the same metabolic markers triggered by different mutations in two different species suggests the existence of common cell death mechanisms, which is a major consideration for any mutation independent treatment

PLoS One

Age-related macular degeneration (AMD) is a common, progressive multifactorial vision-threatening disease and many genetic and environmental risk factors have been identified. The risk of AMD is influenced by lifestyle and diet, which may be reflected by an altered metabolic profile. Therefore, measurements of metabolites could identify biomarkers for AMD, and could aid in identifying high-risk individuals. Hypothesis-free technologies such as metabolomics have a great potential to uncover biomarkers or pathways that contribute to disease pathophysiology. To date, only a limited number of metabolomic studies have been performed in AMD. Here, we aim to contribute to the discovery of novel biomarkers and metabolic pathways for AMD using a targeted metabolomics approach of 188 metabolites. This study focuses on non-advanced AMD, since there is a need for biomarkers for the early stages of disease before severe visual loss has occurred. Targeted metabolomics was performed in 72 patients with early or intermediate AMD and 72 control individuals, and metabolites predictive for AMD were identified by a sparse partial least squares discriminant analysis. In our cohort, we identified four metabolite variables that were most predictive for early and intermediate stages of AMD. Increased glutamine and phosphatidylcholine diacyl C28:1 levels were detected in non-advanced AMD cases compared to controls, while the rate of glutaminolysis and the glutamine to glutamate ratio were reduced in non-advanced AMD. The association of glutamine with non-advanced AMD corroborates a recent report demonstrating an elevated glutamine level in early AMD using a different metabolomics technique. In conclusion, this study indicates that metabolomics is a suitable method for the discovery of biomarker candidates for AMD. In the future, larger metabolomics studies could add to the discovery of novel biomarkers in yet unknown AMD pathways and expand our insights in AMD pathophysiology

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Ophthalmology

OBJECTIVE: In the current study we aimed to identify metabolites associated with age-related macular degeneration (AMD) by performing the largest metabolome association analysis in AMD to date. In addition, we aimed to determine the effect of AMD-associated genetic variants on metabolite levels, and aimed to investigate associations between the identified metabolites and activity of the complement system, one of the main AMD-associated disease pathways. DESIGN: Case-control assocation analysis of metabolomics data. SUBJECTS: 2,267 AMD cases and 4,266 controls from five European cohorts. METHODS: Metabolomics was performed using a high-throughput H-NMR metabolomics platform, which allows the quantification of 146 metabolite measurements and 79 derivative values. Metabolome-AMD associations were studied using univariate logistic regression analyses. The effect of 52 AMD-associated genetic variants on the identified metabolites was investigated using linear regression. In addition, associations between the identified metabolites and activity of the complement pathway (defined by the C3d/C3 ratio) were investigated using linear regression. MAIN OUTCOME MEASURES: Metabolites associated with AMD RESULTS: We identified 60 metabolites that were significantly associated with AMD, including increased levels of large and extra-large HDL subclasses and decreased levels of VLDL, amino acids and citrate. Out of 52 AMD-associated genetic variants, seven variants were significantly associated with 34 of the identified metabolites. The strongest associations were identified for genetic variants located in or near genes involved in lipid metabolism (ABCA1, CETP, APOE, LIPC) with metabolites belonging to the large and extra-large HDL subclasses. In addition, 57 out of 60 metabolites were significantly associated with complement activation levels, and these associations were independent of AMD status. Increased large and extra-large HDL levels and decreased VLDL and amino acid levels were associated with increased complement activation. CONCLUSIONS: Lipoprotein levels were associated with AMD-associated genetic variants, while decreased essential amino acids may point to nutritional deficiencies in AMD. We observed strong associations between the vast majority of the AMD-associated metabolites and systemic complement activation levels, independent of AMD status. This may indicate biological interactions between the main AMD disease pathways, and suggests that multiple pathways may need to be targeted simultaneously for successful treatment of AMD

Prevalence of Age-Related Macular Degeneration in Europe: The Past and the Future

Purpose Age-related macular degeneration (AMD) is a frequent, complex disorder in elderly of European ancestry. Risk profiles and treatment options have changed considerably over the years, which may have affected disease prevalence and outcome. We determined the prevalence of early and late AMD in Europe from 1990 to 2013 using the European Eye Epidemiology (E3) consortium, and made projections for the future. Design Meta-analysis of prevalence data. Participants A total of 42 080 individuals 40 years of age and older participating in 14 population-based cohorts from 10 countries in Europe. Methods AMD was diagnosed based on fundus photographs using the Rotterdam Classification. Prevalence of early and late AMD was calculated using random-effects meta-analysis stratified for age, birth cohort, gender, geographic region, and time period of the study. Best-corrected visual acuity (BCVA) was compared between late AMD subtypes; geographic atrophy (GA) and choroidal neovascularization (CNV). Main Outcome Measures Prevalence of early and late AMD, BCVA, and number of AMD cases. Results Prevalence of early AMD increased from 3.5% (95% confidence interval [CI] 2.1%–5.0%) in those aged 55–59 years to 17.6% (95%

Metabolomics in serum of patients with non-advanced age-related macular degeneration reveals aberrations in the glutamine pathway

Age-related macular degeneration (AMD) is a common, progressive multifactorial vision-threatening disease and many genetic and environmental risk factors have been identified. The risk of AMD is influenced by lifestyle and diet, which may be reflected by an altered metabolic profile. Therefore, measurements of metabolites could identify biomarkers for AMD, and could aid in identifying high-risk individuals. Hypothesis-free technologies such as metabolomics have a great potential to uncover biomarkers or pathways that contribute to disease pathophysiology. To date, only a limited number of metabolomic studies have been performed in AMD. Here, we aim to contribute to the discovery of novel biomarkers and metabolic pathways for AMD using a targeted metabolomics approach of 188 metabolites. This study focuses on non-advanced AMD, since there is a need for biomarkers for the early stages of disease before severe visual loss has occurred. Targeted metabolomics was performed in 72 patients with early or intermediate AMD and 72 control individuals, and metabolites predictive for AMD were identified by a sparse partial least squares discriminant analysis. In our cohort, we identified four metabolite variables that were most predictive for early and intermediate stages of AMD. Increased glutamine and phosphatidylcholine diacyl C28:1 levels were detected in non-advanced AMD cases compared to controls, while the rate of glutaminolysis and the glutamine to glutamate ratio were reduced in non-advanced AMD. The association of glutamine with non-advanced AMD corroborates a recent report demonstrating an elevated glutamine level in early AMD using a different metabolomics technique. In conclusion, this study indicates that metabolomics is a suitable method for the discovery of biomarker candidates for AMD. In the future, larger metabolomics studies could add to the discovery of novel biomarkers in yet unknown AMD pathways and expand our insights in AMD pathophysiology

Mediterranean Diet and Incidence of Advanced Age-Related Macular Degeneration: The EYE-RISK Consortium

Purpose: To investigate associations of adherence to the Mediterranean diet (MeDi) with incidence of advanced age-related macular degeneration (AMD; the symptomatic form of AMD) in 2 European population-based prospective cohorts. Design: Prospective cohort study of the Rotterdam Study I (RS-I) and the Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires (Alienor) Study populations. Participants: Four thousand four hundred forty-six participants 55 years of age or older from the RS-I (The Netherlands) and 550 French adults 73 years of age or older from the Alienor Study with complete ophthalmologic and dietary data were included in the present study. Methods: Examinations were performed approximately every 5 years over a 21-year period (1990–2011) in RS-I and every 2 years over a 4-year period (2006–2012) in the Alienor Study. Adherence to the MeDi was evaluated using a 9-component score based on intake of vegetables, fruits, legumes, cereals, fish, meat, dairy products, alcohol, and the monounsaturated-to-saturated fatty acids ratio. Associations of incidence of AMD with MeDi were estimated using multivariate Cox proportional hazard models. Main Outcomes Measures: Incidence of advanced AMD based on retinal fundus photographs. Results: Among the 4996 included participants, 155 demonstrated advanced incident AMD (117 from the RS-I and 38 from the Alienor Study). The mean follow-up time was 9.9 years (range, 0.6–21.7 years) in the RS-I and 4.1 years (range, 2.5–5.0 years) in the Alienor Study. Pooling data for both the RS-I and Alienor Study, participants with a high (range, 6–9) MeDi score showed a significantly reduced risk for incident advanced AMD compared with participants with a low (range, 0–3) MeDi score in the fully adjusted Cox model (hazard ratio, 0.59; 95% confidence interval, 0.37–0.95; P = 0.04 for trend). Conclusions: Pooling data from the RS-I and Alienor Study, higher adherence to the MeDi was associated with a 41% reduced risk of incident advanced AMD. These findings support the role of a diet rich in healthful nutrient-rich foods such as fruits, vegetables, legumes, and fish in the prevention of AMD