Epigenetic Age Acceleration Is Not Associated with Age-Related Macular Degeneration

Abstract

DNA methylation age (DNAm age) estimation is a powerful biomarker of human ageing. To date, epigenetic clocks have not been evaluated in age-related macular degeneration (AMD). Here, we perform genome-wide DNA methylation analyses in blood of AMD patients with a documented smoking history (14 AMD, 16 Normal), identifying loci of differential methylation (DML) with a relaxed p-value criterion (p ≤ 10−4). We conduct DNAm age analyses using the Horvath-multi tissue, Hannum and Skin & Blood epigenetic clocks in both blood and retinal pigment epithelium (RPE). We perform Ingenuity Pathway Analysis Causal Network Analysis (IPA CNA) on the topmost significantly differentially methylated CpG probes in blood and RPE. Results show poor performance of epigenetic clocks in RPE. Epigenetic age acceleration (EAA) was not observed in AMD. However, we observe positive EAA in blood of smokers, and in smokers with AMD. DML analysis revealed hypomethylation at cg04953735 within RPTOR (p = 6.51 × 10−5; Δβ = −11.95%). IPA CNA in the RPE also identified RPTOR as the putative master regulator, predicted to be inhibited in AMD. In conclusion, this is the first study evaluating an association of epigenetic ageing in AMD. We posit a role for RPTOR as a common master regulator of methylation changes in the RPE in AMD.

Intercellular communication analysis of the human retinal pigment epithelial and choroidal cells predicts pathways associated with aging, cellular senescence and age-related macular degeneration

“…During AMD, lipoproteinaceous and other extracellular debris accumulate between the RPE and the choroid, leading to the formation of drusen ( Ardeljan and Chan, 2013 ). Previous research investigating how this system ages focused on the RPE or the choroid alone ( Paraoan et al, 2000 ; Kay et al, 2013 , 2014 ; Porter et al, 2019 ; Sharif et al, 2019 ; Voigt et al, 2019 , 2020 ; Dhirachaikulpanich et al, 2020 ; Butler et al, 2021 ; Saptarshi et al, 2021 ). However, given that the RPE/choroid system is a complex microenvironment composed of many cell types functioning together, including RPE cells, endothelial cells, fibroblasts and immune cells ( Voigt et al, 2021 , 2022 ), the communication between the cellular components of the RPE/choroid needs also to be characterized.…”

A mathematically rigorous algorithm to define, compute and assess relevance of the probable dissociation constant for every reaction of a constrained biochemical network

“…𝓅 ∶= 𝐵𝑖𝑜𝑐ℎ𝑒𝑚𝑖𝑐𝑎𝑙 𝑛𝑒𝑡𝑤𝑜𝑟𝑘 𝑢𝑛𝑑𝑒𝑟 𝑠𝑡𝑢𝑑𝑦 𝒩 𝓅 ≝ 𝑆𝑢𝑝𝑒𝑟𝑠𝑒𝑡 𝑜𝑓 𝑐𝑜𝑚𝑏𝑖𝑛𝑎𝑡𝑖𝑜𝑛𝑠 𝑜𝑓 𝐽 − 𝑟𝑒𝑎𝑐𝑡𝑎𝑛𝑡𝑠 𝑜𝑓 𝑎 𝑏𝑖𝑜𝑐ℎ𝑒𝑚𝑖𝑐𝑎𝑙 𝑛𝑒𝑡𝑤𝑜𝑟𝑘 (11) ℛ 𝓅 ≝ 𝐶𝑜𝑚𝑝𝑙𝑒𝑡𝑒 𝑠𝑒𝑡 𝑜𝑓 𝑎𝑙𝑙 𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙𝑙𝑦 𝑓𝑒𝑎𝑠𝑖𝑏𝑙𝑒 𝑟𝑒𝑎𝑐𝑡𝑖𝑜𝑛𝑠 𝑓𝑜𝑟 𝑎 𝑏𝑖𝑜𝑐ℎ𝑒𝑚𝑖𝑐𝑎𝑙 𝑛𝑒𝑡𝑤𝑜𝑟𝑘 (12) Since each reaction can have one of three outcomes, i.e., forward (f), reverse (b), equivalent (e), we can define a finite number (𝑧 = 1,2 … 𝑍 = 𝐼 3 ) of possible states of the biochemical network under study,…”

“…The resulting causal networks are probabilistic in construction and the conclusions drawn are inferential [10]. The simple architecture notwithstanding, causal networks have yielded datasets that can be mined for potential biomarkers (genotype, phenotype) and lead molecules as well as aid in decision making and allocating resources [11][12][13][14][15][16][17][18][19][20][21]. The most important limitation is however, a need for previous information which will dictate the weight of a possible outcome and thereby the overall directionality of the biochemical network.…”

Characteristic Hallmarks of Aging and the Impact on Carcinogenesis

“…These modifications are dynamic and affect all cells and tissues throughout life, furthermore, the environment and lifestyle, as well as aging, can lead to remarkable epigenetic alterations [40]. Hence, alterations of the epigenetic mechanisms arising during aging cause a higher frequency of transcriptional changes responsible for aging-related diseases [15,41]. Among the aging-related diseases, cancer may be considered the result of the accumulation of genetic and epigenetic alterations, where perturbations in the genome resulting from changes in the cellular environment, inflammation, impaired immune function and accumulation of DNA damage lead the cells through carcinogenesis and malignant transformation [42][43][44].…”