Abstract
Purpose :
With increasing age, there is a general decline in regulatory elements of the immune system, termed immunosenescence. A clinical study was undertaken to test the hypothesis that systemic immunosenescence is an important etiological factor in AMD and drives disease progression.
Methods :
Sixty participants were recruited to this observational study, including ten age-matched control subjects. Participants with AMD had an identical stage of disease in both eyes (to investigate systemic immunosenescence), with ten participants in each of the following AMD categories: Early; intermediate; intermediate with reticular pseudodrusen (I-RPD), geographic atrophy and neovascular AMD. Proteomic analysis (discovery liquid mass chromatography) and immunophenotyping (8-colour flow cytometry) was undertaken on peripheral blood mononuclear cells (PBMCs) from each participant to identify biomarkers of immunosenescence. Proteomics and Mesoscale V-Plex assays were undertaken on plasma from each participant.
Results :
For proteomic analysis, ANOVA testing was applied to each protein between all groups. Significant results were plotted, a pairwise comparison was undertaken to identify which differences were significant, and p-values were adjusted by the Bonferroni method. Proteomics revealed significant changes in PBMC protein levels between patients with early and intermediate (including I-RPD) stages of AMD and controls for the following proteins (associated gene): mitochondrial aspartate aminotransferase (GOT2), polyubiquitin B (UBB), cyclin-G associated kinase (GAK), transketolase (TKT) and isoamyl acetate-hydrolyzing esterase 1 homolog (IAH).
A stark result was the strongest reductions in protein levels in the I-RPD category, even relative to other AMD categories, for Derlin-1 (DERL1), mitochondrial NADH dehydrogenase subunit (NDUFB11) and an actin-related protein subunit (ARPC5L). Immunophenotyping demonstrated significant changes between groups in the CD57+KLRG1+ and CD57+ memory compartments of cytotoxic and helper T cells, in addition to the CD16+ (non-classical) monocyte and CD16+CD56low (cytotoxic) NK cell populations. Mesoscale assays did not show clear evidence of a circulating/systemic SASP between groups.
Conclusions :
Clinically-detectable biomarkers of immunosenescence could potentially be applied to AMD onset and progression pending validation on larger cohorts.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.