Abstract
Purpose :
Metabolic changes incurred by age-related degeneration (AMD) along the severity spectrum are still poorly understood, yet they provide key insights into the disease etiology. We posit that serum metabolites change as AMD severity increases and that these metabolites reflect disease progression changes that can be monitored, prevented, or targeted. To this end, we conducted a pilot study of Age-Related Eye Disease Study (AREDS) patient metabolomes.
Methods :
The AREDS simplified scale (0 - 4, based on standardized fundus photo gradings) was used to quantify AMD severity for each participant at two time points. Serum samples were collected from 400 AREDS participants (105 no AMD, 295 with early, intermediate, or late AMD) at baseline and 5 years later. Metabolomic profiles were generated on these samples using a comprehensive metabolomics platform measuring 1464 metabolites including lipids, amino acids, nucleotides, and sugars (Metabolon, Inc.). Logistic regression models were calculated for each timepoint and metabolite separately, with AMD severity score as the outcome, adjusting for age, sex, BMI, smoking history, and treatment (at 5 years). A significant model estimate (nominal p-value < 0.05) for a metabolite indicated a hit. Biological pathway enrichment was performed using RaMP (NCATS, NIH).
Results :
At baseline, 32 metabolites were associated with increased risk of late AMD while 17 were associated with lower risk. At 5 years, we found 33 and 25 positively and negatively associated, respectively, with late AMD status. Significant positively associated pathways at baseline include biosynthesis of sphingolipids and of unsaturated fatty acid biosynthesis; while negatively associated chemical classes included phosphatidylcholine and sulfated steroids. In 5-year endpoint data, significant positively associated pathways included: transport of bile salts, nicotinate, and cellular response to stress; and negatively associated were: histidine metabolism, phospholipid biosynthesis.
Conclusions :
We examined patient metabolomes for chemicals associated with AMD severity. Early versus late stages of AMD showed significantly altered lipids and amino acids which may help elucidate the disease mechanisms of action. To validate the findings, we will generate additional metabolomes of all AREDS, AREDS2 participants with available serum.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.