A team of researchers led by New York Eye and Ear Infirmary of Mount Sinai (NYEE) was intrigued by a statistical fact while investigating new approaches to accurately predict the risk of acquiring glaucoma. They learned from their observational study involving a large biobank that only 20 percent of people in the highest risk category for glaucoma based on their genetic scores had the disease.
Which begged the question: How had the other 80 percent managed not to have glaucoma? Just as critically, was there a resilience factor at play with significant implications for not just detection, but treatment, of a progressive neurodegenerative condition with no available cure?
The team’s findings, published in the April 2025 issue of eLife, made a strong and fascinating case for metabolites—the end products of biological processes that drive cellular growth and reproduction—as the molecular ingredient possibly providing a valuable buffer against genetic predisposition to glaucoma. More specifically, they suggest that a key member of that class of metabolites known as pyruvate may confer protective capability and, therefore, needs to be the focus of much additional research.
“We didn’t just stop at reporting that pyruvate could be a resilience biomarker against developing glaucoma in people with a high genetic predisposition,” says senior author Louis R. Pasquale, MD, FARVO, Deputy Chair for Research, and Director of the Mount Sinai/NYEE Eye and Vision Research Institute at the Icahn School of Medicine at Mount Sinai. “We showed that integrating metabolites with genetics allowed us to come up with much stronger prediction models for glaucoma, and possibly better ways of treating and monitoring the disease down the road.”
To determine if metabolites enhanced glaucoma detection, scientists studied 4,658 glaucoma cases from the UK Biobank, a widely researched dataset with more than half a million participants from the United Kingdom. While it is widely known that glaucoma risk is influenced by both genetic and metabolic factors, investigators in the NYEE study learned that metabolites by themselves were weak predictors of glaucoma. They were surprised to discover, however, that when they statistically combined people who had the highest metabolic risk scores with those with the highest genetic scores, the group showed a 25-fold increased risk of glaucoma over those at the bottom rung of both risk categories.
“Whenever we see results like that in epidemiology,” acknowledges Dr. Pasquale, “we know we are potentially on to something that must be seriously explored.”
To be sure, recent advances in metabolomic science have opened new avenues for investigating these small molecules as possible biomarkers for glaucoma and intraocular pressure (IOP), which is typically elevated in glaucoma patients. The new study is the first, however, to examine the utility of incorporating metabolic data into glaucoma genetic prediction algorithms. Furthermore, working in conjunction with Simon John, PhD, at Columbia University, the researchers validated pyruvate as a metabolite that could mitigate genetic risk of glaucoma in a human-relevant mouse model. Pyruvate use in mice with a strong genetic predisposition to glaucoma lowered IOP and protected against optic nerve damage.
“The statistical interaction we demonstrated between metabolite and genetic risk scores helped to identify individuals who, despite high genetic risk, are less likely to develop glaucoma due to favorable metabolic profiles,” sums up Dr. Pasquale, who is also Professor of Ophthalmology, and Artificial Intelligence and Human Health, at the Icahn School of Medicine.
The next step for Dr. Pasquale is to conduct a small study to determine if pyruvate might affect intraocular pressure. And beyond that, the possibility of oral pyruvate supplementation for those with a high predisposition to glaucoma could appear on the radar screen of researchers.
“Though much work remains,” he says, “we’ve opened up important new therapeutic avenues using pyruvate as a resilience factor against glaucoma.”