From Fork to Brain: The Role of AGE-RAGE Signaling and the Western Diet in Neurodegenerative Disease.
Pomroy, Haylie J, Mote, Arjun, Mathew, Simeon et al. · NeuroSci · 2025 · DOI
Quick Summary
This review examines how certain compounds called AGEs (advanced glycation end products) form in food and in our bodies, and how they may contribute to brain damage and disease. AGEs are created when food is cooked at high temperatures or processed, and when they build up in the body, they can trigger inflammation and harm cells. The authors suggest that limiting AGEs in the diet might help prevent or slow down brain diseases, though more research is needed to confirm this.
Why It Matters
ME/CFS is characterized by mitochondrial dysfunction, chronic inflammation, and potential neuroinflammation—all pathways activated by AGE-RAGE signaling. Understanding modifiable dietary factors that may exacerbate these mechanisms is relevant to patient management. This mechanistic framework could inform dietary intervention strategies and identify a potential contributing factor amenable to patient-level modification.
Observed Findings
AGEs are formed through non-enzymatic glycation (Maillard reaction) and accumulate in cells where they impair function.
AGE-RAGE binding activates intracellular signaling that generates reactive oxygen species (ROS).
AGE-RAGE signaling is associated with mitochondrial dysfunction.
AGE-RAGE signaling promotes chronic inflammation linked to neurodegenerative disease.
Dietary sources and food preparation methods contribute significantly to systemic AGE burden.
Inferred Conclusions
AGE-RAGE mediated pathology represents a mechanistically plausible contributor to neurodegenerative disease through ROS generation, mitochondrial dysfunction, and sustained inflammation.
Dietary AGE exposure is a modifiable risk factor that warrants investigation as a prevention or treatment strategy.
Further research is needed to test whether AGE restriction can prevent or slow neurodegeneration in clinical populations.
Remaining Questions
Does reducing dietary AGE intake measurably decrease AGE accumulation and AGE-RAGE signaling in humans, and does this correlate with improved neurological outcomes?
What is the relative contribution of dietary AGEs versus endogenous AGE production in neuroinflammatory diseases like ME/CFS?
What This Study Does Not Prove
This review does not establish that AGEs directly cause ME/CFS or that dietary AGE restriction will improve ME/CFS symptoms—it presents mechanistic plausibility and identifies AGE-RAGE signaling as one of many potential pathogenic pathways. The study does not contain clinical trial data or direct measurements of AGE effects in ME/CFS populations, and correlation between dietary AGE exposure and disease severity has not been demonstrated in this patient population.