Revealing a mechanism by which diets rich in ultra-processed foods damage our health, experiments with rats established that certain compounds, which form when food is heat-treated during production, increase the risk of diseases such as chronic kidney disease. The study found that regularly eating foods cooked or processed at high temperatures, including roast meats, potato chips, and bakery products, causes a component of the innate immune system to become hyperactive, injuring the kidneys. As societies have increased their consumption of processed foods in recent decades, microvascular diseases have increased, too, with chronic kidney disease affecting almost 14% of the general population. Advanced glycation endproducts (AGEs), which are generated from mixtures of amino acids and reducing sugars when food is heat treated to boost its flavor and aroma, are increasingly recognized as disease-causing components of processed foods. However, it has remained unclear how much long-term consumption of processed foods impacts intestinal permeability (potentially enabling bacteria and toxins to enter the blood stream) and microvascular disorders. To better understand the effects of a heat-treated diet, Matthew Snelson and colleagues fed rats either thermally processed or unbaked rodent chow for 24 weeks, finding that the rats fed the heat-treated diet experienced fivefold higher leakage of albumin (a protein that helps keep fluid in the bloodstream) into their urine than controls, indicating kidney damage. Rats on the heat-treated diet also showed additional signs of early chronic kidney disease, including an increase in tubulointerstitial fibrosis and changes to a tuft of capillaries involved in blood filtration. To test whether AGEs were the culprit behind these changes, Snelson et al. administered a drug that contains the AGE pathway inhibitor alagebrium chloride to rats fed the special diet, observing improvements in their kidney injuries and related health problems. To better understand the mechanisms through which heat-treated diets cause kidney disease, the authors analyzed proteins in the rats' serum. The authors noted the presence of a protein, called complement component C3, exclusively in rats fed the heat-treated diet. This protein is part of the innate immune complement system, a sophisticated protein network activated by invading pathogens or tissue injury. "We can make alternative food formulations or functional foods aimed at dampening the response due to eating processed foods," says Melinda Coughlan, corresponding author of the study. "For example, we can add resistant starch into processed foods, which would support growth of beneficial bacteria in the gut and protect from inflammation. Nevertheless, the dietary advice would be to reduce the intake of highly processed foods."