In this educational talk, Dr. David Perlmutter outlines how a variety of factors—including stress, environmental toxins (xenobiotics), infections, gliadin, and especially advanced glycation end‑products (AGEs)—contribute to increased gut permeability, or "leaky gut," which in turn fuels systemic inflammation. He focuses on AGEs, describing them as proteins bound to sugar that accumulate when blood glucose is elevated. Citing a recent Neurology study of non‑demented elderly participants, he explains that higher AGE (or A1C) levels correlate with accelerated brain shrinkage and poorer Mini‑Mental Status Examination scores, indicating faster cognitive decline. He notes that A1C, a routine clinical test for diabetics, serves as a proxy for AGE burden. Perlmutter argues that AGEs are not merely aging markers but actively destabilize gut barrier integrity, amplifying inflammation and promoting neurodegeneration. He concludes with a practical recommendation: lower blood sugar by reducing carbohydrate intake and increasing dietary fat, thereby decreasing AGE formation and helping to protect both gut health and brain function.
Chapters
A variety of factors conspire to lead to leakiness of the gut, and this plays a fundamental role in inflammation. We know that, for example, things like stress and xenobiotics, meaning toxins in the environment, and changes in the gut bacteria can lead to leakiness of the gut, but we now understand that AGEs, meaning Proteins bound to sugar when blood sugar is elevated play an important role in increasing gut permeability. Let's have a look. So again, stress and infection, drugs, toxins called xenobiotics, gliadin found in wheat, barley, and rye, and AGEs destabilize the connection that keeps the gut wall integrity intact. But it's— I want to focus, if we can, on this notion of AGEs. These are proteins that have been bound to sugar. The higher levels of AGEs occur when in fact blood sugar is elevated. Now there's a new study that comes out— has come out indicating that there's a perfect correlation between levels of these AGEs and accelerated cognitive decline published in the journal Neurology. They looked at a group of elderly individuals who did not have dementia. They performed what's called a Mini Mental Status Examination and they measured their AGE levels. And what they found was over time, those individuals with higher levels of protein bound to sugar had a much higher risk of cognitive decline. Now, we don't usually talk about measuring AGEs in clinical practice, but I would guarantee you, many of you have already had this test done. It's called the A1c. If you're diabetic, you've already had a measurement of your AGEs. It's called the A1c test. A1C is a measurement of sugar binding to a protein called hemoglobin, and the higher your A1C, your doctor will tell you, means the higher is your average blood sugar, which we were all over in Grain Brain, I can assure you. That said, this is a very interesting slide that correlates the degree of shrinkage of your brain on an annual basis with your AGE level, your A1C, which any doctor can correlate. And unfortunately, most people that I see have an A1C level on the far right side of your screen, indicating pretty dramatic rate of brain degeneration. This next report indicates that these AGEs are much more than just markers of aging because they have diffuse biological effects on tissues, and what's important about that is that it indicates that there's a variety of changes that happen when we have higher levels of sugar. Binding to protein. Now what we know is that higher levels of sugar binding to protein because your blood sugar has gotten elevated actually increases the leakiness of the gut. In other words, AGEs increase gut permeability that increases inflammation, providing yet another mechanism that leads to degeneration of the brain. Lower your blood sugar. Eat lower carbohydrate food. Increase your dietary fat and your AGEs go down, and you've gone a long way to preventing brain degeneration. I'm Dr. David Perlmutter.
