Glycotoxicity: A New Risk Factor for Alzheimer’s?

by Jim Schnabel

April 16, 2014

Here is another reason, perhaps, to go easy on the fried chicken and the flame-broiled spare ribs: High-temperature-cooked foods, which already have been found to promote cancerdiabetes and cardiovascular disease, may be raising the risk of Alzheimer's too.

That's the suggestion of a new study from researchers at the Mount Sinai School of Medicine. They fed mice a diet in which a "glycotoxin" chemical associated with high-temperature cooking was included or mostly removed, and observed fewer memory and learning deficits in the low-glycotoxin mice as they grew old. The researchers also found that higher bloodstream levels of the glycotoxin in elderly humans predicted a faster cognitive decline.

The involvement of glycotoxins in Alzheimer's is "still a new concept for most scientists," says Weijing Cai, the Mount Sinai researcher who was lead author of the study. But the response so far has been positive, he adds, and he and his colleagues now hope to get funding for clinical trials of glycotoxin-reducing interventions.

What are glycotoxins?

Also known as "advanced glycation end products" or AGEs, glycotoxins are the products ofa process known as glycation: the fastening of a sugar molecule to a protein or fat molecule in a way that isn't mediated by enzymes.

Glycation happens in the body's normal metabolism of foods as well as in the cooking process. The browning of a turkey during high temperature roasting is a classic glycation sign. Once glycated, molecules tend to undergo further chemical reactions until they end up as products-the so-called advanced glycation end-products-that are hard for enzymes and other housekeeping systems in the body to dispose of normally.

Glycation and some of its more reactive products also can "cross link" proteins, potentially reducing their function and flexibility. This is now widely seen as a contributor to the aging of skin and blood vessels, particularly in diabetics and others who have high and relatively uncontrolled blood sugar levels.

Stiffer blood vessels lead to higher blood pressure, which in the brain can cause strokes and mini-strokes, and also has been linked to lower brain volume, worse nerve fiber integrity, cognitive impairment, and dementia.

Glycation and AGEs can harm the brain not just by raising blood pressure but also by cross-linking protein aggregates, such as the amyloid beta and tau aggregates seen in Alzheimer's disease. Cross-linking potentially makes these aggregates tougher to remove by cellular waste-disposal systems such as proteasomes, and thus could enhance the associated disease processes, says longtime AGE researcher Gerald Münch at the University of Western Sydney: "If you cross-link tau with AGEs, for example, it becomes completely undegradable by proteasomes." Moreover, he adds, autopsy studies of Alzheimer's brains have shown that "the amyloid and tau aggregates contain lots of AGEs."

AGEs and associated compounds may hurt the brain in yet another way, by stimulating inflammation, which is known to promote and accelerate Alzheimer's and other neurodegenerative diseases. It appears to do this via several pathways, including the promotion of reactive oxygen species, and the activation of inflammatory cellular receptors known as TLRs and RAGEs (Receptors for AGEs).

A factor in Alzheimer's?

All these potential factors could help explain the striking link between diabetes, a disorder associated with high levels of glycation and AGEs, and Alzheimer's. But although there are many reasons to suspect that glycotoxin-related processes promote and accelerate Alzheimer's, proving a causal link has never been easy, given the many other factors involved in the disease. In the Alzheimer's research world most of the focus has been on amyloid beta and tau.

Even so, there does seem to have been a slow buildup of evidence for the importance of glycotoxins, particularly in the past few years. For example, a study published early in 2013 from Münch's laboratory linked methylglyoxal (MG) a metabolic and dietary product that drives AGE-production, to lower gray matter volume. A study published soon after by researchers at the University of Minnesota found that boosting the activity of an MG-removing enzyme system, the glyoxalases, blocked cognitive dysfunction in an Alzheimer's mouse model.

There is also the fact that the human exposure to these compounds can be reduced immediately by changes in diet-less sugar, lower cooking temperatures-which means that a little evidence in this field could go a long way in terms of the human impact.

Cai's laboratory is part of a research group led by Mount Sinai School of Medicine professor Helen Vlassara, who has been studying AGEs and their harmful effects for three decades. Most of that work has been in relation to diabetes, and to the obesity-linked "metabolic syndrome" that often precedes both diabetes and cardiovascular disease.

In a 2012 study, however, Vlassara and Cai and their colleagues found that mice fed a diet with added MG derivatives developed a host of diabetes-promoting changes that weren't seen in mice fed a low-MG diet. The changes in the mice included increased fat, premature insulin resistance, and increased inflammation, and seemed to be driven in part by falls in levels of a protein called sirtuin 1 (SIRT1) in fat, muscle, and liver.

SIRT1 is of great interest to medical scientists because it appears to switch on programs in cells that increase stress resistance and promote a healthy sensitivity to insulin, among other beneficial effects. SIRT1 activity is boosted by caloric restriction in rodents, fruit flies, and worms, and that appears to account for most of caloric restriction's lifespan-extending benefits in those animals. Drugs that boost SIRT1 artificially are now being developed for use against diabetes.

The same drugs might help prevent Alzheimer's too, for SIRT1 levels decline in key brain areas in the course of that disease, whereas SIRT1-boosting caloric restriction in mice and monkeys appears to protect the brain from age-related neurodegeneration. SIRT1 may help in this regard not only by improving the metabolic state of brain cells, but also by reducing the usual production of the amyloid beta protein (which is cut from a larger protein) by enzymes in the brain.

The SIRT1 connection encouraged Cai and Vlassara and their colleagues to do the new study-of the experimental low-MG diet in the context of brain aging.

The researchers separated the mice into three diet groups: a low-AGE diet, a low-AGE diet supplemented specifically with MG (to isolate MG's harmful effects), and a regular chow diet. The latter two groups, when they grew older, were significantly fatter, showed signs of insulin resistance, showed declines in learning ability and memory on standard tests, had reduced levels of SIRT1, and increased levels of a particularly aggregate-prone form of amyloid beta (Aβ42), compared with the low-MG mice.

In a separate part of the study, Cai and Vlassara and their colleagues evaluated blood samples from 93 elderly humans, and found that those with high levels of MG in their blood were significantly more likely to experience cognitive decline in the ensuing nine months.

More research, and ideas for therapies

Naturally Vlassara's group is hoping to do further research: firstly to understand better the detailed mechanisms by which MG and AGEs might promote Alzheimer's, and secondly to set up clinical trials of interventions against these compounds.

Such trials could involve low-MG/AGE diets in people who have early Alzheimer's or are at high risk for it. (Vlassara and colleagues have written a practical guide to avoiding dietary AGEs.) Yet researchers often shy away from clinical trials of dietary changes, where the ability of the people volunteering in the study to comply with its rules is often in doubt. "If you give them a pill instead-no dramas," says Münch.

As Cai notes, "we hope to explore oral agents that can bind AGEs in the gut and prevent them from entering the body and reach the brain." Initial published studies of the AGE-sequestering drug sevelamer carbonate against diabetic kidney disease have been promising, he says-and "additional trials pending publication have confirmed the initial findings."Other AGE-sequestering drugs include aminoguanidine and tenilsetam.

A North Carolina-based biotech company, TransTechPharma, is taking a similar approach. It has begun testing a RAGE-receptor antagonist drug, TTP488, which is meant to block some of AGEs' pro-inflammatory effects.

Another option, Münch says, is to somehow boost the activity of the body's natural anti-MG system, the glyoxalase I and II enzymes. One way to do this would be to boost levels of glutathione, an important co-factor for glyoxalase activity. Studies have shown that levels of glutathione are reduced in affected brain areas in early Alzheimer's, whereas the principal glyoxalase enzyme, glyoxalase I, is upregulated-a picture that suggests a failing compensatory response due to insufficient glutathione.

How to increase your glutathione levels, and thus increase your defenses against MG and AGEs? Münch points out one of the most potent compounds capable of boosting glutathione production is sulforaphane, which is found in so-called cruciferous vegetables such as cauliflower, cabbage, kale, and, most of all, broccoli.

Another reason to eat your broccoli.




Red Bishop

5/26/2014 11:47:58 AM

I am a researcher in the topic of dietary AGEs. Would like to stress that there is limited evidence for any harmful effect of dietary AGEs - not to say none whatsoever. Better focus on more fibres, and less salt (i.e. vegetables as suggested in the post above). AGEs are a good example of scientific tunnel vision!