Advanced glycation end products (AGEs)

About a decade ago, Michael Brownlee posited that AGEs were one of The Four Horsemen responsible for the microvascular complications of diabetes.

Kill ‘em all

Thereafter, the image below (or a closely related one) appeared in at least one talk at every major diabetes conference for about 5 years.  Then it faded – maybe not because it is wrong, but rather just too simplistic to be useful (similar to CICO & ELMM).

Brownlee

AGEs

AGEs are created by reactions between reducing sugars (eg, glucose, galactose, etc.) and amino acids, fats, and nucleic acids.  There are two fundamentally different sources: 1) endogenous, formed as a normal biological process; and 2) exogenous, present in [mainly animal] foods, depending on cooking temperature.  A low level of exposure is normal and likely harmless, although excessive exposure can be inflammatory and promote oxidative stress.  The latter can conceivably come about via chronic hyperglycemia or eating a lot of cooked/seared/burnt meat (AGEs are very low in most plant foods, cooked or not).

If there is any pathological effect of AGEs, I suspect: 1) it will be restricted to hyperglycemics who eat a lot of burnt meat; and 2) it’ll be difficult to dissociate which is more important (ie, endo vs. exo AGEs).  See review by Han and colleagues for further discussion of this (2013).  There are some interesting differences, eg, endogenous AGEs take much longer to form – they require chronic hyperglycemia – whereas exogenous AGEs can form very rapidly on the surface of a seared steak because of the higher temperature.  However, the difference between endo and exo AGEs is beyond the scope of this article, and I honestly don’t know if the truth of it has been adequately fleshed out.

For a comprehensive list of the AGE content of foods, see the paper by Uribarri and colleagues (2010).  But in brief, different foods can have anywhere from ~0 to about ~20,000 “units” per serving.  So we may get about 10 million “units” per day on average?

In 2002, Vlassara and colleagues tested the effects of 2 diets varying 5x in AGE content on a diabetic population (3.67 vs. 16.3 million AGE units/day) (Vlassara et al., 2002).  The AGE content was manipulated by varying the cooking time and temperature.  Since this affects many aspects of the food, it might have been better to just take two identical diets and spike one of them with AGEs, but there are easily arguments supporting both sides of this decision.

To confirm these two diets did in fact differ in AGE content:

Vlassara 1

…interesting, given  the meal differed 5x in AGEs… but the units are moving in the right directions.

At the end of the first half of this study, a 2 week crossover, there were few metabolic effects, although the high-AGE diet negatively impacted some inflammatory markers:

Vlassara 2

In the 6 week follow-up study, fasting glucose deteriorated in the high-AGE group and significantly improved in the low-AGE group:

Vlassara 3

Not a very damning study, but this piqued my interest.

In 2014, Tantalaki and colleagues assessed the impact of a high or low AGEs diet in a population of weight-reduced PCOS patients (Tantalaki et al., 2014).  The study design was odd, but it didn’t entirely preclude the ability to draw meaningful conclusions.  Design flow: “baseline assessment -> weight loss phase (2 months) -> high AGE diet (2 months) -> low AGE diet (2 months).  Dietary AGEs were 10.9 million at baseline, 9.6 during the weight loss phase, 16 on the high AGE diet, and 5.7 on the low AGE diet.  So, the design was inferior to Vlassara (no crossover and a smaller difference in AGEs between the groups), although this patient population experienced significantly greater improvements by restricting AGEs:

Tantalaki 1

The study is obviously confounded, although many of the changes in metabolic parameters mirror changes in serum AGEs and move in the expected directions:

Tantalaki 2

Also, the difference in dietary AGEs is clearly reflected in changes in serum AGEs, in both studies (although to my knowledge, this isn’t 100% consistent):

Vlassara: 5x difference in dietary AGEs, serum AGEs: 13 vs. 7.7.

Tantalaki: 2.8x difference in dietary AGEs, serum AGEs: 10.4 vs. 8.2.

From what I can gather, the levels of AGEs used in these studies is physiologically relevant.  Sure, this kind of thing is painfully confounded – big differences in cooking temp alter much more than AGEs; also, in real life, AGE content varies widely dependent on the food and its macronutrient composition.

One last paper on AGE restriction, in seemingly uncontrolled type 2 diabetic patients: Luévano-Contreras et al., 2013.

After 6 weeks, the most robust findings were changes in dietary AGE intake (by design), and significantly reduced levels of TNF-alpha (a pro-inflammatory cytokine) and malondialdehyde (a marker of oxidative stress) in the low-AGEs group.

Luévano-Contreras 1

And mixed impact on metabolic parameters:

Luévano-Contreras 2

For patients with hyperglycemia (and thus most likely a higher baseline level of AGEs), a plant-based diet with meats prepared rare or medium-rare whenever possible might help; and lower the carbs to reduce blood glucose.  Check out the paper by Uribarri… this is NOT a restrictive diet.

Disclaimer: my impression is that if you’re lean and healthy, dietary AGEs aren’t a concern (they may not be an issue if you’re not healthy, either, although the jury is still out on this.  See below.)  All of the above data are from patients predisposed to metabolic dysregulation.  And this study showed no significant impact on inflammatory markers in healthy adults after dining on AGE-restricted diets, whereas this one showed only a modest increase in oxidative stress in overweight but otherwise healthy adults.

In patients with more severe conditions, monitoring dietary AGEs might be warranted… especially because it’s rather easy to do (a potentially high benefit-to-cost ratio), because:

“Skin autoflourescence as a measure of advanced glycation end products deposition is independently associated with all-cause mortality and fatal or nonfatal major adverse cardiovascular events in patients with peripheral artery disease after a 5-year follow-up.” (de Vos et al., 2014)

and

“The present study suggests that skin autofluorescence is an independent predictor of cardiovascular mortality in non-Caucasian (Japanese) patients on chronic hemodialysis.” (Kimura et al., 2014)

Note: if the number of review articles on a given topic greatly exceed the number of primary studies, then that might be the makings of a molehill, not a mountain.  

Since pharmacological AGE inhibitors have shown mixed effects, and even worsening of symptoms in one case (ie, aminoguanidine, Freedman et al., 1999 and Engelen et al., 2013), the most reasonable approach, and possibly the furthest you might need to go: don’t eat burnt meat.  Easy peasy.

burnt meat

 

Part 2.

Great observation, as per usual  …and it’s probably true.   Or at least this may be the more potent driver contributing to the results above.  But I don’t think it’s the whole story,  because #1. the Tantalaki study: body weight remained stable yet oxidative stress increased during the high-AGE phase and returned to normal during the low-AGE phase.

#2a. Reductionism: a receptor for AGEs has been identified (“RAGE;” eg, Xue et al., 2014), and genetically deleting it in mice reduces inflammation & improves insulin sensitivity (eg, Song et al., 2014 & Gaens et al., 2014).

#2b. Even more reductionist: exposing immune cells to AGEs enhances the secretion of inflammatory cytokines, and this is blocked by a RAGE antagonist (Shim et al., 2014).

#3. Slightly less reductionist: there is ONE rodent study where dietary AGEs were supplemented directly, in isolation, and all of the expected [negative] effects occurred (Cai et al., 2014)… this seems like an obvious thing that should’ve been done long ago.  And repeated in humans.

Part 3.

Regarding the relative importance of endogenously generated AGEs, which are correlated with (and likely caused by) chronic hyperglycemia:  restricting dietary carbohydrates is the best way to manage hyperglycemia.  It is known.  And interestingly, this study showed that beta-hydroxybutyrate (a ketone that is increased in the blood of people following low carb diets) can directly inhibit the formation of AGEs.

Conclusion: Quantitatively speaking, chronic hyperglycemia is obviously a much greater concern than dietary AGEs, and the human studies may even be systematically bollixed (see Jane’s observation, above).  The animal studies on RAGE don’t differentiate between endogenous vs. exogenous AGEs, although the Cai study suggests dietary AGEs may be a concern, if you like burnt meat.

calories proper

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  • http://ashsimmonds.com/ Ash Simmonds

    Overcooking and combining protein/fat with carbohydrate in the cooking process are the biggest exogenous factors. From what I remember the amount of AGEs in a charred steak are way more than in lightly cooked, but a gazillion times less meaningful than a steak cooked in a sugar-based (fructose most especially) marinade.

    Covalent bonds, cross-linked proteins, and then there’s acrylamides from cooking plants – I’m not sure where the idea that it’s a meat-based problem comes from, it’s only in MIXED diets that it seems to be an issue.

    AVOID ANY MEAT COOKED IN FRUITY STUFF – and don’t eat stuff that will ensure hyperglycemia when you are eating meat. These two things cover 95% of exogenous AND endogenous glycation, and funnily enough basically describes the standard Western diet of combining protein and sugar for a nice delicious assault on the system.

    Got a ton of other resources about overcooking meat and AGEs here:

    –> http://highsteaks.com/carnivores-creed/the-dangers-benefits-of-raw-undercooked-meat/

    But it’s been a couple years since I did any further investigation so the stuff in this post with the 2013/14 references will be useful for me to spelunk through.

    Have you read The Glycation Factor by Greg Ellis?

    • http://www.caloriesproper.com/ William Lagakos

      “I’m not sure where the idea that it’s a meat-based problem comes from”

      “For a comprehensive list of the AGE content of foods, see the paper by Uribarri and colleagues (2010).” :)

      For what it’s worth… cooked meat, almost regardless of how it’s prepared (eg, fried, grilled, broiled, etc.), can easily have over 30x more AGEs than things like nuts, berries, and veggies (even if they’re cooked).

      • http://ashsimmonds.com/ Ash Simmonds

        Yah, that’s why I specified mixed cooking. Plants have their own laundry list of issues, significant AGE contribution is only really when combined with higher protein/fat sources, and that number is ridiculously more than the meat cooked alone levels, which really unless you’re going scorched earth policy for every piece of meat every day, barely outweigh hormesis levels.

        Eg from the Uribarri paper:

        “Grains, legumes, breads, vegetables, fruits, and milk were among the lowest items in dAGE, unless prepared with added fats.”

        Can’t remember the numbers involved, I went over a huge list of this stuff long ago and it indicated that yeah it’s all very much like Joker’s Product X – neither of the food sources are particularly bad unless combined. Unfortunately the list referenced in the papers resides on a site that is gone way of the Dodo, and my Google Fu fails me.

        In the Goldberg paper they put the blame on:

        “foods high in lipid and protein content show the highest AGE levels.”

        But then in the next paragraph, in a fantastic case of forest =/= trees they state:

        “Foods that are composed mostly of carbohydrates contain the lowest AGE concentrations. However, within this group .. 30-g servings of toasted frozen waf?es and biscotti contained 1,000 kU AGE”

        For reference sake, beef grilled for 15 mins (scorched earth) is about double that (I think), so with only a bit of added fat in what I assume is a low protein high sugar/starch item, the AGE levels are easily catching up.

        Now, just like the Glycemic Index, these measurements of single foods in such portions are nigh on useless – when’s the last time you went to try and buy food in a convenient form that wasn’t covered in sugar marinade/pastry/etc and cooked to high hell (likely in seed oil/transfats)?

        THESE are the foods people by and large are eating – Chinese pork in honey glaze, soybean oil fried breaded chicken, meat lovers pizza with HFCS BBQ sauce, donuts with jam and cream, battered fish, teriyaki beef jerky, etc etc, and then follow it up with desserts and sodas etc which will keep them hyperglycemic to really help form those covalent bonds and crosslinks.

        But it’s the fat and protein content that cops the blame. Hmm.

        • http://ashsimmonds.com/ Ash Simmonds

          Having said all that Chris Masterjohn puts forward some arguments to indicate that the measurements themselves might not be very meaningful to start with – noting that in the tables butter comes in stonking with AGEs, but in reality it may not be the case:

          http://blog.cholesterol-and-health.com/2010/10/is-butter-high-in-ages.html

          DESPITE ALL BUTTER’S AGE I’VE STILL GOT GOOD A MACROPHAGE

          • Jack Kruse

            Regarding malondialdehyde (a marker of oxidative stress) in the low-AGEs group we need to all remember that since trans fats were greatly limited by the FDA and in some locales the replacement has been PUFA omega 6 that have an unusual isomeric double bound that allow it to from literally thousands of “new triglycerides and fat aldehydes that cause massive problems for humans. Food manufactures cant go back to saturated fats from animals and they can use tropical oils so they have jumped on these new lipids. The cause massive perioxidation anywhere they are used. I have a friend who 5 McDonalds and this aldehyde fat is everywhere. One of his employees work shirts cause fire in her dryer because these aldehyde fats are highly flammable under any heat pressure. When you understand how fats are constructed and how that double bond changes their chemistry then you realize why this is a big issue.

      • http://itsthewooo.blogspot.com/ Jane Plain (Woo)

        Perhaps this is part of the reason I feel better eating vegetation (usually raw) and nuts.

        Interesting evidence above, bill, to support the idea this is not simply decreased energy absorption but directly related to AGEs themselves. I still think some of the effect relates to energy availability of consumed food but it does suggest AGE themselves may be inflammatory and promoting of IR.

  • Wenchypoo

    L-carnosine breaks the AGE bonds between sugars and proteins.

    http://www.antiaging-systems.com/articles/25-cross-link-breakers-and-inhibitors

    According to MDA, creatine use stops AGEs from forming in the first place: http://www.marksdailyapple.com/wifi-effects-on-health-creatine-and-ages-and-introducing-solids/#axzz330ReVlm9 (scroll down in article)

    • http://www.caloriesproper.com/ William Lagakos

      I didn’t know that about creatine. Interesting!

  • Wenchypoo

    According to this article, erythritol (the darling of the LC community) is also an insecticide: http://drexel.edu/now/news-media/releases/archive/2014/June/Researchers-Find-Sweetener-is-Safe-Insecticide/

    Does it create AGEs in bugs, I wonder?

    Will it work on roaches or fleas? I’m going to test it this summer.

    • http://www.caloriesproper.com/ William Lagakos

      It might! but I suspect the mechanism of toxicity is something much quicker than AGE accumulation :)

      • Jack Kruse

        Glucose and many of the fake sweeteners that are in manufactured low carb food changes the optics in the brain. When this occurs you lose the ability of harness polarized light carried on your electrons that get released to your now glycated brain tissue. Non native EMF exposure raises your perceived need for glucose as laid out in my EMF 4 blog post. I also mentioned the creatine system in this post and wy it is up-regulated when this occurs. The grouping in the NHANES III charts underscores that people with altered HbA1c’s truly represent different populations of brains entirely. One has optimal optic transmission in their brain and the other does not. Here you see the effect of chromophores in the brain. No one seems to see what I see in these charts. This explains how HbA1c ties to Vitamin A and D cycles in the brain. Vitamin A and D cycle link to RXR receptors which directly tie to DHA. It is clear with my view point that they were improperly grouped together in the data and the most important link to longevity was buried.