AGEing gracefully

5. May 2010 William Davis (32)
Advanced Glycation End-products, or AGEs, have the potential to change our entire conversation about diet.

AGEs come from two principal sources:

1) Endogenous--Glucose-protein interactions that arise from high blood glucose levels

2) Exogenous--From diet

The first is sensitive to glucose levels: the higher the glucose level, the greater the AGE formation. The second depends on the quantity of AGE in the food consumed.

A compelling body of evidence points towards AGEs as an agent of aging, as well as kidney dysfunction, dementia, and atherosclerosis. Some of the observations made include:

--If AGEs are infused into an experimental animal, it develops atherosclerosis, kidney disease, and other "diseases of senescence" within weeks to months.

--In endothelial cells (cells lining arteries), AGE induces expression of adhesion molecules and inflammatory signals. In fibroblasts, AGE provokes collagen production. In smooth muscle cells, AGE triggers migration and proliferation. In monocytes and macrophages, AGEs induce chemotaxis and release of inflammation mediators. In short, AGEs have been implicated in just about every step leading to atherosclerosis.

--In humans, greater quantities of AGEs are present in diabetics, pre-diabetics and people with insulin resistance. We all know that these people develop atherosclerosis, kidney disease, cataracts, and other conditions at an accelerated rate.

--Foods containing greater quantities of AGEs cause endothelial dysfunction, i.e., artery constriction via blockade of nitric oxide and other mechanisms.

Short of taking agents that block AGE activity, how can you minimize the absorption or production of AGEs? There are two general strategies:

1) Keep blood glucose low--The Whitehall study demonstrated increased cardiovascular mortality with a postprandial (actually 2-hour post- 50-gram glucose challenge) blood sugar of 83 mg/dl. Lower blood glucose, less glycation. Less carbohydrates in the diet, the lower the blood sugar, the less the glycation. Studies like Whitehall demonstrate that glycation begins with glucose values within the normal range. Thus, aging occurs even with normal glucose levels. It occurs faster with higher glucose levels.

2) Choose and prepare foods with lower AGE content. Food content of AGEs is a major determinant of blood AGE levels. Fats and meats are the primary dietary source of AGEs, particularly if cooked at high temperature (broiling, frying). While this does not mean that meats and fats need to be avoided, it can mean that limiting serving size of meats and fats, while being selective in how they are prepared, are important. This can mean cutting your meats in thinner slices or smaller pieces to permit faster cooking, eating rare when possible (not poultry, of course), avoiding cooking with sauces that contain sugar (which enhances AGE formation). Is this an argument in favor of sashimi?

Minimizing exposure to AGEs, endogenous or exogenous, has the potential to slow the aging process, or at least to lessen the likelihood of many of the phenomena of aging.

More on this to come.
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Comments (32) -

  • yoyo

    5/5/2010 11:17:44 AM |

    I'm more worried about endogenous AGEs; exogenous the evidence seems a bit more mixed.

    Are food advanced glycation end products toxic in biological systems?

    Chuyen NV, Arai H, Nakanishi T, Utsunomiya N.

    Japan Women's University, Department of Food and Nutrition, 2-8-1 Mejiro-dai, Bunkyo-ku, Tokyo 8681, Japan. nvc@fc.jwu.ac.jp
    Abstract

    Model food advanced glycation end products (AGEs) were prepared as glycated casein (GC) and glycated soy protein (GS) by the reaction of casein or soy protein with glucose at 50 degrees C, relative humidity 75% for seven days in a powder state. These browned proteins were used as materials for animal experiments. A mixture of 20% glycated proteins (GC:GS = 1:1) diet was fed to streptozotocin (STZ)-diabetic rats for 11 weeks. The results showed that: (1) fructoselysine was observed in the hepatic portal veins, arteries, and femoral veins of rats fed with glycated proteins after 2 h of feeding; (2) blood sugar of glycated protein-fed rats was lower than that of diabetic rats fed with intact protein, while HbA1C in blood and glucose in urine of both groups were similar; (3) lipid peroxidation status in serum, liver, and kidney of both groups was similar; (4) superoxide dismutase (SOD) and glutathione-S-transferase (GST) enzymatic activity in serum and liver of both groups were also similar; (5) there were no differences in degree of cataract formation and concentration of glucose, fructose, sorbitol, and lipid peroxide in the lenses of both groups. From the above results, it can be estimated that food AGEs are not toxic in biological systems, and reactive oxygen species increase in diabetic rats is not caused by glycated proteins but by other pathways.

    PMID: 16037268 [PubMed - indexed for MEDLINE]

    Unfortunately, starches have much lower AGE content. Any preparation of meat has large amounts, though still variable. This might be why high-carb diets work well for traditional societies where obesity is not common.

  • Joel

    5/5/2010 11:49:11 AM |

    Less carbs, less meats, less fats--sounds like you're just promoting calorie restriction since that doesn't leave much that you can eat in significant quantities.

  • Denny Barnes

    5/5/2010 12:16:33 PM |

    Looking forward to your future writings on AGEs. I hope you will talk about the role of fructose which can form ten times as many AGEs as glucose. Not all carbs are created equal. As a fellow T2 diabetic, I think we focus too much on blood glucose and miss the stealth carb -- frutose.  It is by far the most insidious.

    Forgive me for saying it, but I feel that the ghost of your vegetarian past still haunts your writing.  Yes, barbecued, fried and broiled meats can have way too much AGEs, especially if cooked with sweet sauces, but animal protein cooked with water has 1/10 as many AGEs. I am a happy carnivore who loves stewed meats and chicken and steamed fish.

  • Martin Levac

    5/5/2010 12:49:37 PM |

    Then there's ketosis which stimulates something called chaperone-mediated autophagy (CMA). This process is basically the recycling of junk protein. AGEs would constitute such junk. So it's not only a question of low blood glucose but of ketosis as well. Incidentally, if one eats only meat or very little carbs, then he will be in ketosis most of the time. In that sense, it doesn't matter how much AGEs come from this diet since the same diet would provide the recyclers as well. Here's the post by Eades on the subject:

    http://www.proteinpower.com/drmike/ketones-and-ketosis/ketosis-cleans-our-cells/

  • Ned Kock

    5/5/2010 1:20:12 PM |

    Supporting your point regarding endogenous AGEing, there is also reliable evidence that blood glucose control before age 55 may increase your chances of living beyond 90:

    http://healthcorrelator.blogspot.com/2010/04/blood-glucose-control-before-age-55-may.html

    However, I am yet to see reliable evidence that significant damage can be caused by ingested AGEs through cooked meat and fat (e.g., resulting from Maillard reactions).

    I don't doubt that injecting AGEs into model animals, particularly rodents, will lead to problems. But human digestion in a healthy person (e.g., no leaky gut) is another story. Moreover, cooked meat is denatured and thus rendered more easily digestible.

  • Jen

    5/5/2010 3:42:07 PM |

    Thanks for the post Dr. Davis!

    I would love to get info on what happens to the body as you are lowering your blood sugar via diet.  I have been using a monitor and feel my best at around 85 but at times crave sugar pretty bad and have energy spikes and dips.  I exercise too, so curious how this factors in?

  • Apra -- The Shaman

    5/5/2010 3:42:07 PM |

    I agree with Yoyo.  It seems to me this could be another red herring, like the dietary cholesterol nonsense.  Until they can tease apart whether the issue is due to dietary AGEs of the stuff produced from hyperglycemia then I don't necessarily see any reason to jump on an anti-meat bandwagon.

    Still, if you're truly concerned, invest in some Sous Vide equipment and cook your meat at low temperatures and don't finish it with a nice sear.

  • Stephan

    5/5/2010 6:36:09 PM |

    I just read the Whitehall study, it really didn't show that CHD mortality increases from 83 mg/dL.  That's based on their mathematical extrapolation, which didn't fit the actual data very well at the lower range of blood glucose.  According to the data itself, CHD risk didn't begin increasing until 5.7 mmol/L, or 102 mg/dL.  

    That makes sense because 83 mg/dL is totally normal fasting glucose.

  • Adolfo David

    5/5/2010 9:55:08 PM |

    Sad to say: Dr Michael Holick recommends at the end of his new book VITAMIN D SOLUTION essentially one brand of vitamin D supplements: Nature Made! :S

  • Anonymous

    5/6/2010 1:02:37 AM |

    2 things might help AGE's.
    I read that Carnosine which is a combo of 2 amino acids helps prevent glycation and many anti-aging experts recommend this supplement.
    Metformin reduces glucose production in the liver, reduces glucose absorption in the intestines and increases tissue sensitivity to actual glucose in the blood.
    Also may decrease cancer risk
    I have started these supplements in hopes of combating AGE's

  • Lori Miller

    5/6/2010 1:29:00 AM |

    Another way to cook meat quickly is by using a pressure cooker. The 1.5-pound roast I'm having for dinner was done in 20 minutes--15 probably would have been fine. The package called for roasting it for four hours in the oven.

  • Anonymous

    5/6/2010 2:05:20 AM |

    A fasting glucose of 80-109 mg/dl was optimal for CVD and overall mortality in this paper.

    http://circ.ahajournals.org/cgi/content/full/101/17/2047

  • pmpctek

    5/6/2010 2:51:51 AM |

    I've heard that Benfotiamine (200mg twice/day) is a potent AGE inhibitor.  I haven't been able to find much study on humans that backs up that claim though.

  • Anonymous

    5/6/2010 4:19:34 AM |

    Forgive my extreme ingnorance in this area, but how do meat and fats contain AGEs?

    A grilled steak? An egg fried in coconut oil? Where is the source of glucose here?

  • Fran

    5/6/2010 4:29:09 AM |

    "Fats and meats are the primary dietary source of AGEs..." I'm sorry, but this makes no sense to me... that fats and meats will increase blood sugar levels. My understanding to this point is that carbs are the cause, while good saturated fats and protein stabilize blood sugar levels.

  • Dr. John Mitchell

    5/6/2010 4:31:51 AM |

    I'd like to see references for many of your statements.

  • Bruce

    5/6/2010 4:34:46 AM |

    May I offer a little anecdotal evidence? After hearing a researcher from Australia's Baker Heart Institute describe how a low exogenous AGE diet appeared to reverse the complications of Type II Diabetes - although not Diabetic, I was intrigued enough to devise my own low-AGE regime.

    During the subsequent 5 months, with no attempt to restrict calories, I have lost nearly 15 kg, have had my total Cholesterol drop from 5.9 to 4.6, blood pressure drop from 128/88 to 110/62. Part of my strategy has been to avoid all sugars, including most fructose sources, in the interest of limiting endogenous AGE formation.

    BTW, I am 60 years (suddenly) young.

  • Michael Barker

    5/6/2010 2:57:54 PM |

    Humans have been cooking meats, at least, 100,000 years before the invention of agriculture. The fact that it is so ubiquitous suggests that we are quite adapted to this even without thinner slices or smaller portions.

  • Anonymous

    5/6/2010 3:26:07 PM |

    Marinating meat with acid (vinegar) before grilling greatly reduces the maillard reaction and the formation of AGEs in meat.

  • Peter

    5/6/2010 4:48:23 PM |

    As we learn more about food, we learn more about the downsides: fish have mercury, meat has AGE's, carbs increase insulin sensitivity, etc. If you ask an expert what to eat, each one gives you a different answer.  How can we tell truth from belief?

  • CB Predator

    5/7/2010 10:50:32 AM |

    I wanted to thank you for this great read!! I definitely enjoying every little bit of it I have you bookmarked to check out new stuff you post

  • foodnearsnellville

    5/7/2010 4:54:40 PM |

    At what point is research like this going to limit the use of sugary glazes and marinades in meats and restaurant foods?

  • Anne

    5/8/2010 12:05:57 PM |

    Could adding spices and herbs reduce the bad effects of cooked meat. The study is small and funded by McCormick. Simple Addition to Meat Helps

  • Marianne

    5/8/2010 9:22:51 PM |

    Just discovered this blog so forgive me if this has already been covered.  What about Neu5Gc?  Some recommend all mammal products be avoided as they all contain this substance and it sets up an inflammatory process in the body as humans do not have Neu5Gc and recognize it as foreign.  I  have recently been poking around at eating better (not that my past was bad!) and I have never been so confused in my entire life!!! Everyone has their own opinion and most of it is contradictory. High carb, low carb, no meat, more meat, more fish, all whole grains.  It's like a crap shoot.

  • yoyo

    5/9/2010 10:57:30 AM |

    I don't have access to the original study, but the best one i could find has the food levels of AGEs reproduced with some comments at this gentleman's blog: http://inhumanexperiment.blogspot.com/2009/09/age-content-of-foods.html

    meat, even with low heat low pH preparations, seems to be high. eggs and legumes are low for their protein content.

  • Dr. William Davis

    5/9/2010 12:25:34 PM |

    Yoyo, Joel--

    Much of the work on the AGE content of food, its absorption, and its consequences have been generated by Dr. Helen Vlassara's group in New York. The Japanese group Yoyo cites has, indeed, found some conflicting observations.

    I do not think that we can construct an "AGE-free" diet nor lifestyle, nor are the data on AGE-blockers sufficiently solid to justify taking them, in my view.

    However, this is such a fascinating line of research that I think it's worth being aware of and discussing.

  • Dr. William Davis

    5/9/2010 12:33:50 PM |

    Bruce--

    Fascinating experience!

    How did you handle the AGE in meats issue?

  • Dr. William Davis

    5/9/2010 12:36:17 PM |

    Marianne--

    Sorry, no insights into Neu5Gc.

    As I mentioned in the post, this is not a "no meat" comment. It is simply discussing the fascinating observations made by Helen Vlassara's group that, when taken as a whole, fit like a perfect puzzle piece into the question of why people with high blood sugars, e.g., diabetics and pre-diabetics, develop all the undesirable health effects they do.

  • Bruce

    5/9/2010 11:50:47 PM |

    May I add a few more comments?

    Regarding meat, I have been eating normal and even generous portions - but I purchased a steamer and slow cooker to keep the cooking temps as low as possible. There is a limit in how far you can lower exogenous AGEs unless you adopt an extreme Raw regime.

    Then, your body will still produce its baseline of indogenous AGEs. I eat virtually zero sugar except for a minimal amount of fruit - usually 2 servings or 3 per day at most.

    We're really talking about a low Maillard Reaction Products diet, then I think. AGEs are many in type and the chemistry is complex. But there is good and growing evidence that the overall mix of MRPs are toxic. One study I read stated that lowering the exogenous AGE load by 40% reduces the circulating AGEs  by 60% and at this level, the body's own ability to scavenge out these compounds recovers.

    This suggests to me that we can tolerate MRPs up to a certain level, but the western diet is increasingly loading with these compounds. I wonder if this provides a (at least) partial explanation of the obestity epidemic.

    Food has been plentiful and cheap for at least 3 generations now, yet obesity is 'exploding' at the same time that the food industry is in an 'arms race' to heighten the marketability of their products.

  • Kevin

    5/10/2010 3:38:54 PM |

    I wonder how calorie restriction affects AGEs.  Is this possibly how CR influences longevity?  

    kevin

  • Santiago

    5/10/2010 11:34:41 PM |

    Hi Dr Davis
    I've hear from some diabetics how honey doesn't seem to affect them that bad.
    I looked arround and found some studies showing that honey after eaten for a while lowers blood sugar levels improiving liver function.
    Was wondering if you have an opinion related to honey

  • Anonymous

    8/30/2010 3:50:39 PM |

    So don't eat meat or carbs.  Good advice.

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