Thiamine and thiamine compounds can help make food safer …

Have Your Cake
and Eat It Too

Vitamin B1 and Vitamin B1 compounds help
turn down the heat on AGEs and ALEs
By Will Block


ost people are locked into a belief system that makes them think of foods as either good or bad. The objective and untarnished truth is that nothing is totally good or absolutely safe. But because there is no way to avoid choosing what to ingest …

We should be guided by the probability and extent of harm, not by its mere possibility. The search for possibilities is endless and it trivializes the subject. There is bound to be great diversion of resources without reducing substantial sources of harm. Consternation is created but health is not enhanced. … Weak causes are likely to have weak effects. Our search should be for strong causes with palpable effects, like cigarette smoking. They are easier to find and their effects are much more important to control. … The past necessity of proving harm has been replaced by a reversal of causality: now the individuals and businesses must prove that they will do no harm. My objection to this … is profound: our liberties are curbed and our health is harmed.1

As Paracelsus said, the dose makes the poison (the actual quote is, “All things are poison and nothing is without poison, only the dose permits something not to be poisonous.”) What he meant is that for every ingestible, there is a critical point in the dose beyond which it is a poison, but before which it may be nutritive, or even a remedy. For example, according to Bruce Ames, about 50% of all chemicals—whether natural or synthetic—have been found in standard high-dose animal cancer tests to be rodent carcinogens.2

Diet-derived advanced glycation
endproducts (AGEs) and advanced
lipoxidation endproducts (ALEs) may
harm health significantly.

The real question is: how big of a risk does a food represent, and if that food is so indigenous as to be virtually unavoidable—fats for example—how can the dangerous consequences be minimized or eliminated? One thing is certain: you’re not likely to find out the truth from the same government that tries to regulate or ban cholesterol, trans-fatty acids, high-fat foods, salt, and even sunny side up eggs. It’s not that some of these consumed in excess may cause health problems, but that the knowledge of dose gets buried, and anti-food fads come into fashion.

Take the anti-fat campaign, for example, which has treated dietary fat as the nutritional equivalent of cigarettes. Despite the creation of thousands and thousands of low-fat foods, the crusade has had no obvious effect on the incidence of heart disease, nor have pounds been falling off national waists and hips. To the contrary, Americans are getting fatter. And not only is a low-fat diet largely irrelevant to reducing heart disease, it is partly responsible for the steep rise in diabetes because the fats have been substituted by high-glycemic carbohydrates.

Maillard reaction product

Brioche, by Rainer Zenz

Cakes and ALEs

There is an overlooked and generally hidden danger causing deep concerns among some nutrition researchers: diet-derived advanced glycation endproducts (AGEs) and advanced lipoxidation endproducts (ALEs) may harm health significantly. A recent study examined the effects of the addition of AGE/ALE inhibitors and different types of sugar and cooking oil on Nε-(carboxymethyl)lysine (CML) and Nε-(carboxyethyl)lysine (CEL)—both are AGEs—formation in, of all things, sponge cakes.3 Sponge cakes are a takeoff of angel cakes (aka angel food). Now what could be wrong with that you ask?

The research was conducted by a collaboration from Queen’s University, Belfast, Northern Ireland, the Institute of Food Science Research, Madrid, Spain, and the School of Life Sciences, Northumbria University, Newcastle, England. Curiously, there is an Irish Sponge Cake, a Spanish Sponge Cake, and an English Sponge Cake. What do they have in common? Eggs, sugar, flour, and cooking oil, among other possible ingredients.

Browning is Bad for You

The components of food and how it is processed are the most important factors that determine taste, appearance, texture, and nutritional value. Nutrition can be affected significantly by the loss of available lysine (an amino acid) and formation of Maillard reaction products. The latter is a chemical reaction between an amino acid and a reducing sugar, usually requiring heat. It is of vital importance in the preparation or presentation of many types of food, and, like caramelization, is a form of non-enzymatic browning. The reaction is named after the chemist Louis-Camille Maillard who first described it in the 1910s while attempting to reproduce biological protein synthesis, although it has been used in practical cooking since prehistoric times. Of added concern, the Maillard reaction also occurs in the human body. It is a step in the formation of AGEs (see “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 issue) and should be avoided in one’s choices of food preparation because it can impede proper biophysical function. Steaming food produces low levels; roasting and broiling make for far higher levels.

In the processing of food (and even during its storage), free amino groups on lysine residues of protein can react with the carbonyl group of reducing sugar or lipid oxidation products to form AGEs and ALEs, both of which are associated with aging and various diseases associated with oxidative stress. When planning one’s diet, the presence of AGE/ALEs should weigh in on your risk assessment, because when absorbed through the gastrointestinal tract, an increase in the body’s level of AGEs may occur, leading to the increased risk of disease.

CMLs can be formed through several pathways. Condensation of glucose with the ε-amino group of lysine results in the formation of fructoselysine, an Amadori rearrangement product, which is oxidized to form CMLs. Amadori products are intermediates in the production of AGEs, resulting from glycation. Alternatively, Amadori products can form via a reaction of lysine with glyoxal, a dialdehyde. CELs, the analogues of CMLs, are created primarily by the reaction of lysine residues with methylglyoxal, both an aldehyde and a ketone. Glyoxal and methylglyoxal are produced during lipid peroxidation and sugar degradation.

Defueling the Fire: The Search for Inhibitors

The rate of reaction and the concentration of AGE/ALEs in food is affected by the temperature at which it is cooked, the overall cooking time, the moisture content, the nature and amount of the reactants (e.g., sugars, lipids, and proteins), and the presence of inhibitory compounds (e.g., antioxidants). Antioxidant compounds have been reported to have beneficial and detrimental effects on AGE formation in food, as well as in vitro in vivo studies. Therefore, the search for additional glycation/lipoxidation inhibitors is of significant importance. They would be of particular value in food systems where these desirable components can selectively act on certain reaction pathways, leading to inhibition of undesirable substances. Inhibition of AGE/ALE formation might involve different mechanisms including reactive carbonyl trapping, antioxidant activity, sugar autoxidation inhibition, and amino group binding inhibition/competition.

To date, many studies have honed in on the antiglycation/antilipoxidation characteristics of various agents that can help prevent the formation of AGEs, but much less attention has been given to individual AGE/ALEs formation, such as CMLs and CELs. Research on these mechanisms has been limited to model and physiological studies. Virtually, no research on the activity of inhibitors on CML/CEL formation in food (especially during processing) has been done, until now.

Effect of Oil and Sugar on CMLs and CELs

In the sponge cake study, the goal was to assess the effect of food ingredients and AGE/ALE inhibitors (α-tocopherol, ferulic acid, rutin, thiamine hydrochloride, thiamine monophosphate, and thiamine pyrophosphate) on CML and CEL formation in model sponge cakes.

Of the ingredients used, sugars and the oils became the focus of the research. The cake baked with glucose produced the highest level of CMLs, whereas the cake baked with fructose produced the highest concentration of CELs. However, no matter which cooking oil was used (five in all), there were no significant differences between CML concentrations formed in the cakes. But significant differences were shown between the cakes prepared using different proportions of cooking oil.

Once again, the cakes made with glucose generated higher amounts of CMLs than those made with fructose (about 18% higher), or unrefined sucrose (significantly lower). An up to 7.7-fold higher concentration of CMLs was observed in the cakes using monosaccharide (glucose or fructose) compared to the cakes using disaccharide (refined or unrefined sucrose).

The highest concentration of CELs was found in the cake prepared with fructose, and the lowest concentration was in the cake prepared with unrefined sucrose. The production of CELs was 24-fold higher in cake made with fructose vs cake made with unrefined sucrose. By comparison to the levels of CMLs, CELs were 1.9-, 15.3-, 5.1-, and 4.2-fold higher in the cakes containing glucose, fructose, refined sucrose, and unrefined sucrose, respectively.

Once again, in the presence of cooking oil, the concentration of CMLs found in the cakes baked with sucrose or other sugars was not significantly different. As well, there was no significant difference in the concentration of CMLs in the cakes produced using different types of oil, but surprisingly, a significant 3.8-fold difference was observed in the cakes using a low level of oil compared to a high level of oil. Margarine produced a lower level of CMLs than oil (5-fold lower), in the presence or absence of sucrose. Another interesting discovery was that the sponge cake produced using margarine provided similar levels of CMLs regardless of the amount of margarine used.

Effect of AGE/ALE Inhibitors on CML and CEL Concentration

The AGE/ALE inhibitors α-tocopherol and rutin did not affect CML or CEL formation. By contrast, the inhibition of CMLs and CELs was highest in the cakes made using thiamin, thiamin monophosphate, and thiamin pyrophosphate, and inhibition increased with increasing concentration of thiamin and thiamin derivatives. Also important, CML concentrations in the cake baked with ferulic acid were lower.

The inhibition of AGEs
was highest in the cakes made
using thiamin, thiamin
monophosphate, and
thiamin pyrophosphate, and
inhibition increased with higher
concentrations of the vitamins.

However, CEL concentrations in the cake using the inhibitors α-tocopherol, rutin, and ferulic acid were not significantly different, compared to those without the addition of inhibitors. In contrast, the cake containing just ferulic acid showed significantly lower levels of CMLs and CELs compared to the cake without that additional inhibitor. The inhibitory effect of ferulic acid on CML formation was higher than that on CEL formation.

Effect of Sugar and Temperature on CMLs and CELs

The concentrations of CMLs found in the sponge cakes covered a wide range depending upon the types of sugar present. This data agrees with the level of CMLs reported in white bread crumb, wholemeal bread crumb, cookies, and toasted bread, but higher than in corn flakes and lower than in white bread crust and whole meal bread crust. This is possibly because bread crust attained a higher temperature (about 230–250° C) than sponge cake (temperature in the center of the sponge cake was about 100° C). The cake baked using glucose produced a greater level of CMLs than the cake baked using fructose (1.2-fold). This shows that CML formation from Amadori rearrangement products may be more important compared to CML formation from other rearrangement products. It could also mean that oxidation of glucose generated more glyoxal (a precursor of CML) than oxidation of fructose.

As previously stated, CELs were highest in the cakes baked using fructose, followed by glucose, refined sucrose, and unrefined sucrose. This may be due to fructose oxidation resulting in a greater yield of methylglyoxal (a precursor of CEL), known as reactive carbonyl compound, than glucose. There may be other precursors for CEL formation, but this is still unknown. The levels of CELs formed were higher than those of CMLs. It was thought that this might be due to the reaction of methylglyoxal, with lysine occurring at a faster rate than the reaction of glyoxal with lysine. Alternatively, methylglyoxal might be generated in a greater yield than glyoxal during sugar/fat oxidation. This is the first time that the comparison between CMLs and CELs in bakery products using different types of sugar has been conducted.

Effect of Oil on CML Concentration

CMLs have been quantified in a range of foods including bakery products, but whether sugar or oil is the most important precursor has not yet been established. In the sponge cake study, a 3.8-fold lower level of CMLs were observed in the cake prepared using the low level of oil compared to the high level of oil.

In comparison to the cake produced with refined sucrose, the cake produced without refined sucrose generated a 1.3-fold lower level of CMLs. This showed that sucrose affected CML formation to a lesser degree than oil in the model sponge cake system.

Explaining this, the generation of glyoxal via lipid oxidation may be greater than that produced via sucrose oxidation. The cake produced using margarine gave a lower concentration of CML than the cake baked using cooking oil. As an explanation, margarine contains a lower percentage of lipids (59%) than oil (100%), or there are less reactive lipids in margarine, or margarine is fortified with vitamins, some of which have an antioxidant capacity (e.g., vitamins A and E).

Effect of AGE/ALE Inhibitors on CML and CEL Formation

Oxidation of glucose/fatty acids and the formation of Amadori rearrangement products produce superoxide and free anion radicals, and these oxidative process may be blocked by AGE/ALE inhibitors through different mechanisms. These include chelation of transition metals, free radical scavenging, sugar autoxidation inhibition, and amino group binding inhibition/competition. While a number of AGE/ALE inhibitors have come to light in recent years, including thiamine, benfotiamine, lipoic acid, and carnosine, their efficacy depends not only on the free radical scavenging activity but also on other factors such as type and concentration of ingredients and heating time and temperature. This may be why some researchers found antioxidant compounds such as ferulic acid to have antiglycation properties, whereas others could not find any antiglycation activity. While many papers have reported on AGE/ALE formation inhihition, a direct comparison between the effects of antiglycation/antilipoxidation agents on CMLs and CELs in processed foods is difficult to make.

α-Tocopherol (vitamin E), a lipid-soluble phenolic antioxidant compound that contains one hydroxyl group has been shown to provide free radical scavenging activity and can react directly with free radicals by donation of a hydrogen atom. However, α-tocopherol failed to inhibit CML/CEL formation in the current study, attributable perhaps to the insolubility of tocopherol, as well as thermal baking instability which witnessed a near total loss of antioxidant activity when pork lard was heated to 150° C.

Rutin uses a different route to free radical scavenging activity and has been shown to provide a great inhibitory effect toward all stages of AGE formation. However, these studies were undertaken at moderate temperature (37° C) and in liquid systems. In intermediate-moisture food heated under baking conditions (190° C) no inhibition of CML or CEL was observed. Inhibitor solubility may be one of the multiple factors that affect the inhibitory power, and thermal (190° C, 30 min) stability should also be taken into account, as in the case of tocopherol. Other factors may also be relevant.

As an antioxidant, ferulic acid possesses a phenolic nucleus and conjugated side chain readily forming a resonance-stabilized phenoxy radical. It inhibited both CML and CEL formation in the sponge cake study. This agrees with an earlier study suggesting that ferulic acid reduced the generation of some Maillard reaction products in a low-moisture glucose/glycine model (10% moisture) system heated at 200° C. For this reason, ferulic acid has been used as a food additive to inhibit lipid peroxidation and subsequent oxidative spoilage and as a therapeutic agent against inflammatory disease and cancer.

Thiamine occurs in free and phosphorylated forms such as thiamine monophosphate and thiamine pyrophosphate, which contain an amino group that can compete with lysine during the Maillard reaction. Thiamine and its derivatives have a strong antiglycation effect in vitro and in vivo, and in the sponge cake investigation, where they clearly demonstrate CML/CEL inhibition. It is thought that they work through the inhibition of the intermediate products, glyoxal and methylglyoxal. This involves a competitive mechanism between the amino group of thiamine/thiamine derivatives with the ε-amino group of lysine residues during glycation/lipoxidation. These findings agree with another study suggesting that thiamine administered orally reduces CML (74%) and CEL (118%) concentration in the plasma of diabetic rats.4

From the AGE/ALE inhibitors examined in this investigation, only ferulic acid, thiamine, and thiamine derivatives inhibited CML and CEL formation. But α-tocopherol and especially rutin—which are known as powerful antioxidants and antiglycation agents—had no effect on AGE/ALEs formation. The acid, HCl salt, and phosphate group contained within ferulic acid, thiamine hydrochloride, and thiamine compounds, respectively, may operate to interfere with the reaction of AGE/ALEs and formation during the baking process. Foods supplemented with glycation/lipoxidation inhibitors produce low levels of CML, but may adversely affect food sensorial properties.


  • Sugar, lipid, and protein composition substantially affects AGE/ALE formation.

  • Sponge cake made using glucose produced the highest level of CMLs, and sponge cake made with fructose produced the highest level of CELs.

  • Levels of CELs were higher than those of CMLs in the cake baked using the same sugars.

  • Sucrose produced lower levels of total CMLs and CELs than glucose or fructose. Lipids have a greater influence on CML formation than sucrose.

  • Addition of antiglycation/antilipoxidation compounds, such as ferulic acid, thiamin, thiamin monophosphate, and thiamin pyrophosphate may be an effective means of reducing CML/CEL formation in food systems, although some inhibitors may adversely affect food flavor.

Let Them Eat Cake

While there is no supporting evidence that Marie Antoinette ever uttered the infamous “Let them eat cake” to rioting Parisians in the late 18th century, there may be good reason to proceed judiciaously when your cake is being prepared. Bear in mind that α-tocopherol and the flavonoid rutin did not inhibit CML and CEL formation. In contrast, ferulic acid and thiamine, thiamine monophosphate, and thiamine pyrophosphate reduced CML and CEL formation. The lesson of the study is that adding ferulic acid or thiamine to your recipes, especially with high temperature preparation, can help reduce the production of AGE/ALEs. These findings provide useful information concerning reduction of the level of AGE/ALEs in food systems, which may be beneficial to consumer health in general, but especially consumers who are prediabetics or diabetic.

Have Your Cake and Eat It Too

The take home message should also include the idea, learned from other studies, that you can dismantle or tame the effects of AGE/ALEs by taking anti-AGE supplements (see “How and Why to Prevent AGE Damage” in the March 2008 issue) along with your cake, and all your meals.


  1. Wildavsky AB. But is it true?: A citizen’s guide to environmental health and safety. Cambridge, MA: Harvard University Press;1995.
  2. Ames BN, Gold LS. Paracelsus to parascience: the environmental cancer distraction. Mutat Res 2000 Jan 17;447(1):3-13.
  3. Srey C, Hull GL, Connolly L, Elliott CT, Del Castillo MD, Ames JM. Effect of inhibitor compounds on N(ε)-(carboxymethyl)lysine (CML) and N(ε)-(carboxyethyl)lysine (CEL) formation in model foods. J Agric Food Chem 2010 Nov 2. [Epub ahead of print] PubMed PMID: 21043504.
  4. Karachalias N, Babaei-Jadidi R, Kupich C, Ahmed N, Thornalley PJ. High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats. Ann NY Acad Sci 2005;1043:777-83.

Will Block is the publisher and editorial director of Life Enhancement magazine.

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