Active ingredients to reduce AGEs

Interview with Dr Achim Refisch

Mr Refisch, what are AGEs?

AGE is the abbreviation for ‘advanced glycation end product’, which means ‘end product of glycation’ or ‘advanced saccharification end product’. AGEs are formed in the body as well as during frying and cooking as part of the so-called Maillard reaction, which leads to a beautiful browning and the popular flavour. In this process, proteins or fats are combined with carbohydrates or a non-enzymatic conversion takes place, i.e. one that occurs by itself and slowly progresses through several intermediate stages to a chemical end product that is no longer or barely reactive. This glycation or glycation leads to the end product AGE. The spontaneous formation of AGEs in the body or the intake of these substances through food is a significant medical problem, as it must be assumed that AGEs are at least partly responsible for many diseases that are now wrongly attributed to the ‘normal’ ageing process. In addition to AGEs, there are also ALEs, the ‘advanced lipoprotein end products’. For the sake of simplicity, we will only refer to AGEs in the following; the effects in the body are the same.

What prompted you to become intensively involved with AGEs?

With a healthy lifestyle, we can effectively counteract the diseases of civilisation that usually occur in old age. Although it is now generally known that regular endurance and strength training (3 times a week) and a Mediterranean diet with extensive avoidance of industrially processed foods (convenience food) has a preventative effect and has shown great effects in studies, many patients still come to my practice with at least 5-10 medications for diseases of old age or civilisation. I have realised that AGEs are a very important factor at all stages of the development of these diseases and play a decisive role in their progression. In order to find a way out of this dilemma, I wanted to know whether naturopathy offers any possibilities here.

What did you find out?

Unfortunately, I realised that AGEs are largely unknown in medicine. The succinct standard answer is usually: ‘That’s just old age, you’ll have to put up with it.’ This completely ignores the significant role that AGEs play in the ageing process. In my view, this is also due to the fact that the pharmaceutical industry has recognised the huge potential of AGEs, but has not yet been able to develop a tolerable and effective drug against AGEs despite considerable investment and multiple attempts. All attempts to establish a so-called ‘blockbuster’ against AGEs with a lot of money have failed. And where the pharmaceutical industry has no product, the mostly pharma-sponsored research fails to materialise or is unsuccessful. As a result, there is nothing in the scientific literature or at congresses on this topic, even though it is extremely important for quality of life.

Which path ultimately led to the goal?

As a convinced naturopath who, however, does not neglect the scientific basis of medicine, I have always been convinced that nature, with its genetic experience of more than 1 million years, offers more answers here than AI. It was very exciting and fascinating to search for phytochemicals that have a proven effect on AGEs but do not have any undesirable side effects. I am convinced that I have found a combination of active ingredients that fulfils these requirements.

Why does it take several plant substances to prevent AGEs?

Since the development of AGEs occurs in several stages, via several chemical intermediates, and very slowly leads to age-related and civilisation-related diseases, a product must be effective at all these different stages, which naturally requires several phytochemicals. If we prevent the development of AGEs preventively and at an early stage, we can avoid the development of diseases in many organ systems. This is an effect that should become increasingly important in medicine, in the sense of a ‘multitasking therapy’: intervening in the cell metabolism in such a way that several cell structures in different organs are favourably influenced.

To what extent is this also a small paradigm shift in medicine?

We need to move away from pure ‘repair medicine’ on a single organ, once the damage has already occurred, towards preventive ‘multitasking medicine’. The now highly advanced knowledge of cell functions, including epigenetic cell metabolism regulation, will make it possible in future to develop therapies that intervene in cell metabolism at such an early stage that various cell and organ systems can be favourably influenced simultaneously. If we have tools that can detect disturbed metabolic processes in cells at an early stage and intervene in them therapeutically, preventive therapy will be possible before the disturbed metabolic processes of the cells manifest themselves as damage in various organ systems.

I am fascinated by the fact that the treatment of AGEs using a phytoproduct that contains a whole range of highly potent plant substances goes in this direction. I hope that the product I have helped to develop will help to reduce AGEs and at the same time have a beneficial effect on many of the diseases of civilisation in various organ systems.

You said at the beginning that AGEs are formed by glycation. Can you briefly explain the process?

Initially, sugars or carbohydrates are bound to proteins or fats – in the first case AGEs are formed, in the second case ALEs. This reaction occurs spontaneously in the body or when cooking or frying certain foods. Glycated, i.e. ‘saccharified’ proteins are formed, which accumulate in the body. After a few days, these compounds transform into the so-called Amadori products, which in turn form the AGEs or Maillard products in a few weeks. Glycation is favoured by ‘hyperglycaemia’ in the body, an oversupply of sugar or also by heated, unsaturated or artificially produced fats (trans fats). The risk is therefore even higher in people with hyperglycaemia (diabetes) and increased oxidative stress.

How do AGEs affect the body?

AGEs are very long-lived and accumulate in various organs. They are an essential aspect of ageing and inflammatory processes and are involved in the development of various age-related and civilisation-related diseases. These include chronic inflammatory and degenerative diseases in various organs. Examples of this are Arteriosclerosis, high blood pressure, stroke, heart attack, arthrosis, sarcopenia, chronic kidney failure, macular degeneration, cataracts and glaucoma, diabetes, Alzheimer’s, diseases of the lungs or liver and skin (ageing skin with wrinkling, age spots).

Glycation disrupts the three-dimensional structure of metabolic proteins. As a result, the lock-and-key principle that occurs in many places in nature no longer functions properly. Insulin resistance and diabetes, for example, can develop because the change in the three-dimensional folding of metabolic proteins means that insulin (key) and insulin receptor (lock), for example, no longer fit together perfectly.

Finally, AGEs have the ability to crosslink with each other. This so-called crosslinking leads to the hardening and wrinkling of tissues. This process is particularly visible on the skin in the form of wrinkles and AGE deposits (lipofuscin formation = age spots). However, cross-linking is more dramatic in the vascular walls: if these harden, this can be the first step towards a heart attack or stroke. As you can see, AGEs are a major medical problem. Nevertheless, they are still recognised far too little.

What promotes AGEs and how can they be avoided?

First of all, it should be said that ageing and the associated accumulation of AGEs in the body is the most important factor when it comes to pro-inflammatory AGEs. However, unfavourable dietary habits and smoking can accelerate the formation of AGEs. Exogenous AGEs can be avoided with a healthy lifestyle, which includes in particular an optimised diet. In addition, as already mentioned, AGEs can be favourably influenced with specifically selected plant substances.

Which foods should you avoid?

Ready-made products and fast food should be avoided wherever possible. Fatty, sugary, browned and, above all, burnt foods should also be removed from the diet. The most harmful foods with a Maillard reaction are grilled meat or fish. In principle, however, all foods containing sugar and fat that are cooked, fried or baked at over 120 °C can be affected.

What does a favourable diet look like instead?

We should prepare our food as freshly and as gently as possible. Foods that contain high-quality fats, are very sparing with sugar, are prepared at low temperatures and with more moisture (e.g. by steaming or poaching) contain practically no AGEs. Care should be taken to minimise the use of highly industrially processed foods and to use fats appropriately (e.g. do not heat unsaturated fats). Foods produced under acidic conditions, such as fermented foods, also contain hardly any AGEs. A diet rich in antioxidants helps to combat AGEs by neutralising the associated oxidative stress in the body. A diet rich in natural vegetables (preferably raw), fruit and berries contains many antioxidants such as vitamin C or E, selenium and phytochemicals. In addition to a healthy diet, regular, moderate exercise and good stress management are important.

How can AGEs be favourably influenced with specific plant substances?

Biochemically, AGEs can be counteracted in many ways. It is possible to intervene at many different points in the metabolism to ensure that AGEs are not formed in the first place, cannot be deposited, do not dock to the cells and therefore cannot trigger inflammatory processes in the cells or are dissolved, removed and excreted. In this way, a preparation containing various interacting plant substances can delay or prevent all the unfavourable health effects mentioned above. One particularly noteworthy point is the positive effect on the cells of the vascular walls. The oxidation of LDL, which leads to arteriosclerosis, is reduced, which indirectly prevents heart attacks and strokes. The same applies, for example, to macular degeneration and glaucoma.

Which plant substances are in the foreground?

It is important to mention that only a combination of different active ingredients with effects at several points of action in the metabolism is sufficiently effective. Such a preparation is much more promising and far superior to the administration of individual substances. I am happy to share my favourites of highly effective and proven plant substances here.

Noni fruit

Noni is the fruit of the Indian mulberry tree (Morinda citrifolia), which is favoured on the Polynesian islands. Locals have known about its health-promoting effects for centuries. Ingredients from the noni fruit intercept AGEs that have already formed in the connective tissue (scavenger effect) before they can bind to cell receptors and cause inflammation. These receptors for AGEs on the cell wall, which occur in almost all human organ cell systems including the immune system, mediate a variety of pro-inflammatory metabolic processes via NF-kappa-b. Noni fruits also have an antioxidant effect.

Olive oil polyphenols

Olive oil polyphenols inhibit oxidative damage caused by lipid peroxidation, which is the most important damage caused by free radicals. The effects on LDL are very significant. Only oxidised LDL leads to arteriosclerotic plaques, which play a major role in the development of heart attacks and strokes. Olive oil polyphenols are a key player in the prevention of AGEs caused by lipid peroxidation. When lipid peroxidation is reduced, less oxidised LDL is automatically produced, leading to less vascular hardening and plaque formation. Inhibiting the inflammatory reaction in blood vessels is a recognised treatment approach of great importance in cardiology. The European Food Safety Authority (EFSA) attributes a favourable influence to olive oil polyphenols in these processes. In addition, olive oil polyphenols have a scavenger effect (see noni fruit).

Caper extract

Caper extract inhibits the further development of advanced AGE precursors. This has even been demonstrated for one of these precursors in a human randomised controlled trial (RCT). In addition, caper extract can occupy the RAGE receptor on the cell wall and thus prevent AGEs from docking. Furthermore, caper extract also has an anti-inflammatory effect.

Brown algae extract

Brown algae have always been popular in Japanese and Korean cuisine as a healthy food which, according to local tradition, promotes blood circulation, strengthens the immune system and lowers high blood pressure and high blood cholesterol. The brown algae species Ecklonia cava – also known as ‘Kajime’ in Japan and Korea – is particularly effective and rich in phenols and condensed tannins. Scientific literature describes an effect of brown algae that was long thought to be impossible, known as crosslink breaking: brown algae can break crosslinks that have already formed between AGEs (= hardened tissue). This effect has been demonstrated in laboratory tests.

The pharmaceutical industry had developed such a crosslink breaker called Alagebrium (ALT-711). However, due to the excessive side effects of this artificially designed active ingredient, a drug was not launched on the market. However, Alagebrium is still on the market as a comparative substance (gold standard) in the laboratory. Both brown algae extract and rosemary are more effective in the laboratory than Alagebrium and are therefore contained in the anti-ageing product I have developed. There are therefore good reasons to assume that both substances can also reverse the unfavourable crosslinking of proteins in the body caused by the AGE effect. Other properties described are the reduction of already accumulated AGEs (scavenger effect as with noni fruits) and antioxidant effects.

L-carnosine

Carnosine, not to be confused with carnitine, is a combination of the two amino acids alanine and histidine. It is found in tissues, but its concentration decreases with age. Firstly, it is an antioxidant (by scavenging ROS = reactive oxygen species = free radicals). Secondly, it counteracts AGE formation and glycosylation (by reacting with RCS = reactive carbonyl species). Finally, it has an anti-inflammatory effect. Carnosine is the best scientifically investigated naturally occurring substance in the field of AGEs. Its beneficial effects have already been described in four small randomised controlled human studies and two meta-analyses (summary of the studies that can be found and used in the literature).

Black garlic extract

Fermented black garlic (Allium sativum) has various interesting effects. Among other things, it has antioxidant, anti-inflammatory, immunostimulant, cholesterol, blood pressure and blood sugar lowering and cell-protecting effects. It also inhibits the formation of AGEs and the breakdown of L-carnosine, thereby increasing its effect.

Rosemary extract

Rosemary was named medicinal plant of the year in 2011 for good reason. Its ingredients include carnosolic acid, carnosol and rosmarinic acid. Rosemary has an antioxidant and anti-inflammatory effect and can dissolve cross-linking structures (see brown algae).

B vitamins (B1, B6)

Vitamins B1 and B6 both inhibit the formation and further development of AGEs. Diabetes patients in particular usually have a vitamin B deficiency.

Catechins from matcha

Matcha is green tea leaves ground into a fine powder and has always been celebrated in Japan as a healthy tea drink. The tea contains catechins, which are known as powerful antioxidants with long-lasting effects. Catechins inhibit the formation of AGEs and reduce AGEs that have already accumulated. They also increase the number of free receptors for AGEs in the blood, which are normally located on the cell wall (so-called soluble RAGEs/sRAGEs). These can intercept AGEs before they come into contact with the cell wall receptors for AGEs and trigger the unfavourable NF-kappa-b inflammatory reactions. In addition to the scavenger effect already described, this is a second way of rendering AGEs that have already formed harmless. Finally, catechins can occupy the RAGE receptor on the cell wall and thus prevent AGEs from docking.

Overview of the phytochemicals described and their effects with regard to AGEs

	Vitamin B1	Vitamin B6	Green tea	Rosemary	Brown algae	Noni	Capers	Olive oil polyphenols	Carnosine	Garlic
Prevents glycosylation (early phase)	X		X					X		X
Prevents glycosylation (late phase)		X						X	X	X
Prevents crosslinking			X				X		X	X
Can break up crosslinking				X	X
Destroys free AGE (Scavenger)					X	X	X	X	X
Increases sRAGE activity			X
Blocks RAGE			X				X	X
Makes free radicals harmless	X	X		X	X	X	X		X	X

Is it possible to measure the level of AGEs in the body?

Yes, and fortunately this is also extremely simple. Because many AGEs fluoresce very easily, their concentration in the skin can be measured using light. Appropriate devices enable a simple, non-invasive, painless, reliable and rapid determination of the AGE level. In this way, the metabolic state of the past years or decades can be measured and reproduced. With this measurement, it is even possible to determine whether you are biologically older or younger in comparison with your calendar age (the available data allows a corresponding correlation with the population as a whole).

What should you look out for when searching for a suitable preparation?

If you want to inhibit, reduce, dissolve, break down or fight AGEs, you should look for a product that contains the above-mentioned substances in good quality. As a fairly large amount of these plant substances should be taken daily, powders, sticks or shakes are recommended. These can be dissolved in water, for example, and can also be flavoured. As it takes years or decades for AGEs to accumulate in large quantities in the body, you also need to be patient when taking AGE-influencing phytochemicals. I recommend taking them for at least six months, which should be repeated every one to two years, as new AGEs are constantly being produced. I myself take the substances permanently in order to benefit from the many positive effects mentioned.

Thank you very much for the interview, Mr Refisch!

Studies

Advanced glycation end products are associated with arterial stiffness in type 1 diabetes: https://pubmed.ncbi.nlm.nih.gov/24681829/

Relationship between cardiac tissue glycation and skin autofluorescence in patients with coronary artery disease: https://pubmed.ncbi.nlm.nih.gov/25553578/ 

The autofluorescence of the skin as a measure of the deposition of advanced glycation end products is increased in peripheral arterial disease: https://pubmed.ncbi.nlm.nih.gov/23139292/ 

Autofluorescence of the skin as a measure for the deposition of advanced glycation end products: a new risk marker in chronic kidney disease: https://journals.lww.com/co-nephrolhypertens/abstract/2010/11000/skin_autofluorescence_as_a_measure_of_advanced.4.aspx