Category Archives: Glycation

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Phloridzin Effectively Inhibits Glucose Uptake and Traps Advanced Glycation End Products (AGEs)

Phloridzin, also known as Phlorizin, is a glucoside of phloretin, a dihydrochalcone, in the family of bicyclic flavonoids.  It is chemically known as phloretin-2′-β-D-glucopyranoside. 

Phloridzin is primarily found in the skins of apples, in particular, the Malus species.  It is also found in the leaves, bark and seeds of the Malus species.

Phloridzin has been shown to be very effective against glycation and advanced glycation end products (AGEs).  Glycation is considered a main factor in the aging process, which is irreversible when it occurs but can be controlled by diet and supplementation. 

Glycation can form either outside the body through various cooking methods of certain foods and/or inside the body by certain chemical metabolic reactions.  Glycation that occurs outside the body is called exogenous glycation and glycation occuring inside the body is called endogenous glycation. 

Endogenous glycation is the chemical result of the bonding of a sugar molecule with a protein or lipid molecule that produces nonfunctioning and deformed molecules known as advanced glycation end products (AGEs).

Figure 1.  Formation of AGEs  (Source: Glycation and ageing: measurement and treatment from Prime-Journal)

AGEs that stem from a glycation reaction, produces cells that are stiffer and less pliable and more subject to damage and premature aging. When glycated proteins fuse together, this is known as cross-linking. The skin, eyes and heart are particular organs subject to cross-linking.

Exogenous glycation occurs when AGEs are formed by heating proteins and lipids with sugar. Certain forms of cooking can accelerate the exogenous glycation process, such as grilling and frying.

Figure 2. AGEs  (Source: Glycation and ageing: measurement and treatment from Prime-Journal)

AGEs have a range of pathological effects, such as:

  • Increased vascular permeability.
  • Oxidizing LDL.
  • Binding cells—including macrophage, endothelial, and mesangial—to induce the secretion of a variety of cytokines – promoting chronic inflammation.
  • Inhibition of vascular dilation by interfering with nitric oxide.
  • Enhanced oxidative stress – free radicals.

Once an AGE is produced through the endogenous glycation process, it is irreversible. It is therefore important to seek ways to prevent glycation, both endogenously and exogenously.

Mechanism of Phloridzin Against Endogenous Glycation

Phloridzin attacks endogenous glycation in two steps. 

First, phloridzin inhibits glucose uptake by 52%.  1  It inhibits glucose from attaching to the lining cells of the intestine and then blocks the active transport of some, but not all, glucose out of those intestinal lining cells into the bloodstream.  2  3

Second, the glucose that is transported to the bloodstream is responsible for the formation of the dangerous carbonyl molecules that react with proteins and DNA to form AGEs.  4

The formation of these AGEs are prevented by phloridzin by trapping the remaining AGEs that are generated.  This lessens the chain reaction that can occur with AGEs detrimentally reacting with other molecules in the body.  5

In an important study from 2008, researchers found that both phloretin and its glucoside, phloridzin, could efficiently trap certain reactive AGEs called MGO and GO, under physiological conditions.

More than 80% MGO was trapped within 10 min, and 68% GO was trapped within 24 h by phloretin. Phloridzin also had strong trapping efficiency by quenching more than 70% MGO and 60% GO within 24 h. 

This study suggests that dietary flavonoids that have the same A ring structure as phloretin may have the potential to trap reactive dicarbonyl species and therefore inhibit the formation of AGEs.   6  

Exogenous Glycation: How Many Glycotoxins are You Consuming in Your Diet?

When sugars are cooked with proteins or fat at temperatures over 120°C (~248°F) or at lower temperatures for longer cooking times, a molecule known as advanced glycation end products (AGE) is formed. This AGE is known as exogenous gylcation, as opposed to endogenous glycation, which is created inside the body by metabolic processes.

These orally absorbed reactive glycation products are also known as “glycotoxins” or dietary AGE products (dAGE). The dAGE products are known to contribute to increased oxidant stress and inflammation, and may result in diabetes and cardiovascular disease.

An article that appeared in the Annals of the New York Academy of Sciences in 2006 by Helen Vlassara entitled: Advanced glycation in health and disease: role of the modern environment, demonstrated that there is evidence from animal studies that point to AGE restriction as an effective means for extending median life span, similar to that previously shown by marked caloric restriction. The authors conclusion is quite definitive:

“We conclude that excessive AGE consumption, in the current dietary/social structure, represents an independent factor for inappropriate oxidant stress responses, which may promote the premature expression of complex diseases associated with adult life, such as diabetes and cardiovascular disease.”

(Source: Advanced glycation in health and disease: role of the modern environment.)

Most, if not all, processed foods has some measure of dAGE. Food manufactures will add sugar to their products to enhance the browning effect, thus contributing to the addition of dAGE’s. Any food that is caramelized and browned contains dAGE’s.

The Journal of the Academy of Nutrition and Dietetics published a very interesting Table listing the advanced glycation end product (AGE) content of 549 foods, based on carboxymethyllysine content.

View Table

The method of cooking is also crucial to the production of exogenous AGE’s. Specifically, grilling, broiling, searing, roasting, and frying produce and accelerate new AGE formation in food.

Animal-derived foods that are high in fat and protein have been shown to have higher AGE products and especially after cooking these animal products using the methods described above. Carbohydrate-rich foods such as vegetables, fruits, whole grains, contain relatively few AGEs, even after cooking.

In the August 2004 Journal of the American Dietary Association an article entitled: Advanced glycoxidation end products in commonly consumed foods, listed some interesting results regarding the dAGE content of certain food and the highest dAGE for each cooking method:

“Foods of the fat group showed the highest amount of AGE content with a mean of 100+/-19 kU/g. High values were also observed for the meat and meat-substitute group, 43+/-7 kU/g. The carbohydrate group contained the lowest values of AGEs, 3.4+/-1.8 kU/g. The amount of AGEs present in all food categories was related to cooking temperature, length of cooking time, and presence of moisture. Broiling (225 degrees C) and frying (177 degrees C) resulted in the highest levels of AGEs, followed by roasting (177 degrees C) and boiling (100 degrees C).”

(Source: Advanced glycoxidation end products in commonly consumed foods.)


References:

Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy

Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet

Advanced glycation in health and disease: role of the modern environment.

Advanced glycoxidation end products in commonly consumed foods.

Live Longer By Changing How You Cook! By William Faloon Life Extension Magazine August 2015


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Can D-Ribose Create Advanced Glycation End Products (AGEs)?

Generally yes, but apparently only at artificially high doses, not at the thereapeutic doses recommended by health care professionals for various disease conditions.

Ribose is a pentose monosaccharide (simple sugar) with the molecular form of H−(C=O)−(CHOH)4−H.  It is commonly known as its enantiomer as D-Ribose.

The main source of energy for all cellular processes is a molecule known as ATP (adenosine triphosphate). Under healthy conditions, the cells constantly replenish their supply of ATP.  However, under conditions of stress, injury, or aging, critical body tissues such as heart and skeletal muscles cannot produce ATP quickly enough to perform optimally.

D-ribose, a carbohydrate molecule found in every living organism, facilitates the production of ATP.

D-Ribose has been shown to be effective in a number of disease conditions, including:

  • improve symptoms of chronic fatigue syndrome (CFS)
  • improve symptoms of fibromyalgia
  • improve symptoms of coronary artery disease; D-ribose enhances the recovery of myocardial ATP, which improves overall cardiac function
  • improve athletic performance and the ability to exercise by boosting muscle energy

D-Ribose is treated differently by the body than regular hexose monosaccharides, such as, glucose, sucrose or fructose.  The body preserves D-Ribose for the production of ATP that provides the power to operate the heart, brain, muscles and other tissues.

Using D-Ribose as a treatment for the above-referenced conditions is based on the dosing regimen based on the needs of the person and the condition.  Health care professionals with experience using D-Ribose usually follow these dosing regimens:  1

    • Healthy individuals who want cardiovascular protection and greater comfort following strenuous activity – 5 gram/day
    • Athletes working out in chronic bouts of high-intensity exercise – 10-15 gram/day
    • Patients with mild-to-moderate heart failure, other forms of ischemic cardiovascular disease, or peripheral vascular disease – 10-15 gram/day
    • Individuals recovering from heart surgery or heart attack, for treatment of stable angina – 10-15 gram/day
    • Patients with advanced heart failure, dilated cardiomyopathy, individuals awaiting heart transplant, or people with frequent angina – 15-30 gram/day
    • People with fibromyalgia or neuromuscular disease – 15-30 gram/day

    It is usually recommended to divide the total daily dose into multiple 5-gram individual doses, instead of taking the entire dose at once.  The lowest dose per day is 5 grams and the highest does per day is 30 grams.  One case study from 1992 used 60 grams per day as four divided doses of 15 grams each for a human trial on exercise tolerance in people with coronary artery disease.  2  

    Since D-Ribose is a sugar, the question arises whether it can contribute to the development of harmful and tissue damaging advanced glycation end products (AGEs).

    AGEs are proteins or lipids that become glycated through a process called cross-linking as a result of exposure to sugars in the body.  The formation and accumulation of AGEs has been implicated in the progression of age-related diseases, such as:

    • Alzheimer’s Disease
    • cardiovascular disease
    • stroke

    When D-Ribose is the sugar in the glycation process, as opposed to glucose or fructose, it is called ribosylation. D-ribose is active in glycation and induces protein aggregation, rapidly producing AGEs in vitro and in vivo.  3  Recent studies indicate that ribosylation is a rapid process that causes protein aggregation in vitro and in vivo.  4

    Administration of high doses of D-ribose also accelerated AGE formation in the mouse brain and induced impairment of spatial learning and memory ability according to the performance in the Morris water maze test.  5

    All the referenced studies demonstrated that D-Ribose can cause protein glycation (ribosylation), when D-Ribose is administered in high doses, with resulting damage to tissues.

    The doses in these studies and experiments where intentionally high artificial doses and concentrations of ribose that are not even close to the therapeutic levels and doses recommended by health care professionals, which is from 5 grams per day to as high as 60 grams per day.  6 

    The therapeutic dosage range simply cannot cause serum ribose concentrations to rise high enough to create ribosylation that was found in the laboratory studies.

    To further reduce the risk of ribosylation using D-Ribose, health care professionals recommend that the total amount of the daily dosage be split into three (3) daily doses.  This assures that the D-Ribose serum remains at a safe level.

    Benfotiamine May Delay the Progression of Alzheimer’s Disease

    Thiamine or Vitamin B1 is a vitamin of the B complex.   Thiamine is water soluble and has difficulty penetrating the lipid layer of the cell membrane.  Because thiamine is water soluble, excess doses are usually excreted in the urine. 

    Scientists in Japan researched and experimented with various analogues of thiamine in order to create better bioavailability to the cells.   They created a synthetic S-acyl derivative of thiamine called benfotiamine, which is fat soluble, and thus able to penetrate the lipid layer of the cell membrane and boost thiamine absorption into cells and throughout the body.

    Studies have shown that administration of benfotiamine resulted in a 10 to 40% higher thiamine incorporation into the liver and heart—and a remarkable 5to 25-fold higher thiamine incorporation into muscle and brain.  1

    Benfotiamine has been used clinically for reducing the formation of advanced glycation end products (AGE’s).  A study from May 2000 showed that enhanced bioavailability of benfotiamine caused it to reduce the intracellular formation of AGEs in subjects’ blood cells by 40%.  2 

    Benfotiamine shows promise in enhancing memory and delaying the progression of Alzheimer’s disease.

    Benfotiamine has been shown to:

    • Reduce amyloid plaque numbers in the brain  3
    • Reduce phosphorylated tau protein levels in the brain  4

    According to a study from 2012, thiamine deficiency:

    • Exacerbates plaque formation
    • Promotes phosphorylation of tau
    • Impairs memory

    In contrast, treatment of mouse models of Alzheimer’s disease with the thiamine derivative benfotiamine:

    • Diminishes plaques,
    • Decreases phosphorylation of tau and
    • Reverses memory deficits.  5

    Resources:

    Life Extension – Benfotiamine

    Swanson Health Products – Benfotiamine


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    Endogenous Glycation and its Effect on Human Health

    Endogenous glycation is the chemical result of the bonding of a sugar molecule with a protein or lipid molecule that produces nonfunctioning and deformed molecules known as advanced glycation end products (AGE’s).

    AGE’s that stem from a glycation reaction, produces cells that are stiffer and less pliable and more subject to damage and premature aging. When glycated proteins fuse together, this is known as cross-linking. The skin, eyes and heart are particular organs subject to cross-linking.

    Exogenous glycation occurs when AGE’s are formed by heating proteins and lipids with sugar. Certain forms of cooking can accelerate the exogenous glycation process, such as grilling and frying.

    AGEs have a range of pathological effects, such as:

    • Increased vascular permeability.
    • Oxidizing LDL.
    • Binding cells—including macrophage, endothelial, and mesangial—to induce the secretion of a variety of cytokines – promoting chronic inflammation.
    • Inhibition of vascular dilation by interfering with nitric oxide.
    • Enhanced oxidative stress – free radicals.

    Once an AGE is produced through the endogenous glycation process, it is irreversible. It is therefore important to seek ways to prevent glycation, both endogenously and exogenously.

    Compounds that are thought to inhibit AGE formation, at least in vitro, include:

    Vitamins

    • Vitamin C [1]
    • Vitamin E [2]
    • Nicotinic Acid [3]
    • Benfotiamine [4]
    • Pyridoxamine [5]
    • Alpha-lipoic acid [6]
    • Pyridoral-5-phosphate (P-5-P) [7]

    Amino Acids

    • Taurine [8]
    • Carnosine [9]
    • Beta-Alanine
    • Acety-L-Carnitine [10]
    • Ethylene-Diamine-Tetra-Acetate (EDTA) [11]

    Minerals

    • Chromium [12]
    • Zinc [13]

    Polyphenols

    • Diosmin [14]
    • Oligomeric Proanthocyanidins [15]
    • Quercetin [16]
    • Rutin [17]

    Nootropics

    • Centrophenoxine [18]
    • Dimethylaminoethanol (DMAE) [19]

    Herbs

    • Rosemary [20]
    • Astagalus [21]

    Pharmaceuticals (Prescription required by licensed physician):

    • Acarbose [22]
    • Metformin [23]
    • Aminoguanidine [24]

    Compounds that are thought to break some existing AGE crosslinks include:

    • Alagebrium (and related compounds ALT-462; ALT-486; ALT-946) [25]
    • N-phenacyl thiazolium bromide

    References:

    [1] Krone, C. A., et al. Ascorbic acid, glycation, glycohemoglobin and aging. Med Hypotheses. 62(2):275-279, 2004.

    [2] Alderson, N. L., et al. Effect of antioxidants and ACE inhibition on chemical modification of proteins and progression of nephropathy in the streptozotocin diabetic rat. Diabetologia. 47(8):1385-1395, 2004.

    [3] Rahbar, S., et al. Niacin (3-Pyridinecarboxylic Acid) is a potent inhibitor of advanced glycation endproducts (AGE’s). Diabetes. 48(5):SA375, 1999.

    [4] Stirban, A., et al. Benfotiamine prevents macro- and microvascular endothelial dysfunction and oxidative stress following a meal rich in advanced glycation end products in individuals with type 2 diabetes. Diabetes Care. 29:2064-2071, 2006.

    [5] Jain, S. K., et al. Pyridoxine and pyridoxamine inhibits superoxide radicals and prevents lipid peroxidation, protein glycosylation, and (Na+ + K+)-ATPase activity reduction in high glucose-treated human erythrocytes. Free Radic Biol Med. 30(3):232-237, 2001.

    [6] Jain, S. K., et al. Lipoic acid decreases lipid peroxidation and protein glycosylation and increases (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-treated human erythrocytes. Free Radic Biol Med. 29:1122-1128, 2000.

    [7] Higuchi, O., et al. Aminophospholipid glycation and its inhibitor screening system: A new role of pyridoxal 5′-phosphate and pyridoxal as lipid glycation inhibitor. Journal of Lipid Research. 2006.

    [8] Nandhini, A. T., et al. Stimulation of glucose utilization and inhibition of protein glycation and AGE products by taurine. Acta Physiol Scand. 181(3):297-303, 2004.

    [9] Brownson, C., et al. Carnosine reacts with a glycated protein. Free Radic Biol Med. 28(10):1564-1570, 2000.

    [10] Swamy-mruthinti, S., et al. Acetyl-L-carnitine decreases glycation of lens proteins: in vitro studies. Exp Eye Res. 69(1):109-115, 1999.

    [11] Jorksten, J. Pathways to the decisive extension of the human specific lifespan. J American Geriatrics Society. 25:396-399, 1977.

    [12] Evans, G. W. Conference of the American Aging Association. San Franciscio, California, USA. October 1992.

    [13] Tupe, R., et al. Interaction of zinc, ascorbic acid, and folic acid in glycation with albumin as protein model. Biol Trace Elem Res. 2010.

    [14] Manuel, Y., et al. The effect of flavonoid treatment on the glycation antioxidant status in Type-1 diabetic patients. Diabetes Nutr Metab. 12(4):256-263, 1999.

    [15] Urios, P., et al. Flavonoids inhibit the formation of the cross-linking AGE pentosidine in collagen incubated with glucose, according to their structure. European Journal of Clinical Nutrition. 2007.

    [16] Urios, P., et al. Flavonoids inhibit the formation of the cross-linking AGE pentosidine in collagen incubated with glucose, according to their structure. European Journal of Clinical Nutrition. 2007.

    [17] Cervantes-Laurean, D., et al. Inhibition of advanced glycation end product formation on collagen by rutin and its metabolites. Journal of Nutritional Biochemistry. 2005.

    [18] Nagy, I., et al. On the role of cross-linking of cellular proteins in aging. Mech Aging Dev. 14(1-2):245-251, 1980.

    [19] Nagy, I., et al. On the role of cross-linking of cellular proteins in aging. Mech Aging Dev. 14(1-2):245-251, 1980.

    [20] Dearlove, R. P., et al. Inhibition of protein glycation by extracts of culinary herbs and spices. Journal of Medicinal Food. 11(2):275-281, 2008.

    [21] Motomura, K., et al. Astragalosides isolated from the root of Astragalus Radix inhibit the formation of advanced glycation end products. J Agric Food Chem. 2009.

    [22] Cohen, M. P., et al. Alpha-glucosidase inhibition prevents increased collagen fluorescence in experimental diabetes. Gen Pharmacol. 22(4):607-610, 1991.

    [23] Beisswenger, P., et al. Metformin inhibition of glycation processes. Diabetes Metab. 29(4 Part 2):95-103, 2003.

    [24] Corman, B., et al. Aminoguanidine prevents age-related arterial stiffening and cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America. 95(3):1301-1306, 1998.

    [25] Asif, M., et al. An advanced glycation endproduct cross-link breaker can reverse age-related increases in myocardial stiffness. Proc Natl Acad Sci USA. 97(6):2809-2813, 2000.


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    Rosemary, it’s about Thyme to be a Sage

    Rosemary, with the botanical name, Rosmarinus officinalis, is a woody, perennial herb with fragrant, evergreen, needle-like leaves and white, pink, purple, or blue flowers, native to the Mediterranean region.

    Rosmarinus_officinalis_SHRUB

    It is a member of the mint family Lamiaceae, which includes many other herbs. The name “rosemary” derives from the Latin for “dew” (ros) and “sea” (marinus), or “dew of the sea”.

    Rosemary contains a number of phytochemicals and antioxidants:  1

    • Phytochemicals
      • 1,8-cineol
      • betulinic acid
      • borneol
      • bornyl acetate
      • caffeic acid
      • camphor
      • rosmarinic acid
      • therein
      • ursolic acid
      • α-pinene
    • Antioxidants
      • carnosic acid
      • carnosol

    Most Rosemary supplements are standardized to contain 6% carnosic acid.

    Rosemary has a multitude of health benefits and has been well researched.  These benefits are listed in the Table below:

    Health Benefits of Rosemary

    Rosemary   
    SystemConditionBenefitReferences
    Cardiovascular
    Atherosclerosis
    It is concluded that rosemary and its constituents especially caffeic acid derivatives such as rosmarinic acid have a therapeutic potential in treatment or prevention of bronchial asthma, spasmogenic disorders, peptic ulcer, inflammatory diseases, hepatotoxicity, atherosclerosis, ischaemic heart disease, cataract, cancer and poor sperm motility.1
    Antithrombotic
    Long-term daily intake of rosemary and common thyme has an antithrombotic effect, which is probably due to inhibition of platelets and stimulation of endothelial cells. The antithrombotic effect was not accompanied by prolongation of bleeding time.2
    Detoxification
    Quinone Reductase
    Liver activities of GST and QR, and stomach GST activity were significantly increased in animals fed diets containing rosemary extract. However, diets supplemented with rosemary extract did not affect lung GST and QR activities. These results indicate that components of rosemary extract have the potential to protect mouse liver and stomach from carcinogenic or toxic agents.3
    Heterocyclic Aromatic Amines
    The inhibiting effect of rosemary extracts on HCA formation corresponded to their antioxidant activity based on a DPPH scavenging assay. Rosemary extract 10E and 20E contain a mixture of rosmarinic acid, carnosol, and carnosic acid. It is possible that these compounds might act synergistically in inhibiting the formation of HCAs.4
    Carbon Tetrachloride
    Histological evaluation showed that Rosmarinus officinalis partially prevented CCl(4)-induced inflammation, necrosis and vacuolation. Rosmarinus officinalis might exert a dual effect on CCl(4)-induced acute liver injury, acting as an antioxidant and improving GST-dependent detoxification systems.5
    Leukotriene B4
    Rosmarinic acid is well absorbed from gastrointestinal tract and from the skin. It increases the production of prostaglandin E2 and reduces the production of leukotriene B4 in human polymorphonuclear leucocytes, and inhibits the complement system.6
    Immunity
    Cancer
    Although the extracts exhibited various cytotoxic effects against different cell lines, comparatively low IC(50) values ranging between 12.50 and 47.55 microg/ml were attained against K-562, being the most sensitive cell line. Moreover, carnosic acid caused the lowest cell viability with values ranging from 13 to 30 % at a concentration of 19 muM after 48 h of treatments, resulting in superior antiproliferative effect. Rosemary extract is a potential candidate to be included in the anti-cancer diet with pre-determined doses avoiding toxicity.7
    Breast cancer
    Carnosol is one rosemary constituent that can prevent DMBA-induced DNA damage and tumor formation in the rat mammary gland, and, thus, has potential for use as a breast cancer chemopreventative agent.8
    Skin cancer
    At a dose rate of 500 mg/kg body wt/mouse, the oral administration of rosemary extract was found to be significantly protective against two-stage skin tumorigenesis.9
    Leukemia
    Results suggest that carnosol may be useful as a novel chemotherapeutic agent against B-lineage leukemias, and possibly other types of cancers that express high levels of the protective protein, Bcl-2.10
    Inflammation
    Rosemary can be considered an herbal anti-inflammatory and anti-tumor agent.11 12
    Antimicrobial
    Artemisia afra and R. officinalis showed similar and higher antimicrobial activity than P. incana. Due to their broad antimicrobial activities, the essential oils of the above plants growing in Eastern Cape may have preservative potential for the food and cosmetic industries.13
    Metabolism
    Antioxidant
    Carnosol and carnosic acid have been suggested to account for over 90% of the antioxidant properties of rosemary extract.14
    Liver protective
    Carnosol prevents acute liver damage, possibly by improving the structural integrity of the hepatocytes. To achieve this, carnosol could scavenge free radicals induced by CCl(4), consequently avoiding the propagation of lipid peroxides. It is suggested that at least some of the beneficial properties of Rosmarinus officinalis are due to carnosol.15
    Phospholipids (Peroxidation)
    Rosemary extracts block damaging lipid peroxidation, the destruction of brain cells’ fatty membranes that impairs cognitive performance.16
    Glycation
    Rosemary inhibits fructose-mediated protein glycation.17
    Cataract
    Rosemary and its constituents especially caffeic acid derivatives such as rosmarinic acid have a therapeutic potential in treatment or prevention of bronchial asthma, spasmogenic disorders, peptic ulcer, inflammatory diseases, hepatotoxicity, atherosclerosis, ischaemic heart disease, cataract, cancer and poor sperm motility.18
    Neurological
    Alzheimer’s
    May help to prevent/treat Alzheimer's Disease (by inhibiting the Acetylcholinesterase enzyme)19
    Carnosic acid may be useful in protecting against beta amyloid-induced neurodegeneration in the hippocampus.20
    Depression
    May alleviate Depression21
    Nerve Growth Factor
    May enhance the production of Nerve Growth Factor (NGF) (due to the carnosic acid and carnosol content of Rosemary)22
    Memory
    High concentration of carnosic acid, which helps improve memory 23
    Concentration
    Higher concentrations resulting in improved performance with 1,8-cineole (1,3,3-trimethyl-2-oxabicyclo[2,2,2]octane), one of rosemary's main chemical components. 24
    Parkinson’s
    Carnosol may have potential as a possible compound for the development of new agents to treat Parkinson's disease 25


    Resources:

    Swanson Health Products – Rosemary

    Starwest Botanticals – Rosemary (Varieties)


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    Benfotiamine can be used to block Advanced Glycation End Products (AGE’s)

    Benfotiamine is the fat-soluble synthetic S-acyl derivative and precursor compound of thiamine, vitamin B1. When the body absorbs benfotiamine, the substance gets converted from its inactive form into its active form via the body’s metabolic processes.

    Consumption of benfotiamine can be used to block Advanced Glycation End (AGE) Products, end products of glycation that have negative detrimental effects on the health of individuals with high blood sugar (especially diabetics). Thus, benfotiamine can be used to reduce such complications as the scarring of blood vessels that function to filter urine from the blood in one’s kidneys, scarring/thickening of lung tissues that lead to interstitial lung disease, and factors associated with aging and age-related chronic diseases. For more details, see Advanced Glycation End Products.

    In addition to blocking AGEs, benfotiamine can lessen the severity, delay the progression of, and sometimes even repair damages inflicted by diabetic complications. A case in point would be retinopathy where small blood vessels in the retina are damaged and can gradually lead to blindness. Studies have found that benfotiamine can help prevent this condition.

    Benfotiamine has also been found to delay and reduce nephropathy, a disease of the kidney that causes deterioration in the kidney’s ability to function. Oftentimes, individual with nephropathy will have to become dependent on dialysis. Benfotiamine can help normalize the individual’s glucose levels and interfere with the formation of AGEs.

    In addition, Benfotiamine can also be used to treat neuropathy, a nerve disorder that damages an individual’s nerves and leaves them feeling a burning, tingling or numbness in their body. Studies have found that large doses of benfotiamine can help improve the condition of patients with neuropathy.


    References:

    Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy

    Benfotiamine Prevents Macro- and Microvascular Endothelial Dysfunction and Oxidative Stress Following a Meal Rich in Advanced Glycation End Products in Individuals With Type 2 Diabetes

    Pharmacokinetics of thiamine derivatives especially of benfotiamine

    Effects of low- and high-advanced glycation endproduct meals on macro- and microvascular endothelial function and oxidative stress in patients with type 2 diabetes mellitus1,2,3

    Prevention of Incipient Diabetic Nephropathy by High-Dose Thiamine and Benfotiamine

    Benfotiamine is similar to thiamine in correcting endothelial cell defects induced by high glucose

    High-dose benfotiamine rescues cardiomyocyte contractile dysfunction in streptozotocin-induced diabetes mellitus

    Benfotiamine relieves inflammatory and neuropathic pain in rats

    The multifaceted therapeutic potential of benfotiamine


    PDF Reference Files:

    Note: PDF files require a viewer such as the free Adobe Reader

    Benfotiamine – Fights the “Caramelization of the Flesh”

    Benfotiamine Inhibits Intracellular Formation of Advanced Glycation End Products in vivo


    Informational References:

    Benfotiamine.org

    Benfotiamine at Clinical Trials.gov


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    L-Carnosine: Considered the most effective substance to inhibit AGEs

    L-carnosine is a dipeptide composed of the amino acids β-alanine and histidine. Known for its antioxidant properties, L-carnosine removes free radicals and other related Advanced Glycation End-Products (AGEs) caused by the oxidative stress of glycation. Chronic glycolysis is linked to the progression of many illnesses such as cancer and is a contributing factor in the aging process and age-related chronic diseases.

    L-carnosine is highly concentrated in the brain, muscles, skin, and is also common in herbs such as rosemary and sage. It is a strong neuroprotective agent, as the dipeptide promotes the overall health of neurons. Studies suggest that with these properties, L-carnosine can be used as a therapy against devastating neurodegenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease and other forms of dementia. The positive affects of L-carnosine on such chronic age-related neurodegenerative diseases include the correction of malfunctioning mitochondria and aβ-amlyiod plaque degradation by reactive oxygen species and AGE removal.

    Though L-carnosine can be used as age-related therapy, it is also beneficial to other chronic diseases such as diabetes. Cellular damage to podocytes and mesangial cells, renal cells located in the kidneys, is induced by high glucose conditions. Diabetic nephropathy is the leading cause of end-stage renal failure in the western world; however, with the application of L-carnosine, the oxidative damage caused by mitochondrial overproduction can be reversed. Similarly, this molecule has been experimentally observed to reduce and prevent any oxidative damage caused by ulcers, cancers and tumors. This preventative effect is also seen in patients with chemically induced cardiac damage and cataracts.

    In addition to its wide range of medical application, L-carnosine is a potent aid in the rejuvenation of connective tissue and skin. Carnosine is naturally produced by the connective tissues in muscles in response to exercise allowing optimal mitochondrial function and ultimately, better athletic performance. The positive effects of L-carnosine on such tissue formation have led to studies including sports health. Furthermore, it is comparable to the fountain of youth by not only reducing and preventing age-related disease but also by relieving the physical appearance of aging. By preventing the collagen-skin crossbridges and increasing the Haylflick limit of the existing cells, L-carnosine promotes cell division and elasticity thereby reducing the appearance of fine lines and wrinkles. It may be used as a topical gel or an oral dietary supplement to fight the effects of aging internally and externally.


    References:

    Effects of Dietary Supplementation of Carnosine on Mitochondrial Dysfunction, Amyloid Pathology, and Cognitive Deficits in 3xTg-AD Mice

    L-carnosine (beta-alanyl-L-histidine) and carcinine (beta-alanylhistamine) act as natural antioxidants with hydroxyl-radical-scavenging and lipid-peroxidase activities

    Dietary regulation of intestinal transport of the dipeptide Carnosine

    Carnosine Is Neuroprotective Against Permanent Focal Cerebral Ischemia in Mice

    Anti-oxidative and anti-genotoxic effects of carnosine on human lymphocyte culture

    Glycation of the muscle-specific enolase by reactive carbonyls: effect of temperature and the protection role of carnosine, pyridoxamine and phosphatidylserine

    Identification of factors involved in the anti-tumor activity of carnosine on glioblastomas using a proteomics approach

    Carnosine inhibits degradation of hyaluronan induced by free radical processes in vitro and improves the redox imbalance in adjuvant arthritis in vivo

    Protective effect of carnosine on adriamycin-induced oxidative heart damage in rats


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    Chebulic acid: Is it a potential AGE cross linking breaker?

     

    When discussing cross-linking of proteins through glycation and advanced glycation end products (AGE’s), there are two issues:

    • Inhibiting or preventing cross-linking, and
    • Breaking existing AGE’s (reversing existing AGE cross links)

    There are a number of natural substances that inhibit or prevent AGE’s:

    • Acetyl-L-Carnitine
    • Aged Garlic
    • Allspice
    • Aminoguanidine
    • Arginine
    • Asiatic Dogwood
    • Astragalus
    • Centrophenoxine
    • Chromium (Chromium Picolinate)
    • Cinnamon
    • Cloves
    • Coumestrol
    • Dimethylaminoethanol (DMAE
    • Diosmin
    • Ethylene-Diamine-Tetra-Acetate (EDTA
    • Glutathione Peroxidase
    • Grape Seeds (extract)
    • Green Tea
    • Inositol
    • Korean Ginseng
    • Lipoic Acid
    • Luteolin
    • Marjoram
    • Methylsulfonylmethane (MSM
    • Myricetin
    • N-Acetyl-Cysteine (NAC)
    • Oligomeric Proanthocyanidins (OPCs)
    • Oregano
    • PABA (Para Aminobenzoic Acid
    • Papain
    • Pyridoxamine
    • Quercetin
    • Rosemary
    • Rutin
    • Taurine
    • Vitamin A
    • Vitamin B1
    • Vitamin B5
    • Vitamin B6
    • Vitamin C
    • Vitamin E
    • Zinc

    As can be seen, there are quite a few natural substances that inhibit or prevent AGE’s. However, the real holy grail is in substances that can break or reverse existing AGE’s. 

    AGE’s in humans exist in one of three following molecular structures:

    • Glucosepane
    • Alpha-Diketone linkers
    • Lysine-dihydropyridinium-lysine (L2P or K2P)

    There are two known potential Cross-link breakers that have been studied and researched:

    • Alagebrium (formerly known as ALT-711) (3-phenacyl-4, 5-dimethylthiazolium chloride)
    • N-phenacyl-4,5-dimethylthiazolium bromide (DMPTB)

    Alagebrium was a drug candidate developed by Alteon Corporation. It was the first drug candidate to be clinically tested for the purpose of breaking the crosslinks caused by advanced glycation endproducts (AGEs).

    Alagebrium entered into Phase I and II clinical trials but Alteon Coproration ceased their research due to financial issues. The company that bought Alteon, Synvista Therapeutics, Inc, discontinued further research on Alagebrium in January 2009. [1]

    N-phenacyl-4,5-dimethylthiazolium bromide (DMPTB) is a thiazolium compound which is known to cleave preformed advanced glycation end products. [2] Treatment of pre-glycated αA-crystallin with DMPTB gave evidence for the degradation of the already formed cross–linked HMW aggregates. [3]

    Alagebrium and N-phenacyl-4,5-dimethylthiazolium bromide (DMPTB) are known to only break Alpha-Diketone linkers. They are not known to break the other two AGE’s Alpha-Diketone linkers and Lysine-dihydropyridinium-lysine.

    According to current research, no agent has been found that breaks the prevalent glucosepane and K2P crosslink structures. [4]

    Chebulic acid is a phenolic compound isolated from the ripe fruits of Terminalia chebula. Terminalia chebula is a tree grown in India and Asia. In Ayruvedic medicine it is called Haritaki in the Hindi language. Terminalia chebula extract is also found in the ayruvedic formula called Triphala which means “Three Fruits”.

    TerminaliaChebula

    An interesting article appeared in the April 2014 edition of the Biology & Pharmaceutical Bulletin regarding chebulic acid on advanced glycation end products. It is entitled Effects of chebulic acid on advanced glycation end products-induced collagen cross-links, written by Lee JY, Oh JG, Kim JS, and Lee KW. [5]

    The author’s first state the purpose of their study:

    “We report the antiglycating activity of chebulic acid (CA), isolated from Terminalia chebula on breaking the cross-links of proteins induced by AGEs and inhibiting the formation of AGEs.”

    The author’s research illustrated very promising potential of chebulic acid as a cross-link breaker, stronger than ALT-711.

    “Also, the breaking activity on collagen cross-links induced by glycol-BSA was potent with CA (IC50=1.46 ± 0.05 mM), exhibiting 50-fold stronger breaking activity than with ALT-711, a well-known cross-link breaker (IC50=72.2 ± 2.4 mM).”

    The author’s conclusion shows that chebulic acid is not only an inhibitor of AGE cross linking but also a breaker of AGE cross-linking:

    “Thus, CA could be a breaker as well as an inhibitor of AGE cross-linking, the activity of which may be explained in large part by its chelating and antioxidant activities, suggesting that CA may constitute a promising antiglycating candidate in intervening AGE-mediated diabetic complications.”

    UPDATE:  Michael Rae examines whether Chebulic Acid has potential as an AGE cross link breaker. LINK TO QUORA 


     

    References:

    [1] Synvista Therapeutics Announces Termination of Clinical Trials of Alagebrium and SYI-2074 and Provides Business Update

    [2] The cross-link breaker, N-phenacylthiazolium bromide prevents

    vascular advanced glycation end-product accumulation

    [3] Cleavage of in vitro and in vivo formed lens protein cross-links by a novel cross-link breaker

    [4] Extracellular Glycation Crosslinks: Prospects for Removal

    [5] Effects of chebulic acid on advanced glycation endproducts-induced collagen cross-links


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    Allspice: A Powerful Spice

    Allspice, also called Jamaica pepper, pepper, myrtle pepper, pimenta, pimento, English pepper or newspice, is the dried unripe fruit (“berries”, used as a spice) of Pimenta dioica. 

    allspic2

    Allspice plant

    The follow compounds are found in Allspice:

    Compounds in Allspice

    Allspice 
    CatagoryCompound
    Eugenol
    Eugenol methyl ether
    ellagic acid
    Quercetin
    Terpenes
    myrcene
    1,8-cineol
    α-phellandrene

    The Table below lists the recognized and researched health benefits of Allspice:

    Health Benefits of Allspice

    Allspice   
    BiosystemConditionBenefitReference
    Metabolism
    Glycation
    Inhibits advanced glycation end products1
    Antioxidant
    Two new polyphenolic glucosides, 6'-O-acetylisobiflorin (1) and (2S)-3-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol 1-O-(6'-O-galloyl)-β-D-glucoside (2), showed the most potent antioxidative activity [ORAC value of 39,270 µmol TE (trolox equivalent)/g].2
    Hypertension
    Allspice may help to lower blood pressure in hypertension patients.3
    Trigylcerides
    Allspice may lower elevated triglycerides levels4
    Anti-bacterial
    Allspice may inhibit Shigella flexneri5


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