Bones and Joints

Current conventional lifestyle advice for bone and joint health typically consists of the mantra “weight bearing exercise and calcium supplementation.” While these therapies should comprise the basis of proactive bone and joint care along with Vitamin D3 supplementation, newer, cutting edge information points to a lesser-known way to support long-term bone and joint care.

The formation of substances known as advanced glycation end products, or AGEs, is garnering new attention for their potential role in bone and joint problems as medical science begins to explore more deeply the role diet plays in health and aging. In addition to being exposed to AGEs through the diet, AGEs are also created in our bodies as a byproduct of normal metabolism and more so in conditions of unregulated hyperglycemia, or elevated blood sugar levels.

AGEs are sugar-derived chemicals created as a byproduct of regular sugar metabolism. They are created when sugars (carbohydrates) interact with the free amino acid groups of lipids, proteins and nucleic acids in the body and during the course of food preparation and processing. AGEs accumulate over time in bodily tissues and form irreversible bonds with various proteins.

A heterogeneous group of intermediary molecules are created prior to formation of AGEs. These are termed Schiff bases, Amadori and Maillard products. They comprise a collection of molecules and through a series of subsequent reactions, become AGEs. (Hemoglobin A1C is a well-known Amadori product that is used in tracking historic blood sugar levels.)

The affinity of AGEs for other nucleic acids, fats and proteins and the subsequent formation of permanent cross-links is what make them particularly destructive to the body. As AGEs accumulate and they form cross-links with the aforementioned molecules, alterations in their structure and function occur bringing about pathological changes. AGEs are known to accumulate in the cellular matrix, vessel walls and basement membranes and promote pro-oxidative and pro-inflammatory reactions where they reside.

Near-Constant Exposure

One major area of exposure to AGEs is through cooking. AGEs are created when fats and proteins are heated in the presence of simple carbohydrates.^1-2 Heating of food (specifically dry heat) increases AGE product formation anywhere from 10 to 100 times.^3-4

Heating of food will increase the amount of AGEs found in that food. The higher the heat, the more AGEs are produced. Broiling (225 degrees C) and frying (177 degrees C) produced the highest amount of AGEs, followed by roasting (177 degrees C) and boiling (100 degrees C).⁴ AGEs are also more readily formed in the body under conditions of poorly controlled hyperglycemia, i.e. diabetes. Several areas of research exist that have examined the widespread damaging effects of AGEs in diabetics.^5-7

Bone and Joints: AGEs’ Damaging Effects

One area where the most extensive accumulation of AGEs occurs is in tissues with low turnover. These tissues contain relatively long-lived protiens such as the collagen found in the extracellular matrices of connective tissues, i.e. bone, cartilage, tendon and skin.⁸ AGEs and their effect on bone and articular cartilage are emerging as a possible culprit or contributing factor in degenerative conditions in these tissues. Newer knowledge of AGEs and how they contribute to the breakdown of bone and articular cartilage can help to focus new strategies on protecting these areas, rather than plainly suggesting mineral supplementation.

Bones and AGEs

AGEs are found throughout all cells, tissues and organ systems of the body, including bone.⁹ AGEs in bone matrix alter its mechanical properties, contributing to weakening.^10-12 In vitro studies of AGE accumulation in Type I collagen (the most abundant type found in bone) show that AGEs interfere with production and differentiation of osteoblastic (bone building) cells throughout the stages of the cells’ development.^13-14 The relationship between AGEs in bone and fracture risk is not yet clearly understood, however. This is important to note as AGE accumulation begins at the start of life and diet is a major avenue of introduction.

Osteopenia and osteoporosis are frequently observed in diabetes; it is thought that the reduced quality of collagen cross-linking is caused by the accumulation of AGEs in the bone, in addition to hyperglycemia, high levels of homocysteine and oxidative stress.¹⁵ While type 2 diabetics can typically have higher bone density than non-diabetics, they have an increased risk of fracture possibly explained by the fact type 2 diabetics exhibit higher levels of serum pentosidine, an AGE that is associated with vertebral fractures.^16-17

Elevated AGEs contribute to altered osteoclast (bone resorption-bone breakdown) and osteoblastic (bone formation) activity suggesting an important role in the pathogenesis of osteoporotic bone diseases.¹⁸ This may explain in part why, despite adequate amounts of calcium and weight bearing exercise, many people are still plagued by poor bone strength.

More focused examination of collagen cross-links in bone is becoming increasingly utilized; reduced numbers of enzymatic, immature cross-links and increased non-enzymatic (AGE) provide insight into the variety of fractures in osteoporosis and diabetes.¹⁹

Widespread osteoporosis also often occurs concomitantly in rheumatoid arthritis (RA). Furthermore, increased fracture rates are seen in people with this combination; the role of AGEs in osteoclastic (bone resorption) and osteoblastic (bone building) is thought to play a role. Additionally, AGEs are found in increased amounts in people with RA and their concentration is related to RA disease activity.¹⁸

Joints and AGEs

Just as AGEs occur in bone, AGEs can be found in articular cartilage (the cartilage that provides cushioning between the bones). When AGEs accumulate in articular cartilage and disrupt normal cellular function, the cartilage becomes increasingly stiff, brittle and more prone to damage.^20-21 AGEs are also thought to interfere with cartilage function by impairing proteolytic degradation of damaged or aged cartilage. Degradation of AGE-altered collagen by matrix metalloproteinases is impaired in comparison to normal collagen.²²

AGEs are increasingly indicated as a causative factor in osteoarthritis (degeneration of articular cartilage) and their accumulation in articular cartilage is a notable age-related change. AGEs affect negative cellular changes via the specific receptor for AGEs (sRAGE); these receptors are found in higher reactive levels in mild and severe cartilage degeneration.²³

One interesting study examined the relationship between serum levels of one AGE (carboxymethyl-lysine, CML) and walking speed.²⁴ Once adjusted for age, education, cognitive function, smoking status and chronic diseases, those with the highest plasma levels of CML were at highest “risk” of slow walking speed; In other words, elevated levels of plasma CML are independently associated with slow walking speed as a result of CML’s ability to cross-link collagen and stiffen skeletal muscle and cartilage.

AGE-Blocking Strategies

Prevention of AGE accumulation in the tissues starts with the diet; however, as previously noted the consumption and formation of AGEs is also inevitable, as they are found in nearly all foods to some extent and as a normal aspect of metabolism. Beyond altering dietary intake, targeted nutritional support in the form of N-acetyl cysteine, benfotiamine, carnosine, alpha-lipoic acid, guava and Yerba Maté (all found in AGEBlock®) can assist in an AGE-reduction regimen.

N-acetyl cysteine (NAC) supports the body’s production of glutathione, a potent antioxidant that protects nervous system cells after exposure to AGEs.²⁵ NAC also protects cells of the retina, platelets and LDL (low density lipoprotein) from the damaging effects of AGEs.^26-27 Benfotiamine is a form of vitamin B1 that can block the formation of AGEs after consumption of a high-AGE meal.²⁸ Carnosine, also known as (beta-alanyl-L-histidine), is effective at preventing the transformation of LDL into AGE products²⁹ and “short-circuits” the formation of intermediate chemicals (Schiff bases) in the production of AGEs.³⁰ Alpha lipoic acid is also effective at preventing the formation of AGEs after consumption of AGE-promoting foods.³¹

Other natural substances with AGE-blocking effects are guava (Psidium guajava), which has been shown to inhibit LDL cholesterol glycation in AGEs,³² and Yerba Maté (Ilex paraguariensis), which has been shown to prevent the formation of AGEs comparable to the standard AGE-preventing agent aminoguanidine.³³

Conclusion

Advanced Glycation End Products (AGEs), while a normal aspect of metabolism, can be greatly increased in the body either through cooking and processing of fats and proteins with carbohydrates or in conditions that promote excessively high blood sugars such as diabetes. AGEs bind non-enzymatically with other proteins in the tissues throughout the body, contributing to localized pathology. Emerging research indicates AGES have a surprising role to play in bone and joint health. AGE formation can be prevented by altering dietary intake, cooking methods and through the use of the specific nutrients found in AGEBlock.

References

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