Blog 22 Introduction
AGEs, the acronym for advanced glycation end products are heterogeneous chemical entities of utmost importance in aging and age-related pathologies. These chemical products are generated in the foods we eat and they are also generated in the body. This blog will describe the importance and harm of AGEs and their role in aging.
Initial Importance and Harm of AGEs
The importance and harm of AGEs begins with their discovery. AGEs (also called glyotoxins) were discovered more than 100 years ago by the French physician/chemist, Louis Maillard. He studied the non enzymatic oxidation between sugars and proteins which generated final products of dark polymers. These products were of interest because they were endowed with properties of pleasing aroma and taste, highly desirable in foods. AGEs are one of the many final products of this oxidation reaction, popularly termed, the “browning” reaction. The “browning” reaction is familiar as it occurs in all foods subjected to high temperatures and may involve oxidations by sugars not only of proteins but also lipids and nucleic acids.
External AGEs – Generated in Foods
Foods subjected to high temperatures for short periods of time generate significant amounts of AGEs (see a introductory short list below). Some examples of foods with high concentrations of AGEs include toast, baked goods, processed foods, and fried, broiled and grilled meats. Fresh fruits and vegetables contain minimal amounts of AGEs. In comparison, grilled meats (standard serving size) contain AGEs at several hundred times the amount found in fresh fruits and vegetables. Several specific methods (generally targeting N-carboxymethyl lysine) are used to measure the concentration of AGEs in foods.
Internal AGEs – Generated in the Body
The importance and harm of AGEs continues with the discovery of their internal generation. Thus, in addition to AGEs in certain foods, glycations (oxidation by sugars) also occur in the body at physiological temperatures. Unlike AGEs generated in foods, AGEs generated in the body require a longer time period of generation (months, years). However, AGE formation is accelerated by the presence of persistent high levels of blood sugar. A familiar method that measures internal AGEs is the A1C . This test measures the glycation of sugar with the hemoglobin protein. As such it gives an estimate of blood sugar level over time. Although results of the A1C test are used to manage diabetes, they also give an indication of the oxidative damage occurring elsewhere to other internal proteins.
Internal Pools of AGEs
The body’s internal pools of AGEs are derived from
a) oral intake of exogenous AGEs (10-30% of intake is absorbed by intestines, 30% excreted by the kidneys and 60% remaining, continues to circulate and create problems and
b) endogenous AGE production driven by persistent elevation of blood glucose (resulting from dietary carbohydrates, stress, lack of exercise) further exacerbated by consumption of fructose (sweetened beverages).
Importance of Processing of AGEs
Fortunately, the body’s pool of AGEs is moderated by several cellular detoxification mechanisms. One of the best occurs through the uptake by specialized cells called macrophages. AGEs taken up by these cells are detoxified and create no further problems. However, as this pathway becomes overwhelmed, AGEs are free to bind to and activate specific receptors, termed RAGE receptors found on most cells. Uptake by the RAGE receptor is undesirable because it activates an unwanted chronic inflammatory response.
Harmful Effects of AGEs
1. Activation of RAGE receptors by AGEs initiates an inflammatory response. Acute inflammatory responses are absolutely essential for wound healing but in contrast, continual low level inflammation as with activation of RAGE receptors is detrimental. The response produces an abundance of inflammatory mediators such as cytokines which induce constant tissue damage and thus contribute to the pathologies of atherosclerosis, T2D, uremia and neurodegenerative diseases.
2. AGEs formed internally result in cross linkages between proteins. AGE-dependent cross linkage is abundantly evident in collagen, a long lived support protein found in most tissues. Cross linkage of collagen (or any protein) is harmful because it a) alters structure, b) hinders function and c) results in perturbations of vital matrix, material surrounding cells. In the case of collagen, cross linkage results in tissue stiffness and hence reduced function in arteries, heart, kidney, bone, and skin.
Some important consequences of AGEs are
a) exercise intolerance which means early onset of fatigue during exercise,
b) development of systolic hypertension where systolic pressure is 160 mm Hg or more and diastolic is less than 90 mm Hg,
c) eventual heart and kidney failure and
d) sun-exposed wrinkles and sags.
Avoidance of AGEs
Clinical trial results have validated ways to reduce AGE accumulation in the body. These include consumption of a diet low in AGEs, such as the Mediterranean diet (see blog 10), a diet of fruits, vegetables, legumes, grains, nuts and fish, and adherence to cooking practices that favor poaching and steaming generally at low temperatures for short periods in place of oven-frying, deep frying, broiling, and roasting. Efforts are underway to develop new technologies for cooking foods with minimal generation of AGEs while retaining flavor and taste (a topic of a future blog). Maintaining a fasting glucose level below 100 mg/dl is also prudent (Blogs 18/19 Vicious Cycle – Aging and Declining Blood Sugar Control; Stress Response and Sugar Control)
Conclusions
AGEs are harmful chemical entities. They are ingested in foods that have been prepared at high temperatures. They are made internally in the presence of persistent high glucose levels. AGEs that are not detoxified contribute to chronic inflammation and protein cross linkage, both of which contribute to accelerated aging and disease. For the present, avoidance of foods high in AGEs and maintenance of low blood sugar are the best strategies to avoid accumulation and organ damage from AGEs.