Recent Studies of Advanced Glycation End-Products in Aging and Age-Related Disease

Today I'll link to a few unrelated studies of advanced glycation end-products (AGEs) and their role in aging and the pathology of specific age-related diseases. AGEs are both generated in the body as a side-effect of metabolic operation, but can also be found in the diet. There are numerous different classes of AGE, some more common than others. As a general rule the common AGEs are easily broken down and removed in healthy individuals, while the rare ones are persistent and in some cases cannot be broken down at all by our evolved molecular toolkit. The common AGEs play more of a role in metabolic disease: the dysregulated diabetic metabolism suffers from high levels of circulating AGEs, for example. These AGEs interact with the receptor for advanced glycation end-products, RAGE, to promote chronic inflammation and other bad behavior on the part of cells. As regular readers will know, high levels of inflammation contribute to the progression of damage and disease in aging, and this is one of the ways in which metabolic diseases, such as the varieties of diabetes, shorten life span and raise the risk of suffering age-related conditions.

Long-lasting persistent AGEs are perhaps more dangerous, however. For one they are far less well studied. The predominant form of persistent AGE in humans is glucosepane, and a quick PubMed search will show you that next to no-one is publishing papers on the subject in comparison to other forms of AGE. Glucosepane forms an ever-increasing number of cross-links between macromolecules in the extracellular matrix, and this cross-linking that degrade its structural properties - particularly elasticity in skin and blood vessels. Wrinkled skin we can live with, but blood vessel stiffening produces hypertension, structural failure of tiny vessels in the brain, detrimental remodeling of heart and blood vessel structures, cardiovascular disease, and death. Given all of this it is nothing short of amazing that it remains a struggle to find funding to advance the development of glucosepane cross-link breaker drugs. A single effective drug candidate could largely remove this sizable contribution to the aging process. As a topic this has been discussed in some depth in past posts, so I'll skip that story for the present. Just note that glucosepane isn't a fact of life written in stone; it would take very little investment today to produce drug candidates a few years from now. On that topic, this first paper focuses on AGEs in type 1 diabetes, not the age-related variety, but is unusual for actually including glucosepane in its analysis:

Skin collagen advanced glycation endproducts (AGEs) and the long-term progression of sub-clinical cardiovascular disease in type 1 diabetes

We recently reported strong associations between eight skin collagen AGEs and two solubility markers from skin biopsies and the long-term progression of microvascular disease in in diabetes, despite adjustment for mean glycemia. Herein we investigated the hypothesis that some of these AGEs correlate with long-term subclinical cardiovascular disease (CVD) measurements, i.e. coronary artery calcium score (CAC), change of carotid intima-media thickness (IMT), and cardiac MRI outcomes.

Correlations showed furosine (early glycation) was associated with future mean CAC. Glucosepane and pentosidine crosslinks, methylglyoxal hydroimidazolones (MG-H1) and pepsin solubility (inversely) correlated with IMT change. Left ventricular (LV) mass correlated with MG-H1, and inversely with pepsin solubility, while the ratio LV mass/end diastolic volume correlated with furosine and MG-H1, and highly with carboxymethyl-lysine (CML). In multivariate analysis only furosine was associated with CAC. In contrast IMT was inversely associated with lower collagen pepsin solubility and positively with glucosepane.

In type 1 diabetes, multiple AGEs are associated with IMT progression implying a likely participatory role of glycation and AGE mediated crosslinking on matrix accumulation in coronary arteries. This may also apply to functional cardiac MRI outcomes, especially left ventricular mass. In contrast, early glycation measured by furosine, but not AGEs, was associated with CAC score, implying hyperglycemia as a risk factor in calcium deposition perhaps via processes independent of glycation.

Biological Effects Induced by Specific Advanced Glycation End Products in the Reconstructed Skin Model of Aging

The aging human skin is characterized by decreased elasticity and accumulation of insoluble collagen and impaired wound healing. These changes are worsened in sun-exposed skin in which proinflammatory changes further help remodel the collagen-rich matrix. Two components are expected to participate in the latter process. The first involves a chemical process in which advanced glycation end products (AGEs) are produced from glucose and oxoaldehydes, thereby inflicting damage to the extracellular matrix, which includes protein crosslinking, insolubilization, and loss of elasticity. The second involves interactions between the modified AGE-rich dermal matrix and dermal cells leading to cell activation via AGE receptors (RAGE) and other receptors, eventually resulting in growth factor and cytokine release that profoundly remodel the extracellular matrix. Many of these changes have been observed in two-dimensional models in which cells are grown onto modified matrix. For several years now, our interest has been to evaluate the role of the aging extracellular matrix in three-dimensional models, that is, the reconstructed skin model in which fibroblasts are embedded in a three-dimensional collagen matrix and establish cross-talk with keratinocytes grown on the dermal matrix. Using such system, we were able to demonstrate that the glycated matrix mimicked a phenotype that shared many similarities with the aging skin. In particular, we showed that when AGE-rich glycated matrix formed by the reaction of D-ribose with bovine collagen was used, an aging-like phenotype developed.

Advanced Glycation End Products: Association with the Pathogenesis of Diseases and the Current Therapeutic Advances

Advanced glycation end products (AGE) have been imparted in the development and worsening of complications of diabetes. They are also involved in atherosclerosis, normal aging process, arthritis, cancer and progression of age-related neurodegenerative diseases like Alzheimer's disease. Endogenously, they formed by nonenzymatic glycation by aldoses/ketoses to form intermediates precursor that were slowly converted into AGE. A positive correlation was observed with the level of AGEs formation and progression of the diseases. Exogenously, they formed in foods when they were cooked at very high temperature.

AGEs can interact with the cell surface receptors of AGE (RAGE) to release cytokines, free radicals as well as directly modify the extracellular matrix and action of hormones. Hence, the mechanism of AGE association with pathogenesis of diseases can be ascribed mainly to the generated cytokines and free radicals. Second type of receptors such as AGE receptor-1, 2 and 3 were more specific and involved in their detoxification and clearance. Therapeutic agents were used to inhibit AGEs formation, traps the reactive carbonyl intermediate precursors, interfering with Amadori's products, cross-link breaker and low molecular weight inhibitors of RAGE had been described as well. Despite the several therapeutic agents described so far, none of them have proved to be recommended for clinical use. Furthermore, no methods or standard units were accepted universally to measure AGEs are existing. This review discusses AGEs formation, association with diseases and therapeutic agents to alleviate them.

Advanced Glycation End-Products and Their Receptors: Related Pathologies, Recent Therapeutic Strategies, and a Potential Model for Future Neurodegeneration Studies

Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction between sugars and proteins, lipids, or nucleic acids. AGEs are both consumed and endogenously formed; their accumulation is accelerated under hyperglycemic and oxidative stress conditions, and they are associated with the onset and complication of many diseases, such as cardiovascular diseases, diabetes, and Alzheimer's disease. AGEs exert their deleterious effects by either accumulating in the circulation and tissues or by receptor-mediated signal transduction. Several receptors bind AGEs: some are specific and contribute to clearance of AGEs, whereas others, like the RAGE receptor, are nonspecific, associated with inflammation and oxidative stress, and considered to be mediators of the aforementioned AGE-related diseases. Although several anti-AGE compounds have been studied, understanding the underlying mechanisms of RAGE and targeting it as a therapeutic strategy is becoming increasingly desirable. For achieving these goals efficiently and expeditiously, the C. elegans model has been suggested. This model is already used for studying several human diseases and, by expressing RAGE, could also be used to study RAGE-related pathways and pathologies to facilitate the development of novel therapeutic strategies.

Cellular Mechanisms and Consequences of Glycation in Atherosclerosis and Obesity

Post-translational modification of proteins imparts diversity to protein functions. The process of glycation represents a complex set of pathways that mediates advanced glycation endproduct (AGE) formation, detoxification, intracellular disposition, extracellular release, and induction of signal transduction. These processes modulate the response to hyperglycemia, obesity, aging, inflammation, and renal failure, in which AGE formation and accumulation is facilitated. It has been shown that endogenous anti-AGE protective mechanisms are thwarted in chronic disease, thereby amplifying accumulation and detrimental cellular actions of these species. Atop these considerations, receptor for advanced glycation endproducts (RAGE)-mediated pathways downregulate expression and activity of the key anti-AGE detoxification enzyme, glyoxalase-1 (GLO1), thereby setting in motion an interminable feed-forward loop in which AGE-mediated cellular perturbation is not readily extinguished. In this review, we consider recent work in the field highlighting roles for glycation in obesity and atherosclerosis and discuss emerging strategies to block the adverse consequences of AGEs.

Relationship between advanced glycation end-product accumulation and low skeletal muscle mass in Japanese men and women.

The present study aimed to investigate the relationship between advanced glycation end-product accumulation and skeletal muscle mass among middle-aged and older Japanese men and women. A total of 132 participants enrolled in this cross-sectional study. Skin autofluorescence was assessed as a measure of advanced glycation-end products. Participants were divided into two groups (low skeletal muscle index and normal skeletal muscle index) using the Asian Working Group for Sarcopenia's skeletal muscle index criteria for diagnosing sarcopenia.

Participants consisted of 70 men (mean age 57 ± 10 years) and 62 women (mean age 60 ± 11 years). There were 31 and 101 participants in the low and normal skeletal muscle index groups, respectively. Skin autofluorescence was significantly higher in the low skeletal muscle index group compared with the normal skeletal muscle index group. Skin autofluorescence was a significant independent factor associated with low skeletal muscle index based on multivariate logistic regression analysis.


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