Advanced glycation endproducts (AGEs) are the result of nonenzymatic condensation reactions between sugars and proteins. AGEs accumulate in multiple tissues over the course of aging, and they have been implicated in a variety of age-related diseases. The data connecting them to aging isn’t terribly strong, in part because it’s hard to prevent them from forming and thereby observe aging and disease progression in their absence. Most of the evidence that they’re involved is circumstantial, derived from observations of diseases where they accumulate prematurely (e.g., diabetes, where the “sugar spikes” that result from impaired glucose homeostasis cause increased AGE formation).
A mechanistic understanding of the effect of AGE on tissues and cells, then, would go a long way toward boosting the argument that these compounds are causative in aging, rather than merely a harmless epiphenomenon. To that end, Molinari et al. studied the effect of AGEs on gene expression in fibroblasts (mesenchymal cells that provide support and structure to tissues throughout the body, especially the skin):
Effect of advanced glycation endproducts on gene expression profiles of human dermal fibroblasts
The Maillard reaction and its end products, AGE-s (Advanced Glycation End products) are rightly considered as one of the important mechanisms of post-translational tissue modifications with aging. We studied the effect of two AGE-products prepared by the glycation of lysozyme and of BSA, on the expression profile of a large number of genes potentially involved in the above mentioned effects of AGE-s. The two AGE-products were added to human skin fibroblasts and gene expression profiles investigated using microarrays. Among the large number of genes monitored the expression of 16 genes was modified by each AGE-preparations, half of them only by both of them. Out of these 16 genes, 12 were more strongly affected, again not all the same for both preparations. Both of them upregulated MMP and serpin-expression and downregulated some of the collagen-chain coding genes, as well as the cadherin- and fibronectin genes. The BSA-AGE preparation downregulated 10 of the 12 genes strongly affected, only the serpin-1 and MMP-9 genes were upregulated. The lysozyme-AGE preparation upregulated selectively the genes coding for acid phosphatase (ACP), integrin chain α5 (ITGA5) and thrombospondin (THBS) which were unaffected by the BSA-AGE preparation. It was shown previously that the lysozyme-AGE strongly increased the rate of proliferation and also cell death, much more than the BSA-AGE preparation. These differences between these two AGE-preparations tested suggest the possibility of different receptor-mediated transmission pathways activated by these two preparations. Most of the gene-expression modifications are in agreement with biological effects of Maillard products, especially interference with normal tissue structure and increased tissue destruction.
The authors exposed fibroblasts to two types of AGE-modified (AGE-ylated?) proteins, which had overlapping but non-identical effects on gene expression. The common features of the response to the two proteins are most intriguing, however: increased transcription of matrix metalloproteases (MMPs), which break down the extracellular matrix (ECM), and decreased transcription of ECM components like collagen and fibronectin. Taken together, these effects would result in a net weakening of the ECM, which in turn would have profoundly negative effects on organ function, ranging from skin wrinkling to cardiomyopathy.
On another note: increased MMPs and ECM breakdown are hallmarks of fibroblast senescence, which is usually associated with DNA damage or telomere shortening — could AGEs be stimulating premature senescence, either by damaging DNA or via some other pathway?