Today, we want to highlight a new study that shows, for the first time, that established AGEs can be reversed via therapeutic intervention.

What are AGEs?

Advanced glycation end products (AGEs) are harmful compounds that are created when proteins or fats combine with sugars in the bloodstream in a process known as glycation. AGEs can also be encountered in foods, and foods that have been exposed to high temperatures, such as in grilling or frying, tend to be high in these compounds.

Thankfully, our bodies have ways to eliminate these harmful compounds, including antioxidants and enzymes; however, these mechanisms have their limits, and if we consume too many AGEs, or too many appear through the normal operation of metabolism, they can begin to accumulate, leading to oxidative stress and inflammation [1].

There are various types of AGEs, each with its own unique chemical composition; some of which that the body is able to remove and some that it cannot, as it lacks the biological tools needed to break them down. Both are a problem, and while the former can be somewhat controlled by diet and lifestyle, the latter is something that our bodies cannot deal with.







AGEs can cause random damage by altering protein structure and function, but the inflammation they cause is thought to be a primary contributor to smoldering, chronic age-related inflammation, which typically rises as we age. AGEs interact with the receptor for AGEs (RAGE), causing oxidative stress and the activation of protein complex NF-κB, a master regulator of inflammation, DNA transcription, and cell survival. This activation leads to excessive levels of NF-κB activity and is thought to be responsible for AGE-associated inflammation and cellular damage [2].

High levels of AGEs are linked to a number of age-related diseases, including diabetes, heart disease, and Alzheimer’s [3]. There is also evidence to support that people who have high blood sugar, such as people with diabetes, have a higher risk of producing more AGEs that can accumulate in the body faster than they can be cleared, thus contributing to the decline of multiple organs [4].

So, what is the solution?

It is beyond doubt that large amounts of AGEs are linked to the onset and progression of various metabolic and age-related diseases. However, it has been a challenge for researchers to prove that AGEs are the direct cause of disease, mostly due to the lack of tools needed to investigate and remove established AGEs from the body to see if their removal is a possible treatment.

Multiple researchers have attempted to develop therapies to prevent or slow down the rate of accumulation or to disrupt AGE intermediates before they become established AGEs. However, no researchers had developed a therapy that can break down or repair fully developed AGEs.







This has now changed due to a new study by researchers from the Spiegel Lab at Yale, which was financially supported by the SENS Research Foundation and others. The new study focuses on Nε -(carboxyethyl)lysine (CEL) and Nε -(carboxymethyl)lysine (CML), which are both lysine-derived AGEs.

The presence of CEL and CML are both linked to the progression of various diabetic complications and some neurodegenerative diseases, including Alzheimer’s in the case of CEL. CML is one of the most abundant AGEs found in the renal compartment and is linked to the loss of kidney function in chronic kidney disease.

In this publication, the research team describes an enzyme family known as MnmC that is able to cleave CEL AGE modifications and also CML to a lesser level. This means that it is able to reverse AGE modification and restore the original lysine structure as shown in vitro.

Abstract Advanced glycation end products (AGEs) are a heterogeneous group of molecules that emerge from the condensation of sugars and proteins via the Maillard reaction. Despite a significant number of studies showing strong associations between AGEs and the pathologies of aging-related illnesses, it has been a challenge to establish AGEs as causal agents primarily due to the lack of tools in reversing AGE modifications at the molecular level. Here, we show that MnmC, an enzyme involved in a bacterial tRNA-modification pathway, is capable of reversing the AGEs carboxyethyl-lysine (CEL) and carboxymethyl-lysine (CML) back to their native lysine structure. Combining structural homology analysis, site-directed mutagenesis, and protein domain dissection studies, we generated a variant of MnmC with improved catalytic properties against CEL in free amino acid form. We show that this enzyme variant is also active on a CEL-modified peptidomimetic and an AGE-containing peptide that has been established as an authentic ligand of the receptor for AGEs (RAGE). Our data demonstrate that MnmC variants are promising lead catalysts toward the development of AGE-reversal tools and a better understanding of AGE biology.

Conclusion

The discovery of enzymes that are capable of reversing these AGEs and restoring their original structure is a world first. This is the starting point towards developing new tools and therapies for the reversal of established mature AGEs in organs and tissues and potentially a step towards combating a number of age-related diseases.







CEL and CML are only two of multiple AGEs we need to tackle, but thanks to funding from SENS Research Foundation, the Spiegel lab at Yale has already identified a lead candidate for cleaving glucosepane, the most abundant AGE in the body. Work continues on synthesizing pentosinane, another common AGE; if this is successful, as it was for glucosepane, this will mean an on-demand source of pentosinane on which researchers can experiment and find enzymes that can break it down.

Literature

[1] Uribarri, J., Cai, W., Peppa, M., Goodman, S., Ferrucci, L., Striker, G., & Vlassara, H. (2007). Circulating glycotoxins and dietary advanced glycation endproducts: two links to inflammatory response, oxidative stress, and aging. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 62(4), 427-433.







[2] Xie, J., Méndez, J. D., Méndez-Valenzuela, V., & Aguilar-Hernández, M. M. (2013). Cellular signalling of the receptor for advanced glycation end products (RAGE). Cellular signalling, 25(11), 2185-2197.

[3] Singh, R., Barden, A., Mori, T., & Beilin, L. (2001). Advanced glycation end-products: a review. Diabetologia, 44(2), 129-146.

[4] Semba, R. D., Nicklett, E. J., & Ferrucci, L. (2010). Does accumulation of advanced glycation end products contribute to the aging phenotype?. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 65(9), 963-975.