Reversal of Two Advanced Glycation End Products Achieved


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

To do this, we need your support. Your charitable contribution tranforms into rejuvenation research, news, shows, and more. Will you help?

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-ΞΊB, a master regulator of inflammation, DNA transcription, and cell survival. This activation leads to excessive levels of NF-ΞΊB 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 NΞ΅ -(carboxyethyl)lysine (CEL) and NΞ΅ -(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.


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.


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.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. We are committed to responsible journalism, free from commercial or political influence, that allows you to make informed decisions about your future health.

All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future. You can support us by making a donation or in other ways at no cost to you.

NMN Reduces Systolic Blood Pressure in Clinical Trial

Combining human clinical trial research, cellular analysis, and mouse studies, researchers publishing in the Nature journal Signal Transduction and Targeted...

Rejuvenation Roundup September 2023

On some corners of the Internet, "Spooktober", effectively a month-long Halloween, has just begun. Here at Lifespan.io, though, we talk...

Longevity and DeSci Recap – September 2023

Welcome back to the latest edition of the Longevity and DeSci Recap. Here, you’ll discover the latest interviews, insights, and...

Study: Waist-to-Hip Ratio Predicts Mortality Better Than BMI

A new study suggests that waist-to-hip ratio (WHR) has a more linear correlation with all-cause mortality than either body mass...


[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., MΓ©ndez, J. D., MΓ©ndez-Valenzuela, V., & Aguilar-HernΓ‘ndez, 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.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
  1. Harold Katcher
    August 16, 2019

    Finding that an enzyme can cleave AGE products in a very artificial environment of a “peptomimetic” is not even close to cleaving the same product in a living cell or non-living matrix. full of complex carbs and associated proteins. So I wonder why it wasn’t tried on a more natural substrate? So, then the question becomes, why isn’t it the, AGEase, doing its job of cleaving these AGE-products to restore youthful conditions, the overall picture is a range of AGE products some of which are enzymatically malleable. Doesn’t sound like a workable approach.

    • August 17, 2019

      We will have to wait and see Harold.

  2. taz
    April 18, 2020

    Is any supplement available containing MnmC? Any thing that can be used/practiced/ingested in lieu of this

  3. timfrancis57
    November 1, 2021

    Linus Pauling was the first to hypothesize the ability of Lysine to be used to combat Glycation. The medical community ridiculed him. We now see his genius.

Write a comment:


Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.