Literature Review

1) In this Nature paper, the authors engineered an enzyme capable of converting Nε-carboxymethyllysine (CML), a common advanced glycation end product (AGE), back into its native amino acid, lysine. Rather than relying on the body to degrade and replace damaged proteins, this approach directly repairs a key form of age-related protein damage. "AGE accumulation contributes to the stiffening and loss of elasticity observed in aging tissues by crosslinking collagen and inhibiting normal protein turnover. Moreover, AGEs promote chronic inflammation by acting as neoepitopes that engage the adaptive immune system and by activating the innate immune system via the Receptor for Advanced Glycation End Products (RAGE)" (Trabosh et. al. 2026)

CML is more than a marker of aging; it is a biologically active AGE that activates the receptor for advanced glycation end products (RAGE), amplifying oxidative stress, NF-κB signaling, and chronic inflammation. Because CML accumulates on long-lived extracellular matrix proteins such as collagen and elastin, persistent RAGE activation may contribute to tissue stiffness, impaired repair, and immune dysregulation with aging.

If this enzymatic repair strategy can be translated successfully in vivo, in humans, a critical question that remains unanswered, it has the potential to reduce age-related immune activation by removing one of the major inflammatory triggers embedded within the extracellular matrix. Rather than simply slowing damage, it represents the possibility of repairing a fundamental molecular hallmark of aging.

They did test on human tissue: "We then sought to test the ability of CMLase to reverse endogenously formed CML modifications. CML accumulation occurs predominantly in long-lived organisms making short-lived animal models ill-suited for studying the buildup of this AGE. We therefore tested CMLase directly on human tissues where CML has had decades to accumulate. Here, we show that CMLase reverses the majority of endogenously produced CML modifications in human lens, skin, and arterial tissue."

This work is an extraordinary advance in the emerging field of rejuvenation biology. While much remains to be proven in living organisms, it opens the door to a new therapeutic paradigm: reversing extracellular matrix aging by repairing glycated proteins and interrupting chronic RAGE-driven inflammation at its source. If we can get a grip on this in vivo, we may be able to intervene very early in the aging process, in kids!

Abstract: "The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, Nε-carboxymethyl-lysine (CML) is particularly abundant in aging tissues, where it modifies proteins and acts as a ligand for the receptor for advanced glycation end products (RAGE), thereby perpetuating chronic inflammation and oxidative stress. While endogenous detoxification systems exist for reactive precursors, the stable CML adduct has historically been considered irreversible. Here, we report the development of CMLase - an enzyme engineered through the directed evolution of over 500 million variants to specifically oxidize CML and restore the native lysine residue. We demonstrate that CMLase effectively reverses CML modifications in model proteins in vitro and in human tissue samples from elderly donors, providing proof-of-concept that protein damage previously deemed irreversible is amenable to enzymatic repair. Collectively, our approach establishes a platform for developing enzymes to reverse age-related molecular damage and ultimately repair tissue proteins compromised by aging and disease." (Trabosh et. al. 2026)

Dr. M

Trabosh Nature

Hernandez Bellido Nature