Engineered enzyme erases a stubborn mark of aging by up to 70% in human tissue samples

A biotech company called Revel Pharmaceuticals is looking into ways to reverse aging, and the company's science team, along with researchers from the company Calico and the University of Colorado, may be a step closer to realizing the so-called fountain of youth. The team recently published their study in Nature Communications detailing how they engineered an enzyme capable of reversing a particular form of age-related damage and demonstrated its competence with test results.

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CML buildup, aging and inflammation

One common sign of aging in the cells of living organisms is a type of protein damage called N^ε-carboxymethyl-lysine (CML). CML is part of a group of harmful compounds aptly named "AGEs" (or advanced glycation and lipoxidation end products). Oddly enough, it is also part of the Maillard reaction, known for causing the browning in cooked food that creates rich, savory flavors, complex aromas and golden-brown crusts. In living organisms, CML builds up on long-lived proteins, like those in skin, blood vessels and the eye. This stiffens tissues and can fuel chronic inflammation through an immune-signaling receptor called "RAGE."

"The engagement of the CML-RAGE axis triggers a signaling cascade that activates NF-κB and stimulates the release of pro-inflammatory cytokines and profibrotic growth factors. In the context of the central nervous system, CML accumulation has been linked to oxidative stress and mitochondrial damage in microglia, further disrupting brain homeostasis during aging," the authors of the new study explain.

Until now, CML was widely considered an essentially irreversible protein modification. Previous approaches to dealing with CML mostly focused on preventing new damage, leaving aged individuals with high accumulations of CML without recourse. However, some drugs have been investigated to slow the formation of advanced glycation end products, and some research suggested that microbial enzymes might be able to act on free CML. Still, an enzyme that could efficiently repair CML attached to full proteins had not been found.

Directed evolution creates a CML-erasing enzyme

The researchers decided that if a CML-fighting enzyme could not be found, they could make one through a process called "directed evolution." They first searched for a microbial enzyme starting point and then used directed evolution to improve it through five rounds of engineering. They screened more than 500 million enzyme variants for the ability to process CML.

Then, the chosen enzyme, which they call CMLase, was tested on modified proteins, human lens proteins and preserved human skin and artery sections. Antibody-based tests and mass spectrometry were used to measure how much CML had been removed.

In laboratory-made damaged proteins, the CMLase enzyme reduced detectable CML by 52% and removed 97% when left to act overnight. The activity depended on the protein and the site. The team says that variation in the amount of CML removal between proteins was likely due to variability in the enzyme's accessibility to lysine side chains and local structural context. In proteins from a 64-year-old human eye, CMLase reduced total CML by 45% in one test, while CML was reduced by more than 70% in sections of elderly human arteries and by 55% in human skin tissues.

The study authors write, "The ability of CMLase to reduce CML burden by over 70% and 55% in elderly human arterial and skin tissue, respectively, demonstrates that the enzyme functions effectively in the heterogeneous and sterically complex environment of the aging human extracellular matrix (ECM)."

A promising start for future age-reversal therapies

For now, this study provides proof-of-concept results, not an anti-aging treatment ready for use in people. The concept needs further testing to determine whether the enzyme can safely enter living tissues and reach damaged proteins in dense extracellular structures, and whether CML removal actually reduces inflammation or improves tissue mechanics in living systems.

However, this study does represent a step forward into the uncharted territory of CML reversal. The team notes that similar strategies could potentially be adapted to other age-related protein damage marks. If shown safe and effective, a CML-removing enzyme might one day be developed to repair damaged skin, blood vessels or eye tissues.

The study authors write, "The successful engineering of CMLase suggests that other oxidative or hydrolytic enzymes could be evolved to target the chemically diverse landscape of age-related protein modifications. By reversing a hallmark of aging, CMLase provides a powerful tool for dissecting molecular causality and offers a foundation for developing regenerative therapies that repair damaged tissues."

Written for you by our author Krystal Kasal,edited by Lisa Lock, and fact-checked and reviewed by Robert Egan—thisarticle is the result of careful human work. We rely on readers like you to keep independent science journalism alive.If this reporting matters to you,please consider a donation (especially monthly).

More information: Narisa Trabosh et al, Reversal of protein chemical aging by enzymatic deglycation, Nature Communications (2026). DOI: 10.1038/s41467-026-75141-2

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