Engineered Enzyme Reverses Decades of Molecular ’Rust’ in Human Tissue

The aroma of warm, freshly baked bread comes from sugars and proteins that react under heat, forming compounds that give crusts their golden hue. These same compounds—known as advanced glycation end products (AGEs)—also accumulate inside our bodies, which run at roughly 98 °F. Over decades, AGEs stiffen elastic tissues and fuel chronic inflammation.

AGEs are a classic marker of aging, linked to heightened risks of cardiovascular disease, diabetes, and damage to the eyes and kidneys. While scientists have imagined that removing these molecules could reset the biological clock, earlier attempts fell short, reinforcing the notion that once formed, AGEs are permanent.

New evidence suggests otherwise.

Scientists at Revel Pharmaceuticals in San Francisco, together with collaborators, created a synthetic version of a microbial enzyme that specifically targets the most prevalent AGE in human tissues. When applied to a sample from a 75‑year‑old donor, the enzyme cut AGE levels down to those typical of a 30‑year‑old, opening the possibility that damaged cells and their surrounding matrix could begin to heal.

“This work establishes that damage to aging proteins previously thought to be irreversible can be repaired,” the authors reported in Nature Communications. Revel CEO Aaron Cravens added in a press release: “More work is needed, but these results alter the starting assumption for how we think about this fundamental aspect of the aging process.”

Why AGEs Are Called the Body’s Rust

AGEs act like corrosion on structural proteins, gradually eroding their function much like rust on metal. Discovered in the 1980s, they have been a target for researchers seeking ways to cleanse them from the body.

Most anti‑aging strategies focus on preserving cellular health, yet the extracellular matrix—the scaffold that supports cells—makes up about 70 % of the body and turns over very slowly. For instance, it takes roughly 15 years for half of the collagen in the body to be replaced. The longer these proteins persist, the more vulnerable they become to AGE‑induced damage, which contributes to skin laxity, tendon weakness, joint stiffness, and organ decline.

Existing drugs can block the formation of new AGEs, but they do not eliminate those already embedded in tissue, nor do they reverse damage to the underlying proteins. Efforts to engineer enzymes capable of cutting AGEs have been hampered by the lack of natural human enzymes that serve as templates for redesign.

To overcome this gap, the research team turned to microbes—organisms that naturally break down AGE‑laden proteins after death. They hypothesized that such microbes might possess enzymes that could be repurposed to repair living tissue.

Finding a Molecular “Lawnmower”

The investigators zeroed in on N‑carboxymethyl‑lysine (CML), the most abundant AGE type. CML not only resists removal but also provokes inflammation, prompting cells to secrete factors that stiffen tissues and harm microglia, the brain’s immune cells, thereby accelerating cognitive decline.

“We believe you can remove [CML damage] enzymatically, by going in and developing these lawnmower enzymes that can just cut and clip these changes off of the proteins,” Cravens told The Scientist.

Using artificial intelligence, the team screened DNA from more than 50,000 microbial species and modeled the structures of the encoded enzymes. They filtered candidates for those capable of accessing CML hidden within large proteins such as collagen. The top hit originated from a bacterium that thrives in geothermal hot springs.

Although the initial enzyme could cleave CML, its activity was modest. The researchers applied directed evolution—a Nobel‑prize‑winning method that accelerates natural selection—to improve performance. After five rounds and over 500 million variants, they produced CMLase, an engineered enzyme more than ten times faster than its predecessor.

Laboratory tests with CML‑modified collagen, retinal proteins, and hemoglobin demonstrated that CMLase stripped the chemical adducts and restored the native protein conformations, effectively “repainting” the damaged molecules.

The critical question was whether the enzyme could act in real tissue.

Rather than rely on mice, whose short lifespans limit accumulation of decades‑old damage, the team applied CMLase to thin sections of human tissue donated for research. In aortic samples from a 75‑year‑old donor, CML levels dropped by roughly 70 %, reaching concentrations typical of a 30‑year‑old. Similar reductions were observed in skin and eye‑lens proteins from a 64‑year‑old donor.

“We were pretty floored,” Cravens said.

While chemical reversal does not automatically translate to functional rejuvenation, the results challenge the long‑standing belief that AGE‑related damage is immutable. They also draw attention to the extracellular matrix as a vital target for age‑related repair strategies.

Potential applications could include eye‑drop formulations to clear CML from the lens, topical treatments to reinforce skin integrity, or therapies aimed at restoring cardiovascular and renal function—particularly for individuals with type 2 diabetes, who accumulate AGEs more rapidly.

Several hurdles remain. Because CMLase derives from a bacterial protein, the immune system might recognize it as foreign and mount a response, especially with repeated dosing. Native enzymes could also degrade it before it reaches its targets, and the dense extracellular matrix poses a physical barrier to enzyme penetration. Ongoing work aims to enhance the enzyme’s stability, safety, and delivery efficiency.

Beyond CML, the platform could be adapted to target other AGE variants and forms of molecular damage once thought permanent. If successful, a suite of engineered enzymes might gradually erase the biochemical footprints of aging.