The scent of fresh bread straight from the oven is intoxicating. As sugars and proteins react under heat, they create compounds that give golden-brown crusts their rich aroma. Called advanced glycation end products (AGEs), these molecules also form inside us. Our bodies are essentially ovens running at around 98 degrees Fahrenheit, and AGEs slowly build up over decades. They stiffen bouncy, elastic tissues and trigger lasting inflammation.
One of the hallmarks of aging, AGEs drive a range of age-related problems, increasing the risk of heart disease, diabetes, and eye and kidney troubles. In theory, clearing them out could turn back the clock. But previous attempts have failed, leading some scientists to suspect that the damage is irreversible. Once AGEs form, they stay.
Or maybe not.
A team at Revel Pharmaceuticals in San Francisco and colleagues took a new approach: They designed a synthetic version of an enzyme found inside microbes that targeted the most abundant type of AGE in several human tissues. In tissue from a 75-year-old donor, the enzyme reduced AGE levels to those seen in a 30-year-old, potentially giving the cells and their surrounding scaffold a chance to repair and rebuild.
“This work establishes that damage to aging proteins previously thought to be irreversible can be repaired,” wrote the team. Study author and 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.”
Rusting Away
AGEs are often nicknamed the body’s rust. They coat structural proteins, and like rust eating away at a car, gradually damage them. Scientists discovered AGEs in the 1980s and have sought ways to scrub them away ever since.
Most aging research has focused on keeping cells healthy. The scaffolding surrounding those cells has received far less attention, even though it makes up roughly 70 percent of the body. These structural materials are especially long-lived. It takes the body 15 years to replace half of its collagen, for example. That longevity comes with a price. The longer these proteins stick around, the more likely they’ll incur damage from accumulating AGEs. The result isn’t just loose skin, weakened tendons, and creaky joints. The heart, kidneys, brain, and eyes also suffer.
Scientists have developed drugs to intervene. Some are able to stop new AGEs from forming but fail to clear those already embedded in tissue or restore damaged proteins. Attempts to develop enzymes that could cut them apart have also been unsuccessful, largely because there aren’t obvious natural enzymes in the body to use as a starting point for protein engineering.
The authors of the new study looked outside the body, starting with an unusual idea. Human remains, including AGE-laden proteins, are eventually decomposed by microbes. The team reasoned these bugs may harbor enzymes that can be engineered to clean up the molecular debris while we’re still alive.
Needle in a Haystack
For the search, the team focused on CML, the most abundant type of AGE.
CML is both notoriously stubborn and detrimental to our health. It triggers cells to release inflammatory molecules that stiffen tissues and damage microglia, the brain’s immune cell guardians, contributing to cognitive decline during aging.
“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.
The team screened DNA sequences from over 50,000 microbes with AI and predicted the structures of the enzymes they encoded. They narrowed the candidates by looking for those capable of reaching CML buried within larger proteins like collagen. The winner came from a type of bacteria that thrives in geothermal hot springs.
The enzyme could cleave CML molecules, but barely. To boost its effectiveness, the team turned to directed evolution, a Nobel Prize-winning technique that mimics natural evolution at breakneck speed. After five evolutionary rounds and more than 500 million variants, they landed on CMLase, an engineered enzyme over 10 times more efficient than its ancestor.
To test its activity, the team created CML-laden versions of several proteins, including collagen, retinal proteins, and hemoglobin, which carries oxygen in blood. Initial test-tube experiments showed the enzyme worked as expected. It stripped away the chemical modification and restored the proteins’ original structures, as if they had never reacted with sugar. Think Rust-Oleum, but for damaged proteins.
But does it work in actual tissues?
Mice might seem like the obvious next test, but their short lifespans make them poor models for decades of accumulated molecular damage. Instead, the team tested CMLase on thin slices of donated human tissue.
In aortic tissue—the aorta is the body’s largest blood vessel—from a 75-year-old donor, the enzyme slashed CML by roughly 70 percent, bringing levels down to those seen in a 30-year-old. Skin and eye lens proteins from a 64-year-donor also showed significant reductions.
“We were pretty floored,” said Cravens.
Chemical reversal, however, isn’t the same as tissue rejuvenation. It’s still unknown if stripping away CML can actually restore tissue. But the finding challenges a decades-long assumption this kind of molecular damage can’t be treated. It also highlights long-ignored structural proteins as a crucial part of damage repair during aging, paving the way for new treatments.
An enzyme like CMLase could, in theory, be formulated as eye drops to clear CML from the lens or be used to plump up the skin’s protective barrier or restore hearts and kidneys. It would be especially valuable for people with type 2 Diabetes, who accumulate these compounds faster than usual.
Plenty of roadblocks remain. Safety is a concern. Because CMLase evolved from a bacterial protein, the body could label it foreign and launch immune attacks (especially with repeated doses). The body’s own enzymes could also break it down before it has a chance to work. And the enzymes will have to tunnel through a dense protective biological sheath that surrounds organs to reach their target. Work is underway to improve its activity, stability, and safety.
But the team is already looking beyond CMLase. Engineered enzymes could potentially erase other forms of molecular damage once considered permanent. CML is just one member of the AGE family. If the approach works, other targets could follow and one by one, they might chip away at the molecular scars of time.
