Revel Pharmaceuticals Publishes Nature Communications Study Demonstrating Enzyme That Reverses Age-Related Protein Damage
Revel Pharmaceuticals has announced the publication of new research in Nature Communications describing a breakthrough enzyme capable of reversing a long-recognized form of age-related protein damage. The study, conducted by scientists from Revel Pharmaceuticals in collaboration with researchers from Calico and the University of Colorado Anschutz Medical Campus, introduces CMLase, an engineered enzyme designed to remove Nε-carboxymethyl-lysine (CML), a chemically modified protein residue that accumulates in human tissues throughout life.
The findings represent a significant advance in aging research by demonstrating, under laboratory conditions, that a stable form of protein damage previously considered essentially irreversible can be substantially reduced without disrupting the underlying protein structure. According to the researchers, the work provides new evidence that certain molecular changes associated with aging may be amenable to targeted therapeutic intervention.
While the research remains in the experimental stage and further studies will be required to determine its clinical potential, the publication offers new insight into strategies aimed at repairing accumulated biological damage rather than simply slowing its formation.
Understanding Advanced Glycation End Products
One of the defining characteristics of biological aging is the gradual accumulation of molecular damage within cells and tissues. Among the many chemical modifications that occur over time are advanced glycation end products (AGEs), a diverse group of compounds formed when sugars react with proteins, lipids, or nucleic acids through a series of non-enzymatic chemical reactions.
These reactions occur naturally throughout life and become increasingly common with advancing age. Elevated AGE accumulation has also been associated with conditions such as diabetes, cardiovascular disease, kidney disease, and other age-related disorders.
One of the best-known AGEs is Nε-carboxymethyl-lysine (CML), which forms when sugars chemically modify lysine residues within proteins. Once created, CML can remain embedded within long-lived proteins for many years, gradually accumulating in tissues that undergo relatively slow turnover.
Researchers have long regarded CML as one of the molecular signatures of aging because of its persistence and widespread presence in human tissues.
The “Browning” Process Inside the Body
The chemical process responsible for AGE formation is similar to the familiar browning reaction observed during cooking.
When bread is toasted or foods are baked, sugars react with proteins to create new chemical compounds responsible for color, flavor, and aroma. This reaction, known as the Maillard reaction, also occurs inside the human body, although at a much slower pace.
Over decades, circulating sugars interact with structural proteins found in tissues such as skin, arteries, connective tissue, and blood vessels. These gradual chemical reactions produce AGEs including CML.
Unlike many other forms of cellular damage that can be repaired through natural biological mechanisms, CML has traditionally been viewed as highly stable and effectively permanent.
As a result, scientists have considered AGE accumulation to be one of the irreversible hallmarks of aging.
Engineering an Enzyme to Remove CML
The newly published study describes the development of CMLase, an engineered enzyme specifically designed to remove CML modifications from proteins.
To create the enzyme, the research team employed directed evolution, a powerful protein engineering technique that mimics natural evolution within the laboratory.
Rather than relying on naturally occurring enzymes, researchers generated and screened an enormous collection of enzyme variants to identify molecules capable of recognizing and repairing CML damage.
According to the study, the investigators evaluated more than 500 million enzyme variants during the optimization process.
The final enzyme was engineered using a bacterial glycine oxidase scaffold, which served as the starting framework for repeated cycles of mutation and selection.
Through successive rounds of engineering, researchers produced an enzyme capable of selectively targeting CML while preserving the overall integrity of the affected proteins.
Testing Human Tissue Samples
Following laboratory optimization, investigators evaluated CMLase using human tissue samples obtained from donors ranging in age from 20 to 75 years.
The researchers focused on tissues known to accumulate substantial AGE damage over time, including arterial tissue and skin.
The experimental findings demonstrated substantial reductions in CML following enzyme treatment.
Among arterial samples obtained from a 75-year-old donor, CMLase reduced CML levels by more than 70 percent.
Similarly, enzyme treatment reduced CML concentrations by more than 55 percent in aged human skin samples.
One particularly notable observation involved comparison with younger tissue.
Following treatment, CML concentrations in aged skin were reduced to levels below those typically observed in skin from a 31-year-old individual.
These results suggest that the enzyme was capable of removing a significant proportion of accumulated glycation damage from long-lived structural proteins.
Preserving Protein Integrity
A major challenge in repairing damaged proteins is avoiding disruption of their underlying biological function.
Many chemical treatments capable of modifying proteins can also alter their structure, potentially reducing stability or impairing normal biological activity.
According to the published study, CMLase successfully repaired the majority of CML modification sites across several model proteins while leaving the proteins themselves structurally intact.
This selectivity represents an important feature of the enzyme because therapeutic strategies designed to reverse age-related molecular damage must ideally restore normal protein function without introducing additional injury.
The researchers concluded that CMLase achieved both effective removal of CML and preservation of the surrounding protein architecture under laboratory conditions.
Challenging Long-Standing Assumptions About Aging
For decades, scientists have regarded CML accumulation as an unavoidable consequence of aging.
Since the 1980s, AGE damage has generally been considered largely irreversible because no biological mechanism capable of efficiently removing these stable chemical modifications had been identified.
Aaron Cravens, corresponding author of the study and Chief Executive Officer of Revel Pharmaceuticals, believes the new findings challenge that long-held assumption.
“This class of damage has been seen as a fixed part of aging since the 1980s,” Cravens said.
“What we’ve shown is that CML damage in human tissue can, in fact, be reversed under laboratory conditions. More work is needed, but these results alter the starting assumption for how we think about this fundamental aspect of the aging process.”
His comments emphasize that although the work remains preclinical, the research demonstrates the possibility that molecular aging processes previously considered permanent may eventually become amenable to therapeutic repair.
Collaboration Across Academic and Industry Research
The study represents a collaborative effort involving investigators from multiple scientific institutions.
Researchers from Revel Pharmaceuticals worked alongside scientists from Calico, a biotechnology company focused on aging research, as well as investigators from the University of Colorado Anschutz Medical Campus.
Combining expertise in protein engineering, molecular biology, enzymology, and aging research allowed the team to develop and validate the engineered enzyme using advanced laboratory techniques.
The publication in Nature Communications, a peer-reviewed scientific journal, provides broader visibility for the research within the biomedical community and allows independent scientists to evaluate the experimental findings.
Potential Implications for Healthy Aging Research
Although CMLase has not been tested as a therapeutic treatment in humans, the study highlights an emerging strategy in longevity science that focuses on repairing accumulated biological damage rather than simply slowing aging-related processes.
Much of current aging research seeks to delay the onset of age-associated diseases by targeting inflammation, cellular senescence, mitochondrial dysfunction, or metabolic pathways.
The approach described by Revel Pharmaceuticals instead seeks to directly eliminate molecular damage that has accumulated over decades.
If future research demonstrates that repairing AGE damage improves tissue function or delays age-related disease progression, enzymes such as CMLase could eventually contribute to therapies targeting cardiovascular disease, skin aging, connective tissue disorders, or other conditions associated with long-lived protein damage.
However, important questions remain regarding enzyme delivery, tissue penetration, long-term safety, durability of repair, and whether removal of CML alone produces measurable clinical benefits.
These questions will require extensive preclinical investigation followed by carefully designed human clinical trials before any therapeutic applications can be established.
The publication of the CMLase study represents an important scientific milestone in the field of aging biology. By engineering an enzyme capable of substantially reducing Nε-carboxymethyl-lysine, one of the most persistent advanced glycation end products, researchers have demonstrated that a form of molecular damage once considered irreversible can be repaired under laboratory conditions while preserving the underlying protein structure.
Although the findings are limited to experimental laboratory studies and should not be interpreted as evidence of clinical efficacy in humans, they open new avenues for investigating damage-repair approaches to healthy aging. As researchers continue exploring the biological mechanisms underlying age-related protein modifications, technologies such as directed evolution and engineered enzymes may play an increasingly important role in developing future interventions designed to restore tissue function and address the molecular consequences of aging.
About Revel Pharmaceuticals
Revel Pharmaceuticals is a biotechnology company developing engineered enzymes to reverse structural damage associated with aging. Using directed evolution, Revel’s platform aims to reverse accumulated crystals, as well as oxidative and glycation damage in aging tissues. The company’s research is supported in part by Small Business Innovation Research (SBIR) grants from the National Institutes of Health (NIH). Revel is Headquartered in San Francisco, California.