Calico and Revel scientists reverse age-related protein damage
Researchers from Calico and Revel Pharmaceuticals have engineered an enzyme that removes stubborn age-related damage from human tissue, marking a significant step for the longevity industry's quest to develop age-reversal therapies.
Scientists from Calico, Revel Pharmaceuticals, and the University of Colorado have developed an enzyme that removes a specific type of age-related protein damage previously considered irreversible. The study, published in Nature Communications, details how the engineered molecule successfully cleared decades of accumulated chemical modifications from human tissue samples.
The research targets an advanced glycation end product (AGE) known as CML. Over years or decades, sugars spontaneously attach to long-lived proteins like collagen, forming CML. This damage makes tissues stiffer and triggers inflammatory signaling, contributing to the chronic diseases that drive healthcare costs across Europe's ageing population. The human body has no natural mechanism to reverse this accumulation.
Removing CML has been one of the hardest problems in geroscience. The researchers initially searched databases like AlphaFold, screening over 44,000 candidate enzymes. They found that a bacterial glycine oxidase could process free CML, but its physical structure blocked access to CML embedded in proteins.
To solve this, the team weaponized evolution. They created massive libraries of mutated enzyme variants and introduced them into an E. coli strain that required lysine to survive. By feeding the bacteria CML, only the cells carrying successful enzyme variants could grow. Across five rounds of mutation, this process produced the final enzyme, named CMLase.
The results on human tissue were significant. CMLase reduced CML burden in an artery from a 64-year-old donor by 70% and in skin tissue by 55%. After treatment, the skin sample showed CML staining below the levels observed in tissue from a 31-year-old.
For the longevity industry, this represents a critical proof of concept that accumulated protein damage can be pharmacologically reversed, not just slowed. Calico and Revel Pharmaceuticals are now positioned at the forefront of this next phase of geroscience. However, translating this into a marketable therapy faces substantial hurdles.
The experiments were conducted on very thin tissue sections, meaning the enzyme's ability to penetrate living organs or intact skin remains unproven. Furthermore, the researchers did not perform functional rescue experiments to prove that the treated tissues actually worked better. An enzyme of bacterial origin also presents an untested risk of immunogenicity, a major barrier for clinical trials and regulatory approval.
CML is also a relatively straightforward target. The industry's next major challenge is tackling glucosepane, a complex AGE that physically crosslinks collagen molecules and severely restricts tissue elasticity. While CMLase does not solve that puzzle, it proves the underlying concept of enzymatic deglycation is viable.
