Engineered enzyme reverses protein damage linked to aging
Proteins that persist in the body for decades slowly accumulate sugar-linked damage. This damage has long been considered irreversible. A newly engineered enzyme may change that assumption.
The connective tissue surrounding cells contains proteins that can remain in the body for years or even decades. Collagen is the most familiar example. Over time, sugars spontaneously attach to these proteins in a process called glycation. Some of these attachments become chemically stable and are known as advanced glycation end products (AGEs). AGEs can stiffen tissue, alter protein structure, and activate receptors that trigger inflammation.
Searching for a molecular tool
The body has no natural mechanism to remove AGEs, making them one of the hardest problems in geroscience. The researchers, affiliated with Calico and Revel Pharmaceuticals, searched for an enzyme capable of removing a specific AGE called carboxymethyl-lysine (CML), which forms on the amino acid lysine.
They found that glycine oxidases from bacteria could act on CML chemically. However, initially none could process CML when it was embedded within a protein chain. A structural element of the enzyme physically blocked access. The team then searched databases of over 44,000 candidate enzymes for variants lacking that obstruction and found one with weak but detectable activity on peptide-bound CML.
Refined through directed engineering
Through targeted structural modifications to that enzyme, the researchers substantially improved its performance. The engineered enzyme could remove CML from protein chains and convert it back to normal lysine, producing two byproducts. These results were demonstrated under laboratory conditions using model peptides, not in living cells or tissues. Whether this works inside a living organism remains an open question.
Even so, the finding is scientifically notable. The study, published in Nature Communications, offers what may be the first proof that enzymatic removal of AGEs is possible in principle. From a longevity perspective, this is potentially significant: if AGEs contribute to tissue stiffening and chronic inflammation, reversing them could influence multiple aging processes simultaneously. That broader link, however, was not tested in this study.
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