Revel Pharmaceuticals co-founder chose enzymes to repair aging proteins over cell reprogramming, using differences between old and young tissue to identify repair targets
Revel Pharmaceuticals co-founder chose enzymes to repair aging proteins over cell reprogramming, using differences between old and young tissue to identify repair targets
On November 3, Aaron Cravens spoke on the Free Radicals podcast about how Revel selects damage to repair and why he sees delivery as a barrier to reprogramming, an attempt to restore cells to a youthful state.
Collagen and other proteins that form the structural framework of tissues last for decades. The cells around them are replaced, while the proteins remain and accumulate chemical damage. Cravens calls this damage rust and uses one question to decide what to remove:
“What is present in old tissue that is absent from young tissue? If something is present in old tissue and absent from young tissue, apart from wisdom, we want to get rid of it.”
This question reflects his hypothesis: removing all the damage that distinguishes an old organism from a young one should restore it to a youthful state.
He says Revel largely sets cell biology aside because it is too complex. The chemical structures of the damage are known, and the damage accumulates linearly with age, whereas senescent cells are also present in young organisms. Experience with senolytics, drugs that target senescent cells, provides another reason for caution: these cells may be needed for wound healing. In his view, reprogramming faces a delivery barrier. To rejuvenate all fibroblasts, the cells that produce collagen, the intervention would need to reach “more than 90 percent” of those cells, and DNA-based technologies are difficult to deliver.
Revel’s first target was carboxymethyllysine (CML), the amino acid lysine carrying an extra chemical group left by reactions with sugars and fats. He says CML accumulation has been known about for roughly forty years, and the team expected to succeed with this target within six years. He explains that CML blocks the lysine residues in collagen through which cells bind to it and causes inflammation: injecting products of this damage into the bloodstream of mice causes inflammation throughout the body. In humans, CML is associated with mortality. In an Italian study of 1013 people over 65, the third of participants with the highest plasma CML levels had 2,1 times the risk of dying from cardiovascular disease over six years compared with the remaining participants.
His theory is that damage causes regenerative capacity to decline with age: that capacity has “rusted in place.” As he describes it, proponents of reprogramming expect reprogrammed cells to restore this capacity.
Cravens chose enzymes, drawing on the treatment of lysosomal storage diseases. In these conditions, an enzyme that breaks down waste inside cells does not function, so waste accumulates, and patients are given the missing enzyme. The body has no enzymes to address damage that accumulates over decades. He argues that these enzymes never evolved because there was no need to live far beyond reproductive age.
On July 14, Revel described CMLase, an enzyme engineered from a bacterial enzyme, in a Nature Communications paper. It converted CML back into lysine. In donor tissue sections, staining for CML fell by more than 70% in the aorta of a 75-year-old and by more than 55% in the skin of a 74-year-old, reaching a level below that in the skin of a 31-year-old.
Cravens wants to use CMLase for diabetic retinopathy (a retinal disease; damage accumulates faster in diabetes), kidney disease and skin aging. He hopes to make it available for topical use “within a year.” Starting with CMLase, he wants to bring at least four to six drugs targeting different forms of damage to market. He also hopes they will work synergistically with reprogramming if someone finds an effective reprogramming cocktail.