Scientists Just Reversed a Form of Aging Once Thought Permanent
“This work establishes that damage to aging proteins previously thought to be irreversible can be repaired.” That’s the line from a new paper...
“This work establishes that damage to aging proteins previously thought to be irreversible can be repaired.”
That’s the line from a new paper published 3 days ago in Nature Communications.
Bold words.
But they’re backed by data showing—for the first time ever—that age-related protein damage can be reversed.
Now, there are caveats. We haven’t found the Fountain of Youth just yet. But I’d be lying if I said this paper didn’t bring us one jump closer.
So, let’s do like CMLase to Nε-carboxymethyl-lysine... and break this down. (That horribly nerdy joke—if it didn’t scare you away—will make sense in just a moment.)
First, though, I need to arm you with a little background.
And it starts with a simple question:
What Causes Aging?
The answer, of course, is many things.
But one of the foundational drivers of aging is damage to what’s known as the “extracellular matrix.” Think of it as the rebar in reinforced concrete—the scaffolding that holds your cells and tissues together so you don’t simply become a homogeneous blob.
The problem is that, over time, sugars attach to proteins within the extracellular matrix and begin to damage them.
You can think of it as a kind of biological rusting. And to be clear, these aren’t just passive biomarkers or innocent bystanders. They’re not merely correlated with aging—they actively drive it.
These modifications, known as “advanced glycation end products” (AGEs), activate several inflammatory pathways, including a receptor appropriately named RAGE. That signaling fuels chronic inflammation, creating a slippery slope toward aging.
This accumulated damage, produced by the normal metabolic processes that are almost impossible to avoid, leads to more oxidative stress, more mitochondrial dysfunction, and more inflammation, perpetuating a vicious cycle.
Organs age. They begin to fail. Eventually, we die.
Or, if you want another analogy:
Imagine your body is like a car. For years it runs beautifully. But every year, normal environmental conditions leave behind just a little more rust. At first, it’s cosmetic and doesn’t impact how your car runs. But then, the suspension weakens, the frame stiffens, and parts begin to fail, and the engine gradually conks out on you.
The rust doesn’t just tell you the car is old—it causes it to become old.
That’s what’s going on here, irreversible molecular rust.
Sugars slowly react with proteins throughout your body, permanently damaging the scaffolding that holds your tissues together.
And it’s worse that my car analogy suggests.
Because once that rust forms, it doesn’t just sit there. It sparks inflammation, oxidative stress, and mitochondrial dysfunction, accelerating even more damage.
So, here’s the main point and the big problem:
Once these advanced glycation end products form, they become embedded in our tissues. A slow poison. And they’ve long been thought to be irreversible.
Our bodies simply don’t have the molecular tools to remove them.
At least... not until now.
Building A First-of-its-Kind De-Rusting Protein
The researchers set out to build one—a molecular tool capable of de-rusting our organs, i.e. removing chemical modifications once thought to be permanent, modifications that are not only associated with aging but actually help drive it.
And if they can do that, it’s a big deal.
So, here’s exactly what they did, what they built... and what it means for you and me.
Among the many types of AGEs, one stands out as particularly abundant and particularly nasty: Nε-carboxymethyl-lysine, or CML for short.
If you want help remembering CML, just think “Cellular Marshmallowization Layer.”
It’s not what it stands for, but it’s pretty much what’s going on.
CML is formed when sugars react with a particular amino acid, lysine (the “L” in CML), which is one of the basic building blocks of proteins. In the process, the positively charged lysine gets converted into a negatively charged “carboxymethyl” (the “CM”) group.
That charge flip alone is enough to distort structure and disrupt function.
But CML doesn’t stop there.
CML is also the primary trigger for RAGE (4, above)—the receptor I mentioned earlier—which activates NF-κB, one of the master switches of inflammation in the body.
For example, in the brain, CML accumulation has been linked to oxidative stress and mitochondrial damage in microglia, the immune cells of the central nervous system.
So CML is both structurally destructive and a signaling molecule that perpetuates chronic inflammation. A double threat.
And here’s the kicker: CML has historically been categorized as “chemically stable and irreversible.”
Once the CML modification is locked onto a protein?
Game over.
No known biological tool could undo it.
Until the researchers in this paper engineered one.
Now, for my nerdy joke to land: “CMLase” is the name of the enzyme they built.
*Nuance note: If you want some scientist vocabulary insider knowledge, the suffix -ase refers enzymes that break down “X,” where “X” is the prefix. So “lactase” breaks down “lactose” sugar. And my late dog with my sock would be a “sockase.” You get the idea.
CMLase removes the CML off proteins and restores the original structure and function.
Hence: “Let’s do like CMLase to CML... and break this down.”
I told you it would make sense. Whether it’s actually funny is a separate conversation I’m choosing not to have.
Anyway, this is effectively a reversal of molecular rusting.
How They Built It: Engineering a Molecular De-Ruster
Now, I want to back-up and answer the question: “how did they build it?”
Because the method is as important as the ‘end product.’ (Another horrible nerd joke. Did you catch it?)
Observation: CML has a chemical structure that closely resembles the amino acid glycine. And there exists a well-known family of enzymes that chew up glycine.
So they asked: Could we take one of those enzymes and force it to evolve to chew up CML instead?
Think of it like this:
You have a key that opens Lock A (glycine).
You need a key that opens Lock B (CML).
Locks A and B look pretty similar—but not identical.
So instead of building a new key from scratch, you start with the key you have and file down the edges until it fits the new lock.
That’s essentially what they did. But the “filing” involved screening over 500 million enzyme variants across five rounds of what’s called “directed evolution.”
Directed evolution deserves a brief detour because it’s a brilliant method—and one that won its inventor, Frances Arnold, the Nobel Prize in Chemistry in 2018.
The concept is simple: mimic natural evolution, but in the lab, at warp speed.
You take an enzyme. You introduce random mutations into its DNA. You screen millions of variants for the ones that work best.
Then you take the winners, mutate them again, and repeat.
Each round selects for better and better performance.
In this case, the researchers started with an enzyme from a heat-loving bacterium called Calidithermus roseus (CrGO). The enzyme had a tiny, barely detectable ability to act on CML when it was attached to a protein fragment.
From that faint whisper of activity, they amplified it through directed evolution into a full-blown CML-cleaving machine.
The final enzyme—CMLase—specifically chews up CML and restores the “unrusted” proteins.
Critically, it doesn’t touch other amino acids. And it doesn’t destroy the protein it’s repairing.
It’s not a molecular wrecking ball. It doesn’t demolish the building—it just scrapes off the rust.
It’s a precision tool.
Which raises the only question that actually matters: Did it work?
Not in a test tube. Not in theory.
In real human tissue.
In the rest of this letter, StayCurious Metabolism Premium members we dive into:
The evidence from real human tissues—including lens proteins, arteries, and skin
An honest discussion of what’s most exciting about this research, what hurdles remain before it reaches the clinic.
High-yield strategies to reduce AGE formation that you can start using today.
If you’re ready to take your metabolic health education to the next level, I’d love to have you join the StayCurious Metabolism Premium community.
And unlike CML—if you don’t think you’re getting value—your subscription is completely reversible today. But based on community reviews and our retention rate, I think you’ll stick around.
