Enzyme Reverses Skin Aging — Full Breakdown & Transcript

[00:11] reverses decades of protein aging. Think about what happens when you toast a piece of bread. The soft, flexible dough turns brown, dry, and rigid. This isn't just a culinary trick. It is chemistry. It's called the Maillard

[00:25] reaction, a non-enzymatic bonding of sugars to proteins. This same browning process is happening slowly inside your body right now at normal body temperature over the course of decades. For generations, the biogerontologists

[00:40] this slow chemical aging of our longest-lived structural proteins, like the collagen in our skin, the elastin in our arteries, and the crystallins in our eye lens was considered an irreversible reaction. Once these sticky sugar

[00:54] compounds, known as advanced glycation end products, or AGEs, locked onto your tissues, they were deemed permanent. The body has no native enzymes capable of

[01:06] breaking down mature, stable AGEs, like carboxymethyl lysine, or CML. All existing longevity protocols could only hope to slow down the creation of new damage. But CML is not just a passive indicator

[01:22] of aging. It's a highly toxic molecular signal. It binds directly to the receptor for advanced glycation end products, known advanced glycation end products, known as RAGE, R A G E. This binding fires up

[01:34] a perpetual inflammatory signal through the NF-κB pathway, driving oxidative stress, mitochondrial decay, and systemic inflammaging. So, reversing CML isn't just about restoring tissue flexibility. It's about

[01:50] silencing a major biochemical engine of human aging. To tackle this supposedly irreversible damage, a team of researchers from Revah or Pharmaceuticals, Calico Life Sciences, and the University of Colorado

[02:04] Anschutz undertook an extraordinary molecular engineering campaign. Starting from a natural bacterial enzyme, they created a highly optimized variant, which they named CMLase, meaning an

[02:18] enzyme which breaks down CML. This enzyme was more than 10 times as efficient at breaking down the peptide bond in CML. To confirm that CMLase worked, first, they tested it in vitro on a

[02:32] standard model protein. Second, they tested it ex vivo on real human donor tissue, including water-soluble lens proteins from 64-year-old donors and

[02:44] preserved slices of human abdominal aorta and skin from donors ranging in age from 20 to 75. Each of these was run side by side with an inactive control enzyme to prove that any clearing of damage was due to

[02:59] precise CMLase catalysis, and not simple non-specific protein destruction. So, how does CMLase work? Its mechanism is through a process called oxidative deglycation, essentially using oxygen to snip the

[03:14] sticky sugars off the protein. It docks precisely with the carboxymethyl lysine modification, targeting the specific carbon-nitrogen bond that links the sugar-derived damage to the amino acid side chain.

[03:29] The enzyme cleaves this bond, consuming oxygen and producing a single molecule of hydrogen peroxide as a byproduct. Once reaction is complete, the native, undamaged, positively charged lysine residue is completely restored to its

[03:46] original youthful state. In their in vitro test, the enzyme successfully stripped away between 52% and 97% [clears throat] of CML modifications across all model

[03:59] To understand the exact depth of this repair, the team mapped 33 distinct CML modified sites on the standard protein. They found that CMLAs successfully

[04:12] cleared damage from 30 of the 33. Turning to ex vivo human cells, first they treated sections of an abdominal aorta taken from a 75-year-old human

[04:24] donor. After overnight incubation with CMLAs, they saw a greater than 70% reduction in CML damage compared to the inactive control. This represents a literal clearing of

[04:37] arterial stiffness pathways that have built up over three-quarters of a century. Next, they tested skin sections from a 75-year-old donor. The results here were even more striking. CMLAs reduced the

[04:50] even more striking. CMLAs reduced the CML burden by more than 55%. This single enzymatic treatment effectively dropped the chemical damage marker in 75-year-old skin to a level below the baseline found in their

[05:03] healthy 31-year-old control. Finally, the team applied CMLAs to water-soluble eye lens proteins from a 64-year-old donor. Lenses are notorious for accumulating irreversible glycation because their

[05:18] proteins are almost never turned over during your lifetime. Yet, they verified that CMLAs successfully reversed bulk CML modifications, restoring the clean chemical profile of the lens proteins. These experiments show that molecular

[05:33] damage previously deemed permanent is open to enzymatic repair. So, what are the practical takeaways? This paper is an historic proof-of-concept milestone, but there is no solution available today.

[05:47] We will almost certainly see CMLAs enter the market in localized applications first. Perhaps topical cosmetic skin treatments to reverse structural skin treatments to reverse structural skin aging or targeted ophthalmic eye drops

[06:00] to reverse lens stiffening in cataracts and improve vision. Systemic therapies like treating arterial stiffness or diabetic kidney damage are much further down the line. However, while we wait for biotech to

[06:14] catch up, we can use these findings to optimize our lifestyle protocols today. There are three powerful ways you can slow down and prevent this glycation now. First, minimize your intake of dietary

[06:30] or exogenous CML. Exogenous AGEs are formed in high quantities when sugars and proteins are cooked together using dry, high-heat methods like grilling, air frying, and charring.

[06:43] By switching to wet cooking methods like steaming, boiling, or poaching, or by using acidic marinades like lemon juice or vinegar, you can inhibit this or vinegar, you can inhibit this damaging chemistry by up to 50%.

[06:57] Second, keep your blood sugar tightly controlled. Endogenous glycation is directly driven by the concentration of glucose circulating in your blood. Keeping your post-meal glucose spikes low prevents the initial chemical bonds

[07:11] from ever forming. Third, support your body's natural precursor clearing systems. Your body has a built-in defense network primarily driven by an defense network primarily driven by an enzyme called glyoxalase 1 or GI1.

[07:26] This system neutralizes reactive sugar precursors before they can change lysine into CML. You can boost GI1 activity by consuming compounds like sulforaphane, which is highly concentrated in broccoli sprouts.

[07:41] As exciting as CMLAs is, there are critical caveats and translation challenges we have to discuss. There are, of course, multiple steps to go through to take this from testing in the lab to the clinic.

[07:54] On top of which, CML is only one element in cross-linking and fibrosis. We must understand the vital distinction between protein adduct and the structural cross-link. CML is a side chain, meaning it modifies

[08:09] a protein but does not physically tie two separate protein fibers together. Removing CML is an incredible victory for silencing rage-mediated inflammation and stopping cellular decay. However, CML is not a structural

[08:23] cross-link. The primary cross-link responsible for physical stiffness of aged arteries and tissue is a separate molecule called glucosapane. CMLase does not break down glucosapane.

[08:37] Therefore, while CMLase will likely quiet inflammaging, whether it actually restores youthful physical elasticity to stiff tissue remains to be proven in And finally, we must note that this research was funded and conducted in

[08:52] close collaboration with Revel Pharmaceuticals and Calico Life Life Sciences, Google's longevity venture. Both companies hold substantial intellectual property on these enzymes, meaning their commercial interests are

[09:06] heavily tied to these findings. This study is an historic victory that proves aging damage is not a one-way street. But we must watch the upcoming preclinical trials closely to see if

[09:19] this molecular lawnmower can truly perform its magic in living, breathing Thank you for your attention and I wish Thank you for your attention and I wish you all well.