From Irreversible to Repairable: Reversing AGEs

A new study published in the journal Nature Communications last week has me optimistic about reversing some of the detrimental effects of aging.

The study, titled “Reversal of protein chemical aging by enzymatic deglycation”, explains that the researchers created an enzyme to undo a previously irreversible hallmark of aging.

Background on AGEs:

Advanced glycation end products (AGEs) are compounds that naturally form in the body due to the glycation of proteins or fats. This is a process that is (or was) irreversible and causes the altered protein or fat molecules to be combined with a sugar or PUFA-derived molecule to form a new compound that is hard to break down or get rid of.

We are all actually really familiar with AGEs through our diet — the Maillard reaction that causes the browning of steak on a grill or bread crust in the oven is forming AGEs. This same Maillard reaction is going on in our bodies, just at a slower pace and lower temperature.

The problem with AGEs is that the altered proteins can trigger an inflammatory reaction in the body to get rid of the AGEs. The advanced glycation end products can bind receptors, called RAGEs, that then initiate inflammation.

AGEs can crosslink proteins like collagen, making it stiffer and less elastic. So tissues relying on collagen for elasticity, like blood vessels, skin, and the eye, become less flexible in aging. Yes - this means wrinkles, stiff and painful joints, and cataracts all trace back in part to AGEs.

New study:

In this new study, researchers figured out how to create an enzyme that will remove the unremovable advanced glycation end product called N^ε-carboxymethyl-lysine (CML). CML forms when reactive carbonyls modify lysine amino acids on proteins. Carbonyls are formed during lipid peroxidation and from the incomplete breakdown of glucose or fructose.

When carbonyls attach to a lysine side chain on a protein, it changes from a positive charge to a negatively charged carboxymethyl adduct. Essentially, it impairs the protein’s function. Proteins aren’t just shaped by the amino acid sequences, but also by the way that they fold. When the positive and negative charges get changed, the folding of the protein and its interaction with other ions is fundamentally different.

The researchers screened over 44,000 enzymes to find ones that theoretically should act on the CML bond. They found one from a bacterium called Calidithermus roseus, and then used multiple rounds of directed evolution to refine it into a highly active and very specific enzyme to remove CML - dubbed CMLase.

What can this CMLase do?

The researchers used human tissues from older individuals to test out the effects of CMLase.

• In human eye lenses, an overnight treatment of CMLase reduced the CML concentration by 78%.

• In artery tissue, the CML levels in 25-year-olds are negligible, but in 75-year-old arteries, there is a significant amount of CML (causing arteries to stiffen). Overnight incubation with CMLase reduced the 75-year-old artery CML levels by 70%.

• In elderly skin, CMLase turned the clock back to the same CML levels seen in 31-year-old skin sections.

What does this mean? CML is a fundamental part of what happens in aging - collagen crosslinking, less elasticity in the skin and blood vessels. Moreover, it is a major reason for increased inflammation in aging. Beyond the eyes, skin, and arteries, CML is a problem in cartilage in the joints, blood vessels and cortical neurons, kidneys, heart, lungs, and intestines. Yes - this touches on pretty much everything that goes wrong in aging (dementia, heart disease, lung diseases, gut problems, arthritis, and more).

Practically speaking, if someone sells an enzyme that can return my skin CML levels to those of a 30-year-old (collagen and elastin back to where they should be), then sign me up! Return my eye lenses to normal and turn back the clock 40+ years on artery stiffness… icing on the cake. This is a billion-dollar product and one that will fundamentally change how we age, if it comes to market.

Can diet alone help prevent AGEs?

When you read about AGEs and RAGEs and inflammation in aging, there is usually a section on how your poor diet is why you’re unhealthy and old. The narrative is that you eat too much sugar and grilled steak — sugar turns into AGEs in the body, and grilled meat contains AGEs that will be absorbed and age you.

While there is some truth there, it’s a question of how much food actually matters.

Eating a low glycemic diet and avoiding foods containing AGEs (e.g. grilled meats, grilled vegetables, foods fried in omega-6 oils, baked goods, anything cooked with high heat, etc.) makes a difference in the amount of AGEs that accumulate in the body. That said, studies show only a minor fraction (~10%) of dietary AGEs are absorbed, and then partly eliminated through the urine.

Studies on low AGEs diets show a modest effect on cardiometabolic parameters, such as lowering cholesterol a little and decreasing insulin resistance a bit. These randomized trials are reducing circulating CML levels by 10% or more. By comparison, the CMLase engineered enzyme was able to remove 70-80% of the accessible CML from eye lenses, arteries, and skin samples and restore the tissue to normal.

So while eating a low AGEs diet (low in sugar, meat cooked slowly over low heat, no toasted bread, crackers, or cookies) can help to slow the accumulation of AGEs a little bit, the ability to reverse the endogenous accumulation of AGEs with an enzyme is a whole different ball game. CMLase is a fundamentally different class of intervention, and the methods used to create CMLase can theoretically be used for engineering enzymes that can reverse other AGEs as well.

What do you think?
Drop a comment below to let me know if you think that CMLase is a potentially game-changing billion-dollar longevity drug. (Or if you’re a conspiracy-minded individual, let me know that this will never happen because the pharmaceutical-industrial complex will prevent it from coming to market and eliminate the need for statins, blood pressure medicines, arthritis medicines, and many other drugs used by millions for age-related conditions.)