Can Aging be Reversed? (my title)

I'm a cardiologist. For my entire career I've told patients arterial stiffness can only be slowed, never undone. I may have been wrong — and I'm glad.

Something recent was framed as a skincare story. It isn't. For the first time, scientists erased a form of damage considered permanent since the 1980s — in a human artery.

Sugar reacts with proteins the way heat browns bread, leaving CML (Nε-carboxymethyllysine), the most abundant advanced glycation end-product. It welds onto collagen and elastin in arteries, skin, and the eye lens. Arteries stiffen. CML binds RAGE (receptor for advanced glycation end-products), fueling chronic inflammation that drives cardiovascular disease. The body has no enzyme to remove it. All prior approaches only slowed new damage.

Scientists recently engineered CMLase — an enzyme that does not exist in nature — by screening 45,000 structures and evolving over 500 million variants. Applied to a 75-year-old donor aorta, it removed over 70% of the CML, restoring levels seen in a 30-year-old artery. It cleared over 55% from elderly skin (below 31-year-old levels) and 45-78% from lens proteins. The work was published in Nature Communications by Revel Pharmaceuticals with Calico and the University of Colorado.

Arterial stiffness drives systolic hypertension, heart failure with preserved ejection fraction, kidney disease, and stroke. I have no drug that reverses it. This paper suggests it may be possible.

Caveats: the enzyme work was done on donated tissue in a dish, with no functional elasticity data. Delivering a large enzyme into living tissue remains unsolved; trials are years away. Senolytic data is largely preclinical. No one should self-experiment.

Aging is largely an accumulation problem on permanent proteins — collagen, elastin, crystallins — that are never recycled. Someone has now shown one category of that damage can be erased.

We spent a century learning to slow the clock. Someone just handed us the first tool that might turn it back.

NOTE: The above is a Grok condensation Dr. Emrani's original post on X. He is rather wordy.

Here is the paper he cites:

Reversal of protein chemical aging by enzymatic deglycation.” Nature Communications
By Trabosh N, et al.
DOI: 10.1038/s41467-026-75141-2.

Abstract

The accumulation of advanced glycation end products (AGEs) in long-lived proteins is a hallmark of mammalian aging and implicated as a driver of metabolic dysfunction. Among these adducts, Nε-carboxymethyl-lysine (CML) is particularly abundant in aging tissues, where it modifies proteins and acts as a ligand for the receptor for advanced glycation end products (RAGE), thereby perpetuating chronic inflammation and oxidative stress. While endogenous detoxification systems exist for reactive precursors, the stable CML adduct has historically been considered irreversible.

Here, we report the development of CMLase - an enzyme engineered through the directed evolution of over 500 million variants to specifically oxidize CML and restore the native lysine residue. We demonstrate that CMLase effectively reverses CML modifications in model proteins in vitro and in human tissue samples from elderly donors, providing proof-of-concept that protein damage previously deemed irreversible is amenable to enzymatic repair. Collectively, our approach establishes a platform for developing enzymes to reverse age-related molecular damage and ultimately repair tissue proteins compromised by aging and disease.

Introduction

A defining feature of mammalian aging is the persistent accumulation of chemical damage on proteins of the extracellular matrix (ECM). Advanced glycation and lipoxidation end products (AGEs), formed by the nonenzymatic reaction of sugar- and lipid-derived reactive carbonyls with amino acids, stand out for their abundance and pathogenic effects. Substantial evidence indicates that these abundant adducts are not merely passive biomarkers but active mediators of age-related morbidities. For example, AGE accumulation contributes to the stiffening and loss of elasticity observed in aging tissues by crosslinking collagen and inhibiting normal protein turnover. Moreover, AGEs promote chronic inflammation by acting as neoepitopes that engage the adaptive immune system and by activating the innate immune system via the Receptor for Advanced Glycation End Products (RAGE).

Among the heterogeneous group of AGEs, Nε-carboxymethyl-lysine (CML) has emerged as a critical, chemically stable adduct found abundantly in long-lived proteins during aging. Beyond structural compromise, driven by the conversion of cationic lysine residues to anionic carboxymethyl adducts, CML exerts deleterious effects through cellular signaling, serving as a specific ligand for RAGE. The engagement of the CML-RAGE axis triggers a signaling cascade that activates NF-κB and stimulates the release of pro-inflammatory cytokines and profibrotic growth factors. In the context of the central nervous system, CML accumulation has been linked to oxidative stress and mitochondrial damage in microglia, further disrupting brain homeostasis during aging. Despite the association between CML accumulation and tissue dysfunction, therapeutic strategies to reverse this modification remain elusive.

A long-standing goal in the fields of diabetes, vascular biology, and aging has been to slow or reverse the accumulation of AGEs in the body. Endogenous detoxification networks, such as the glyoxalase system (Glo1), exist to scavenge reactive dicarbonyl precursors like methylglyoxal, but they do not reverse stable AGE adducts once formed on proteins. Pharmacological interventions, such as aminoguanidine and alagebrium, have demonstrated the ability to inhibit formation by trapping or breaking up reactive intermediates. While this strategy can reduce the formation of new AGEs, it does not address the substantial pool of pre-existing AGEs that have accumulated over decades and these approaches do not restore the native protein structure.

Here we describe the development of CMLase, an enzyme engineered to specifically reverse CML modifications formed on protein substrates. Through computational screening and directed evolution, we engineered glycine oxidase to oxidize CML and restore the native lysine. We show that CMLase reverses CML modifications on model proteins as well as in aged human tissues known to accumulate substantial AGE burden. This work establishes that damage to aging proteins previously thought to be irreversible can be enzymatically repaired, providing a foundation for developing interventions that target the molecular underpinnings of human aging.

"In the not distant future the tools will be available to reverse aging."

Yes, that's exactly what this research is all about.

Adducts are stable covalent chemical attachments formed when reactive molecules permanently bond to proteins (especially lysine residues). In aging, the most relevant adducts are advanced glycation end-products (AGEs) and advanced lipoxidation end-products (ALEs).These form non-enzymatically when sugar-derived or lipid-derived reactive carbonyls react with proteins.

Excess sugar (especially chronic high blood glucose) drives the glycation pathway; oxidized or high-heat-cooked fats drive the lipoxidation pathway. Both produce the same class of damaging adducts (e.g., CML, the most abundant AGE in aging tissue).

Once attached, these adducts accumulate on long-lived structural proteins such as collagen and elastin in arteries, skin, and the eye lens. Consequences include tissue stiffening and binding to the RAGE receptor, which fuels chronic inflammation—the core driver of much cardiovascular and age-related damage.

The body has no effective enzyme to remove the stable ones, so they build up over a lifetime. In short: sugar and certain fats accelerate the formation of irreversible protein adducts that chemically “age” tissues by stiffening them and promoting inflammation.

Sounds like a good regimen. How's your weight? Sodium intake? Sleep? Visceral fat? I'm guessing you must be pretty lean with the intermittent fasting and strong workouts.

I'm six years older than you and lost 35 pounds the past year (now at 165) by eliminating sugar, cutting out almost all alcohol, greatly reducing carbs, ramping up exercise (lots of hiking, mostly below 3,000 ft elevation, but lots of hill work with 20 pound pack), and focusing on a very "clean" diet with no processed foods and minimal restaurant food (horribly high in sodium). I am on three low-dose BP meds (down from four) that have three different complementary modes: losartan, chlorthalidone, amlodipine. My BP runs in high 120s - low 130s.

There are lots of approaches to dealing with treatment resistant hypertension. Have you talked to your doc or cardiologist about what to do? I find AI systems to be very helpful for education and figuring out what to talk to the docs about.

Here's what Grok says about treatment-resistant hypertension (I'm not a doc and neither is Grok -- thoughts about how to proceed only):

Treatment-Resistant Hypertension Overview

This is general information based on current guidelines including the 2025 AHA/ACC guideline and recent reviews. It is not personalized medical advice. Always work with a physician or hypertension specialist, as management must account for individual factors like kidney function, electrolytes, comorbidities, and medication tolerance.

Definition

Resistant hypertension is blood pressure that remains above goal (typically ≥130/80 mm Hg in U.S. guidelines or ≥140/90 mm Hg in European ones) despite concurrent use of at least three antihypertensive medications from different classes at maximally tolerated doses, including a diuretic. It also includes cases controlled only with four or more agents. True resistant hypertension is diagnosed only after excluding “pseudoresistance.”

Step 1: Confirm True Resistance and Exclude Pseudoresistance

Ensure accurate blood pressure measurement technique.
Use out-of-office monitoring (home BP or 24-hour ambulatory BP monitoring) to rule out white-coat effect.
Assess and improve medication adherence (common issue; single-pill combinations help).
Review and discontinue or minimize substances that raise BP: NSAIDs, certain antidepressants (e.g., SNRIs), decongestants, oral contraceptives, stimulants, excessive alcohol, illicit drugs (e.g., cocaine), high-sodium antacids, or licorice.
Screen for secondary causes (more common in resistant cases), especially: primary aldosteronism (screen all patients with resistant hypertension, even without low potassium, per 2025 AHA/ACC guidance); obstructive sleep apnea (treat with CPAP if confirmed); chronic kidney disease, renovascular disease, pheochromocytoma, Cushing’s, coarctation, or thyroid disorders.

A more detailed evaluation for secondary causes and interfering medications is recommended.

Step 2: Lifestyle Modifications (Essential Foundation)

These can produce meaningful BP reductions:

Restrict sodium to <1,500 mg/day.
Weight loss if overweight/obese.
Aerobic exercise ≥150 minutes/week of moderate intensity plus resistance training ≥2 days/week.
Limit or avoid alcohol.
Follow a DASH-style diet rich in fruits, vegetables, and potassium (if kidney function allows).
Address sleep apnea and optimize sleep.

Step 3: Optimize Pharmacologic Therapy

Preferred initial triple therapy (at maximally tolerated doses, preferably as single-pill combinations for better adherence):

Renin-angiotensin system blocker (ACE inhibitor or ARB)
Long-acting dihydropyridine calcium channel blocker
Thiazide-like diuretic (prefer chlorthalidone or indapamide over hydrochlorothiazide for greater efficacy; switch if currently on HCTZ). Use a loop diuretic if eGFR is significantly reduced (e.g., <30 mL/min/1.73 m²) or volume overload is present.

Fourth-line agent (strongest evidence): Add a mineralocorticoid receptor antagonist (MRA), preferably spironolactone 25–50 mg daily, if eGFR ≥45 mL/min/1.73 m² and serum potassium ≤4.5 mmol/L. This typically lowers office systolic BP by ~8–13 mm Hg and ambulatory SBP by ~8 mm Hg more than placebo or alternatives like doxazosin or beta-blockers (supported by PATHWAY-2 and meta-analyses). Alternatives if spironolactone is not tolerated (e.g., gynecomastia, hyperkalemia):

Eplerenone
Amiloride (10–20 mg)
Beta-blocker, alpha-blocker (e.g., doxazosin), central agent (e.g., clonidine), or other agents not already in use
Direct vasodilators (hydralazine or minoxidil) later in the sequence, usually with a beta-blocker and diuretic to counter reflex effects

Monitor electrolytes and kidney function closely when adding an MRA or intensifying diuretics. Newer option: Aprocitentan (Tryvio), a dual endothelin receptor antagonist approved by the FDA in 2024 for use in combination with other antihypertensives in adults with inadequately controlled hypertension. It provides modest additional BP lowering (roughly 4–6 mm Hg ambulatory SBP) via a novel pathway.

Step 4: Device-Based and Specialist Options

Renal denervation (catheter-based disruption of renal sympathetic nerves) may be considered in carefully selected patients with confirmed resistant hypertension after optimal medical therapy (or intolerance), following multidisciplinary evaluation. It produces modest average reductions (~4–7 mm Hg ambulatory SBP) with variable individual response. It is not first-line.
Refer to a hypertension specialist or multidisciplinary team if BP remains uncontrolled, secondary causes are suspected, or complex issues (e.g., advanced CKD) are present.

Monitoring and Prognosis

Patients with resistant hypertension have higher cardiovascular risk. Regular follow-up with home or ambulatory BP checks, lab monitoring, and adherence support is critical. Many cases can be controlled with systematic optimization. Work closely with your healthcare provider to tailor this approach—do not adjust medications on your own. Early specialist input improves outcomes.

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