Bringing Methionine Restriction to the Masses — Is It Possible?

Methionine restriction (MR) has been known for decades to extend lifespan across multiple organisms, dating back to the seminal publication Low Methionine Ingestion by Rats Extends Life Span (N. Orentreich et al). Unlike other pro-longevity interventions—such as calorie restriction, intermittent fasting, or ketogenic diets—MR has yet to gain traction among health-conscious individuals. This is largely due to the overabundance of methionine in most dietary protein sources, making it nearly impossible to achieve the necessary low levels of methionine while still meeting basic protein requirements.

Over thirty years later, a recent review in Trends in Endocrinology and Metabolism outlines several promising innovations that might finally make methionine restriction a practical reality. The authors detail three emerging strategies—pharmacologic interventions, xenotopic approaches, and dietary modifications—to help induce a methionine-restricted state, characterized by reduced body mass, improved glucose and lipid metabolism, and lower circulating IGF-1 levels, in real-world settings.

Pharmacologic Approaches

Pharmaceuticals, the mainstay of modern medicine, can now be leveraged to target methionine metabolism directly. The authors highlight two enzymes of particular interest.

Methionine adenosyltransferase 2A (MAT2A) is central to the methylation process, whereby methionine is converted into S-adenosylmethionine (SAM)—the body’s universal methyl donor. Since methylation plays a crucial role in gene regulation, lowering SAM levels has the potential to mimic the effects of dietary MR. Much of the clinical work involving methionine restriction has been done in the context of cancer therapeutics. Many forms of cancer are methionine dependent, their cells having a unique metabolism requiring unusually high amounts of methionine compared to non-cancerous cells. This characteristic has been leveraged to facilitate the treatment of specific tumor types. Trials using MAT2A inhibitors to treat solid tumors and lymphomas have shown reductions in SAM levels by 54–70%, suggesting a potential route to lower available methionine and mimic MR pharmacologically.

The second enzyme involves protein synthesis and methionine’s unique role in this process. The initiating amino acid in all proteins the body creates is always methionine. After a newly synthesized protein is created, the initiating methionine is removed through the action of an enzyme known as methionine aminopeptidase 2 (MetAP2). Once removed, the methionine reenters the intracellular pool, making it available for other processes. Inhibiting MetAP2 would “lock-up” methionine in the protein and consequently lower availability, thereby mimicking a low-methionine state. In trials, MetAP2 inhibitors have so far been shown to induce weight loss and elevate levels of FGF-21 and adiponectin—hallmarks of the MR phenotype.

While both of these approaches are promising, more research is needed to fully understand their safety, efficacy, and long-term potential as MR mimetics.

Xenotopic Interventions

Another novel strategy involves borrowing molecular tools from other species—particularly bacteria.

Some bacteria express methionine gamma-lyase (MGL), an enzyme that breaks down methionine. Similar to the MAT2A and MetAP2 enzymes, MGL has been tested in human cancer trials. While effective at lowering methionine and shrinking tumors, immune responses against the bacterial protein have limited its therapeutic application. However, ongoing efforts are focusing on making the enzyme less immune responsive.

In a more synthetic biology–oriented approach, researchers have genetically engineered E. coli to express MGL in the gut in a probiotic fashion. The gut is home to an abundance of microorganisms, each type playing its own role in the overall nutritional and metabolic state of an organism. By expressing MGL in the gut, an immune response can be mitigated and methionine can be destroyed before ever entering the blood stream, subsequently limiting the available intracellular methionine. This engineered probiotic approach has been shown to significantly lower circulating methionine levels in mice and may represent a viable, low-cost method of mimicking dietary MR through microbiome manipulation.

Dietary Modifications

Directly altering dietary methionine intake remains the most intuitive—but most challenging—approach.

In rodent studies, MR is typically achieved using synthetic diets that provide not complete proteins, but individual amino acids—allowing for adequate provision of all essential amino acids except methionine. Unfortunately, these diets are highly unpalatable and unlikely to be adopted by humans on a long-term basis, even among individuals with metabolic disorders who require such regimens.

The review discusses two creative workarounds: methionine oxidation and intermittent dietary restriction.

In addition to methionine being the initiating amino acid in synthesized proteins, another characteristic that sets it apart from many other amino acids is it’s potential to be readily oxidized. Treating protein sources with oxidizing agents (e.g., hydrogen peroxide, ozone) can convert methionine to methionine sulfone—its biologically inactive form that can no longer be utilized by the body. Animal studies using oxidized protein diets successfully recapitulate the MR phenotype. However, this approach faces major hurdles: there are currently no high-throughput manufacturing methods for food treated in this way, and oxidation efficiency and taste vary widely by protein source.

While chemical oxidation offers a direct means of neutralizing dietary methionine, its practical limitations highlight the need for more user-friendly approaches. One such strategy gaining momentum involves not altering the methionine content of food itself, but instead manipulating the timing of its intake.

Intermittent diets have gained popularity in recent years due to their ease of adoption and efficacy. Both calorie restriction and the ketogenic diet have been shown to impart benefits when applied intermittently. Recent studies in mice have shown that restricting methionine for just three days per week can produce robust metabolic benefits, even in the context of an unhealthy diet high in fat. Moreover, the study finds that an intermittent methionine restricted diet provides advantages over chronic methionine restriction by reducing body fat while preserving muscle mass. These findings suggest that continual restriction may not be necessary—opening the door to more sustainable, flexible dietary regimens for humans.

Methionine restriction remains one of the most compelling, yet underutilized, dietary interventions in aging biology. But recent advances—spanning pharmaceuticals, engineered probiotics, and creative dietary strategies—suggest we may finally be on the cusp of bringing this intervention from the lab to the general public. Whether through a MAT2A inhibitor, a gut-resident enzyme, or simply a well-designed meal plan, the future of methionine modulation looks far more accessible than ever before.