Intermittent Methionine Restriction for Longevity
Most of the benefits without the drawbacks
A new study just came out that looked at intermittent methionine restriction, with some very interesting results in terms of longevity and healthspan.[ref]
Studies on longevity in animals have shown for decades that calorie restriction increases lifespan. More recently, researchers have looked at whether it is specific amino acids or overall calorie restriction that gives longevity benefits, with studies showing that restricting the amino acid methionine is likely the reason that calorie restriction works for longevity. Methionine restriction (MR) has been studied extensively in the context of longevity and aging. Numerous studies have shown that reducing methionine intake can increase lifespan and improve health markers in various animal models. For example, a methionine-restricted diet increased maximal lifespan by 45% in mice.[ref]
However, methionine restriction is hard — and there are a lot of tradeoffs and potential negatives to eating a methionine-restricted diet long-term.
Let’s dig into the background of methionine restriction research and then look at the results of this interesting new study!
What is methionine?
Methionine is an essential amino acid, meaning that it cannot be synthesized by the body and must be obtained through diet. It is important in a bunch of biological processes, including protein synthesis, methylation reactions, and the production of other important compounds like cysteine and glutathione.
When it comes to dietary methionine, most protein-rich foods contain methionine.
So a low-methionine diet is going to restrict meat, fish, dairy, eggs, soy, nuts, and beans. Essentially, it is a low-protein vegan diet, which brings to my mind concerns about muscle mass and frailty in aging.
(Let me state my biases up front here: I like meat and protein and consider them healthy to eat, so it is hard for me to wrap my head around the idea that methionine/protein restriction is good. I’m not trying to push any diet or political agenda on readers - instead, this is my attempt to understand the science here.)
What is methionine used for in the body?
Methionine is incorporated into proteins in the body (just like it is in protein-rich foods). It is also can be converted into cysteine, which is the precursor for glutathione, an important intracellular antioxidant.
For those two purposes, it makes no sense that methionine restriction would be beneficial for longevity… muscle mass and glutathione are pro-longevity. (However, methionine is also needed for protein synthesis in cancer, which we will come back to in a minute.)
Another important role of methionine in cells is as a precursor for S-adenosylmethionine (SAMe), which is used as a methyl donor. SAMe gives up a methyl group and becomes s-adenosylhomocysteine (SAH). The methyl groups are used in a bunch of important reactions, such as neurotransmitter production, converting serotonin to melatonin, detoxifying certain toxins, methylation of DNA, and more. SAH (s-adenosyl homocysteine) is converted to homocysteine. Homocysteine can then be re-methylated back to methionine, using a methyl group from folate/B12. Or, homocysteine can be converted into cysteine. Importantly, too much homocysteine is linked to cardiovascular disease, neurodegenerative diseases, and more.[article on homocysteine] The role of methionine in the methylation cycle makes sense as a key to longevity - or rather, avoiding the more common causes of death.
Let’s take a look at what the research shows.
Studies on methionine in the diet:
A 2019 study in animals looked at what happens with a diet high in methionine and low in folate and low in B6/B12. Essentially, this is going to add more methionine without the needed B vitamins to remethylate homocysteine back to methionine. The researchers fed the young mice the high methionine/low B vitamin diet for six weeks. They found that there was a significant decrease in short-term memory along with neuronal dysfunction and damage to the blood-brain barrier. The mice also developed vascular dysfunction. The authors of the study point out that a diet high in methionine (protein) and low in folate (low leafy greens) is pretty common. [ref]
In mice, a high-fat diet causes obesity and all kinds of negative effects. A study looked at mice on a normal diet, mice fed a high-fat diet that contained methionine, and mice fed a high-fat diet that was low in methionine (HF, MR). Restricting methionine in the high-fat diet group protected the mice against the normal damage to the brain from a high-fat diet. Essentially, methionine restriction preserved neuron function and stopped apoptosis of the neurons. The mechanism involves a long non-coding RNA (H19) that regulates neuron death in neurological diseases through modifying DNA methylation.[ref]
Glucose restriction can extend lifespan, but it is thought to depend on the downregulation of methionine pathways. Adding methionine alongside the glucose restriction negates the life extension benefits of glucose restriction. [ref]
What about in people? A study of older adults with mild cognitive impairment found that “ methionine intake was found to be positively associated with the increased risk of MCI”. The study went further to look at a mouse model of Alzheimer’s to see what methionine restriction would do. The results showed that methionine restriction reduced amyloid-beta, balanced redox status, and activated the CBS pathway.[ref]
A study of amino acid intake found that methionine (and alanine) intake correlates to higher blood pressure. The study included 92 people with blood pressure and food intake tracked for two years.[ref] (I’m not sure that the correlation here is causation - or perhaps it is a mix of methionine, B vitamin intake, and homocysteine levels…)
You may be thinking, as I was, that methionine restriction would cause a lack of cysteine for glutathione. However, there are a lot of studies showing that methionine restriction, at least partial methionine restriction, actually upregulates glutathione levels everywhere except for the liver.[ref]
What else is methionine restriction good for? Well, there are a bunch of studies on it for cancer treatment, especially in conjunction with chemo. Cancer cells need a lot of methionine to divide and proliferate.[ref] Acutely depleting methionine using a non-recombinant enzyme is an active area of clinical research in cancer patients.[ref]
The three big causes of death are heart disease, cancer, and neurodegenerative diseases. Methionine restriction hits all of those, so it makes sense that it would extend lifespan in animals (especially animals prone to cancer).
Why is intermittent methionine restriction a good idea?
The new study caught my eye because it makes sense to me that intermittently restricting methionine could provide benefits without the drawbacks of muscle loss or other nutrient deficiencies on a low-protein diet.[ref] I don’t want to live to old age just to be frail and have osteoporosis due to a long-term low-protein diet.
The study looked at the effect of intermittent methionine restriction compared to full methionine restriction in animals. The intermittent methionine-restricted diet was fed three days a week, followed by a standard methionine diet for the next four days. The study lasted for a year.
The results showed that the intermittent methionine restriction produced similar benefits to full methionine restriction in terms of changes to IGF-1, which is thought to be key in healthy longevity. IGF-1 reduction is thought to be key to the benefits of calorie restriction, intermittent fasting, the ketogenic diet, and protein restriction. Animals with reduced IGF-1 signaling are long-lived, and IGF1 variants in humans are linked to longevity. Additionally, the intermittent methionine restriction didn’t have as much of a negative impact on bone health and lean muscle loss. Essentially, it looks to have most of the longevity benefits with fewer drawbacks.
What would this look like in real life?
Essentially, a low-methionine diet three days a week would be a mainly vegan diet on those days. Meatless Monday (and Tuesday and Wednesday, but without the alliteration)…
One protein source that doesn’t contain much methionine is gelatin/collagen. So for someone wanting to include protein without methionine, collagen or gelatin plus fruits, vegetables, and low-protein grains would work. Animal fats, like butter or ghee, also won’t contain methionine. Think dinner at Grandma's with a Jello mold, lots of vegetables, but no roast beef. In fact, an argument could be made that our ancestors likely did intermittent methionine restriction fairly often when meat wasn’t constantly available.
What about intermittent fasting? Well, not eating would also be very low in methionine… The fasting-mimicking diet is also low in methionine and has been shown to help with neurodegenerative diseases in aging.[ref]
Are there any drawbacks to methionine restriction (other than bone and muscle health)? Research does show that long-term methionine restriction can bring the Epstein-Barr virus out of latency, likely through restricting the methylation of the viral replication genes. This is likely a tool that could be used when fighting cancers related to EBV, but I don’t know what it would mean for, say someone who has a compromised immune system.[ref] I also don’t know if there are other latent viruses that have their replication mechanisms methylated.
Concluding thoughts:
All in all, the studies on methionine restriction show that amino acids are important regulators of health in different ways. There’s more to longevity than just macronutrient ratios.
I would love to see longer-term studies on intermittent methionine restriction, especially in terms of cancer prevention. If three days a week of methionine restriction (or one week a month?) would significantly reduce cancer risk, then it would likely be worthwhile. All the studies that I found on methionine restriction for cancer prevention were in animals, and human studies would definitely be needed here to understand the timing and benefit.
I would also like to know if someone with low homocysteine and who carries an IGF1 variant linked to longevity would gain any benefit from an intermittent methionine-restricted diet... More questions than answers here!