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Methionine (Met) is an essential amino acid for maintaining the growth and development of mammals. The level of dietary methionine intake has a wide range of effects on body functions. The fact that dietary methionine restriction can slow the aging process was first reported by the Orentreich group in 1993. The study found that reducing methionine in the diet can increase the lifespan of rats by 30% (Chen Qiuyue et al. 2021).
However, methionine restriction also has disadvantages. In youth, restricting methionine intake will affect fertility. The solution was first proposed by Duke University. The article "Separation of reproductive decline from lifespan extension during methionine restriction" published by Duke University in Nature pointed out that an effective way to solve the problem of methionine restriction affecting fertility is to take a larger dose of folic acid (5 times the standard dose) while restricting methionine intake. Folic acid supplementation not only avoids the decline in fertility, but also makes up for the poor effect of restricting methionine in late life to a certain extent.
However, here, we do not advocate self-implementation of methionine restriction. The reasons are: First, methionine restriction is very effective when implemented early in life. This refers to implementation from a young age. However, when it is implemented in middle age and old age, the impact on the body, especially in terms of prolonging life, basically has no great effect. Second, most of the people who come here to discuss life extension interventions have implemented calorie restriction themselves. In most cases, calorie restriction is beneficial for prolonging life. However, methionine restriction and calorie restriction are in conflict in terms of life extension. A 2020 paper from the University of California pointed out: There is a crosstalk between glucose sensing and the regulation of intracellular methionine: GR downregulates the transcription and translation of methionine biosynthetic enzymes and transporters, resulting in a decrease in intracellular methionine concentration; external supplementation of methionine offsets the life extension of GR. (Zou Ke et al. 2020? Life span extension by glucose restriction is abrogated by methionine supplementation: Cross-talk between glucose and methionine and implication of methionine as a key regulator of life span) This means that if you implement methionine restriction while experiencing calorie restriction, then your calorie restriction is equivalent to doing nothing. Moreover, if you are over 45 years old, methionine restriction may not have much effect. In terms of amino acid restriction, we recommend only isoleucine restriction. This is mainly within the scope of branched-chain amino acids, and no major crosstalk has been found.
Isoleucine is an amino acid in branched-chain amino acids. The so-called branched-chain amino acids are a general term for leucine, isoleucine and valine. These three amino acids account for 35% of human protein. In human metabolic synthesis, branched-chain amino acids are mainly completed through insulin release and growth hormone. Some studies call branched-chain amino acids, especially leucine and isoleucine, the cornerstones of human life. Whether this statement is exaggerated or not, it at least shows the key significance of leucine and isoleucine to life span.
Leucine and isoleucine have many differences in structure, in addition to the position of the methyl group. Isoleucine plays a very important role in the effect on life span.
In the mouse feeding experiment, the most obvious feeling of the researchers was that the low-isoleucine diet effectively promoted the metabolic health of mice by regulating glucose control and lipid metabolism, and the frailty was significantly improved, the body weight decreased significantly, the blood sugar homeostasis improved, and the liver's sensitivity to insulin and energy consumption increased. These easy-to-measure data show that isoleucine restriction can create an excellent living environment for living organisms.
From a molecular level, under normal body conditions, when isoleucine is sufficient, it promotes pancreatic development by promoting the proliferation of mouse pancreatic β cells through phosphorylation of S6K1 in the mTOR pathway, and promotes protease synthesis at the translation level (Hashimoto, Hara, 2003). This will lead to frequent diseases and a shortened life span. Our common asthma is caused by isoleucine phosphorylation of the downstream factor 4EBP1 of the mTOR pathway.
Isoleucine restriction is one of the necessary sites for humans to achieve a healthy body and prolong life.
There are several reasons why isoleucine restriction can prolong life;
Isoleucine restriction can inhibit the activity of mTORC1, and its downstream substrate SK6-1 also loses its activity, thus forming a pattern of life extension; in fact, a low-isoleucine diet can completely reverse the effects of aging on molecular markers related to the MAPK ERK and CIT pathways, and maintain interconnection with multiple life-span-affecting channels.
The speed of RNA polymerase II (Pol II) in the body increases with age. The higher the Pol II speed, the shorter the life span of the organism. Restricting energy intake will lead to a significant decrease in the speed of Pol II. At the same time, the low isoleucine environment promotes an increase in the levels of histones H3 and H4. The mechanism of HSF-1 to extend life span ends with the extension of life span through histone H4. Here, the increase in H3 and H4 levels will naturally increase life span.
When isoleucine is restricted, it will reduce global translation and improve translation accuracy by phosphorylating eIF2α. At the same time, activated eIF2α strengthens autophagy. All of these strongly support life extension. A careful analysis will find that in many cases, low isoleucine does not rely on mTOR to work, but operates in an independent routine.
There are many ways to limit isoleucine restriction. One is to limit the abundance of methionine in the human body by inhibiting intestinal bacterial isoleucine synthesis. This method uses β-glucan arabinogalactan, and there are also direct uses of probiotics and prebiotics; some small molecule drugs can also inhibit isoleucine synthesis, such as sodium-glucose cotransporter 2 inhibitors, thiazolidinediones and fibrates; there are also SGLT2 inhibitors, cholinesterase inhibitors, etc. However, due to the difficulty in obtaining them, fewer people use them. The most easily available and relatively easy to use are the common supplement capsules of berberine and the alcohol extract of Sargassum fusiformis. The paper by Mr. Wang Wenxiao and others (Research Progress on the Relationship between Branched-Chain Amino Acids and Cardiovascular Diseases and Intervention Measures) also mentioned that some people can successfully reduce isoleucine synthesis by taking black spade and loofah orally. It seems that inhibiting isoleucine levels is not a difficult thing.
We suggest that you only use berberine. Don't make the dosage too large.
https://www.nature.com/articles/s41467-023-43550-2 Early-adult methionine restriction reduces methionine sulfoxide and extends lifespan in Drosophila；
https://www.sciencedirect.com/science/article/pii/S216183132200309X#:~:text=Methionine%20restriction%20(MR)%20extends%20lifespans,(IGF%2DI)%20signaling. Methionine Restriction–Induced Longevity—A Possible Role for Inhibiting the Synthesis of Bacterial Quorum Sensing Molecules
https://www.nature.com/articles/s41598-022-08978-4 Metabolic benefits of methionine restriction in adult mice do not require functional methionine sulfoxide reductase A (MsrA)
https://www.pnas.org/doi/10.1073/pnas.2110387118 A genetic model of methionine restriction extends Drosophila health- and lifespan
https://www.science.org/doi/10.1126/sciadv.aba1306 Life span extension by glucose restriction is abrogated by methionine supplementation: Cross-talk between glucose and methionine and implication of methionine as a key regulator of life span
http://www.heartj.cn/cn/article/pdf/preview/10.12125/j.chj.202108095.pdf Research progress on the relationship between branched-chain amino acids and cardiovascular diseases and intervention measures
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(23)00374-1_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS1550413123003741%3Fshowall%3Dtrue Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice
https://www.sciencedirect.com/science/article/pii/S246850112100002X Regulation of healthspan and lifespan by dietary amino acids
https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2024.1393216/full Amino acid restriction,aging, and longevity
https://www.nature.com/articles/s43587-024-00744-7 Late-life protein or isoleucine restriction impacts physiological and molecular signatures of aging
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