Glycine Supplementation as a Methionine Restriction Mimetic
Supplementation with the non-essential amino acid glycine has been shown to modestly slow aging in short-lived laboratory species. In today's open access review paper, researchers note glycine supplementation as essentially a calorie restriction mimetic approach that works primarily through effects on methionine sensing. Much of the broadly beneficial metabolic response to lowered calorie intake occurs because cells react to low levels of the essential amino acid methionine in ways that increase efficiency of protein production and reuse of materials. For example, this increases the activity of cellular housekeeping activities such as autophagy. More housekeeping means better functioning cells and tissues, and kept up over the long term this has the desirable outcome of lengthening healthy life span.
Unfortunately we know that while short-term benefits to health metrics achieved via this sort of approach are much the same in mice versus humans, and thus some form of calorie restriction seems a sensible health practice, long-term effects on life span are much smaller in long-lived species. It remains to be understood as to exactly why this is the case, but from an evolutionary perspective one might argue that many of the metabolic changes taking place in response to calorie restriction in a short-lived mammals are already permanently turned on in a long-lived mammal in order to enable individuals of that species to be long-lived in the first place.
Glycine and aging: Evidence and mechanisms
The restriction of calories, branched-chain amino acids, and methionine have all been shown to extend lifespan in model organisms. Recently, glycine was shown to significantly boost longevity in genetically heterogenous mice. This simple amino acid similarly extends lifespan in rats and improves health in mammalian models of age-related disease. While compelling data indicate that glycine is a pro-longevity molecule, divergent mechanisms may underlie its effects on aging.
Glycine is abundant in collagen, a building block for glutathione, a precursor to creatine, and an acceptor for the enzyme Glycine N-methyltransferase (GNMT). A review of the literature strongly implicates GNMT, which clears methionine from the body by taking a methyl group from S-adenosyl-L-methionine and methylating glycine to form sarcosine. In flies, Gnmt is required for reduced insulin/insulin-like growth factor 1 signaling and caloric restriction to fully extend lifespan. The geroprotector spermidine requires Gnmt to upregulate autophagy genes and boost longevity. Moreover, the overexpression of Gnmt is sufficient to extend lifespan and reduce methionine levels. Sarcosine, also known as methylglycine, declines with age in multiple species and is capable of inducing autophagy both in vitro and in vivo.
Taken all together, existing evidence suggests that glycine prolongs life by mimicking methionine restriction and activating autophagy. In this review, we provide a detailed overview of the current evidence that glycine is a pro-longevity molecule, a so-called geroprotector. By exploring and synthesizing available data, we also offer a tentative mechanistic explanation for how this simple amino acid may target biological aging and prolong life.
OT: progress against dementia:
https://www.dailymail.co.uk/health/article-11973457/MIT-scientists-new-way-reverse-Alzheimers-trial-participant-dies-previous-drug.html
Erasmus, interesting. Can we identify the peptide? Can we research a natural specific CDK15 inhibitor to use now?
CDK inhibitors including natural ones are being studied for cancer but there are quite a few of them.
There are clinical trials targeting CDKIs in cancer therapy. Most of them target several CDK types. Selective CDK inhibitors should be superior to their nonselective counterparts since fewer adverse and toxic effects have been observed for the selective ones
I have asked this question many times, but no one has been able to give me a really good answer. Does Betaine/TMG/ Trimethyl Glycine also act as a a Methionine Restriction Mimetic? I thought that TMG might cause homocysteine to convert to Methionine, thereby increasing blood levels of Methionine? Would TMG cause an increase in Methionine and do the opposite of a Methionine restriction mimetic?
Hi Brad! Just a 2 cents.
You are not that off, about your answer to your question....quite close, actually;
Betaine, TMG/Trimethylglycine, Choline, methylcobalamin, cyanocobalamin...are methyl donors in general...
Methionine is rather 2-faced....I mean, that, Methionine is selected against...in animals like mouse; because, it has, as protein residue, a substantial 'oxidizing, glycating, aggregating' capability; i.e. it's More Vulnerable, unstable, volatile... and it is why, there is pressure on that one and the system Selectively tries to reduce that one amino acid in proteins (instead of others).
Methionine restriction makes sense...but it also 2-faced....
Because, as you said, raising the level methyl donors will make Methionine levels rise...
This methylated form of Glycine amino acid (which is an amino acid block/part of/for Glutathione GSH formation first antioxidant/thiol; the other big one is 'Cysteine' thiol) will increase the s-adenosyle-methionine (SAMe) content (and therefore, methionie too); SAMe rises when methylation increases, while homocysteine, reduces. Or, more specifically, SAHe (s-adenosyl-homocysteine). Homocysteine elevation is the culprit of many diseases; likewise, for SAHe. Like, for example, in atherosclerosis, homocysteine is higher (and methionine may be higher too..albeit it should be the inverse...methionine rising, homocysteine lowering). Homocysteine, like cysteine, is toxic in high doses..cysteine is protective antioxidant/thiol (and is 1 of 3 building blocks of total blood GSH)...but, at high doses, it is very toxic. There were studies that showed cysteine was powerful Radical Quencher...but highly toxic and cause could cell death -- also; depending dose etc...
So....it's reallt '2-faced'....this whole methionine, homocysteine/sulfur metabolism..
For, you Need some (small) methionine level -- or else, you demethylate.
Yet -- methionine is highly vulnerable and is 'selected against', in order to mitigate problems with this specific amino...hence, it gets removed and is not 'incorporated'...or used as fuel. Because, it causes too much damage --when in high dose; hence, mouse benefit of Methionine Restriction.
But, as said, (For humans, at least); it's a double-edged sword...
People (and many scientists) are not realizing the elephant...methionine for all the 'bad' about it...Without It....you age MUCH faster....there were even studies that showed methionine could Boost GSH content (so, litterally, glutation formation...when methionine rised); and it is not simply a feedback/answer... to 'counter' the damage by methionine..it's rather a protection...and not a
'counter-protection' ('counter-response') --- against methionine itself as damager. So, it's a boost of the thiol system...and not to mop up the methionine-caused damage.
Methionine, homocysteine, cysteine, sulfur-thiols...are All Highly Volatile...and can be highlyll toxic to the cell.
Hence, it'S why you may see 'small amounts' of them (allowed); in higher doses they may cause imbalance and seious damage.
2-faced.
Just a 2 cents.
PS: In my POV, 2c, it is better to have methionine (in controlled dose) than not. Or, 'Restrict it'...like methione restriction...(via CR/Calorie Restriction...that ends up being 'protein restriction'----> Methionine Proteine/Amino acid restriction);
Because, the clock is 100% to the methionine metabolism, and slowed by it. Epigenetic clock that represents the Methylome. With age, there is a clear global demethylation happening in the methylome; epigenetic reprogramming partially reverses this; the part that are demethylated are the 'inflammation' genes and there is less 'gene silencing'...and there is a methylation that happens for anti-inflammation...in the sense, that genes that are anti-inflammatory cease to be active...and inflammatory ones..begin to be active; that translates as systemic inflammation 'Inflammaging'...and it causes DNA damage/cell destruction...
on top of the Telomeres...that become demethylated with age..and short. Tall Telomere Hypermethylation is extremely important to maintain telomere structure...histone structure; centromere/sub-telomere/histone structures are 'Tri-Methylated'...just like TMG....with age, you lose histones, chromosomal methylation and telomeres shrink --- due to this demethylation.
Methionine is one of the first element necessary to maintain this methylation active; via the DNMT/Methyl-Tranferases..so, again, double-edged sword; if you have too low methionine...you age Faster as the methul/epiclock runs 'doubletime....
@brad
This is what ChatGPT thinks:
Betaine (trimethylglycine or TMG) has been shown to increase methionine oxidation and lower homocysteine levels in the body. However, it is not considered a methionine restriction mimetic, as it does not restrict the dietary intake of methionine.
Methionine restriction mimetics are compounds that mimic the effects of methionine restriction, which has been shown to increase lifespan and healthspan in various animal models. Methionine restriction can also reduce the risk of chronic diseases such as cancer, diabetes, and cardiovascular disease.
Some compounds that have been identified as potential methionine restriction mimetics include resveratrol, metformin, spermidine, and 2-deoxy-D-glucose. These compounds act through various mechanisms such as activating AMP-activated protein kinase (AMPK), inhibiting the mechanistic target of rapamycin (mTOR), and modulating mitochondrial function.
Thanks CANanonymity, Thanks Lee.
Lee: It is interesting that ChatGpt failed to name Glycine as a Methionine restriction mimetic.