Sarcosine Is Uniquely Modulated By Aging And Dietary Restriction In Rodents And Humans

[Terma]

Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans

A hallmark of aging is a decline in metabolic homeostasis, which is attenuated by dietary restriction (DR). However, the interaction of aging and DR with the metabolome is not well understood. We report that DR is a stronger modulator of the rat metabolome than age in plasma and tissues. A comparative metabolomic screen in rodents and humans identified circulating sarcosine as being similarly reduced with aging and increased by DR, while sarcosine is also elevated in long-lived Ames dwarf mice. Pathway analysis in aged sarcosine-replete rats identify this biogenic amine as an integral node in the metabolome network. Finally, we show that sarcosine can activate autophagy in cultured cells and enhances autophagic flux in vivo, suggesting a potential role in autophagy induction by DR. Thus, these data identify circulating sarcosine as a biomarker of aging and DR in mammalians and may contribute to age-related alterations in the metabolome and in proteostasis.

We also show that sarcosine feeding reduces Met levels in old animals and is a strong activator of macroautophagy in vitro and in vivo. Taken together, these data identify sarcosine as a potentially important biomarker of diet and aging in mammals and suggest that this metabolite plays a previously unappreciated role in mediating at least some of the beneficial effects attributed to DR on proteostasis.

A comparative analysis of several well-known inducers of autophagy with sarcosine. Sarcosine is more effective than metformin at inducing autophagy but less effective than rapamycin and spermidine (n > 2,500 cells).

These results suggest that sarcosine is able to stimulate macroautophagy over a background of enhanced mTOR signaling [!!], likely by potentiating the stimulatory effect of AMPK on macroautophagy.
[...]
Although a complete dissection of the mechanism behind sarcosine-induced autophagy requires further investigation, it was of interest that mTOR signaling and the AMPK pathway were both increased in response to sarcosine feeding. These findings suggest that sarcosine may be able to sustain enhanced autophagic flux in the context of mTOR activation by acting on AMPK, a well-known enhancer of autophagy.

Furthermore, the major inducer of GNMT is Retinoic Acid, in other words RA produces all the sarcosine that apparently modulates the autophagy. This all makes perfect sense.


They even throw in this freebie:

Studies have shown that increased incorporation of unsaturated phospholipids in the membrane lipid bilayer increases with age and that long-lived species have correspondingly lower levels of unsaturated fatty acids and a lower peroxidation index than their shorter-lived counterparts (Jové et al., 2013).

 

[olive]

Cool study. To put this into practice would one supplement sarcosine directly or just continue taking glycine and eating sufficient levels of vitamin a?

 

[Whichway?]

What is GNMT? I can’t see it defined anywhere in that text.

You should post this over in the Grant Generaux Vitamin A is toxic thread. They believe there is a lot to be gained by lowering vitamin A as much as possible, however I’ve seen studies where it is required for normal proliferation and maintenance of stem cells. And now this finding.

 

[Terma]

Cool study. To put this into practice would one supplement sarcosine directly or just continue taking glycine and eating sufficient levels of vitamin a?

I do both, basically. Sarcosine crosses the blood-brain barrier (I don't know to what degree it could be a natural neurotransmitter, but is NMDA agonist in 1-3g+ doses), however I don't know about its transport mechanism into cells.

I see no reason to think RA + glycine would be particularly better because GNMT is mainly liver enzyme, so that forces the liver to do all the work and then export it to blood, even though it may be relatively "safer".

GNMT is mentioned in the full paper link, you'll have to look around.

 

[bdawg]

Can sarcosine be described as a glycine reuptake inhibitor due to inhibiting the transporter?

 

[Terma]

That was the assumption behind its benefits on schizophrenia, but this opens a giant new field for it.

Hell, for a supplement it even tastes good and foods already contain some.

(I wonder if the body even prefers it to glycine to some extent)

 

[bdawg]

Ive ordered some as I have schizophrenia in the family.

Lets see the results, apparently its much more effective than glycine at hitting the glycine receptors

 

[Terma]

Well, all I can tell you is that as someone who can't stand NMDA antagonists for long, sarcosine is like a breath of fresh air.

That said although it works for schizophrenia, it's probably a downstream treatment of sorts, so don't get your hopes too far up:
Sci-Hub | | 10.1016/j.psychres.2018.08.002

The supplement company I bought from recommended using it for 6 months before judging difference (yeah... I know, but given what is found in OP there's something to it), though I didn't have to wait at all, I use it a few times a week and it does its job.

------------

For the sake of full disclosure, it IS a marker for prostate cancer, but personally doesn't worry me this far:
https://febs.onlinelibrary.wiley.com/doi/abs/10.1002/1878-0261.12439

DNA hypermethylation is one of the most common epigenetic modifications in prostate cancer (PCa). Several studies have delineated sarcosine as a PCa oncometabolite that increases the migration of malignant prostate cells while decreasing their doubling time. Here, we show that incubation of prostate cells with sarcosine elicited the up‐regulation of sarcosine N‐demethylation enzymes, sarcosine dehydrogenase, and pipecolic acid oxidase. This process was accompanied by a considerable increase in the production of the major methyl‐donor S‐adenosylmethionine (SAMe), together with an elevation of cellular methylation potential. Global DNA methylation analyses revealed increases of methylated CpG islands in distinct prostate cell lines incubated with sarcosine, but not in cells of non‐prostate origin. This phenomenon was further associated with marked up‐regulation of DNA methyltransferases (Dnmts). Epigenetic changes were recapitulated through blunting of Dnmts using the hypomethylating agent 5‐azacytidine (5‐Aza), which was able to inhibit sarcosine‐induced migration of prostate cells. Moreover, spatial mapping revealed concomitant increases in sarcosine, SAMe, and Dnmt1 in histologically‐confirmed malignant prostate tissue, but not in adjacent or non‐malignant tissue, which is in line with the obtained in vitro data. In summary, we show here for the first time that sarcosine acts as an epigenetic modifier of prostate cells, and that this may contribute to its oncometabolic role.

Metabolism of sarcosine is vital for PCa. It has been previously reported that the sarcosine-forming enzyme GNMT is up-regulated in localized and metastatic PCa relative to benign tissue and that high GNMT cytoplasmic expression is associated with lower disease-free survival rates of patients with PCa ( Khan et al., 2013 ; Song et al., 201 1 ). In contrast, the sarcosine N-demethylating enzymes SARDH and PIPOX were down-regulated in PCa tissues ( Khan et al., 2013 ) .

It is worth to note that sarcosine did not cause an increase in the DNA methylation of tested cells of non-prostate origin, and thus, the described phenomenon is most likely predominant for prostate cells. Noteworthy, it has been found that human epidermal growth factor-2 ( HER-2 ) positive breast tumours display up-regulation of sarcosine metabolism-related enzymes (GNMT, SARDH, PIPOX) ( Yoon et al., 2014 ) . Thus, investigation of linkage between sarcosine and DNA methylation status in these cells might be performed to elucidate importance of sarcosine for HER - 2 positive breast tumours .

(keep in mind cancer cells seem to aggressively increase methylation if you try to lower it any way)

 

[Goobz]

Hi all, first time poster, interested in this topic. Will go into much more detail in a later post, but just for now...

I wonder what the effect of sarcosine supplementation is, in comparison to high dose glycine? Both have been used for schizophrenia.

I would assume it would mean you would preserve both your glycine (i've seen this mentioned in one sarcosine study on PD dementia, that it "replenished glycine pools") and sAME? Since those two are converted into Sarcosine via the GNMT enzyme.

But sarcosine can also be formed from the tri and di methylated versions, TMG/betaine and DMG. I wonder how this compares to simply taking the other methylated glycines - TMG and/or DMG, as supplements?

Interesting that disorders like Parkinsons involving protein accumulation (would seem a sign of a lack of autophagy) first present with REM sleep disorder years earlier - which researchers believe is a sign of low glycine, since glycine as a neurotransmitter is what usually paralyses the muscles during REM sleep. Also interesting that Vitamin A levels are typically low in Parkinsons patients. And that Vitamin A appears to help dissolve the Lewy Bodies that accumulate in that disease.

 

[Goobz]

(Oh and as mentioned above, Vitamin A induces the GNMT enzyme so should upregulate conversion to sarcosine)

 

[Terma]

Well, sarcosine works at 1-4g doses in schizophrenics, whereas you may need up to 60g glycine for similar effect. (I tend to think the former is safer due to dosages alone, but who knows)

I've taken choline, TMG and DMG, sarcosine and glycine as supplements (gotta catch 'em all). To me they feel very different but some people get an "excitatory" reaction from TMG as well as depression, which might considered similar to sarcosine's effects, but I'm not sure it has anything to do with sarcosine.

Greetings I guess, also goodbye in case this is the last time we talk.

 

[Goobz]

Thanks for the greetings. Ive tried all those supplements as well! Haha.

I feel "safest" with choline, TMG, and glycine, since they're part of the human diet. I read somewhere that TMG can safely accumulate in cells without impairing function. But yes as you say, 60g of glycine is anything but natural.

But I have had DMG, which seems more like a drug, recommended to me for a chronic infection similar to Lyme (chlamydia pneumoniae) and they believe that DMG is helpful for it. Can't tell if the effects are that strong, but may possibly help me feel better.

Sarcosine seems to make me more relaxed, but slow.

I've also read that sarcosine and or high doses of glycine caused disordered breathing like sleep apnea in rats. Sarcosine is a glycine re uptake inhibitor in the brain, and causes more glycine to be available to use as (an inhibitory) neurotransmitter, and can inhibit breathing. I don't think I've noticed anything like this myself, but I have mild sleep apnea and need to be wary.

 

[Terma]

That's an interesting remark about sleep apnea. Although I've had no issues with sarcosine, several people on the internet including myself have this problem with taking 3g+ glycine before bed, that causes a deep sleep for 3 hours followed by waking and inability to fall asleep again (does not seem to be blood sugar, at least for me). So I wonder if that is not related. (There are other aspects as well: glycine and sarcosine might indirectly interact with histamine and other things, but don't ask for now) However, I think the deep sleep paralysis required the combinations of GABAA+B+glycine, so it's not much a worry on its own.

DMG I saw various positive descriptions on paper, but it did nothing noticeable (it was the Now! supplement - no idea the quality).

 

[bdawg]

Sarcosine, beyond making me nearly fall asleep and experience some form of anhedonia after taking 3gs, has done nothing noticable for me

I take it daily now at <1g doses as its meant to aid ADHD symptoms according to the NMDAR theory of ADHD

For sleep, try glycine + theanine + gaba - i sleep like a rockstar despite a deviated septum. The theanine+gaba combo is supported here:

GABA and l-theanine mixture decreases sleep latency and improves NREM sleep. - PubMed - NCBI

 

[haidut]

For the sake of full disclosure, it IS a marker for prostate cancer, but personally doesn't worry me this far:

This is far from settled and in fact may be just due to data analysis error.
Serum sarcosine is not a marker for prostate cancer. - PubMed - NCBI

 

[David PS]

https://journals.sagepub.com/doi/pdf/10.1258/acb.2010.009270

 

[Terma]

That's good, thanks.

The post above me shows empty.

So I took my "need" for sarcosine as a diagnostic marker for NMDA under-activation and with a whole constellation of symptoms settled on taking DHEA before bed instead of more sarcosine. DHEA never did a thing good for me but it was because I took it during the day. I believe it partially fills in for growth hormone decline if you take it at night, since for one both GH and DHEA improve joint recovery in an anabolic way. Progesterone on the other hand increases MMP for joint remodeling, but that's why it's not enough to help joints, either GH or DHEA is needed for the actual anabolic effect (and local IGF-1). Of course joints mainly heal during the night (that's when fat oxidation and carnitine are at their most important), and if I could get my youthful GH spike back, I would certainly do that, but in the meantime, DHEA seems to be the best stand-in. DHEA also is more forgiving for eating closer to bedtime. In one or two ways it's almost like the "resource abundance" growth hormone but that's stretching it. The day after I take DHEA + progesterone my stress levels are flat and my brain behaves more similar to the way it does on THC, but with a more relaxed, social and loving character, though I can also reach that more dramatically with varying combinations of supplements + THC. Since progesterone upregulates CB1 that would seem to liken them, and NMDA is likely involved (I also tried sarcosine with THC and there's something there), but there's probably more to that story. So I kinda ditched the topic of sarcosine for the time being, yet it was more important than I realized.

 

[Goobz]

That's good, thanks.

The post above me shows empty.

So I took my "need" for sarcosine as a diagnostic marker for NMDA under-activation and with a whole constellation of symptoms settled on taking DHEA before bed instead of more sarcosine. DHEA never did a thing good for me but it was because I took it during the day. I believe it partially fills in for growth hormone decline if you take it at night, since for one both GH and DHEA improve joint recovery in an anabolic way. Progesterone on the other hand increases MMP for joint remodeling, but that's why it's not enough to help joints, either GH or DHEA is needed for the actual anabolic effect (and local IGF-1). Of course joints mainly heal during the night (that's when fat oxidation and carnitine are at their most important), and if I could get my youthful GH spike back, I would certainly do that, but in the meantime, DHEA seems to be the best stand-in. DHEA also is more forgiving for eating closer to bedtime. In one or two ways it's almost like the "resource abundance" growth hormone but that's stretching it. The day after I take DHEA + progesterone my stress levels are flat and my brain behaves more similar to the way it does on THC, but with a more relaxed, social and loving character, though I can also reach that more dramatically with varying combinations of supplements + THC. Since progesterone upregulates CB1 that would seem to liken them, and NMDA is likely involved (I also tried sarcosine with THC and there's something there), but there's probably more to that story. So I kinda ditched the topic of sarcosine for the time being, yet it was more important than I realized.

Thanks for the contribution I might try DHEA at night some time.

Have you considered low dose lithium or something else to increase deep sleep? If you do that perhaps your GH secretion will improve, since I think that’s mostly released during deep sleep.

I believe sarcosine may be involved in a very important pathway for me personally, but more of a downstream effect (I think I have issues with kynurenine pathway being activated)

 

[LeeLemonoil]

Supplemental GABA increases GH and might help with sleep

GABA - An Effective Sleep Aid W/ GH Boosting Effects that Works Within 30 Minutes - Only 100 mg Pre-Bed Will Suffice - SuppVersity: Nutrition and Exercise Science for Everyone

Will Adding 100mg of GABA to Your Whey Turn You into GH-ulk? RCT Finds 10x Higher Total Lean Mass Gainz, BUT... - SuppVersity: Nutrition and Exercise Science for Everyone

 

[Terma]

Thanks for the contribution I might try DHEA at night some time.

Have you considered low dose lithium or something else to increase deep sleep? If you do that perhaps your GH secretion will improve, since I think that’s mostly released during deep sleep.

I believe sarcosine may be involved in a very important pathway for me personally, but more of a downstream effect (I think I have issues with kynurenine pathway being activated)

Yes I did try lithium orotate, but in doses >= 1mg I can only handle it for one day at time (500mcg or less is fine but not very noticeable). I had conflicting information on that one (e.g. Paul Jaminet said it needed to be taken in the morning). Iirc it delays sleep phase, at the time was the opposite of what I needed.

Kynurenine gets messed up in many disease, but it's the same dilemma of up vs downstream. I'm certain I have issues with that too. Though I suspect dynorphin as much or more.

Supplemental GABA increases GH and might help with sleep

GABA - An Effective Sleep Aid W/ GH Boosting Effects that Works Within 30 Minutes - Only 100 mg Pre-Bed Will Suffice - SuppVersity: Nutrition and Exercise Science for Everyone

Will Adding 100mg of GABA to Your Whey Turn You into GH-ulk? RCT Finds 10x Higher Total Lean Mass Gainz, BUT... - SuppVersity: Nutrition and Exercise Science for Everyone

Exactly I wanted Baclofen for that, but couldn't get it. Those are the regular preformed GABA supplements? That's a little surprising, I might try it when I get a chance, thanks. I tried them years ago.