A venerable theory of aging is the Mitochondrial Free Radical Theory (MFRTA). Mitochondria are the energy factories of the cell, where sugar is burned to create electrochemical energy. Of necessity, the mitochondria use high-energy chemistry, and this creates toxic waste in the form of ROS–pieces of molecules that are too eager to combine with delicate biomolecules, turning useful compounds to toxic waste.
The MFR theory says that these ROS cause mutations in the DNA of the mitochondria that build up over time and cause the mitochondria to perform less well with age. Mitochondria are constantly turning over, that is, creating new mitochondria that inherit the mutations and accumulate new ones.
Over the years, this story has come apart. The key finding goes back to 1980 : mutations (for whatever reason) are not more severe in older people than in younger people. The mutations that appear in mitochondria with age are at a low level, and inconsistent with the assumed ROS mechanism .
But it remains undeniable that we have fewer mitochondria as we get older, and those we have become less efficient. Brain and muscle cells are the most energy intensive, and we have less energy for everything from running to thinking. Mitochondria are not the source of age-related decline; nevertheless maintaining (or restoring) mitochondrial health should be a part of any strategy to resist the ravages of age.
I recently became aware of this Nature paper from Japan: More important than genetic changes in old mitochondria are the epigenetic changes (changes in gene expression) that render them less efficient. Is there a way to restore the gene regulation in aging mitochondria to look more like the gene expression in energetic, young mitochondria?
“When glycine was added to culture media containing cells from the 97-year-old, the mitochondria in these cells became like new.” [quote from summary by PD Mangan]. Glycine is the simplest of the 20 amino acids that are building blocks of proteins in all eukaryotes. It is not classed as an “essential amino acid” because our bodies can manufacture glycine, but maybe we don’t make enough of it to maximize our lifespans.
The theory in the Japanese paper is that glycine treats the downstream symptom of epigenetic reprogramming in the mitochondria. In other words, glycine does not stop the detrimental epigenetic changes in mitochondria that come with age, however one of the most important of these changes results in a glycine shortage in the mitochondria. Hence, glycine supplementation effectively attacks the problem at an intermediate stage.
Could a molecule as simple (non-specific) as glycine be an anti-aging compound? Glycine comes to us with a sketchy but promising history. In one rat study, a hefty dose of glycine increased lifespan by 27% longer than controls. “Hefty” is the human equivalent of ~3 ounces per day. I’m tentatively filing this study in the “too good to be true” drawer, because it appeared only as a conference abstract 5 years ago and has never been fleshed out with a peer-reviewed full text.
A shortage of protein has a powerful anti-aging effect across many species. And a shortage of one critical amino acid–methionine–is sufficient to trigger this response. This may be because methionine is the “start codon”; every gene begins with a methionine, and a severe shortage of methionine can slow down all protein synthesis.
Directly engineering a shortage of methionine in the human body is just too difficult to manage, because too many protein foods have methionine, and we’re too fond of protein. (Animal proteins are consistently loaded with methionine, whereas some vegetable sources have less.) In studies of lab animals, a methionine shortage is engineered by using fully artificial protein sources, constituted from individual amino acids. People would never want to live this way on synthetic food, even if we could afford it; but using glycine to create a methionine shortage sounds more palatable. Glycine plays a role in breaking down methionine in the liver, and if the glycine level is jacked up super-high, it is (theoretically) possible to force this reaction so far as to create a methionine shortage.
For some of us, methionine restriction holds up the tantalizing prospect of gaining benefits of dietary restriction while allowing us to eat to satiety. But the idea remains untested in humans. Protein deficiency can lead to loss of strength and endurance and the ability to concentrate–even as it increases life expectancy. Depression is another risk. Rats that have tried methionine restriction are not recommending it for humans; in fact, they quickly come to crave methionine; they recognize methionine-deficient foods and shun them.
On the other hand, there are other diverse benefits documented for glycine supplementation, beginning with better sleep, insulin sensitivity and cancer resistance. A minimum of 3 or 4 grams is required to have any effect. You can buy it in powder form by the pound. From Finland, here’s Valdu Heiskanen’s comprehensive page on glycine.
Mitochondria have their own DNA
Hundreds (sometimes thousands) of mitochondria dot every cell in our bodies. They perform the task of burning sugar in a controlled process that captures most of the energy in electrochemical form (ATP) that is convenient for all the cell’s usage. In the deep evolutionary past, mitochondria were an invading bacteria, which gradually lost their virulence, then became domesticated in a symbiotic relationship, then fell into line doing the bidding of the cell nucleus (like other parts of the cell). But from that distant era they still retain a snippet of their own DNA–just 37 genes, all essential for the energy metabolism.
In the old MFR theory, mitochondria were thought to lose genetic integrity through mutations. In the new view, the genetic information isn’t lost, but the mitochondrial DNA is reprogrammed later in life, with the result that their performance suffers. Nominally, this is a promising finding; random mutations in a hundred trillion mitochondria would not be a feasible target for anti-aging interventions; but epigenetic reprogramming is presumably something the cell already knows how to do. The cell knows, but we don’t; our understanding of epigenetic markers and the way that they are programmed is still rudimentary (even in the nucleus, let alone the mitochondria). Our best hope for the near term would be if we don’t have to understand the process, because the nucleus takes care of the details. This brings us back to the general strategy of signaling to make each cell think it’s part of a young body.
How does PQQ work?
PGC-1a is a circulating hormone that says to the cell, “make more mitochondria.” You can’t take PGC-1a orally because it is a large protein molecule, and does not survive digestion. PQQ is a small molecule, more bioavailable when ingested, that increases circulating PGC-1a. The two-step process has been documented in rodents; oral PQQ leads to more mitochondria [ref, ref].
Does CoQ10 help?
CoQ10 (or ubiquinone) is essential to the metabolic function of mitochondria. Supplementation with CoQ10 has been found to enhance athletic stamina in most human studies [ref, ref, ref, exception]. This benefit is not to be sneered at, though it is unrelated to aging. Heart patients taking statin drugs have an induced deficiency in CoQ10, and need to take supplements. Other studies of CoQ10 suggest benefits for cardiovascular risk [ref] and for maintaining insulin sensitivity [ref]. On the negative side, CoQ10 cannot stimulate growth of new mitochondria, and rodent studies with CoQ10 have never demonstrated increased life span [ref, ref].
Exercise is the best thing we know for promoting replication of mitochondria. This has been substantiated in humans and in rodents. Exercise is a powerful stimulant for producing PGC-1a, and there are additional channels by which exercise promotes mitochondrial biogenesis, apart from PGC-1a [ref]. There is evidence for endurance exercise and interval training, but maybe not for strength training [another ref]. I was unable to find any direct comparison of the three.
Fasting and Ketogenic Diets
Fasting promotes mitochondrial biogenesis by a different pathway: AMPK [ref]. AMPK is expressed in response to a tight energy budget, but the AMPK response also decreases with age [ref]. Ketogenic diets (very low carb) also promote increases in mitochondria [in humans, in mice].
Chronic caloric restriction (as opposed to intermittent fasting) contributes to the health of mitochondria, but not to their number [ref].
The Bottom Line
Loss of Mitochondrial energy is connected to many of the deficits of old age; but most of the things you can do to improve mitochondrial function are the same things we do for a generalized anti-aging program. The new thing here is glycine. It’s $10 a pound and helps you sleep better.
I’m grateful to P. D. Mangan at Rogue Health for providing the inspiration and seed references that got me started on this story [link].
Hey, thanks for the mention, Josh, glad I could be of use.
Would trimethylglycine work as well or better than glycine possibly at a lower dose?
No, betaine accelerates the methylation reactions, so it has an opposite effect than glycine in mitochondria. But you can take the tablets DMG and then intermittently exchanged for glycine, thereby mute methylation reactions at some time. So occurs the reconstitution of mitochondria.
I have written about Hayashi’s paper last year in my blog because it one my favorite papers in recent times. I have also written about it in replies on Josh’s earlier posts. Just as Josh says it debunks the mutation accumulation theory of aging due to its finding that rate of mutations remains the same for the young and the old only the repair mechanism loses its efficiency probably caused by epigenetic instructions. Plus it confirms that the damage is reversible in this case just by adding a simple amino acid! By the way David Sinclair’s finding of reversing another damage to the mitochondrial function by upregulatung NAD+ also works in conjunction to this finding. I have taken both Glycine 1gram as well as NR – Nicotinamide Riboside 200 mg and the effect is instant! Next day itself when I woke up I could feel a significant difference in many things – for example orgasms become deep as in youthful peak and one can run almost double but muscle recovery time is shorter. My personal issue is that the Glycine I use from a reputed vendor Life Extension gives me gas and bloating – I am not able to digest it well. So I had to discontinue. I have now read in another message forum that I should try to dissolve it in hot water only it gets fully dissolved – apparently then it should not cause the gastric discomfort so I am going to try that. So this goes with my theory that if each of these resurrections are tentpoles and if we raise sufficient poles we can raise the tent again – reverse back the damage.
i had the same problem with gelatin. I can tolerate it only with sufficient amount of butter / beef tallow and with a meal (although melas have shrunken a lot since adding gelatin). My own speculation: fatty tissue is made up of gelatinwith fat, therefore that should be a natural way to digest it.
Very nice paper.
And best part, Josh not in business of selling glycine.
Alan Green, M.D.
So I’m aware that Glyphosate…GMO roundup is also from glycine which can come from corn or soy, I forget, but glycine also tastes sweet which makes me think it’s a by-product of high fructose corn syrup..?? 2 years ago I was set to buy some glycine after I heard some great lectures on the benefits, but when I looked at the bottle, I couldn’t determine the source, so I didn’t buy it. Where is it coming from and what else might it be contaminated with? Powders coming out of China are now picking up lead & cadmium from the machines used to grind them.
ashkay – what on earth does nicotinamide riboside have to do with upregulating NAD+??
This is at best spreading misinformation and at worst …
As you no doubt have seen in PART 4 (above) it appears that eventually NAD+ returns to normal levels.
Have a look at some of the references and comments … any concern of brain cancer or diabetes?
From Michael Rae:
“I should, however, say that the evidence supporting the benefits of NR certainly look better today than they did at the time I wrote my post for the SENS Research Foundation Blog. There’s now evidence that NMN can work after oral administration, and the same study reported finding elevated NMN in plasma following oral gavage — and appeared to show benefits in aging mice. And a recent detailed study of NR and NMN metabolism seems to suggest that any benefits found in NMN should be translatable to NR.
The fact that all of these studies involve such extremely high doses, however, remains a significant question mark for people actually using the stuff and not ready to take such extremely high doses or shell out so much money to do so. And as noted above, I’d strongly urge caution about using the much cheaper and better-studied niacin as an NAD booster to NR.” (Editor on SENS website and moderator on CR Forums as well as Co-Author w. Aubrey de Grey on his main book).
Hi Aslan In fact I am a big fan of Vince Guiliano and his friend Watson. I read his analysis of the important breakthroughs in aging for the year 2015 which I really enjoyed. He is no doubt one of the best minds analyzing aging science in the world. I havent found the time to read all the what seems like very interesting 4 part series by Vince on NAD+ yet but I surely plan to do that soon. I also have immense respect for your collaborator Aubrey de Grey but I do not agree with all the anti aging strategies of SENS Foundation. So your comment above has been taken very seriously by me and I will do further research to see if my opinion changes. Having said that proof is always in the pudding: I did take 1mg Glycine and 250mg Elysium Basis and I did find very noticeable difference for the better. If what you cite about NR is true then it may be solely due to Glycine. But Elysium is founded by Dr. Leonard Guarante a highly reputed Professor of biology at MIT and has 4 Nobel Laureates on his companies board who I will assume to his science. They have done human trials on 60-80 year olds also done at University of Iowa on younger volunteers 35-50. Both shows significant increase in NAD+ levels by NR – summary here http://alivebynature.com/nicotinamide-riboside-optimum-dosage/
at dosages of 250 mg to 1,000 mg with levels peaking at 24hrs post ingestion. NR’s ability to upregulate NAD+ significantly was discovered by Sauve Lab at Cornell University: https://www.google.co.in/url?sa=t&source=web&rct=j&url=http://www.ctl.cornell.edu/events/ctvf12/Sauve.pdf&ved=0ahUKEwihn9WW-YnSAhVLP48KHa4bCCsQFggqMAA&usg=AFQjCNFuzp-7qtiSv_YQXRXVwey–mkWhw&sig2=Dm7BaCn9e8c1Fl-ogWbFcg
Apart from this part of research I do focuses on improving absorption and bioavailability of natural compounds and I have seen a case recently where a compound when taken along with resveratrol increases its bioavailability by 10x thereby allowing for reduction of dosage by 10x. Elysium may have added Pterostilbene to NR for that reason. I do not sell any product nor do I take advertisements at my blog. So I have no motive in misinforming anyone. I have been funding my own research so far and it seems to me that I may have found how to stall if not reverse the damage caused by aging. Without using any synthetic molecule. I also do not believe in inhibition as an intervention as I believe many of the actions are multifaceted and we may inadvertently block benefits as well. We have also done a lot of research on the bioavailability of these natural interventions and methodology of metering and measuring dosage for each individual – as each of us need a different dose depending on multiple factors. I will be conducting pre-clinical and clinical trials which hopefully may validate my research. For me finding a cure for aging is the biggest achievement that humanity can attempt and it doesn’t matter who succeeds first. If its not me then I will be the first volunteer or customer of the scientist who does find it.
Ashkay – thank you for your response. As I understand it to date, we cannot upregulate NAD+ with NR. That was my point and although the concept is seductive we must scrutinize any claims thereof.
Did James/Vince prove that or was it just the way that they felt based on their experience? I read their posts a long time ago. If the latter then other experiences are just as valid. There probably needs to be more research on this.
Nothing to do with experiences. I am not interested in what someone ‘feels’ – just the peer-reviewed published research papers.
Basically what VG/James Watson said iirc in part 3 was (I’d recommend going back and reading it all) that first of all the only data showing that NR upregulates NAD+ was for a 2 week period – nothing longer than that. They then discussed that (iirc) there is a negative feedback loop and that NAD+ levels will eventually return to baseline. Further on they discussed that appears that what regulates NAD+ in the NQO1 gene and that unless it is upregulated, that NAD+ will not likely be sustainably raised.
I apologize if I have mistaken or misrepresented what VG/James Watson said or if I’ve jumped to incorrect conclusions here.
Personally I had boughten several bottles of NR and other than the first bottle it is all sitting unopened as a result of this … sincerely – Aslan
It amazes me how interrelated everything seems to be in our biology – so one of the natural interventions we are studying is activation of Nrf2. (ARE) and Nrf2 are known to regulate the expression and coordinated induction of genes encoding detoxifying enzymes including NAD(P)H:quinone oxidoreductase1 (NQO1). So it seems from Vince and Watson’s conclusion if we are successful in activation of Nrf2 in the old we may not need to use glycine for NAD+ upregulation!
I once read that for a long time lab mice and rats were dying early because the kibble they were fed wasn’t their natural diet. So you have to wonder if these rats lived longer because they ate less of their kibble when fed a lot of glycine.
Trust me !! just take as much glycine as you can stand. Min two heaping table spoons a day And watch yourself. Get younger, and stronger, no talking just do it. You will notice. Changes happing after 10-12 days ,,, this is no joke!! This is the real deal!!! I have been taking high dosage glycine for a year. The changes are profound!!!
Can you elaborate? I.e. it would be nice for you to add a few details about how it has helped you. Also, it appears that if some people are genetically wired toward glutamate synthesis, supplemental glycine will aggravate excitotoxicity. I stopped eating gelatin for that very reason.
First and foremost, after discovering your book and now your blog, I want to thank you for taking the time to share your evidence based insights into optimizing longevity. I have truly learned much from your writing, but have only now realized I ought to share with you that there are many who likely consume your content with great benefit who do not post their appreciation of your work – I am one such individual – thanks again.
Secondly, I did have a question. For a long time I practiced a diet that was largely plant based but included <5% calories from animal products. Principally these were clean wild salmon and chicken-based bone broth 2x weekly for use in otherwise vegetable based soups.
Glycine (and gelatin) is rich in homemade pastured chicken bone broth (we source from neighbours farm), and I have read various positive papers on glycine. However, having a higher risk for lymphoma after a diagnosis many years ago, I stopped consuming the broth after reading this paper:
Metabolite Profiling Identifies a Key Role for Glycine in Rapid Cancer Cell Proliferation
I am not sure if the material in the Science article is pertinent. To this layman, it appears the research is about is the use of glycine is certain pathways. However, it was alarming enough that I discontinued bone broths.
I hate to be a nutritional reductionist, but I would welcome your insight on this research as you otherwise make a compelling case for glycine, which I would prefer to consume via a whole food. Is glycine contraindicated for those with or at high risk of cancer?
The most extensive discussions of Glycine I have seen are from Prof. Joel Brind. He has written 4 or 5 guest posts on the 180degreeheath blog (his posts are by far the best content there IMO) and he has addressed the cancer question in detail in several of the post-article comments in response to questions like yours so I would recommend checking out all his posts, especially the comments. The detailed answer he gave was that no, glycine is not pro-cancer, it is actually anti-cancer. I don’t remember all the details however one aspect of glycine supplementation is that is has an anti-infammatory affect (ina good way) which itslef is strongly anti-cancer. But check out his writings. Note: he does sell a glycine/proline supplement, however I think he makes a compelling case and it is consistent with other evidence like what Josh is providing.
Thank you very much for the pointer, I will head over now to review!
Here is a relevant paper that refers to, but clarifies the paper in science by Jain et al.
“Serine, but Not Glycine, Supports One-Carbon Metabolism and Proliferation of Cancer Cells”.
I have to say, as a club-footed ignoramus,
I wasn’t 100% completely relaxed by Prof Joel Brind’s response,
(and fwiw he does have an interest)
but this cell paper clarified the mechanisms involved
and quieted somewhat the sceptical throbbing in my club-foot.
Thanks for sharing!
It seems the essence of the research is as follows:
in the absence of exogenous serine, glycine does not enter the one-carbon cycle, but is converted into serine, a process that consumes rather than produces one-carbon units and prevents nucleotide synthesis.
Would the correct interpretation of this be to only supplement glycine on an empty stomach (late in the evening perhaps, or better yet upon waking) to reduce it’s potential to interact with dietary serine?
Hm, Glycine is prescribed in Russia as a sedative to be taken sub-lingually. It seems to be working somewhat (although there’s plenty of talk whether it’s placebo or not). Nevertheless most of students here prefer to carry a bunch of those sweet pills along during stressful exams (I took them myself back in my university days).
I wonder if these effects are connected. But what really doesn’t add up, is the fact that glycine doesn’t penetrate the blood-brain barrier, hence it shouldn’t really affect the brain much.
Dear readers, I want to contribute to the topic a very important point on the glycine, mentioned decades behind (1972) and not spread.
Dr. Joel Brind emphasizes the factor anti inflammatory from the product but beyond it, there are ancient studies (not mentioned) that emphasize another function.
in these studies there indicates itself a use of a lot of importance for the men – most of the readership of this blog – and is already indicated the use of the gelatine as cheap provider of glycine.
I believe that the readership of its blog must throw a look to two sheets of the study: Palliative Effect of Gelatine in Benign Prostatic Hypertrophy, And. Aschheim, University of Singapore, October 1972 which cost is insignificant before the information that it provides.
Also we have this one studio:Specific dynamic action expert to means of augmenting peripheral blood flow; Moore uses of aminoacetic acid:Gubner, R., DiPalma, J. R., and, E.: Am J. M. Sc. 213:46 (Seed drill)., 1947
On the other hand the glycine, it has charitable effects in the memory and attention of the adults, to see: https://www.ncbi.nlm.nih.gov/pubmed/10587285
Its sources are great http://www.supplementnews.org/wiki/glycine, http://nutritiondata.self.com/foods-000094000000000000000.html
Gubner’s et al study is in http://www.ahjonline.com/article/0002-8703(47)90325-6/abstract.
Just because the rate of mtDNA mutations does not rise with age doesn’t discredit the mitochondrial theory of aging – a constant rate is more than sufficient to be causal in aging. All you need is a deletion of a gene that facilitates some part of the ETC and hey presto you have a non functioning mitochondria that will be duplicated every time mitogenesis happens.
It appears likely to me that glycine supplementation is competing with methionine in some way and the improvements in mitochondria from its use are the same you’d see from dietary or methionine restriction.
the cause seems to be decline in the coping mechanism
Another published study -Swedish- http://www.nature.com/articles/ncomms14533
reinforces Hayashi’s findings. The research team’s studies have shown that many age-related changes in the blood system cannot be explained by mutations in the cells’ DNA. If the changes depended on permanent damage at the DNA level, the damage would still be present after the re-set. Instead, epigenetic changes appear to underlie the decline in function associated with advancing age.
Any comment on a concern Glycine can act as a brain excitotoxin at higher does in the presence of serine and or glutamate?
I read something about this and stopped taking it fearing I could be killing off brain cells.
Hi, one review article from yesterday:
Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review Oxidative Medicine and Cellular Longevity
Published 1 March 2017
Following up on my earlier comments with some new findings. This piece would seem to further muddy the picture:
“Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models7, 8. Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. “
Interestingly, glycine is currently tested at the ITP (cohort 2014):
We should know soon if it has any potential as a life extending drug,
You mentioned that the minimum dose of glycine to match those used in some of the studies you cite would be around three grams. That is not much glycine is it? That would be less than a teaspoon of typical commercial glycine powders.
You also mentioned that the human equivalent of the rodent life extension glycine research would be around three ounces. What is the equivalent dose in grams? In weight that is 85 grams, but maybe there is some conversion factor attributable to molecular weight?
That would be about seven *tablespoons* of glycine per day?
Although in-vitro, there seems to be some concern regarding glycine supplementation in regards to prostate cancer.
Sarcosine-related amino acids (glycine, dimethylglycine, and sarcosine) can exceptionally affect the behavior of benign and malignant prostate cells.
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