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Glycine and Epigenetics of Mitochondrial Aging

glycine epigenetics methionine

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#1 BrianMDelaney

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Posted 27 May 2015 - 11:36 AM

This does not constitute evidence that we should be supplementing with glycine, but I'm filing it under "an additional small reason to think that the glycine I take for sleep might not be so bad":

 

University of Tsukuba. "Scientists reverse aging in human cell lines and give theory of aging a new lease of life." ScienceDaily. www.sciencedaily.com/releases/2015/05/150526085138.htm (accessed May 27, 2015).

 

(http://www.scienceda...50526085138.htm)

 

But mostly, it's just a really cool finding!

 

Brian

 

P.S. Full text of research report:

 

http://www.nature.co.../srep10434.html

 

 


Edited by BrianMDelaney, 27 May 2015 - 11:52 AM.


#2 Saul

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Posted 29 May 2015 - 10:24 AM

Hi Brian!

 

One interesting observation in the article:  Tests were made on fibroblast cells, taken from very young and very old humans.  The team found no difference in the level of mitochondrial DNA damage between the two groups; the tentative hypothesis made in the article was that epigenetic factors were involved.  They studies possible such effects on two genes.

 

Of course, this tudy was small; also, in vitro, not in vivo.

 

But, the results (if accurate) would indicate that the mitochondrial theory of aging was wrong, at least in emphasis.

 

In particular, it would contradict Mifra.

 

Michael, take note!

 

:mellow:

 

(Just kidding -- there's not enough evidence to concude anything).

 

  -- Saul



#3 Michael R

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Posted 30 May 2015 - 05:54 PM

You will not be surprised to learn that we've several inquiries put to Dr. de Grey and/or Dr. O'Connor who heads our mitochondrial mutations obviation lab at SENS Research Foundation ;) . It also roused significant interest on FightAging! and other Forums.  I'm not terribly impressed with the science underlying the main findings in the report, the analysis is worse (see a bit more below), and the concentrations of glycine they used for the cell culture study required are much higher than the physiological range -- high enough that they would be life-threatening if they are even achievable.

There is also a rodent glycine supplementation study that was only ever presented as a meeting abstract, whose results nominally support a lifespan effect. The reason for this is  the usual problem, with which long-time followers of the List will be familiar because I've hammered at it so often, of short-lived controls. I actually contacted the researchers who conducted this study, and they agree that the short lives of all the cohorts involved makes it impossible to draw any real conclusions from the study.

On the analysis, here are Dr. de Grey's comments thereon (and remember, his PhD project and earliest work in biogerontology were on mitochondria and their role in degenerative aging):
 

Unfortunately this paper is not exciting to anyone who has been paying attention to the mitochondriology literature since, oh I don’t know, 1990 or so. It has long been very obvious that mito dysfunction in the elderly is hardly at all caused by mitations and almost entirely by “deliberate” (i.e. regulated) nuclear gene expression changes, occurring as an adaptation to other things that are going wrong. That’s not to say that mito mutations are harmless though, not at all - but that their harm is via other means, such as my “reductive hotspot hypothesis” from 1998.

There is one interesting result in the paper, namely that glycine supplementation partly rejuvenates mito function - but I don’t think the authors believe that the result is reproducible, because they have relegated it to one sentence at the end of the results and one supplementary figure.

This is just a sketch: there's been enough interest that I'm going to address it more fully in the next "Question of the Month" column.

"What's the 'Question of the Month' column?" you ask? You would know if you subscribed to our Newsletter!



#4 Saul

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Posted 30 May 2015 - 07:09 PM

Thanks, Michael.

 

You've convinced me.  I've subscribed to the SENS nesletter.

 

:mellow:

 

  -- Saul



#5 BrianMDelaney

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Posted 28 June 2015 - 01:04 AM

Thanks to James for the pointer (on Facebook) to:

 

http://www.longecity...it/#entry733879

 

Brian



#6 Michael R

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Posted 30 June 2015 - 10:56 AM

The promised discussion of this study is now up on the  SENS Research Foundation website, as Newsletter Question of the Month #11: Are Mitochondrial Mutations Really All That Important?



#7 BrianMDelaney

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Posted 01 July 2015 - 12:52 AM

Thanks, Michael. Very helpful analysis.

 

I'd love to get feedback from the Orentreich Foundation.

 

http://www.orentreich.org/

 

In fact, I'd love to learn more about the foundation and its work. (I struck up a correspondence with them a while back that petered out.) They've sponsored or conducted a lot of the methionine restriction work, and were involved in the glycine experiment reported in FASEB [1].

 

- Brian

 

[1] http://www.fasebj.or...Abstracts/528.2



#8 Saul

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Posted 01 July 2015 - 03:32 PM

Thanks Michael. I hadn't known about the Aubrey's thesis --.and you brought up many interesting messages. Your picture of what happens to muscle fibers, withe deletion mutations in just a few mitochondria was fascinating.
All our members should carefully read your post.
-- Saul

#9 Dean Pomerleau

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Posted 12 September 2015 - 01:40 PM

Since we started discussing it on the Genetics of Obesity thread, I've gotten interested in epigenetics, the regulation of gene expression by environmental factors.

 

By far the best introduction to the mechanism and significance of epigenetics that I've come across is this video of a three leading researchers in the field discussing it at the World Science Festival. Its long (1:20min), but I highly recommend it for anyone interested in learning about this fascinating and important subject. It has a good 10min explanation (with graphics) starting at 10:30sec of histones, methylation, acetylation, etc. Here is the key graphic depicting how the double helix of DNA can be wrapped up (preventing transcription) or unwrapped (allowing transcription) from their histones "spools" by methyl groups (Me) or acetyl groups (Ac), respectively (click to enlarge):

 

Epigenetics.JPG

 

This wrapping and unwrapping of DNA to control its transcription seems to be a (the?) key epigenetic regulatory mechanism by which environmental factors can influence gene expression, and therefore health.

 

With that background, I came across this interesting recent study [1] on the importance of epigenetics for mitochondrial dysfunction. Recall the mitochondrial free radical theory of aging holds that since mitochondria are the "powerhouse" of the cell, they generate the most free radicals, and therefore are most likely to cause mutations in both their own (i.e. mitochondrial) DNA as well as nuclear DNA, which in turn leads to the mitochondria not working as well to produce energy, and to other free radical-induced cellular dysfunction.

 

But this new study [1], seems to call this standard model of free radical-induced cellular aging into question, and instead suggest that mitochondrial dysfunction may be a result of epigenetic "programming".

 

The authors first compared the mitochondria of fibroblast cells (collagen-producing cells responsible for connective tissue synthesis/maintenance) in cell lines extracted from young children and elderly people. They found that old fibroblasts were indeed impaired in their rate of respiration compared with the young cells, as expected. But surprisingly, the old fibroblasts didn't exhibit more mitochondrial mutations of various types than the young fibroblasts. Nor did the old cells seem to be producing more free radicals than the young cells.

 

So the authors figured "hey, maybe these old mitochondria aren't really damaged, but are just not working well because of their epigenetic programming." So they reset the old fibroblasts by genetically reprogramming them to an embryonic stem cell-like state, figuring this would remove any epigenetic changes associated with the mitochondrial DNA.

 

Sure enough, they found that when the cells were converted to stem cells and then back to fibroblasts, their respiration rate returned to the same level as the young fibroblasts. Since their 'old' DNA was preserved by this procedure, this would seem to show that neither mitochondrial nor nuclear DNA mutations were the cause of their original dysfunction.

 

The researchers then looked for genes that might be controlled epigenetically resulting in these age-associated mitochondrial defects. Two genes that regulate glycine production in mitochondria, CGAT and SHMT2, were found. The researchers showed that by changing the regulation of these genes, they could induce defects in young fibroblasts, or restore mitochondrial function in old fibroblast cells, supporting their hypothesis that the old mitochondria weren't working because of epigenetic programming, rather than because of free radical-induced damage.

 

Interestingly, in the conclusion section the authors' speculate about the possible benefits of glycine supplementation in the elderly to improve mitochondrial function:

 

Because continuous glycine treatment restored respiration defects in elderly human fibroblasts (Supplementary Fig. 6), glycine supplementation may be effective in preventing age-associated respiration defects and thus benefiting the health of elderly human subjects.

 

Michael, since you are the resident expert on the mitochondrial free radical theory of aging, perhaps you could comment on the results of this paper and their implications?

 

--Dean

 

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

[1] Sci Rep. 2015 May 22;5:10434. doi: 10.1038/srep10434.

Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human
age-associated mitochondrial respiration defects.

Hashizume O(1), Ohnishi S(1), Mito T(1), Shimizu A(1), Iashikawa K(1), Nakada
K(2), Soda M(3), Mano H(3), Togayachi S(4), Miyoshi H(5), Okita K(6), Hayashi
J(7).

 

Full Text: http://www.nature.co...icles/srep10434

 

ABSTRACT

Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has
been proposed to be responsible for the age-associated mitochondrial respiration
defects found in elderly human subjects. We carried out reprogramming of human
fibroblast lines derived from elderly subjects by generating their induced
pluripotent stem cells (iPSCs), and examined another possibility, namely that
these aging phenotypes are controlled not by mutations but by epigenetic
regulation. Here, we show that reprogramming of elderly fibroblasts restores
age-associated mitochondrial respiration defects, indicating that these aging
phenotypes are reversible and are similar to differentiation phenotypes in that
both are controlled by epigenetic regulation, not by mutations in either the
nuclear or the mitochondrial genome. Microarray screening revealed that
epigenetic downregulation of the nuclear-coded GCAT gene, which is involved in
glycine production in mitochondria, is partly responsible for these aging
phenotypes. Treatment of elderly fibroblasts with glycine effectively prevented
the expression of these aging phenotypes.

PMID: 26000717 [PubMed - in process]


Edited by Dean Pomerleau, 12 September 2015 - 02:22 PM.

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#10 Michael R

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Posted 12 September 2015 - 09:43 PM

I wrote a detailed demolition of the glycine/mitochondrial epigenetic aging paper not long after we first started discussing it when the paper came out.

 

(Dean, with your permission I'll merge this thread with that one; ditto, your thread on the New CALERIE Study Results with my previous one).



#11 Dean Pomerleau

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Posted 13 September 2015 - 01:25 PM

Michael,

 

I wrote a detailed demolition of the glycine/mitochondrial epigenetic aging paper not long after we first started discussing it when the paper came out.

 

My bad. I should have searched the forums for the PMID of [1] before posting. You did indeed "demolish" the paper in question in your amazingly thorough blog post on the SENS Foundation website. Thanks for the pointer to it, and for all the work that must have gone into writing it.  It brought back fond memories of the old days of the list trying to wrap my head around Aubrey's version of the Free Radical Theory of Aging. I highly recommend it to anyone interested in gaining an appreciation of just how subtle and complex mitochondrial (dys)function is, and how they contribute to the aging process. 

 

(Dean, with your permission I'll merge this thread with that one; ditto, your thread on the New CALERIE Study Results with my previous one).

 

Again I apologize. I should have searched for "CALERIE" myself and added to your thread rather than starting a new one. But I was pleased and relieved to see that at least in this case my post added some details and analysis that you weren't able to do based solely on the abstract.

 

You are more than welcome to merge the two threads I started on these topics with your prior ones. I'd do it myself, but I presume that is an operation that only a moderator can perform.

 

--Dean

 

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

[1] Sci Rep. 2015 May 22;5:10434. doi: 10.1038/srep10434.

Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human
age-associated mitochondrial respiration defects.

Hashizume O(1), Ohnishi S(1), Mito T(1), Shimizu A(1), Iashikawa K(1), Nakada
K(2), Soda M(3), Mano H(3), Togayachi S(4), Miyoshi H(5), Okita K(6), Hayashi
J(7).

 

Full Text: http://www.nature.co...icles/srep10434

 

ABSTRACT

Age-associated accumulation of somatic mutations in mitochondrial DNA (mtDNA) has
been proposed to be responsible for the age-associated mitochondrial respiration
defects found in elderly human subjects. We carried out reprogramming of human
fibroblast lines derived from elderly subjects by generating their induced
pluripotent stem cells (iPSCs), and examined another possibility, namely that
these aging phenotypes are controlled not by mutations but by epigenetic
regulation. Here, we show that reprogramming of elderly fibroblasts restores
age-associated mitochondrial respiration defects, indicating that these aging
phenotypes are reversible and are similar to differentiation phenotypes in that
both are controlled by epigenetic regulation, not by mutations in either the
nuclear or the mitochondrial genome. Microarray screening revealed that
epigenetic downregulation of the nuclear-coded GCAT gene, which is involved in
glycine production in mitochondria, is partly responsible for these aging
phenotypes. Treatment of elderly fibroblasts with glycine effectively prevented
the expression of these aging phenotypes.

PMID: 26000717


Edited by Dean Pomerleau, 13 September 2015 - 01:26 PM.

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#12 Dean Pomerleau

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Posted 18 October 2015 - 08:28 AM

Also on the topic of glycine, Al Pater posted (thanks Al!) the following study [1] that found (in mice) that glycine (as opposed to l-alanine) supplementation reserved muscle mass and instead encouraged fat mass during relatively rapid weight loss.

I'm still reluctant to supplement with individual amino acids, and I'm not in the weight loss phase of CR, but it might be something worth considering for those who are, particularly in light of the other positive effects of glycine discussed above.

--Dean

--------
[1] Clin Nutr. 2015 Sep 25. pii: S0261-5614(15)00241-1. doi: 10.1016/j.clnu.2015.08.013. [Epub ahead of print]

Lycine supplementation during calorie restriction accelerates fat loss and protects against further muscle loss in obese mice.
Caldow MK, Ham DJ, Godeassi DP, Chee A, Lynch GS, Koopman R.

Abstract

BACKGROUND & AIM:

Calorie restriction (CR) reduces co-morbidities associated with obesity, but also reduces lean mass thereby predisposing people to weight regain. Since we demonstrated that glycine supplementation can reduce inflammation and muscle wasting, we hypothesized that glycine supplementation during CR would preserve muscle mass in mice.

METHODS:

High-fat fed male C57BL/6 mice underwent 20 days CR (40% reduced calories) supplemented with glycine (1 g/kg/day; n = 15, GLY) or l-alanine (n = 15, ALA). Body composition and glucose tolerance were assessed and hindlimb skeletal muscles and epididymal fat were collected.

RESULTS:

Eight weeks of a high-fat diet (HFD) induced obesity and glucose intolerance. CR caused rapid weight loss (ALA: 20%, GLY: 21%, P < 0.01), reduced whole-body fat mass (ALA: 41%, GLY: 49% P < 0.01), and restored glucose tolerance to control values in ALA and GLY groups. GLY treated mice lost more whole-body fat mass (14%, p < 0.05) and epididymal fat mass (26%, P < 0.05), less lean mass (27%, P < 0.05), and had better preserved quadriceps muscle mass (4%, P < 0.01) than ALA treated mice after 20 d CR. Compared to the HFD group, pro-inflammatory genes were lower (P < 0.05), metabolic genes higher (P < 0.05) and S6 protein phosphorylation lower after CR, but not different between ALA and GLY groups. There were significant correlations between %initial fat mass (pre CR) and the mRNA expression of genes involved in inflammation (r = 0.51 to 0.68, P < 0.05), protein breakdown (r = -0.66 to -0.37, P < 0.05) and metabolism (r = -0.59 to -0.47, P < 0.05) after CR.

CONCLUSION:

Taken together, these findings suggest that glycine supplementation during CR may be beneficial for preserving muscle mass and stimulating loss of adipose tissue.

PMID: 26431812
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#13 Michael R

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Posted 18 October 2015 - 10:59 AM

Also on the topic of glycine - Al Pater posted the following paper [1] that found (in mice) that supplementing with glycine (as opposed to l-alanine) Caused the rats to preferentially lose fat mass and retain muscle mass during relatively rapid weight loss due to CR.

 

(This really fits better in your (Dean's) cross-post to the topic of muscle sparing on CR). The two quite substantial caveats are that (a) this was not CR proper, but weight loss in very obese animals with lots of fat to burn generated by dietary energy deficit, and the effects may not be the same in an animal (including H. sapiens) that starts off witht a more reasonable level of adiposity; and (b] as you say, this was very rapid weight loss, which is inappropriate for CR: the effect may be a wash if one is losing weight responsibly for CR — meaning slowly, with plenty of resistance training, and (IMO) with a relatively high-protein diet until one reaches one's intended/expected long-term stable CR weight.







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