9 replies to this topic

[Positronix]

I'm basing this opinion off of this body of knowledge:

 

2009 Caloric restriciton and resveratrol promote longevity through sirtuin-1-dependent induction of autophagy

2014 Caloric restriction and the aging process - a critique

2011 Caloric Restriction

2011 Calorie restriction like effects of 30 days of resveratrol

2014 Inactivation of yeast lsw2 chromatin remodeling enzyme mimics CR

2013 Metabolic adaptations to methionine restriction that benefit health and lifespan in rodents

2005 Overview of caloric restriction and aging

2013 Short term calorie restriction protects against renal senescence of aged rats by increasing autophagic activity

 

I think caloric restriction doesn't work to improve lifespan because humans already engage in caloric restriction.  In the studies, an obese or otherwise unhealthy phenotype is rescued by caloric restriction, and that rescue is labeled life extension.  It's like the difference between dying at 50 from a heart attack and dying at 100+ from something else.  That's a lifespan extension of 100%, but is it really 'lifespan extension'?

 

If you eat 3 meals a day and don't stuff your face with food throughout the day, you are already engaging in caloric restriction.  Also, every day you have a fasting period known as sleep.  

 

Um... yeah that's all I have to say about CR - I guess I'll end with a question

 

Why methionine and not cysteine?

 

There's a body of evidence for methionine restriction having longevity effects.  I think the reason is related to ROS damage.  Methionine has a sulfur group and so ingesting large quantities could potentially lead to aggregations of damaged methionine building up.  Also I read a paper that describes methionine acting in the same way as galvanized steel - methionine lines the active sites of some proteins absorbing oxidative damage before it can affect the important sites.  However, if this is true, why wouldn't cysteine restriction have the same effect since it has a sulfur group?  I haven't read much about it but if anyone can link to some good papers it would be appreciated.

 

Here's one to start:

 

Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase

 

google it, it's directly linked as a pdf as one of the first hits on google.  I can't post links yet as this is a new account.

[Positronix]

Whoops I came back and the title looks confusing - I don't think CR will extend lifespan beyond what is currently seen.  I think CR definitely works to let you live past 50-60's.

[Michael]

I'm basing this opinion off of this body of knowledge:
2009 Caloric restriciton and resveratrol promote longevity through sirtuin-1-dependent induction of autophagy

It's not at all clear that sirtuins are important to CR in mammals, and resveratrol does not increase lifespan in normal, healthy, nonobese, non-genetically-fucked-up mice
 

Caloric restriction and the aging process - a critique

 Sohal's CR studies are not well-done.
 

I think caloric restriction doesn't work to improve lifespan because humans already engage in caloric restriction.  In the studies, an obese or otherwise unhealthy phenotype is rescued by caloric restriction, and that rescue is labeled life extension.  It's like the difference between dying at 50 from a heart attack and dying at 100+ from something else.  That's a lifespan extension of 100%, but is it really 'lifespan extension'?

 
It wouldn't be, but that isn't CR. There are some studies that are mistakenly reported as being about "CR" that work exactly as you say, which causes a lot of problems in the field because the results are artifacts and don't likely apply to properly-done CR. But in properly-done CR, the ad libitum controls aren't literally "ad libitum," but are "restricted" by ≈10-15% from what they'd eat if allowed to just sit around stuffing their faces, exactly to avoid confounding by obesity-avoidance.
 

If you eat 3 meals a day and don't stuff your face with food throughout the day, you are already engaging in caloric restriction.  Also, every day you have a fasting period known as sleep.

 
Fasting per se is not CR, and neither is eating 3 meals a day and without stuffing your face with food throughout the day,
 

Why methionine and not cysteine?

It's both. If you actually read the papers with the "methioinine restriction" shorthand, the investigators restrict both amino acids. And as you've just shown, replenishing Cys blunts the effects of MetR accordingly.

[Positronix]

Can you link to relevant papers and describe why they are more viable than the ones I listed?

 

It's important to me to read everything that I can on this

[Michael]

Can you link to relevant papers and describe why they are more viable than the ones I listed?
 
It's important to me to read everything that I can on this

 
You don't have enough time to read everything that you can on this . Seriously: you list quite a few papers, and don't give links, authors, or citations to any of them so I'm not sure to which papers several of them are, but as to the ones I criticized:
 

 

I'm basing this opinion off of this body of knowledge:
2009 Caloric restriciton and resveratrol promote longevity through sirtuin-1-dependent induction of autophagy

It's not at all clear that sirtuins are important to CR in mammals, and resveratrol does not increase lifespan in normal, healthy, nonobese, non-genetically-fucked-up mice

 

 
http://www.ncbi.nlm....pubmed/20974732
http://www.ncbi.nlm....pubmed/22451473
http://www.cellmetab...550413108001824
http://www.sens.org/...limited-benefit
http://www.ncbi.nlm....pubmed/22818625
http://www.longecity...ns-no-lifespan/
 
 

 

Caloric restriction and the aging process - a critique

 Sohal's CR studies are not well-done.

 
http://www.longecity...ndpost&p=295266
 

 

I think caloric restriction doesn't work to improve lifespan because humans already engage in caloric restriction.  In the studies, an obese or otherwise unhealthy phenotype is rescued by caloric restriction, and that rescue is labeled life extension.  It's like the difference between dying at 50 from a heart attack and dying at 100+ from something else.  That's a lifespan extension of 100%, but is it really 'lifespan extension'?

 
It wouldn't be, but that isn't CR. There are some studies that are mistakenly reported as being about "CR" that work exactly as you say, which causes a lot of problems in the field because the results are artifacts and don't likely apply to properly-done CR. But in properly-done CR, the ad libitum controls aren't literally "ad libitum," but are "restricted" by ≈10-15% from what they'd eat if allowed to just sit around stuffing their faces, exactly to avoid confounding by obesity-avoidance.

 
http://link.springer...6/fulltext.html
 http://www.longecity...ndpost&p=249450
 

 

If you eat 3 meals a day and don't stuff your face with food throughout the day, you are already engaging in caloric restriction.  Also, every day you have a fasting period known as sleep.

 
Fasting per se is not CR, and neither is eating 3 meals a day and without stuffing your face with food throughout the day.

See above
 

 

Why methionine and not cysteine?

It's both. If you actually read the papers with the "methioinine restriction" shorthand, the investigators restrict both amino acids. And as you've just shown, replenishing Cys blunts the effects of MetR accordingly.

As indicated, the very study you posted here shows this, and if you look at the full text of any decent MetR study you'll see that the diets are either devoid of, or extremely low in, cystine -- eg,

http://onlinelibrary...6.2006.00220.x/
http://onlinelibrary...05.00152.x/full

[Saintor]

 

 

It's not at all clear that sirtuins are important to CR in mammals, and resveratrol does not increase lifespan in normal, healthy, nonobese, non-genetically-fucked-up mice

 

Mr. Dave Sinclair wants to have a little talk with you. 

[Darryl]

Why methionine and not cysteine?

 

Methionine, uniquely among amino acids, increases mitochondrial free radical production. Its the anti-uncoupling agent. Gustavo Barjo's lab pretty much owns the topic:

 

Sanz, A., ... & Barja, G. (2006). Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins. The FASEB journal, 20(8), 1064-1073.

Caro, P.,  ... & Barja, G. (2008). Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver.Biogerontology, 9(3), 183-196.

Gomez, J, ... & Barja, G. (2009). Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart.Journal of bioenergetics and biomembranes, 41(3), 309-321.

Caro, P., ... & Barja, G. (2009). Effect of 40% restriction of dietary amino acids (except methionine) on mitochondrial oxidative stress and biogenesis, AIF and SIRT1 in rat liver. Biogerontology, 10(5), 579-592.

Gomez, J.,... & Barja, G. (2011). Methionine and homocysteine modulate the rate of ROS generation of isolated mitochondria in vitro. Journal of bioenergetics and biomembranes, 43(4), 377-386.

 

Cysteine spares methionine requirements, but methionine to cysteine metabolism is one-way, each cysteine produced removes methionine/homocysteine.

[Positronix]

 

Why methionine and not cysteine?

 

Methionine, uniquely among amino acids, increases mitochondrial free radical production. Its the anti-uncoupling agent. Gustavo Barjo's lab pretty much owns the topic:

 

Sanz, A., ... & Barja, G. (2006). Methionine restriction decreases mitochondrial oxygen radical generation and leak as well as oxidative damage to mitochondrial DNA and proteins. The FASEB journal, 20(8), 1064-1073.

Caro, P.,  ... & Barja, G. (2008). Forty percent and eighty percent methionine restriction decrease mitochondrial ROS generation and oxidative stress in rat liver.Biogerontology, 9(3), 183-196.

Gomez, J, ... & Barja, G. (2009). Effect of methionine dietary supplementation on mitochondrial oxygen radical generation and oxidative DNA damage in rat liver and heart.Journal of bioenergetics and biomembranes, 41(3), 309-321.

Caro, P., ... & Barja, G. (2009). Effect of 40% restriction of dietary amino acids (except methionine) on mitochondrial oxidative stress and biogenesis, AIF and SIRT1 in rat liver. Biogerontology, 10(5), 579-592.

Gomez, J.,... & Barja, G. (2011). Methionine and homocysteine modulate the rate of ROS generation of isolated mitochondria in vitro. Journal of bioenergetics and biomembranes, 43(4), 377-386.

 

Cysteine spares methionine requirements, but methionine to cysteine metabolism is one-way, each cysteine produced removes methionine/homocysteine.

 

 

THAT is interesting!

 

Thanks for the links

 

For anyone who doesn't know, proton leakage controls ATP production rate.  Protons pumped through the membrane via the electron transport chain are sometimes allowed to travel back without passing through ATP synthase.  The reason is that the pH differential across the membrane modulates free-radical production, so that a lower differential means less free radicals generated.  Keeping the membrane differential low is preferable for the cell's maintenance but higher differentials mean faster ATP production.  In my mind, I think the mitochondria's best strategy is a high rate of proton movement coupled with a high rate of leakage.  That allows more control over ATP production - you can just close off the leaking proteins rather than having to ramp up production at the level of the electron transport chain.

At least, that's the first thing that came to mind when you called it the anti-uncoupling protein.  Reading through the first paper (it's the only non-paywalled one, I'll find the rest later) it seems that methionine restriction decreases electron leakage from the ETC.  Roughly 1-2% of the electrons passing through the ETC leak out prematurely from various complexes which is where the reactive oxygen species come from.  I mean I know you probably know this already but I was just repeating it to allow anyone to correct me if I'm wrong.  I'll read the rest later, thanks!

[Darryl]

I don't think the chemical mechanism for methionine increasing mitochondrial ROS production is known at present, other than that it occurs at complex I during forward electron flow.

 

I should have omitted the sentence "its the anti-uncoupling agent" or inserted "virtually acts like" but it was late. Sorry for the confusion.

 

However, some very intriguing life extention interventions may act through uncoupling  (DNP, SkQ1, MitoBHT possibly C₆₀) while reducing ROS production, so in the past I've done reflexive Scholar searches for uncoupling activity when I see lipophilic/penetrating cations active around mitochondria. For example, metformin and berberine were candidates, but they just upregulate endogenous uncoupling proteins.

 

[niner]

However, some very intriguing life extention interventions may act through uncoupling  (DNP, SkQ1, MitoBHT possibly C₆₀) while reducing ROS production

 

I really don't think that C60 acts as an uncoupler, at least not in the way that Chistyakov et al. hypothesize with their chemically ludicrous Density Functional Theory structure.  More detail here.