22 replies to this topic

[pmcglothin]

All,

I use calorie restriction science to decide what supplements to take. Here 75 years of research have defined many of the pathways that must be activated or deactivated for CR to extend life and prevent disease. Any supplement that I even consider must complement, rather than conflict with, those pathways. Downregulation of the insulin/IGF-1 pathway is a good example, and there are quite a few other related pathways that work thematically with each other to move the body away from growth operations.
I am pained to see many who are trying for longevity, taking supplements that generate exactly the opposite biochemistry to CR – with little or no evidence backing usage and certainly nothing remotely comparable to the scientific literature that supports calorie restriction with optimal nutrition.

To help people make objective decisions, I developed a new section of LivingTheCRWay.com called “Essential Cell Signaling.” Here one can find a diagram of the actions and description of basic CR cellular chemistry. Before you take anything, I would consider it from a CR science perspective, whether or not you follow a CR diet. That’s the beauty of CR science: It has revealed many of the pathways that reduce chronic disease, that improve many essential physiological functions, and that lengthen life. To whatever degree you want, you can apply the principles.

I hope this is helpful, especially to many who are trying to make supplement decisions

Paul

Edited by pmcglothin, 22 July 2010 - 02:06 AM.

[outsider]

Looks a bit complicated but good luck anyway.

[chrono]

I couldn't find it after signing up for the forum, so I'm assuming it's somewhere in the pay site.

Also, the password character variety requirement is stronger than my bank. I'll rest easier

PS: Like your book!

[Gerald W. Gaston]

Chrono,

Try here:

http://www.livingthe...lsignaling.aspx

[pmcglothin]

I couldn't find it after signing up for the forum, so I'm assuming it's somewhere in the pay site.

PS: Like your book!

Thank you for your kind words. This content is free to everyone. We kept it that way because it is also vital information for lots of people who are using CR to fight cancer. If you became a healthy Start member to access the forum, which is free, you can also easily access Essential Cell Signaling, which is in the Science behind the benefits section. It may look complex, but it is worth it to study the diagram so you have a clear guide for CR biochemistry.

I will explain more here, on the CR Way Forum, and the CR Society email list, but am at work now and must run.

Paul

[aLurker]

I am pained to see many who are trying for longevity, taking supplements that generate exactly the opposite biochemistry to CR – with little or no evidence backing usage and certainly nothing remotely comparable to the scientific literature that supports calorie restriction with optimal nutrition.

Any specific examples of such supplements and why they might be counter-productive?

[chrono]

Thanks for the link. I missed that section.

I too would be curious about what you're thinking might interfere with CR, or the CR-related pathways. Please let us know here, or link to the relevant discussions on your forum.

The only one that comes to mind specifically is ALA (see this thread, and especially Michael's post for some of the confounding factors). I'm going to be easing myself into CR over the next half year or so, and have been avoiding ALA because of its apparent epigenetic effects (even though it's the classic pairing for ALCAR).

[pmcglothin]

Any specific examples of such supplements and why they might be counter-productive?

Thanks for your question. A specific example is nicotinamide, which we have been discussing on the CR way forum here:

SIRT1 & Nicotinamide

Another discussion of the subject is found here on livingthecrway blog: http://www.livingthe...t_with_CR.aspx. You must sign in as a Healthy Start member(free) or longevity Level member to access this content.

Must run to work. Will be back to answer other questions in this thread.

Have an extraordinary day!

Paul

[Anthony_Loera]

Any specific examples of such supplements and why they might be counter-productive?

Thanks for your question. A specific example is nicotinamide, which we have been discussing on the CR way forum here:

SIRT1 & Nicotinamide

Another discussion of the subject is found here on livingthecrway blog: http://www.livingthe...t_with_CR.aspx. You must sign in as a Healthy Start member(free) or longevity Level member to access this content.

Must run to work. Will be back to answer other questions in this thread.

Have an extraordinary day!

Paul

I think there are some old posts discussing SIRT1 & nicotinamide here on this forum:
http://www.imminst.o...ch&fromsearch=1

Now, nicotinamide riboside does not have the same issues with SIRT1 (again discussed way back in November 2008 in this forum)
http://www.imminst.o...ndpost&p=279245

Isn't the search function great, and it doesn't cost 0.16 cents a day to boot!

A

[stephen_b]

Now, nicotinamide riboside does not have the same issues with SIRT1

It still doesn't seem possible to find a source for it. Have you heard of any?

[Anthony_Loera]

Yes, I have a source... trying to get another product off the ground before moving in that direction...

A

[markymark]

.... Any supplement that I even consider must complement, rather than conflict with, those pathways. Downregulation of the insulin/IGF-1 pathway is a good example, and there are quite a few other related pathways that work thematically with each other to move the body away from growth operations.
I am pained to see many who are trying for longevity, taking supplements that generate exactly the opposite biochemistry to CR – with little or no evidence backing usage and certainly nothing remotely comparable to the scientific literature that supports calorie restriction with optimal nutrition.

snip

This is a very good idea! I would love to see the collective knowledge of ImmInst visitors and members to compile a supplement regimen based on hormesis (CR is IMHO just another hormetic technique). There are efforts to do so, which are shown in another thread here at ImmInst.

I also guess, that I am not telling big news for a lot of ImmInst members, by saying that selecting supplements based on CR / hormetic sciences will all be about timing, a) on a daily basis and b) on longer scales (cycling supplements: being some weeks on a some weeks off) and c) on a person's genetic make up and lifestyle.

I would like to see a complete supplement regimen, which circumvents the "mistakes", which were made by monotoniously swallowing high doses of only the old-school antioxidants.

BTW (sorry slightly off topic) are there any comprehensive comments and critiques regarding the Ristow AOX trial: PMID: 19433800 out there? IMO, he overdoes it and is very much premature by taking two old-school AOX Vitamin E (without gammaT. and tocotrienols) and vitamin C and then boldly stating that the AOX are worthless. Their findings, however, need to be taken into consideration, but it's likely not the end of the AOX-story.

[pmcglothin]

>The only one ( supplement) that comes to mind specifically is ALA (see this thread, and especially Michael's post for some of the confounding factors).
[/quote]

Thanks for providing a great example for this discussion. I enjoyed reading the link you provided. However, I think ALA was suspect before the study by Merry came out.

Take a look at the Essential Cell Signaling section that I included in the original thread. To get the full benefit, keep the AMPK chart open on another browser. Now look at this study. (I included some comments in parenthesis)



The antihyperglycemic drug alpha-lipoic acid stimulates glucose uptake via both GLUT4 translocation and GLUT4 activation: potential role of p38 mitogen-activated protein kinase in GLUT4 activation.

Diabetes. 2001 Jun;50(6):1464-71.

Konrad D et al


The cofactor of mitochondrial dehydrogenase complexes and potent antioxidant alpha-lipoic acid has been shown to lower blood glucose in diabetic animals. alpha-Lipoic acid enhances glucose uptake and GLUT1 and GLUT4 translocation in 3T3-L1 adipocytes and L6 myotubes, mimicking insulin action. (This is exactly the opposite of what you want to enhance CR.) In both cell types, insulin-stimulated glucose uptake is reduced by inhibitors of p38 mitogen-activated protein kinase (MAPK). Here we explore the effect of alpha-lipoic acid on p38 MAPK, phosphatidylinositol (PI) 3-kinase, and Akt1 in L6 myotubes. alpha-Lipoic acid (2.5 mmol/l) increased PI 3-kinase activity (31-fold) and Akt1 (4.9-fold) (Opposite of CR– both of these kinases are associated with accelerated aging and increased cancer risk) . Both activities were inhibited by 100 nmol/l wortmannin. alpha-Lipoic acid also stimulated p38 MAPK phosphorylation by twofold within 10 min. The phosphorylation persisted for at least 30 min. Like insulin, alpha-lipoic acid increased the kinase activity of the alpha (2.8-fold) and beta (2.1-fold) isoforms of p38 MAPK, measured by an in vitro kinase assay. Treating cells with 10 micromol/l of the p38 MAPK inhibitors SB202190 or SB203580 reduced the alpha-lipoic acid-induced stimulation of glucose uptake by 66 and 55%, respectively. In contrast, SB202474, a structural analog that does not inhibit p38 MAPK, was without effect on glucose uptake. In contrast to 2-deoxyglucose uptake, translocation of GLUT4myc to the cell surface by either alpha-lipoic acid or insulin was unaffected by 20 micromol/l of SB202190 or SB203580. The results suggest that inhibition of 2-deoxyglucose uptake in response to alpha-lipoic acid by inhibitors of p38 MAPK is independent of an effect on GLUT4 translocation. Instead, it is likely that regulation of transporter activity is sensitive to these inhibitors.

PMID: 11375349 [PubMed

>'m going to be easing myself into CR over the next half year or so,

Congratulations for planning to enhance your happiness and health with CR. Also many kudos for easing into it in your own natural way.


>and have been avoiding ALA because of its apparent epigenetic effects (even though it's the classic pairing for ALCAR).
[/quote]

Would suggest applying the same objective look we have discussed here to anything else you take.

Wishing you extraordinary health!


Paul

[mikeinnaples]

Sorry for the quote nastiness ...however, I have to ask ...ALA != Na-RALA. Given that ALA is both S and R and the latter is just R, and that S is counterproductive to the benefits of R .......would the effects be the same in this case? Please pardon my ignorance.

Thanks

[pmcglothin]

Sorry for the quote nastiness ...however, I have to ask ...ALA != Na-RALA. Given that ALA is both S and R and the latter is just R, and that S is counterproductive to the benefits of R .......would the effects be the same in this case? Please pardon my ignorance.

Thanks

Great question, Mike. Indeed the R form has been highly touted as being more beneficial than the S version. From a chemistry point of view I find it interesting that one is the mirror image of the other.

However, to bring the discussion back to my point that I do not take supplements that act in opposite ways to CR, I would think that the R version would be much worse. It plays a key role in oxidative phosphorylation – facilitating that process – exactly the opposite of calorie restriction, which makes ATP less available -- facilitating energy production)


For example (My comments are in bolded in parens):

Age-associated deficit of mitochondrial oxidative phosphorylation in skeletal muscle: role of carnitine and lipoic acid.

Mol Cell Biochem. 2005 Dec;280(1-2):83-9.


Kumaran S et al.

Mitochondrial damage has implicated a major contributor for ageing process. In the present study, we measured mitochondrial membrane swelling, mitochondrial respiration (state 3 and 4) by using oxygen electrode in skeletal muscle of young (3-4 months old) and aged rats (above 24 months old) with supplementation of L: -carnitine and DL: -alpha-lipoic acid. Our results shows that the mitochondrial membrane swelling and state 4 respiration were increased more in skeletal muscle mitochondria of aged rats than in young control rats, whereas the state 3 respiration, respiratory control ratio (RCR) and ADP:O ratio decreased more in aged rats than in young rats. After supplementation of carnitine and lipoic acid to aged rats for 30 days, the state 3 respiration and RCR were increased, whereas the state 4 and mitochondrial membrane swelling were decreased to near normal rats. ( But will it stay that way? and what has it done to their overall rate of aging. Very likely increased it , I believe). From our results, we conclude that combined supplementation of carnitine and lipoic acids to aged rats increases the skeletal muscle mitochondrial respiration, thereby increasing the level of ATP. ( exactly the opposite of what you want. Consult the link that I provided earlier and you will find that AMPK, which is expressed when ATP levels are low, is a primary facilitator of formation of new mitochondria. Now that is the way to rejuvenate a cell, have more energy, and the best chance for longer life.)

PMID: 16311908


Wishing you a terrific day in Naples,

Paul

[mikeinnaples]

Paul,

Oddly enough, I was under the impression that Na-Rala activated AMPK, not supressed it. Stupidly, I did not make note of the studies I saw that in, so I have to do some research again.

Thanks

[Gerald W. Gaston]

PMID: 15913551 - Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle.

Triglyceride accumulation in skeletal muscle contributes to insulin resistance in obesity. We recently showed that alpha-lipoic acid (ALA) reduces body weight and prevents the development of diabetes in diabetes-prone obese rats by reducing triglyceride accumulation in non-adipose tissues. AMP-activated protein kinase (AMPK) is a major regulator of cellular energy metabolism. We examined whether ALA lowers triglyceride accumulation in skeletal muscle by activating AMPK. Alpha2-AMPK activity was decreased in obese rats compared to control rats. Administration of ALA to obese rats increased insulin-stimulated glucose disposal in whole body and in skeletal muscle. ALA also increased fatty acid oxidation and activated AMPK in skeletal muscle. Adenovirus-mediated administration of dominant negative AMPK into skeletal muscle prevented the ALA-induced increases in fatty acid oxidation and insulin-stimulated glucose uptake. These results suggest that ALA-induced improvement of insulin sensitivity is mediated by activation of AMPK and reduced triglyceride accumulation in skeletal muscle.

But then there is this:


PMID: 19690335 - Prevention of high-fat diet-induced muscular lipid accumulation in rats by alpha lipoic acid is not mediated by AMPK activation.

Skeletal muscle triglyceride accumulation is associated with insulin resistance in obesity. Recently, it has been suggested that alpha lipoic acid (ALA) improves insulin sensitivity by lowering triglyceride accumulation in nonadipose tissues via activation of skeletal muscle AMP-activated protein kinase (AMPK). We examined whether chronic ALA supplementation prevents muscular lipid accumulation that is associated with high-fat diets via activation of AMPK. In addition, we tested if ALA supplementation was able to improve insulin sensitivity in rats fed low- and high-fat diets (LFD, HFD). Supplementing male Wistar rats with 0.5% ALA for 8 weeks significantly reduced body weight, both on LFD and HFD (-24% LFD+ALA vs. LFD, P < 0.01, and -29% HFD+ALA vs. HFD, P < 0.001). Oil red O lipid staining revealed a 3-fold higher lipid content in skeletal muscle after HFD compared with LFD and ALA-supplemented groups (P < 0.05). ALA improved whole body glucose tolerance ( approximately 20% lower total area under the curve (AUC) in ALA supplemented groups vs. controls, P < 0.05). These effects were not mediated by increased muscular AMPK activation or ALA-induced improvement of muscular insulin sensitivity. To conclude, the prevention of HFD-induced muscular lipid accumulation and the improved whole body glucose tolerance are likely secondary effects due to the anorexic nature of ALA.

But there is also this:

PMID: 16224049 - Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase.

OBJECTIVE: Lipid accumulation in vascular endothelial cells may play an important role in the pathogenesis of atherosclerosis in obese subjects. We showed previously that alpha-lipoic acid (ALA) activates AMP-activated protein kinase (AMPK) and reduces lipid accumulation in skeletal muscle of obese rats. Here, we investigated whether ALA improves endothelial dysfunction in obese rats by activating AMPK in endothelial cells. METHODS AND RESULTS: Endothelium-dependent vascular relaxation was impaired, and the number of apoptotic endothelial cells was higher in the aorta of obese rats compared with control rats. In addition, triglyceride and lipid peroxide levels were higher, and NO synthesis was lower. Administration of ALA improved all of these abnormalities. AMPK activity was lower in aortic endothelium of obese rats, and ALA normalized it. Incubation of human aortic endothelial cells with ALA activated AMPK and protected cells from linoleic acid-induced apoptosis. Dominant-negative AMPK inhibited the antiapoptotic effects of ALA. CONCLUSIONS: Reduced AMPK activation may play an important role in the genesis of endothelial dysfunction in obese rats. ALA improves vascular dysfunction by normalizing lipid metabolism and activating AMPK in endothelial cells.

And then here it depends on where what when:


PMID: 16752177 - alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells.

AIMS/HYPOTHESIS: The antioxidant compound alpha-lipoic acid (alpha-LA) possesses antidiabetic and anti-obesity properties. In the hypothalamus, alpha-LA suppresses appetite and prevents obesity by inhibiting AMP-activated protein kinase (AMPK). Given the therapeutic potential of alpha-LA for the treatment of type 2 diabetes and obesity, and the importance of AMPK in beta cells, we examined the effect of alpha-LA on pancreatic beta cell function. MATERIALS AND METHODS: Isolated rat islets and MIN6 beta cells were treated acutely (15-90 min) or chronically (18-24 h) with alpha-LA or the known AMPK-activating compounds 5'-amino-imidazole-4-carboxamide ribonucleoside (AICAR) and metformin. Insulin secretion, the AMPK-signalling pathway, mitochondrial function and cell growth were assessed. RESULTS: Acute or chronic treatment of islets and MIN6 cells with alpha-LA led to dose-dependent rises in phosphorylation of the AMPK alpha-subunit and acetyl CoA carboxylase. Chronic exposure to alpha-LA, AICAR or metformin caused a reduction in insulin secretion. alpha-LA inhibited the p70 s6 kinase translational control pathway, and inhibited MIN6 growth in a manner similar to rapamycin. Unlike AICAR and metformin, alpha-LA also acutely inhibited insulin secretion. Examination of the effect of alpha-LA on mitochondrial function showed that acute treatment with this compound elevated reactive oxygen species (ROS) production and enhanced mitochondrial depolarisation induced by Ca(2+). CONCLUSIONS/INTERPRETATION: This study is the first to demonstrate that alpha-LA directly affects beta cell function. The chronic effects of alpha-LA include AMPK activation and reductions in insulin secretion and content, and cell growth. Acutely, alpha-LA also inhibits insulin secretion, an effect probably involving the ROS-induced impairment of mitochondrial function.

And I'm sure we that is just scratching the surface.

Edited by frankbuzin, 30 July 2010 - 02:24 AM.

[mikeinnaples]

alpha-LA suppresses appetite and prevents obesity by inhibiting AMP-activated protein kinase (AMPK).

The chronic effects of alpha-LA include AMPK activation and reductions in insulin secretion


The last study contradicts itself ...or am I missing something? I just read your quote not the actual study. The part about reducing mitochondrial function by increasing ROS activity is kind of scary ....but again, all of the studies you cited are using ALA ..not R-ALA. I think it makes a difference.

Edited by mikeinnaples, 30 July 2010 - 03:19 PM.

[chrono]

The part about reducing mitochondrial function by increasing ROS activity is kind of scary ....but again, all of the studies you cited are using ALA ..not R-ALA. I think it makes a difference.

I think the current hypothesis is that ALA functions by briefly stressing the system, which induces activity of endogenous antioxidants. See this thread: Sustained Release ALA? The duration of the ROS elevation isn't clear from the abstract, but that might be what's going on. Though it is still creepy

In the last study, AMPK inhibition occurred in the hypothalamus, while the activation was found in pancreatic beta cells.

Also, be sure to check out this thread: AMPK activators. Some exotic ones, but also a few (like ALCAR) which are pretty common.

Edited by chrono, 31 July 2010 - 01:42 AM.

[Gerald W. Gaston]

alpha-LA suppresses appetite and prevents obesity by inhibiting AMP-activated protein kinase (AMPK).

The chronic effects of alpha-LA include AMPK activation and reductions in insulin secretion


The last study contradicts itself ...or am I missing something? I just read your quote not the actual study.

well I prefixed that quote with 'depends on where' and put the relevant section in bold but maybe this will help you understand better:

In the hypothalamus, alpha-LA suppresses appetite and prevents obesity by inhibiting AMP-activated protein kinase (AMPK). Given the therapeutic potential of alpha-LA for the treatment of type 2 diabetes and obesity, and the importance of AMPK in beta cells, we examined the effect of alpha-LA on pancreatic beta cell function. ... : This study is the first to demonstrate that alpha-LA directly affects beta cell function. The chronic effects of alpha-LA include AMPK activation and reductions in insulin secretion and content, and cell growth.

[Gerald W. Gaston]

Off topic, but personally ALA (Na-RALA included) didn't seem to have much affect on my BG levels. But I've kept it around for mercury chelation. As my amalgams are in 18, 19, and 31 and are all coming out due to cracked teeth and fillings (so not a debate about amalgams safety but they have to go). Once they are out, I'll us it amount other things. Currently using PCC beforehand.

[mikeinnaples]

Yeah, Frank ...apparently I was in a lack of coffee induced coma when I read that. Thanks for the clarification.

[pmcglothin]

Thanks to all who contributed to this thread. I stopped by to take a look at what you said and considered adding a reply. However at the time we were having this discussion, I received an invitation to speak at the ImmunInst International conference, which I will be doing virtually on Sunday. Here is the link for more information ImmInst Conference.

Here I will discuss some of the underlying cell signals that are essential for calorie restriction benefits, which are also relevant to selection of supplements.I thought the Immortality Institute would be better served if I shared that info at the conference rather than just on this thread. I hope you attend and that we have the opportunity to continue this important discussion.

Wishing you much happiness and extraordinary health,

Paul