80 replies to this topic

[Dizzon]

There was a chinese paper recently claiming honokiol has PPAR-delta agonising activity. I would have to search for the reference, but that's why I included it. AFAIK, PPAR-gamma tends to prevent weigh gain and lipogenesis, whereas PPAR-alpha causes lipogenesis and weight gain. FWIW, resveratrol agonizes both PPAR-alpha and PPAR-delta. I surmise the balance of the action is dependent on dose (or perhaps other factors) , which would explain the sometimes contradictory results reported for this often-studied substance. Most PPAR-gamma agonists also affect PPAR-alpha.

Based on my self-experimentation, I believe bitter melon is more effective than honokiol for our purposes, but Micardis beats both of them for PPAR-delta agonism.
Whether this will make you live longer is an open question.

Could you post a link to that chinese study that points to honokiol being a ppar-delta agonist?

By the way you've mixed the 2 ppar's up. PPAR Gamma (specifically PPAR-γ2) is the master regulator of lipogenesis, whose natural primary activating ligands are fatty acids from the diet, and is activated by the TZD class of diabetic drugs. PPAR-alpha is responsible for regulating fat burning during fasting, and its primary activating ligands are mobilized fatty acids during fasting, and are activated by fibrates.

As far as Im aware Berberine, TUDCA, bitter melon extract and technically Vitamin D (and also technically Vitamin A but this has no applicable use) are the only supplements showing potential for being PPAR-delta agonists in humans, with berberine being the most promising by far (mainly via AMPK activation instead of ppar-delta activation)

Edited by Dizzon, 06 December 2013 - 05:55 PM.

[Dizzon]

Couldn't find any direct agonism but shows lots of potential in conjunction with other substances.

We investigated the properties of honokiol, a natural rexinoid, as a regulator of retinoid X receptor (RXR) heterodimers with various partner nuclear receptors (NRs), in comparison with those of the synthetic rexinoid bexarotene. Honokiol alone was hardly capable of activating peroxisome proliferator-activated receptor (PPAR) γ/RXR, RXR/liver X receptor (LXR), and RXR/vitamin D receptor (VDR) heterodimers, whereas it effectively potentiated their activation by agonists for the partner NRs of the RXR heterodimers. These findings were further supported by increased mRNA and protein levels for the respective NR target genes. Bexarotene alone activated PPARγ/RXR and RXR/LXR heterodimers, but not RXR/VDR heterodimers, and facilitated the activation of all three RXR heterodimers by the respective PPARγ, LXR, and VDR agonists. When the potencies of honokiol and bexarotene were compared, honokiol was able to serve as a subsidiary agonist in the activation of RXR heterodimers in a similar manner to bexarotene. However, it seemed to potentiate the activation of PPARγ/RXR heterodimers by the PPARγ agonist rosiglitazone more efficiently than bexarotene, and was a less potent RXR agonist than bexarotene. In conclusion, we have demonstrated that honokiol is a rexinoid that possesses distinct properties from bexarotene, and mainly has subsidiary roles in the activation of RXR heterodimers by potentiating the activation of RXR heterodimers by agonists for the partner NRs.

http://www.ncbi.nlm.nih.gov/pubmed/22223330

sorry for the threadjack.

[Bateau]

Could you post a link to that chinese study that points to honokiol being a ppar-delta agonist?

looks like it was a misunderstanding maxwell had when discussing honokiol earlier. It was mentioned that it was a ppar-gamma agonist and i think maxwell accidentally thought delta
http://www.longecity...tc/#entry614989

[blood]

LEF Copper 2mg (2/7)

I'm curious to know the rationale for copper supplementation.

"2/7" - so you take it 2 days/ week?

Yes Blood, that is it: 2x per week to balance with zinz 1x evey two days. I wonder if I should increase it a little (was sligthly outside norm on the low side) or reduce the zinc.

I'd personally be very cautious about supplementing with copper. If I really did have strong evidence of deficiency, I might set about incorporating foods into my diet which contain a high copper content (in preference to consumption of copper containing supplements, which are highly bioavailable to a dangerous extent).

Use of copper supplements has been implicated in accelerated cognitive decline, among other things.

See these threads for more:

http://www.longecity...ng-supplements/
http://www.longecity...opper-and-iron/
http://www.longecity...upplementation/

Edited by blood, 07 December 2013 - 07:48 AM.

[blood]

Couldn't find any direct agonism but shows lots of potential in conjunction with other substances.

We investigated the properties of honokiol, a natural rexinoid, as a regulator of retinoid X receptor (RXR) heterodimers with various partner nuclear receptors (NRs), in comparison with those of the synthetic rexinoid bexarotene. Honokiol alone was hardly capable of activating peroxisome proliferator-activated receptor (PPAR) γ/RXR, RXR/liver X receptor (LXR), and RXR/vitamin D receptor (VDR) heterodimers, whereas it effectively potentiated their activation by agonists for the partner NRs of the RXR heterodimers. These findings were further supported by increased mRNA and protein levels for the respective NR target genes. Bexarotene alone activated PPARγ/RXR and RXR/LXR heterodimers, but not RXR/VDR heterodimers, and facilitated the activation of all three RXR heterodimers by the respective PPARγ, LXR, and VDR agonists. When the potencies of honokiol and bexarotene were compared, honokiol was able to serve as a subsidiary agonist in the activation of RXR heterodimers in a similar manner to bexarotene. However, it seemed to potentiate the activation of PPARγ/RXR heterodimers by the PPARγ agonist rosiglitazone more efficiently than bexarotene, and was a less potent RXR agonist than bexarotene. In conclusion, we have demonstrated that honokiol is a rexinoid that possesses distinct properties from bexarotene, and mainly has subsidiary roles in the activation of RXR heterodimers by potentiating the activation of RXR heterodimers by agonists for the partner NRs.

http://www.ncbi.nlm....pubmed/22223330

sorry for the threadjack.

Honokiol is a very exciting, promising compound - see http://www.longecity...okiol-magnolol/

Could you post a link to that chinese study that points to honokiol being a ppar-delta agonist?

looks like it was a misunderstanding maxwell had when discussing honokiol earlier. It was mentioned that it was a ppar-gamma agonist and i think maxwell accidentally thought delta
http://www.longecity...tc/#entry614989

It's my fault - I posted a study on a PPAR-gamma agonising compound in a PPAR-delta oriented thread.
My excuse - honokiol "acts like" a PPAR-delta agonist when you feed it to mice.

[albedo]

...
As far as Im aware Berberine, TUDCA, bitter melon extract and technically Vitamin D (and also technically Vitamin A but this has no applicable use) are the only supplements showing potential for being PPAR-delta agonists in humans, with berberine being the most promising by far (mainly via AMPK activation instead of ppar-delta activation)

Reading positive stuff on berberine:

Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression.
http://www.ncbi.nlm....pubmed/19800084

despite criticisms on the study:
http://www.pointinst...trol-an-update/

Do we have a good source of berberine? LEF carries this and this. I am already taking Zyflamend which includes about 5mg berberine.

[Bateau]

I use Dr. Whitakers, but my sister uses GlycoX 500 (has insignificant amounts of Banaba Leaf as well) which is cheaper. Both have the advertised amount of berberine. Berberine is a difficult extract to mimic, the color, smell and taste are very unique. It's used as a natural yellow dye in certain parts of the world and tastes pretty foul. Both are simply encapsulated, not pilled, so you can check the extract for yourself. I haven't checked out Swansons product, since its 400mg per serving instead of 500mg, but they have the cheapest option IIRC.

What was said about PPAR delta agonists is not correct. Bitter melon and Vitamin D are not true agonists, almost any fatty acid acts as a more potent agonist than them. Berberine indirectly activates PPAR delta through ampk, not direct activation either. TUDCA is not an agonist either, however TTA (a fatty acid) is, but it's a fairly in-optimal agonist (expensive, understudied, unhealthy due to loss of omega 3's). The most potent PPAR delta agonists, believe it or not, are food. Certain unsaturated fatty acids (particularly oleic acid, ALA, DHA, EPA), as well as retinol and provitamin A through RXR-alpha heterodimerization of PPAR delta, and believe it or not, milk. (don't shoot the messenger). All have been shown to cause a 7-11 fold increase in ppar-delta.

p.s. Im dizzon, deleted my email attached to the dizzon account and lost access to account, so there's no real disagreement here, just me bickering with myself. After a review of the literature I realized I made a few mistakes.

Edited by Bateau, 14 December 2013 - 05:50 PM.

[APBT]

....
Thank you. LEF carries this supplement - I always try to consolidate in one shipment possibly from the same source to save on shipping costs:
http://www.lef.org/V...tter-Melon.html
I wonder if you have a take on it as it looks not standardized. I might give it a try prior to the next test. I really wish to correct that fasting BG marginally high value (100, ref. 70-105) and hopefully bring down also A1C now at 5.5

Thumbs down. It is the dried fruit, ground to a powder. You would possible take half the bottle at a time for an effect. You want to look for an extract that is standardized to 10 or 20 percent charantin. It is at least 10 times more potent.

There's this from Solaray at 15% charantin http://www.vitaminsh...67#.UrNWjWeA2Uk

[albedo]

Looks like Berberine is the most supported supplement to reduce BG and even compares to metformin.
E.g. see here: http://examine.com/s...linical_results and the two cited studies.

[albedo]

Just got my last lab results after one year. To my surprise and satisfaction DHEA-S level has increased 4.5 fold, re-entering the range despite on the low side (69.2 mcg/dl, ref. range: 50-377). Level of T and freeT also increased while DTH (watched for my prostate condition) and E2 are well under control.

 

I wonder if you can challenge the following tentative explications, probably in that order of priority:

1. A more regular strength (and aerobic) training program
2. A rise in cholesterol
3. An almost "homeopathic" supplementation (2x25mg per week!)

[serp777]

Why would you take selenium supplements? Huge mistake--

 

http://www.webmd.com...prostate-cancer

[albedo]

Thank you for reminding this. I already cut on both selenium and Vitamin E and closely monitoring both.

[timar]

Why would you take selenium supplements? Huge mistake--

 

http://www.webmd.com...prostate-cancer

 

But these findings jibe with other studies that have linked taking large amounts of supplements with increased cancer risk, Kristal said. Such studies have tied large amounts of omega-3 fatty acids to endometrial cancer, excess folate to colon cancer and beta carotene supplementation to lung cancer, he said. High doses of selenium have also been linked to skin cancer, he added.

"As humans, we evolved with the levels of micronutrients you'd normally get with food," Kristal said. "There's no benefit to taking high doses of these micronutrients. There's only risk."

 

*sigh*

 

I find it really upsetting when scientists who should know better indulge in such biased, exaggerated, simplistic and sensationalist statements. Why the hell are they doing that? Are they that desperate for media attention? This whole paragraph is full of overgeneralizations and misrepresentations. The link between both omega-3 fatty acids and folate and certain cancers is spurious at best. (The study relating negligibly higher levels of omega-3 in red blood cells with an increased risk of prostate cancer is actually one of the best example of the sensationalist BS that unfortunately seems to be on the rise in scientific publishing). The relation between beta-carotene and lung cancer has been limited to smokers and asbestos workers and is most likely due to the extreme conditions of oxidative stress in their lung tissues. The last statement is particulalry infuriating, as he commits the inexcusable fallacy of generalizing from those very specific examples to all micronutrients! By doing so he is really making a fool out of himself, as anyone having some knowledge of the literature sees that his statement is factually wrong, as there have been numerous examples where "high" doses (e.g. above the RDA) of certain micronutrients have shown benefical effects in RCTs (think of nicin, EPA and DHA, etc.; for a lot of micronutrients beneficial effects have been shown under certain conditions).

 

Moreover, what are the "levels of micronutrients you'd normally get with food"? (Appeal to nature, anyone?) What does normally mean? When you are living in Northern or Central Europe, you normally get far less selenium from the diet than people living in North America, because the Ice Age glaciers have depleted the soil of selenium (in fact, American wheat may contain up to 50(!) times more selenium than European wheat). When you are a Guarani indian living in the Amazon rainforest you normally get several milligrams(!) of selenium a day, because brazil nuts are one of your main dietary staples. Hence I expect from a serious scientist to refrain from such nonsensical statements.

 

Considering your supplement regime, albedo:

 

LEF Multi MIX caps (1/5)
LEF Fish Oil 2000mg (1/4)
LEF R-LA 600mg
LEF ALCAR 620mg
LEF Super Carnosine 500mg (1/2)
LEF Cognitex (cycling)
LEF Vit D3 (1000-2000IU)
LEF Super Ubiquinol 50mg
LEF Gamma Tocopherols/Tocotrienols (2/7)
LEF Caloric Restriction Mimetic w/ t-resveratrol (1/2)
LEF Super Zeaxanthin
LEF Advanced Natural Prostate Formula
LEF Super BioCurcumin 400mg (1/2)
LEF Super Selenium complex 200mcg (2/7)
LEF Optizinc 30mg (1/2)
LEF Magnesium 320mg
LEF Endothelial Defense (cycling)
LEF NAC 600mg (1/2)
LEF Mega Green Tea
LEF Chlorophyllin
NewChapter Zyflamend
LEF Lycopene 10mg (1/2)
LEF Super K w/ K2 complex
CellForte IP6 & Inositol
Piracetam 800-1600mg
Jarrow Dophilus EPS Probiotics
LEF Melatonin 1mg (2/7)
Dragon River Cilantro extract
LEF HepatoPro PPC 900mg (Polyunsaturated Phosphatidylcholine) (cycling)
LEF B Complete Complex (1/4)
Nat&Form Red Yeast Rice (1200-1800 mg)
LEF TMG (1000mg) (cycled)
LEF Optimized Garlic
VitImmune I3C w DIM 200 mg
LEF Vanadyl Sulfate 7.5mg (2/7)
LEF Copper 2mg (2/7)

 

I would refrain from taking any supplemental copper, which is already abundant in any decent diet, particularly if it includes nuts, seeds and some dark chocolate. In fact, the major advatages of zinc supplementation may be due to the lowering in copper status. High-dose Lipoic acid may be a bit of a gamble because it is a potent antioxidant and we know that high-dose supplemental antioxidants can have detrimental effects by interfering with hormesis. Moreover, there are some overlapping supplements in your supplement regime that may add up to undesirably high levels of some of the included micronutrients but at the given dose are probably just uneconomical. I have those supplements in mind:

 

LEF Multi MIX caps (1/5)
LEF Vit D3 (1000-2000IU)
LEF Gamma Tocopherols/Tocotrienols (2/7)
LEF Super Selenium complex 200mcg (2/7)
LEF Optizinc 30mg (1/2)
LEF B Complete Complex (1/4)

 

You could easily replace all of them except the mix by:

 

LEF Two-per-Day (1/2) - which provides levels of B vitamins almost identical to 1/4 dose of B complex, 1000 IU D3, 33 mg of alpha-tocopherols plus 10 mg of other tocopherols (as I said, I would rather go easy on antioxidants, so this is plenty), 100 mcg selenium complex (with selenocysteine and not selenomethionine being the predominant form of selenium, which may be crucially important - maybe I'm going to write about that in the selenium topic) and 15 mg of zinc - and by doing to safe a lot of money. As the Two-per-Day also contains all the remaining essential micronutrients you could even think about cutting out the Mix and thereby only missing out on the very low doses of additional phytochemicals from the 1/5, which really shouldn't be much of a loss for anyone eating a decent diet.

 

Btw, I have developed a little tool in an excel sheet to keep control of my own micronutrient intake from diet and supplements and to make sure it stays within the safe range. I even have devised my own upper limits for defining that range, by including and reviewing both the IOM's and the EFSA's upper limits, taking into account more recent evidence as well as the life extensionist's perspective. If there's interest, I could dress it up and publish it as google document...

Edited by timar, 17 July 2014 - 11:38 AM.

[APBT]

Btw, I have developed a little tool in an excel sheet to keep control of my own micronutrient intake from diet and supplements and to make sure it stays within the safe range. I even have devised my own upper limits for defining that range, by including and reviewing both the IOM's and the EFSA's upper limits, taking into account more recent evidence as well as the life extensionist's perspective. If there's interest, I could dress it up and publish it as google document...

 

I'm interested. 

[albedo]

Thank you Timar. I would be also interested to your spreadsheet, that looks impressive! Btw that is where technology should really be more helpful, e.g. with your own App on say an IBM's Watson cloud or similar.

 

I am tuning my list, being more focused to conditions and matching blood tests. There are things which really seem having worked for me (e.g. IP6 for my iron/ferritin, Vitamin D, probiotics) and other to be adapted. E.g. despite supplementation I found to be deficient in RBC magnesium and went to a prescription formulation. Copper is away and selenium is cut. I am still struggling with high homocysteine and considering cycling again with l-methylfolate, TMG, methycobalamin and B6. For the latter issue I am wondering if would make more sense to increase my plant based foods, hence reducing methionine intake in the first place.

[timar]

Thank you Timar. I would be also interested to your spreadsheet, that looks impressive! Btw that is where technology should really be more helpful, e.g. with your own App on say an IBM's Watson cloud or similar.

 

Well, expect nothing too fancy. It's really just a spreadsheet providing an overview of the US and EU RDAs and ULs, my own ULs and a table to enter your intakes from diet and supplements. Anyway, I'll publish it after adding some more references and annotations
 

 I am tuning my list, being more focused to conditions and matching blood tests. There are things which really seem having worked for me (e.g. IP6 for my iron/ferritin, Vitamin D, probiotics) and other to be adapted. E.g. despite supplementation I found to be deficient in RBC magnesium and went to a prescription formulation. Copper is away and selenium is cut. I am still struggling with high homocysteine and considering cycling again with l-methylfolate, TMG, methycobalamin and B6. For the latter issue I am wondering if would make more sense to increase my plant based foods, hence reducing methionine intake in the first place.

 

Dito regarding IP6, vitamin D and probiotics. It always makes sense to increase whole plant foods (french fries are plant-based too ), unless they already provide the majority of your calories, but I think that is is unlikely that methionine moderation helps with homocysteine, as the availability of dietary methionine is generally not the rate-limiting factor (unless you severely restrict methionine, which would be difficult even on a strictly plant-based diet and not advisable anyway) but it is puzzling that you are still struggling with high homocysteine while taking all those B vitamins. As both the transsulfuration and the BHMT-dependent pathway should be bathed in cofactors from your supplement regime, I suspect the remethylation pathway be to be the culprit. If you have a mutation in the MTHFR gene, you may require high levels of folate which most supplements don't provide, out of concerns that it may mask B12 deficiency and support cancer growth.

Edited by timar, 18 July 2014 - 10:24 AM.

[albedo]

 

.....  it is puzzling that you are still struggling with high homocysteine while taking all those B vitamins. As both the transsulfuration and the BHMT-dependent pathway should be bathed in cofactors from your supplement regime, I suspect the remethylation pathway be to be the culprit. If you have a mutation in the MTHFR gene, you may require high levels of folate which most supplements don't provide, out of concerns that it may mask B12 deficiency and support cancer growth.

 

 

Thank you Timar.

 

You are right on spot: those are exactly my concerns (not for B12 as I measure it) but unless I misunderstood my 23andme/GeneticGenie results and interpretation which might be the real problem here, I do not have that MTHFR mutation (*). One culprit might have been also some Niacin supplementation but only at ~500mg/d it looks to be far too low for any effect on homocysteine. I do have mutations on BHMT which however does not explain my high homocysteine as they look to produce results similar to CBS mutations, i.e. up-regulating hence reducing homocysteine.

 

I remain puzzled by all this.

 

(*)

MTHFR C677T rs1801133 GG -/-
MTHFR 03 P39P rs2066470 GG -/-
MTHFR A1298C rs1801131 GT +/- (mutation seems not leading to elevated homocysteine levels)

 

BHMT-01 not found n/a n/a
BHMT-02 rs567754 TT +/+ (mutation seems producing similar effects to CBS mutations)
BHMT-04 rs617219 CC +/+ (ditto)
BHMT-08 rs651852 TT +/+ (diito)

 

CBS C699T rs234706 AG +/- (mutation seems up-regulating, hence often giving lower homocysteine and cystathionine since there is a rapid conversion to taurine)
CBS A360A rs1801181 AG +/- (ditto)
CBS N212N rs2298758 GG -/-

 

[Dolph]

One culprit might have been also some Niacin supplementation but only at ~500mg/d it looks to be far too low for any effect on homocysteine.

500mg niacin could be well enough to raise homocysteine significantly, but normally this can be controlled with B6 (that is also part of your stack if I remember correctly).
http://www.ncbi.nlm....pubmed/9040554/

To be honest, while a low homocysteine may give some peace of mind, I wouldn't worry too(!) much about it. It's a highly inconclusive biomarker anyway.

Edited by Dolph, 18 July 2014 - 03:02 PM.

[albedo]

Thank you Dolph, interesting link. Maybe another confounding factor is some chlorogenic acid (green coffee extract) I used for reducing post postprandial glucose spikes (actually also something which looked to work as I got A1C under 5 for the second time after I am testing since many years). Was thinking about metformin too but not ready now for the same reasons. I cut out niacin, unfortunately I must say because of other potential advantages and reduced chlorogenic. I agree you need to put homocysteine in context and take into account internet hype around it (despite J Braly and P Holford wrote an entire book on it - The H Factor Solution)

Edited by albedo, 18 July 2014 - 04:31 PM.

[albedo]

As we are here in particular on homocysteine,  I found this interesting video on the link between oxidative stress, homocysteine levels and brain disorders. The video (in 3 parts) is from Dr. Andrew Rostenberg, explains the balance you need to achieve in homocysteine levels (not too low, not too high, possibly 4-8) and provides also some clinical evidence from his practice:

 

http://beyondmthfr.c...teine-part-iii/

 

 

[albedo]

I run a second set of blood (and urine) tests and compared with last year. Overall, they are not bad but neither excellent. Please feel free to comment and criticize! Again thank you to everyone here bothering to look at this as last year!

 

link to my June 2014 blood tests

 

Positive

 

- I am really much more satisfied with my hormones panel:

• Finally I could get DHEA-S in range. I think I could accomplish this with an extremely low supplementation (2x25mg per week) but I am sure the most important factor has been an increase in my strength training shown to increase this hormone.
• IGF-1 has been slightly lowering which is an objective for cancer growth control.
• Testosterone and free-T have been increasing while doing ok on DHT (and E2, to less extent)
• DHT has been lowering which is an objective for by prostate condition, trying not to fuel its growth in size (due to my BPH, had to go - successfully to TURP). Maybe a protective effect of my prostate protection formula.
• E2 has been increasing but still in the norm and aligned with values I had over almost 10 years. I am not taking any pharmaceutical aromatase inhibitor beside probably the gently acting stinging nettle contained in my prostate protection formula.
• TSH was and still in the norm. However it went down from a worrying 4 to 2.9. I reduced soy foods intake but did not stop it to grasp some benefits of its genistein content. I checked my iodine.
• For the slightly high calcium level I went and checked my PTH for first time which is in the norm. I did not cut out dairy but will further reduce.

- Ferritin went unfortunately up from a wonderful 98 to 115 (despite my IP6 supplementation) but still not that high as I had in my past (was up to 450!)

 

- I look to do better on my FFA panel as my palmitic acid (saturated FFA) has normalized. I need to address the GLA and DGLA though (see below).

 

- For the second time in 10 years, A1C went below 5, possibly due to the green coffee extract supplementation (chlorogenic acid) which however might have been negatively impacting homocysteine (see below).

 

- The objective of lowering chronic inflammation as much as I can is achieved with a consistently low hr-CRP.

 

Negative

 

- GLA (and DGLA) is consistently very low (which also brings to low Arachidonic Acid, a good thing for inflammation but not too much as it is important for cognition). I am considering a moderate supplementation of GLA.

 

- Total cholesterol and LDL went up, despite supplementation with red yeast rice (1200mg)! Unfortunately I relaxed on my diet (dairy in particular), which was particularly stupid maybe relying on some supplement protection! Not good for my prostate too!! I will control my diet more strictly but still continue to supplement. My doctor was not that worried by the values and also recommended this approach.

 

- Homocysteine went up to very high values (16.1) despite supplementation of B-complex and TMG. I am pretty sure my niacin supplementation (despite only 400-500 mg) affected this as well as some green coffee extract (chlorogenic acid) to control post prandial glucose spikes. Both are confounding! I also may not well absorbing folate and considering giving another try to methylfolate 1000mcg. My 23andMe results also look quite good on the methylation pattern. Please challenge this! I do not want to use high folate for too long not to fuel cancer!

 

- Fasting glucose is still worrying (despite very good A1C though). Doctor was not that worried at this (when looking at A1C) and recommended to watch what I was eating prior to the test. I am still confused on the labs: they also did a serum measurement which turned to be 68.5 (ref 72-108) and calculated insulin sensitivity (HOMA) based on that value at 0.79  (the calculation is: Glucose is mg/dl * Insulin in mIU/l / 405).

 

- RBC magnesium was also a negative surprise despite some supplementation (160mg). I upped the dose and got prescribed a special formula/dose (Diasporal/300mg) which was more effective in the past. This is a possible additional explication of my high homocysteine level (Mg is needed in the conversion of homocysteine to SAMe, via methionine).

 

- Calcium is again on the high side. I checked PTH which is normal though. I did not cut out dairy but will further reduce. Please challenge this!

 

- I did not report, for simplicity, my spot urine tests but maybe you can help understanding (so far absolutely no clue or preoccupation from doctors) the urine low creatinite value (5.8 mmol/l with ref range 8.8-16) and urea 188 mmol/l which gives a urea/creatinine ratio of 32.4 which is 10x higher than the ref range (2.54-2.82). This is now so for the 4^th year in a row and I still do not understand it. Can you explain?

 

Lesson (re)learned

 

I am still studying all this and try to understand/find fixes. GP docs are often lost at much of this stuff and of course cannot come up with sensible replies when only given 10-15 mins max. to tell you all!  It's good to have Forum like this one and people as you to discuss! Supplementation can help but if you relax on diet and exercise it turns to be almost useless and might unbalance markers. You need to keep fixing big things first. Still reduce animal fats, dairy, increase whole plant foods and … be happy

 

Thank you for your criticisms!!

 

 

Edited by albedo, 03 August 2014 - 04:42 PM.

[krillin]

DHEA has never had an effect on my estradiol. My estradiol has only responded to anastrozole and letrozole (lowered) and Erase, Formadrol, and Triazole (raised). Letrozole's drawbacks were weight gain and elevated blood sugar and liver enzymes. Anastrozole elevated blood sugar and liver enzymes in doses high enough to raise testosterone, but at lower doses its only effect is to lower estrogen. I am shocked, shocked that the bodybuilding supplements raised estrogen while not affecting testosterone. Someone mentioned taking DHEA sublingually, which doesn't work for me, probably because DHEA needs to be sulfated in the gut to survive liver processing. Nettle root supplements (including the special extract Nutra Planet sells) have never affected my results.

 

Your 131 ng/ml selenium is perfect. Zinc should be zinc citrate to inhibit prostate cancer growth. NAC is one of the worst antioxidants you can take because of how it interferes with metabolic signalling. 300 mcg is closer to a physiological melatonin dose. TMG has risks, so I prefer gobs of glycine, which might be a methionine restriction mimic. Whey is an mTOR stimulant so should be used sparingly, if at all. Berberine is an antibiotic so I'm concerned about a possible negative impact on gut flora. Lipoic acid consumes methyl groups via S-methylation, so you could try dumping it to see if homocysteine will decline.

[pamojja]

 

Thank you Timar. I would be also interested to your spreadsheet, that looks impressive! Btw that is where technology should really be more helpful, e.g. with your own App on say an IBM's Watson cloud or similar.

 

Well, expect nothing too fancy. It's really just a spreadsheet providing an overview of the US and EU RDAs and ULs, my own ULs and a table to enter your intakes from diet and supplements. Anyway, I'll publish it after adding some more references and annotations

 

Though this spreadsheet is more to get second interpretations for my labs, it also monitors my supplementation (Disclaimer: the therapeutic doses [TD] ranges are meant only when working with a knowledgeable orthomolecular physician!).

 

Feel free to comment.

Edited by pamojja, 06 August 2014 - 08:47 PM.

[albedo]

DHEA has never had an effect on my estradiol. My estradiol has only responded to anastrozole and letrozole (lowered) and Erase, Formadrol, and Triazole (raised). Letrozole's drawbacks were weight gain and elevated blood sugar and liver enzymes. Anastrozole elevated blood sugar and liver enzymes in doses high enough to raise testosterone, but at lower doses its only effect is to lower estrogen. I am shocked, shocked that the bodybuilding supplements raised estrogen while not affecting testosterone. Someone mentioned taking DHEA sublingually, which doesn't work for me, probably because DHEA needs to be sulfated in the gut to survive liver processing. Nettle root supplements (including the special extract Nutra Planet sells) have never affected my results.

 

Your 131 ng/ml selenium is perfect. Zinc should be zinc citrate to inhibit prostate cancer growth. NAC is one of the worst antioxidants you can take because of how it interferes with metabolic signalling. 300 mcg is closer to a physiological melatonin dose. TMG has risks, so I prefer gobs of glycine, which might be a methionine restriction mimic. Whey is an mTOR stimulant so should be used sparingly, if at all. Berberine is an antibiotic so I'm concerned about a possible negative impact on gut flora. Lipoic acid consumes methyl groups via S-methylation, so you could try dumping it to see if homocysteine will decline.

 

Thank you Krillin for the broad range of your reply!

 

Let me only get to the lipoic acid and homocysteine issue which I completely forgot (!) (http://www.longecity...e-2#entry507466):

 

http://www.ncbi.nlm....les/PMC2782850/

 

“…In summary, we have demonstrated that a common experimental dose of LA causes massive depletion of liver SAM, elevation of serum SAH and increased tHcy in rats…”

 

This goes with your reply even if 100mg/kg of R-LA for rat body weight (“…This dose was chosen because of the large number of published reports using similar doses and route of administration…”) looks massive when compared to what I am taking (600mg). However, the study also mentions “…Commonly used doses of LA in human disease range from 600-1800 mg/day (1), which for a 70 kg person will range from roughly 9-26 mg/kg, thus 4-10-fold less than in our rat model. However, at the higher doses it is likely that LA might pose a methylation burden and human subjects should be investigated for changes in the transmethylation and transsulfuration metabolites. A recent report suggests that an improved formulation of R-(+)-LA has significantly higher bioavailability and thus, might be expected to have more effect on methylation status (38)…”

 

So I take the point and probably the best strategy would be rather than adding supplements (e.g. extra folate as methylfolate, TMG, etc.) to reduce them adding R-LA to the list of stuff to temporarily remove and see results.

 

I also need to come back to my previous reply to Timar and correct it.

 

The same study goes on to say: “... Homocysteine can be methylated by either betaine to produce methionine and N, N-dimethylglycine by betaine homocysteine methyltransferase (BHMT) or by 5-methyltetrahydrofolate (5MTHF) by methionine synthase, a reaction dependent on folate and methylcobalamin (MECbl)...” As I am homozygous on BHMT mutations, I might have that part of the non-folate dependent remethylation path not working properly (even if mutation doesn't necessarily mean there is a problem with the functioning of that gene). I probably was confused in my reply to Timar, as in my methylation report I read “…According to Dr. Yasko, a homozygous mutation of BHMT 01, BHMT 02, BHMT 04, can produce results similar to one with a CBS upregulation even if you don't have a CBS upregulation…” “…CBS defects are actually upregulations. This means the enzyme works too fast. In these patients, it's common to see low levels of cystathionine and homocysteine since there is a rapid conversion to taurine…”. So I did not pay adequate attention to the BHMT gene (rather than the MTHFR gene where I seem not having homocysteine rising mutations).

 

The following study also might suggest that even if I increase my folate, which I am resisting to as long term strategy, I might not be reducing total homocysteine when BHMT does not work properly: “…We conclude that the BHMT pathway is a major route for the elimination of Hcy in mice and that the MS pathway has little excess capacity to methylate the Hcy that accumulates when the BHMT pathway is blocked…”

http://jn.nutrition....42/11/1964.full

 

 

 

 

[albedo]

I have run a subset of tests after 5 months to see if the changes in my supplementation made a change on glucose, cholesterol, homocysteine and RBC magnesium. Two questions in red:

• Total cholesterol went down from 247 to 151 (ref. range < 193).
• HDL remained at 69.5 (ref. range > 39).
• Ratio Total/HDL improved at 2.2
• LDL went down from 154.4 to 88.8 (ref. range < 131)

I associate this to the RYR supplementation (1800mg) and maintaining a good exercise program.

• The homocysteine went down from 16.1 to 10.0.

I associate this to having removed R-ALA, Niacin and the Green Coffee Extract (probably in that order of importance) while keeping 1/2 dose of the LEF B-Complex providing the RDA of folate 400mcg and adding methycobalamin. I intend to continue so while I admit I am unhappy for R-ALA and Niacin which I liked to supplement (btw, does anyone know if, similarly to Niacin, there might be an homocysteine rising effect by Nicotinamide Riboside?)

• Fasting glucose was 83 (ref. range 79-115) and A1C 5.1 (ref range 4.0-6.0)

• Unfortunately for my RBC magnesium and despite an increase from 4.09 to 4.26 (I am supplementing with 1800mg of magnesium citrate prescribed by my doctor providing 300mg of magnesium) I am still under the ref range (4.77-5.84). I also noticed a muscular cramp happening in the night about 2 weeks ago which is very rare but a sign I need to increase maybe absorption or dosage. What would you recommend?

         

 

[serp777]

 

Why would you take selenium supplements? Huge mistake--

 

http://www.webmd.com...prostate-cancer

 

But these findings jibe with other studies that have linked taking large amounts of supplements with increased cancer risk, Kristal said. Such studies have tied large amounts of omega-3 fatty acids to endometrial cancer, excess folate to colon cancer and beta carotene supplementation to lung cancer, he said. High doses of selenium have also been linked to skin cancer, he added.

"As humans, we evolved with the levels of micronutrients you'd normally get with food," Kristal said. "There's no benefit to taking high doses of these micronutrients. There's only risk."

 

*sigh*

 

I find it really upsetting when scientists who should know better indulge in such biased, exaggerated, simplistic and sensationalist statements. Why the hell are they doing that? Are they that desperate for media attention? This whole paragraph is full of overgeneralizations and misrepresentations. The link between both omega-3 fatty acids and folate and certain cancers is spurious at best. (The study relating negligibly higher levels of omega-3 in red blood cells with an increased risk of prostate cancer is actually one of the best example of the sensationalist BS that unfortunately seems to be on the rise in scientific publishing). The relation between beta-carotene and lung cancer has been limited to smokers and asbestos workers and is most likely due to the extreme conditions of oxidative stress in their lung tissues. The last statement is particulalry infuriating, as he commits the inexcusable fallacy of generalizing from those very specific examples to all micronutrients! By doing so he is really making a fool out of himself, as anyone having some knowledge of the literature sees that his statement is factually wrong, as there have been numerous examples where "high" doses (e.g. above the RDA) of certain micronutrients have shown benefical effects in RCTs (think of nicin, EPA and DHA, etc.; for a lot of micronutrients beneficial effects have been shown under certain conditions).

 

Moreover, what are the "levels of micronutrients you'd normally get with food"? (Appeal to nature, anyone?) What does normally mean? When you are living in Northern or Central Europe, you normally get far less selenium from the diet than people living in North America, because the Ice Age glaciers have depleted the soil of selenium (in fact, American wheat may contain up to 50(!) times more selenium than European wheat). When you are a Guarani indian living in the Amazon rainforest you normally get several milligrams(!) of selenium a day, because brazil nuts are one of your main dietary staples. Hence I expect from a serious scientist to refrain from such nonsensical statements.

 

Considering your supplement regime, albedo:

 

LEF Multi MIX caps (1/5)
LEF Fish Oil 2000mg (1/4)
LEF R-LA 600mg
LEF ALCAR 620mg
LEF Super Carnosine 500mg (1/2)
LEF Cognitex (cycling)
LEF Vit D3 (1000-2000IU)
LEF Super Ubiquinol 50mg
LEF Gamma Tocopherols/Tocotrienols (2/7)
LEF Caloric Restriction Mimetic w/ t-resveratrol (1/2)
LEF Super Zeaxanthin
LEF Advanced Natural Prostate Formula
LEF Super BioCurcumin 400mg (1/2)
LEF Super Selenium complex 200mcg (2/7)
LEF Optizinc 30mg (1/2)
LEF Magnesium 320mg
LEF Endothelial Defense (cycling)
LEF NAC 600mg (1/2)
LEF Mega Green Tea
LEF Chlorophyllin
NewChapter Zyflamend
LEF Lycopene 10mg (1/2)
LEF Super K w/ K2 complex
CellForte IP6 & Inositol
Piracetam 800-1600mg
Jarrow Dophilus EPS Probiotics
LEF Melatonin 1mg (2/7)
Dragon River Cilantro extract
LEF HepatoPro PPC 900mg (Polyunsaturated Phosphatidylcholine) (cycling)
LEF B Complete Complex (1/4)
Nat&Form Red Yeast Rice (1200-1800 mg)
LEF TMG (1000mg) (cycled)
LEF Optimized Garlic
VitImmune I3C w DIM 200 mg
LEF Vanadyl Sulfate 7.5mg (2/7)
LEF Copper 2mg (2/7)

 

I would refrain from taking any supplemental copper, which is already abundant in any decent diet, particularly if it includes nuts, seeds and some dark chocolate. In fact, the major advatages of zinc supplementation may be due to the lowering in copper status. High-dose Lipoic acid may be a bit of a gamble because it is a potent antioxidant and we know that high-dose supplemental antioxidants can have detrimental effects by interfering with hormesis. Moreover, there are some overlapping supplements in your supplement regime that may add up to undesirably high levels of some of the included micronutrients but at the given dose are probably just uneconomical. I have those supplements in mind:

 

LEF Multi MIX caps (1/5)
LEF Vit D3 (1000-2000IU)
LEF Gamma Tocopherols/Tocotrienols (2/7)
LEF Super Selenium complex 200mcg (2/7)
LEF Optizinc 30mg (1/2)
LEF B Complete Complex (1/4)

 

You could easily replace all of them except the mix by:

 

LEF Two-per-Day (1/2) - which provides levels of B vitamins almost identical to 1/4 dose of B complex, 1000 IU D3, 33 mg of alpha-tocopherols plus 10 mg of other tocopherols (as I said, I would rather go easy on antioxidants, so this is plenty), 100 mcg selenium complex (with selenocysteine and not selenomethionine being the predominant form of selenium, which may be crucially important - maybe I'm going to write about that in the selenium topic) and 15 mg of zinc - and by doing to safe a lot of money. As the Two-per-Day also contains all the remaining essential micronutrients you could even think about cutting out the Mix and thereby only missing out on the very low doses of additional phytochemicals from the 1/5, which really shouldn't be much of a loss for anyone eating a decent diet.

 

Btw, I have developed a little tool in an excel sheet to keep control of my own micronutrient intake from diet and supplements and to make sure it stays within the safe range. I even have devised my own upper limits for defining that range, by including and reviewing both the IOM's and the EFSA's upper limits, taking into account more recent evidence as well as the life extensionist's perspective. If there's interest, I could dress it up and publish it as google document...

 

 

Well, on the flip side, people on this forum tend to be very lenient to supplements, probably because they have taken it at some point or recommended it.  Is it possible that overdoses of some vitamins and minerals could lead to negative health effects? Yes. You also talk about minerals from food vs a supplement, which are two different things. Food makes a huge impact on the mineral vs just taking it by itself or in a vitamin.

 

And also, it's not just one study. There are a variety of studies, which question the usefulness and possible danger of selenium excess.

 

"However, the large prevention study SELECT (Selenium and Vitamin E Cancer Prevention Trial) ⁽⁸⁾, based on previous data indicating that selenium and vitamin E reduced the incidence of prostate cancer, did not find evidence of protective effects of selenium. The trial was suspended in January 2009, when initial data analysis showed no reduction in the risk of prostate cancer with selenium alone or with vitamin E ⁽²¹⁾. Another study showed selenium, when used together with soy and Vitamin E, did not prevent prostate cancer progression ⁽²⁷⁾. Moreover, results from a cross-sectional analysis of men with prostate cancer indicate that selenium levels may influence the risk of aggressive prostate cancer ⁽²²⁾. Further, a revie"

 

http://www.mskcc.org...e/herb/selenium

 

"

A new report in the Journal of the National Cancer Institute clarifies the picture. A team of researchers from across the U.S. looked specifically at almost 5,000 of the SELECT volunteers who sent in toenail clippings when they joined the trial. Toenail clippings are a great way to measure how much selenium is in a man’s (or woman’s) body. The new study showed that:

• Taking vitamin E alone boosted the risk of developing high-grade prostate cancer, but only in men who started the study with low selenium levels.
• Taking selenium, either alone or in combination with vitamin E, increased the risk of high-grade prostate cancer in men who started the study with high selenium levels, but not in those with low selenium levels.
• Among men who didn’t take either vitamin E or selenium, those who started the study with high selenium levels were no more likely to have developed prostate cancer than men who started it with low selenium levels. (This means the culprit is added selenium from supplements, not selenium from food.)

“The new data are very troubling, and emphasize that supplements can cause real and tangible harm,” says Dr. Garnick. “Any claims of benefits from dietary supplements must be ignored unless large, controlled, and well-conducted investigations confirm such benefits—which I believe will be a very rare occurrence.”"

 

http://www.health.ha...sk-201402287059

 

Since you're so interested in bashing studies, perhaps you could actually find counter research instead of pointlessly poking holes in the claims of a single researcher. So what if a researcher makes a fallacious argument? A researcher's arguments don't reflect on the quality of a study.

 

But regardless of all your claims here, what benefit does an excessive amount of selenium provide? Unless you are deficient I can't fathom the use of taking selenium. Maybe you have some studies I haven't heard of showing benefits of increased selenium dosages?

Edited by serp777, 01 December 2014 - 04:18 AM.

[MachineGhostX]

Unfortunately for my RBC magnesium and despite an increase from 4.09 to 4.26 (I am supplementing with 1800mg of magnesium citrate prescribed by my doctor providing 300mg of magnesium) I am still under the ref range (4.77-5.84). I also noticed a muscular cramp happening in the night about 2 weeks ago which is very rare but a sign I need to increase maybe absorption or dosage. What would you recommend?         

 

 

I'm surprised you don't have relentless diarreah from that much magnesium citrate.  I'd suggest switching to a more bioavailable form, i.e. magnesium glycinate from Albion.  600mg elemental in 3 caplets from VitaCost.

Edited by MachineGhostX, 01 December 2014 - 05:48 AM.

[MachineGhostX]

 

But regardless of all your claims here, what benefit does an excessive amount of selenium provide? Unless you are deficient I can't fathom the use of taking selenium. Maybe you have some studies I haven't heard of showing benefits of increased selenium dosages?

 

Two quick points.  The so-called "Vitamin E" was alpha-tocopherol which displaces the other E isomers in the body.  There are various forms of selenium and not all are natural; selenium also has a pretty narrow toxicity range.  Selenium defenciency isn't uncommon.  200mcg yeast-derived selenium is prudent insurance unless you're a Brazil Nut gobbler.

 

Edited by MachineGhostX, 01 December 2014 - 05:50 AM.

[serp777]

 

 

But regardless of all your claims here, what benefit does an excessive amount of selenium provide? Unless you are deficient I can't fathom the use of taking selenium. Maybe you have some studies I haven't heard of showing benefits of increased selenium dosages?

 

Two quick points.  The so-called "Vitamin E" was alpha-tocopherol which displaces the other E isomers in the body.  There are various forms of selenium and not all are natural; selenium also has a pretty narrow toxicity range.  Selenium defenciency isn't uncommon.  200mcg yeast-derived selenium is prudent insurance unless you're a Brazil Nut gobbler.

 

 

Well i wasn't really discussing vitamin E, that just happened to be included in the quote from the Harvard review. Also the daily recommended dosage is 75 ug, and 200 ug exceeds that by 2.66667 times. Thats in addition to the selenium you're already getting. And it's only not uncommon because China contains most of the world's population and the soil there has low levels of selenium.

 

If anything you should probably do a blood test or urine test to see what you're deficient in and supplement the difference to meet the recommended level. Otherwise it has almost no benefits im aware of for exceeding that dosage. Perhaps you have a study showing that 200 ug is somehow more beneficial than the recommended 75 ug?

 

According to the NIH, most Americans get enough selenium in their diet, and I think most people on this forum are Americans, or maybe Europeans idk.

 

http://ods.od.nih.go...thProfessional/

Edited by serp777, 01 December 2014 - 06:15 AM.

[albedo]

 

Unfortunately for my RBC magnesium and despite an increase from 4.09 to 4.26 (I am supplementing with 1800mg of magnesium citrate prescribed by my doctor providing 300mg of magnesium) I am still under the ref range (4.77-5.84). I also noticed a muscular cramp happening in the night about 2 weeks ago which is very rare but a sign I need to increase maybe absorption or dosage. What would you recommend?         

 

 

I'm surprised you don't have relentless diarreah from that much magnesium citrate.  I'd suggest switching to a more bioavailable form, i.e. magnesium glycinate from Albion.  600mg elemental in 3 caplets from VitaCost.

 

 

Thank you. No it looks like I do not have a major problem with that despite sometime I noticed stool is not well formed and this might be an hint I need to change. This is the composition of the product:

 

• magnesium citrate (calc. anhydrous) 1830 mg
• magnesium content: 12 mmol = 24 mEq = 295.7 mg

Yes I will discuss a possible change with my doctor. I wonder what is the best form of magnesium in general, there is so much on the market today! What about L-Threonate which LEF makes a case for better absorption ? At VitaCost I could only find a 400mg version of glycinate. Can you provide a link?