mk4 dosing?

[GRay]

@sunsunsun thank you.

Basically, I'm gathering that for general health purposes, Mk4 should be supplemented at 1mg per day.

[GRay]

I'm looking at Ratio of Ca to mk4 in aged cheese and Milk.

Parmesan cheese has a ratio of about 250mg Ca to 15mcg mk4.
Milk has even less.

I guess the 1mg daily estimate is probably a generous amount then

[LucH]

@GRay said in mk4 dosing?:

I think RP recommends more than 850mg Ca, but to my understanding it depends on the ratio of Ca to Phosphorus. For example, I need a total of 1500mg Ca to keep my ratio to phosphorus I believe at 1:1 or 1:2, I totally forgot what is the ratio goal.

Ca supplement
*) RP target
If I remember well, RP's advice was between 850 – 1200 mg Ca, with the ratio P / Ca being the most important (see details beneath): Ratio P / Ca close to 1 – 2.2

What difference between calcium and phosphorus would be acceptable?
For a Ca:P ratio of 1-2.2, a difference of about 1:1 to 2:1 is generally considered acceptable (if temporary situation),with a 2:1 ratio often cited as ideal (Ca:P), especially for bone health. A ratio of 1.5:1 to 2:1 is also commonly recommended. Deviations from this range, particularly a higher phosphorus intake relative to calcium, can negatively impact calcium absorption and bone health.
Mind when eating some kind of hard cheese if you’ve eaten 5 oz. beefsteak the meal before or after. (acid-base balance). Hard cheeses like Cheddar, Parmesan, and Gruyere are generally good sources of calcium.
However, the P content can also be relatively high, so moderation is key to maintaining a healthy Ca:P ratio.
We’ll have to balance Na:K too when eating hard cheese.
*) Example:
A 1-ounce serving (28 g) of Gouda cheese has 101 calories, 7.1 grams of protein, 7.8 grams of fat, and 232 milligrams of sodium. When I eat Gouda 1.5 – 2 g salt => 625 – 833 mg Na. One slice Gouda for vitamin K2.
Macronutrients and minerals for 1 slice Gouda cheese 50 g ; from Cronometer.com:
178 K/cal.
P12.5 L13.7/8.8 G0
PUFA: 0.2
Ca350 P273 Na 409
K2 1.2 mcg

*) Range target set in Cronometer log for calcium: 850 – 1200 mg.
I generally aim for 80% of my goals. Don't be too strict (in order to avoid orthorexia-like behavior).
*) Special case
Last evening, when I controlled my food intake on Cronometer.com (gold version), I saw I was under 500 mg Ca, ¾ for Mg and a bit lower for K.
For my evening meal, I ate 2 fruits, one biscuit (dried waffle 22 g) and 4 oz. beef.
Daily fiber 25 g. Target at 25-30 g. I didn't want to cook (weather too hot + laziness).
*) Undertaken correction (3 hours after the last meal)
One shake water with supplement in powder:

• 1 dose phosphacal 1 g: 146 mg P, 191 mg Ca. (optimal ratio 1/1.3 according to nutrixeal.com)
• 1 dose potassium bicarbonate 3.2 g: 1248 mg K
• ¾ dose magnesium bisglycinate powder. ¾ of 200 mg Mg.
  1 dose = 2.5 g = 10 ml, or 200 mg of elemental Mg per dose. 18% Mg and 55% glycine per 100 g.

*) Alternative Ca
When I eat rhubarb or spinach – only in this case–I take one tablet calcium citrate to capture oxalate (kidney stones => lithiasis prevention). Not the ideal excipient (Kal Calcium Citrate 1000: with Mg stearate) but from time to time, it’s OK for me.
=> Ca citrate 1585 mg: 333 mg Ca (21% Ca) (big tablet, difficult to swallow if without fat).
NB: I’ve calcium citrate powder too (Now Foods). I preferably use powder but not when I need a high level citrate in once.

*) Phosphorus / calcium ratio
1/1 to 1/1.3 for Ray Peat.
Less if you eat meat with broccoli for Chris Masterjohn. Why? Meat has amino acids that help you absorb calcium better from your diet.
Excerpts (from Chris Masterjohn):

• “So, you have processed foods = bad, meat = neutral, dairy products = good, in terms of affecting the balance of vitamin D, calcium, and phosphorus. So, the reasons for that, probably has something to do with the forms of phosphorus that are added to the food. They might be much more absorbable than the phosphorus from natural food.
  Meat isn’t just providing phosphorus, it’s also facilitating better calcium status when it’s consumed in the context of a mixed diet”.
• So my opinion is (CM speaking), you know, shoot for the 1,000-milligram mark, you can probably get away with consuming maybe 600 or 700 milligrams of calcium if you optimize everything else."
  Source: Chris Masterjohn has said in a post on “Decoding what your body needs”
  https://wellnessmama.com/podcast/256/

Useful links
*) Fructose and phosphorus
The ratio between Ca and P should be maximum 1/1, and in any case phosphorus should be lower than Ca, in the medium term.
Source: From Ray PEAT’s article “Phosphate, activation, and aging”
Excerpt:
"While fructose lowers intracellular phosphate, it also lowers the amount that the intestine absorbs from food (Kirchner, et al., 2008), and the Milne-Nielsen study suggests that it increases phosphate loss through the kidneys. The "anti-aging" protein, klotho, increases the ability of the kidneys to excrete phosphate (Dërmaku-Sopjani, et al., 2011), and like fructose, it supports energy production and maintains thermogenesis (Mori, et al., 2000).”

Useful link (in French, Translator needed)
https://mirzoune-ciboulette.forumactif.org/t1646-cles-pour-comprendre-le-fructose-quelle-place
*) Lowering inflammation by lowering excess phosphate
Interview of Ray PEAT PhD on KMUD Radio. 2012.
https://mirzoune-ciboulette.forumactif.org/t1646-cles-pour-comprendre-le-fructose-quelle-place#20235

Optimal calcium intake 520 - 840 mg for RP.

NB: Make the difference between the amount of calcium RP advised for others and what he got when drinking milk. He didn’t mind the amount much, but rather the ratio between P and Ca, provided the sources were assimilated …
That's another subject.

[GRay]

@LucH my Ca needs to be at least 1600mg to get to 1:1 with Phosphorus. Basically, I need to supplement with 1000mg Ca, and I generally use grassfed living bone from ancestral, or cheese or a combo of the two.

Are you in France or US? if the latter where do you get your mk4?

[LucH]

@GRay said in mk4 dosing?:

Basically, I need to supplement with 1000mg Ca, and I generally use grassfed living bone from ancestral, or cheese or a combo of the two.

Are you in France or US? if the latter where do you get your mk4?

Ok, right.
Remind we better absorb 4 x 250 mg Ca element than 2 x 500 mg when taking a supplement.
I live in Belgium. My MK4 comes from iherb.com in USA. Could be bought in France:
Thorn Research, liquid. Not cheap but high dose and proportionally not expensive if used as I do: 1 drop at breakfast, with minimum 25 g fat, most of the time. Otherwise, to be taken at another meal (14 - 25 - 35 g threshold).
I protect my bottle from light.

Advise: I 'd take potassium bicarbonate powder, as well as potassium citrate. Alternate.
Mine come from France, la Compagnie du bicarbonate. I buy it in one Kg (2 pounds). - 1 kg potassium bicarbonate. 1 dose 3.2 g
1 kg sodium bicarbonate (NaHCO₃)
I use NaHCO₃ in 2 ways: 1. To get rid of toxins from my fruits (pH 8.5 => 1 big tsp in water). (study, not from a post on internet) 2. when I make a cure with 2 g NaHCO₃ to reset Th1 >< Th2.

[16characterstwas]

@GRay good to take it with a little d3. There is no upper limit but as @sunsunsun said the osteoporosis studies (in japan I believe) used 45mg a day in divded doses. Some people take as little as a few mg a day.
High doses may lower blood pressure, not necessarily a problem.

Post in thread 'Ray Peat Email Advice Depository'
https://lowtoxinforum.com/threads/ray-peat-email-advice-depository.1035/post-875295

Aug 6, 2021, 9:29 PM

Q: Hello Dr. Peat

Do you know what is the best way to supplement Vitamin K?
In pill form or liquid type?
Do you know any brand that you feel comfortable recommending?
Much love

RP: I have used various forms, the important thing is that the excipient be safe, without silica, preferably no MCT.

Q: Is there any way to measure the effectiveness of the given VIT K supplement?
Should we aim for both MK-4 and MK-7?
Can you remember any that you liked specifically?
Thank you Dr. Peat

RP: The liver modifies it, so I think K1 or K2 is adequate. In a large dose, vitamin K can quickly normalize high blood pressure.

Q: Hello Dr. Peat

Do you think that maltodextrin is a safe excipient in a VIT K powder supplement?

Are the requirements for K1, K2 [MK-4] and [MK-7] different?
What is the optimal dose for someone with IBD and fibrosis/calcification symptoms?

RP: I think it’s safe if it’s the only excipient. I think any vitamin K will support the functions that depend on K; the liver can interchange the forms.
In case there are impurities in it, I think the first doses should be very small; then, 45 mg per day has been used without side effects other than lower blood pressure.

[LucH]

Liver modulation for Vitamin K
Highlights
• In theory the liver can interchange the forms of vitamin K: K1 and K2 types (Mk4 and Mk7) according to needs. However, the process is aleatory and is often deficient / insufficient when aging.
• Taking high dose Vit K (> 2 mg / 2 000 mcg) affects the mitochondrial function. Vit K assimilation leaves quinones.
• Too much of a good thing is bad: Chris Masterjohn says it could affect blood sugar control, insulin sensitivity, our metabolic rate, and, in males, testosterone production.
• Vitamins E and K are broken down in similar pathways.
• High doses of vitamin K can inhibit bone resorption, which is probably the mechanistic basis by which 45 mg/day reduce fracture risk (Iwamoto, 2013). There are several aspects of vitamin K’s biochemistry that suggest high doses vitamin K could have adverse effects on our health.
Details on next post (excerpts)

1. See my intervention on this post (Excerpts 1 & 2 on next post)
   K2 Mk4 or Mk7?
   Discussion in 'K' started by Momado965, Nov 29, 2016.
   Supplemental > K2
   Post 6 p1
   https://raypeatforum.com/community/threads/k2-mk4-or-mk7.13828/
2. See this discussion, from Mito, with studies sources and an excerpt from Chris Masterjohn “The ultimate vitamin k2 resource”
   Does vitamin K supplementation deplete vitamin E?
   https://raypeatforum.com/community/threads/does-vitamin-k-supplementation-deplete-vitamin-e.39564/post-622839

[LucH]

*) Excerpt 1
Haidut said:
MK-4 is also the form used by the humans for functions such as electron transport carrier and co-factor for the carboxylation of osteocalcin. MK-7 is at best a surrogate for MK-4.
Excerpt from my answer (LucH):
Well seen
MK-4 has effects on gene expression in bone tissue that MK-7 doesn't have.
"The investigators found that MK-4 strongly activates transcription of two specific genes in osteoblast cells. Osteoblasts are cells that create bone tissue. The genes are GDF15 and STC2 and they're involved in bone and cartilage formation. They tested K1 and MK-7, and in contrast to MK-4, they did not activate transcription of the genes in the slightest. This shows that MK-4 has effects on gene expression in bone tissue that MK-7 doesn't have."
MK-7 has also less interaction with enzymes that would bring it into the cells (due to a longer side-chain, more lipophile)
Source: Mk4 is preferably used by body
“Vitamin K2 induces phosphorylation of protein kinase A and expression of novel target genes in osteoblastic cells”
T Ichikawa1, K Horie-Inoue1, K Ikeda1, B Blumberg2 and S Inoue1,3 1
I would not recommend taking more than 2 mg / day, given the fact that the menaquinones (K2 family) are broken down into menadiones, which can be "toxic" If repeated.
References
http://ajplung.physiology.org/content/ajplung/262/5/L637.full.pdf
http://www.ncbi.nlm.nih.gov/pubmed/1990978
=> Stress bringing depletion of Glutathion
NB 2 mg = 2000 mcg.

*) Excerpt 2: How much could give side-effects?
Haidut asking:
“Does it mean that more than 2mg K2 at a time will lead to toxic levels of K3?”
LucH answers:
=> Well, we don't know exactly. This is a supposed by-side effect. I explain.
Conversion of excess menaquinones in menadiones
We know menadione is a metabolite of oral vitamin K supplement.
Phylloquinone (K1) is converted into menaquinone-4 and accumulates in extrahepatic tissues. Neither the route nor the function of the conversion is totally known. One supposed metabolic route is the conversion of 5 – 25 % of menadione from phylloquinone by catabolic activity. 10 – 15 % is most likely converted. But this is aleatory (due to intestinal absorption) and not equally distributed. We can only measure the presence of menadione in urine and make deductions when excreted. (1)
When taking excess menadiones, through conversion / excretion it would be quite advisable to take some NAC to get enough selenium to neutralize ROS. Adaptive response. (2) Menadione generates ROS through redox cycling, and high concentrations trigger cell death. If lack of glutathione. (3 – 4)
Note: Avoid high dose NAC (> 2 500 mg) if supplementing B3 vitamin.
Menadione in excess clearly affects the mitochondrial function. (5)
However there is no reported health risk when taking K2. Excess K2 is excreted through urine and feces (through bile). No direct adverse effect doesn’t mean there is no impact on energy level. This is a personal comment. It depends on the way the body neutralizes an excess oral supplement.
Mind excess alpha-tocopherols too (vitamin E) because it may interfere with synthesis of K2. (6- 7) Also if you take phytonutrients as AINS (curcumine or aspirin) because it affects cytochrome P450 (detox pathway). You need a recovery period between 2 cures.

1. https://www.researchgate.net/publication/7305589_Menadione_is_a_metabolite_of_oral_vitamin_K
2. http://www.jbc.org/content/281/52/40485.full.pdf
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005834/
   Oxidative Stress-Induced Apoptosis by Menadione at high concentration.
3. https://www.ncbi.nlm.nih.gov/pubmed/20937380 +
4. http://www.sciencedirect.com/science/article/pii/S1521661601951290
5. http://jcs.biologists.org/content/106/1/309
6. http://health.oregonstate.edu/biblio/vitamin-e-decreases-extra-hepatic-menaquinone-4-concentrations-rats-fed-menadione-or
7. http://www.pubpdf.com/pub/22707266/Vitamin-E-decreases-extra-hepatic-menaquinone-4-concentrations-in-rats-fed-menadione-or-phylloquinon
   α-Toco may interfere with the side chain removal of phylloquinone (PK) to form menadione (MN) as an intermediate for synthesis of tissue-specific menaquinone-4 (MK-4).

[GRay]

@16characterstwas

Thank you. I have seen now that study.

I made a research on how much mk4 is found in meat eggs and dairy, and it seems to me that doses of mk4 in the mg’s are more pharmacologic rather than physiologic

[GRay]

@LucH

Thanks. I think I will stick to 1mg daily then. It makes sense to me that higher doses are more pharmacologically. As I stated in a prior comment, we would have never obtained mk4 in mg’s through food alone. Probably 1mg a pretty good dose of it.

Question for you, I was looking at the Throne K2 as well, using one drop it means it will last long time, do you know if there is a shelf life after the product is being opened?

I was looking at Kuionone from haidut, 2mg per drop over 700 drops, but I was told it last 12 months only.

[16characterstwas]

@GRay you’re welcome. Also good to to keep in mind that epidemiologically most people tend to be deficient in vitamins d and k.

[LucH]

@GRay said in mk4 dosing?:

Question for you, I was looking at the Throne K2 as well, using one drop it means it will last long time, do you know if there is a shelf life after the product is being opened?

I was looking at Kuionone from haidut, 2mg per drop over 700 drops, but I was told it last 12 months only.

Yes, liquid form of Mk4 could last one year, once open. Deduction. If in dark bottle, put in a cupboard (not in the light), at constant temperature.
Not for Mk7. 3 months only if not in softgel. Long tail, more fragile.
Remember: 6 days of the week, I take one drop MK4 (1 000 mcg) at breakfast, with minimum 25 g fat. Otherwise at midday.
The next meal, I take D3 ( 2 000 UI in summertime if I don't go outside; 5 000 UI in winter time, for 6 months). Half life of MK4 is short (a few hours).
So you could take a second drop MK4 at the following meal (evening meal). I don't do it usually.

Once a week I take 10 000 UI retinol palmitate (vitamin A). kept in the fridge (it lasts longer). Always on Monday or Tuesday, not to forget it. At first meal (breakfast) vit A, later K2, and at last D3.
When I take vit E (mix toco 400 UI), I take it with a snack, in the afternoon. Only 6 g fat required. Vit E twice a week.
2x/wk I take 100 mcg selenium. With a meal. Not at the same time as vitamin E.
Once a week I take a very high dose of a mix K1 and k2 Mk4 + MK7 in a softgel.
Of course, it's a pharmacological dosage. Not a RDA.