Life Extension Magazine®
Scientist doing a vitamin study taking account of magnesium deficiencies

Why Vitamin Studies Can Sometimes Fail

Eye-opening reports reveal how deficiencies in magnesium and vitamin K can negate the benefits of vitamin D.

By William Faloon.

William Faloon
William Faloon

A study published in 2020 evaluated vitamin K and vitamin D status in a large group of people, average age 70.1

Over a 17-year period the researchers found:

  • A death rate of 68.2% in the low vitamin K and low vitamin D group.
  • Fewer deaths (38.6%) in the normal vitamin D and normal vitamin K group.

This translates into a 60% increased mortality risk in the low vitamin D and low vitamin K group after adjusting for variables such as age and glycemic control.1

This 2020 published report describes mechanisms by which the body needs ample levels of vitamin D and vitamin K to derive their benefits.

What struck me about this study is how it pulls together conflicting findings about the disease-preventing potential of vitamin D.

Studies that fail to show robust benefits might involve population groups that are deficient in other nutrients required for vitamin D to function, such as vitamin K and magnesium.

Most Life Extension® readers supplement with these complementary nutrients, but much of the public remains deficient in magnesium, with less-than-optimal intake of vitamin K.

A meta-analysis of 84 articles published in 2019 reported reductions in all-cause mortality in people with higher blood levels of 25-hydroxyvitamin D.2

Another meta-analysis of 21 randomized clinical trials published the same year did not show significant longevity benefits using vitamin D supplements.3

In 2007, a randomized placebo-controlled study found a 60% reduced risk for developing any cancer in those supplementing with vitamin D and calcium.4

When cancers diagnosed the first year were excluded from this2007 study, the overall cancer risk was reduced by about 77%.4

The 2007 study received widespread media coverage and led more Americans to supplement with vitamin D. Other studies, however, did not find the same cancer rate reductions.

These conflicting data sets about vitamin D caused some doctors to discredit its lifesaving potential. Others said more research is needed before higher-potency vitamin D supplementation is recommended.

Much of the public remains confused.

Putting the Pieces Together

Scientist taking notes on vitamin D and K effects

Studies published in the 2003-2007 period suggest a synergistic effect of vitamins D and K on cardio-vascular health.5-8

Calcifications of coronary arteries and valves are common causes of heart disease.9,10

Vitamin D upregulates a protein (matrix GLA)11 that is a powerful inhibitor of vascular calcification.

The upregulated matrix GLA protein then requires vitamin K to activate into calcium-blocking mode.

Deficiency of either vitamin D or vitamin K prevents proper activation of this calcium-blocking protein, which leads to vascular calcification.12

The introduction of this editorial described a 2020 published study showing a statistically significant 60% increased mortality risk, after adjustment for age, gender, and glycemic control, in people with low vitamin D + low vitamin K status.1

The authors of this study emphasized the synergistic effects of vitamin D and vitamin K and concluded their paper stating:

“Future studies should investigate whether vitamin D and K supplementation could help improve cardiovascular health and decrease cardiovascular disease risk.”1

We at Life Extension® partially concur with this recommendation but opine that greater synergistic benefits might occur if supplemental magnesium is also included.

Conversion Steps Needed To Obtain Active Vitamin D

Infographic of how vitamin d is metabolized

Magnesium is involved in the conversion of vitamin D from dietary supplements and/or sunlight to a biologically active form.

Vitamin D from sunlight or supplements is converted in a magnesium-dependent enzymatic reaction to 25-hydroxyvitamin D in the liver.

It then converts to its biologically active 1,25-dihydroxy-vitamin D form in the kidneys via a magnesium-dependent enzymatic reaction.

Activated vitamin D (1,25-hydroxy-vitamin D) is transported throughout the body in the blood via vitamin D-binding protein, for which magnesium is a cofactor.

Magnesium Activates Vitamin D

Magnesium activates over 300 enzymes in the body, including enzymes needed for vitamin D to become functional.13-15

Optimal benefits of vitamin D might not be achieved without adequate magnesium.

That’s because the biological activity of vitamin D is dependent on magnesium!

When you swallow a capsule of vitamin D, it is first converted in the liver into 25-hydroxyvitamin D, and then further transformed in the kidneys into biologically active 1,25-dihydroxyvitamin D.15 (See graphic above.)

The transformation into activated vitamin D that occurs in the liver and kidneys is required, whether you obtain your vitamin D from sunlight, food, or supplements.

Both liver and kidney enzymatic conversions of vitamin D are magnesium-dependent. This means that without adequate magnesium, people might not derive optimal benefits of vitamin D because it will not convert into its active form.

The major carrier of vitamin D in blood throughout the body is vitamin D-binding protein. The activity of vitamin D–binding protein is also a magnesium-dependent process.

The graphic above depicts how magnesium is essential for vitamin D to activate and be transported throughout the body.

Researchers continue to explore the degree of magnesium deficiency that has the greatest negative effect on vitamin D activation in the body.16,17

Widespread Magnesium Deficit

It is estimated that the magnesium content in various food and vegetables is 25% to 80% lower compared with the levels before 1950.18

Today’s drinking water contains little or no magnesium.

Approximately 64% of men and 67% of women in the U.S. have inadequate dietary intake of magnesium.

Among those above age 71, roughly 81% of men and 82% of women have inadequate dietary intake of magnesium.19,20

Inadequate magnesium levels have been linked with an increased risk for cardiovascular disease, including stroke, coronary heart disease, heart failure, arrhythmia, and death.21,22

Higher blood levels of magnesium are associated with a lower cardiovascular disease risk.22

Are Vitamin D Studies Influenced by Magnesium Intakes?

Lab tech examining vitamin d study sample

In the conventional medical setting where vitamin D is used to treat rickets, magnesium supplementation was shown to improve vitamin D status.23-25

In observational studies where vitamin D deficiency was associated with increased cardiovascular mortality risk, consumption of magnesium yielded favorable results.26

The activities of vitamin D–converting enzymes in the liver and kidneys, along with vitamin D–binding proteins in blood rely on magnesium.

According to data from the National Health and Nutrition Examination Survey, higher consumption of magnesium was associated with a reduced risk of vitamin D deficiency or insufficiency.26

Magnesium is an essential cofactor to transform vitamin D into its active form (1,25-dihydroxyvitamin D).

Vitamin D in turn can increase intestinal absorption of magnesium.

Clinical Trials Should Include all Three Nutrients

Blood vial labeled for magnesium testing

Despite this array of data, clinical trials often test vitamin D by itself.

If miraculous benefits are not found, vitamin D is proclaimed to have failed by the study authors and this is parroted by the media.

I wish there were a way to analyze the studies showing vitamin D’s robust benefits and compare them to those that fail. It could be that the magnesium content of food and water in the area where studies were conducted varied widely.

Dietary intakes of magnesium and vitamin K can be unaccounted confounding factors in studies that test vitamin D alone.

I look forward to studies that combine vitamin D + vitamin K + magnesium to ascertain what degree of overall mortality risk reduction might occur.

These nutrients are inexpensive.

Widespread use might induce meaningful improvements in healthy longevity and lower medical expenditures faced by today’s aging population.

In this month’s issue…

Scientist looking at sample for immune function method

Research into the regenerative properties of NAD+ continues to yield intriguing findings. The article on page 26 describes why increasing numbers of people are using precursors like nicotinamide riboside to boost cellular NAD+.

Immune senescence is a widespread cause of chronic inflammation and inability to mount immune responses against pathogens and aberrant cells. Defective immune responses are a common cause of premature illness and mortality, especially in persons over age 65.

The article on page 36 describes a low-cost method of improving immune function.

Summary

The title of this editorial is:

“Why Vitamin Studies Sometimes Fail”

The succinct answer in many cases is the failure to include cofactors like magnesium to enable vitamin D to convert to its active form.

Even more intriguing is 2020 published data showing a 60% increased risk of death in people with low vitamin D and low vitamin K status.

Life Extension® readers should feel vindicated that they long ago began supplementing with vitamin D + magnesium + vitamin K.

For longer life,

For Longer Life

William Faloon

References

  1. Dal Canto E, Beulens JWJ, Elders P, et al. The Association of Vitamin D and Vitamin K Status with Subclinical Measures of Cardiovascular Health and All-Cause Mortality in Older Adults: The Hoorn Study. J Nutr. 2020 Dec 10;150(12):3171-9.
  2. Heath AK, Kim IY, Hodge AM, et al. Vitamin D Status and Mortality: A Systematic Review of Observational Studies. Int J Environ Res Public Health. 2019 Jan 29;16(3).
  3. Barbarawi M, Kheiri B, Zayed Y, et al. Vitamin D Supplementation and Cardiovascular Disease Risks in More Than 83000 Individuals in 21 Randomized Clinical Trials: A Meta-analysis. JAMA Cardiol. 2019 Aug 1;4(8):765-76.
  4. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91.
  5. Bolton-Smith C, McMurdo ME, Paterson CR, et al. Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women. J Bone Miner Res. 2007 Apr;22(4):509-19.
  6. Braam LA, Hoeks AP, Brouns F, et al. Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: a follow-up study. Thromb Haemost. 2004 Feb;91(2):373-80.
  7. Braam LA, Knapen MH, Geusens P, et al. Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age. Calcif Tissue Int. 2003 Jul;73(1):21-6.
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  12. Hou YC, Lu CL, Zheng CM, et al. Emerging Role of Vitamins D and K in Modulating Uremic Vascular Calcification: The Aspect of Passive Calcification. Nutrients. 2019 Jan 12;11(1):152.
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  14. Available at: https://lpi.oregonstate.edu/mic/minerals/magnesium. Accessed April 19, 2021.
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  17. Dai Q, Zhu X, Manson JE, et al. Magnesium status and supplementation influence vitamin D status and metabolism: results from a randomized trial. Am J Clin Nutr. 2018 Dec 1;108(6):1249-58.
  18. Thomas D. The mineral depletion of foods available to us as a nation (1940-2002)--a review of the 6th Edition of McCance and Widdowson. Nutr Health. 2007;19(1-2):21-55.
  19. Qu X, Jin F, Hao Y, et al. Magnesium and the risk of cardiovascular events: a meta-analysis of prospective cohort studies. PLoS One. 2013;8(3):e57720.
  20. Kostov K, Halacheva L. Role of Magnesium Deficiency in Promoting Atherosclerosis, Endothelial Dysfunction, and Arterial Stiffening as Risk Factors for Hypertension. Int J Mol Sci. 2018 Jun 11;19(6).
  21. DiNicolantonio JJ, Liu J, O’Keefe JH. Magnesium for the prevention and treatment of cardiovascular disease. Open Heart. 2018;5(2):e000775.
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  23. Reddy V, Sivakumar B. Magnesium-dependent vitamin-D-resistant rickets. Lancet. 1974 May 18;1(7864):963-5.
  24. Rude RK, Adams JS, Ryzen E, et al. Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol Metab. 1985 Nov;61(5):933-40.
  25. Fuss M, Bergmann P, Bergans A, et al. Correction of low circulating levels of 1,25-dihydroxyvitamin D by 25-hydroxyvitamin D during reversal of hypomagnesaemia. Clin Endocrinol (Oxf). 1989 Jul;31(1):31-8.
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