Life Extension Magazine

Life Extension Magazine April 2006

Report

Vitamin K's Delicate Balancing Act

By Julius G. Goepp, MD

Advances in health, nutrition, and the biology of aging are enabling growing numbers of adults to achieve extended life spans.1 Some of the most surprising research findings of recent years revolve around vitamin K.2,3

Scientists have discovered that vitamin K regulates several biochemical processes that require exquisite balance to function normally, including blood coagulation, bone mineralization, and vascular health. Through these diverse actions, vitamin K holds promise in helping to prevent and manage some of the most crippling conditions associated with advancing age, including osteoporosis, coronary artery disease, and blood clots that can induce heart attack or stroke.

Observations of how vitamin K affects the health of domestic cattle led to fundamental discoveries about the vitamin and to breakthroughs in our ability to treat some of the most debilitating diseases associated with aging.4 Warfarin (Coumadin®), the drug derived from these observations, has saved millions of lives by preventing or reducing blood clots.5 Advanced surgical techniques such as the use of artificial heart valves and vascular shunts are made possible by the careful interplay between warfarin-like drugs and vitamin K itself.6

This article will focus on how vitamin K works to maintain tight control over three vital bodily processes: blood coagulation, bone mineralization, and vascular health and elasticity This article also describes breakthrough research indicating that the use of low-dose vitamin K supplements might reduce the side effects associated with long-term Coumadin® drug therapy.

Unique Among All Vitamins

Vitamin K is unique among the vitamins in several respects. It is the only vitamin that can be produced within the human body, but not by the body (to be defined as a vitamin, a substance cannot be produced by human tissue).7 Beneficial bacteria in the human intestine produce about 75% of the vitamin K the body absorbs each day, with the other 25% coming from dietary sources.8 The amount of vitamin K absorbed each day from both sources usually is equal to the minimum amount required for normal bodily function.9

Like the body’s absorption of other fat-soluble vitamins (A, D, and E), vitamin K absorption depends on healthy liver and gallbladder function.10-13 Unlike the other fat-soluble vitamins, however, vitamin K is not stored in the body.9 Taken together, these factors explain why the net daily balance of vitamin K is so delicate. As people live longer and vitamin K-dependent processes are discovered in more and more tissues, more scientists are suggesting that vitamin K is needed in larger quantities than what was once thought, particularly in aging adults.14,15

Vitamin K occurs in nature in two major forms—K1 and K2—with molecular structures that are similar to cholesterol. These structures make the molecules fat soluble, and seem to be what gives the vitamin its activity. The terminology about vitamin K can be confusing, partly because researchers are learning more about the vitamin each day. In general, K1 (phylloquinone) is the form of the vitamin chiefly derived from dietary sources such as leafy green vegetables and soybean oil, while K2 (menaquinone) is produced by bacteria in the intestine.16 While K2 may be more important in bone mineralization than K1, the amount of K2 absorbed from the gut provides only a fraction of the total daily requirement.17 Laboratory and some human data now suggest that K1 is in fact converted to K2 in tissues.18,19 This means that supplementing with vitamin K1 produces reliable absorption and supports all the important functions discussed in this article.

Although vitamin K affects many vital processes, it has the same fundamental action in all tissues. Vitamin K acts as a cofactor in converting the amino acid glutamate into gamma-carboxyglutamate, or Gla.20 Gla-containing proteins (Gla-proteins) regulate many of the myriad physiological processes controlled by calcium. Vitamin K thus participates in some of the body’s most finely tuned systems. Vitamin K’s action was first discovered, and is still most thoroughly understood, in the control of blood coagulation. It is now known to be fundamental as well in regulating the mineral content of bone and of blood vessel walls, with important implications for aging.

Regulating Blood Coagulation

The coagulation system is one of the body’s most tightly regulated systems. Blood must flow smoothly as a liquid through miles of blood vessels each day, yet also be capable of starting a solid clot within seconds of encountering a breach in the vascular system, such as a laceration or other injury. If the blood fails to clot reliably, fatal hemorrhage can result; if the blood clots just a little too readily, blood vessel blockage can occur, leading to rapid tissue and organ damage called ischemia. This delicate balance is maintained, with the help of vitamin K, by a system known as the coagulation cascade.21

Gamma-carboxylation by vitamin K activates many of the Gla-protein molecules that are essential to coagulation (pro-coagulants).22 When triggered by a stimulus, these proteins work together to create the dense mesh of fibrin that traps platelets and stanches the flow of blood.

Vitamin K promotes the gamma-carboxylation of certain naturally occurring anticoagulant proteins as well. These proteins, known as proteins C and S, are intimately involved in the delicate balance between coagulation and anticoagulation.23 Low levels of active forms of these proteins produce increased coagulation within blood vessel that can result in abnormal clotting, sometimes with devastating consequences.24 Fortunately, because vitamin K seems to activate the pro-coagulation parts of the pathway simultaneously and proportionately to its activation of the anticoagulation branches, most people maintain fairly normal clotting levels across a wide range of vitamin K status.25

The protein C anticoagulant pathway has some natural anti-inflammatory effects, which are down-regulated during inflammation.24,26 Protein C’s anti-inflammatory activity is potent enough to prevent the inflammatory-mediated fatal effects of bacterial sepsis (blood poisoning) in laboratory animals, and to improve the outcome of human patients with severe sepsis. These effects have been shown to be mediated by reducing organ damage in animal models of sepsis, ischemic injury, and stroke.23

Effects on Bone Mineralization

Scientific attention remained focused on vitamin K’s action in the clotting cascade for nearly two decades after it was discovered in the 1970s.23 Only in last 10 years has vitamin K’s importance in other major biological processes been recognized. The body’s need for vitamin K to form critical Gla-proteins is the key to vitamin K’s activity in systems other than the clotting cascade.22 Scientists’ growing awareness of how the vitamin helps form these proteins is providing insights into two crucial aspects of the science of aging: bone and vascular health.27 Many different health and disease processes affect both areas. Bone and vascular health are also affected not only by vitamin K intake, absorption, and metabolism, but also by the use of vitamin K antagonists such as the drug warfarin (Coumadin®).

THE COAGULATION CASCADE: TO CLOT OR NOT TO CLOT?

Vitamin K-dependent Gla-proteins are critical in the “coagulation cascade” that controls whether blood clots, how much it clots, and when to reverse the process and destroy the clot.

The primary stimulus for normal clotting is triggered when platelets stick to damaged blood vessel walls with exposed collagen and other proteins. This process happens within seconds of an injury. Aggregated platelets and damaged vessel walls release tissue factor, which combines with circulating factor VII. This complex then activates other factors, which in turn trigger the conversion of pro-thrombin (factor II) to thrombin. This active enzyme in turn converts fibrinogen, a dissolved protein, to fibrin. Fibrin forms long strands to create a semisolid mesh that traps platelets, ultimately forming the firm clot that blocks further blood flow.

To prevent overactive clotting, tissue factor pathway inhibitor combined with antithrombin, protein S, and activated protein C acts to inhibit the pro-coagulation system at several points in the cascade. Under normal circumstances, this finely tuned system maintains a perfect balance, permitting clot formation where necessary, but beginning the process of taking down the clot almost as soon as it has begun to form. This minimizes the risk of blood clots forming within vessels, and allows for rapid “cleanup” of those clots that are necessary.21

Adequate intake or supplementation with vitamin D and calcium is required to prevent osteoporosis. Neither vitamin D nor calcium, however, can produce healthy bone mineralization without adequate supplies of vitamin K. Bone is a complex living structure comprising cells, mineral crystals, and thick matrix proteins that, like glue, hold the entire bone together. The chief bone matrix protein, osteocalcin, is a Gla-protein that is dependent on vitamin K for its production.20 A deficiency of vitamin K causes impaired activation of osteocalcin and reduced activity of bone-forming cells, thereby resulting in decreased new bone formation.28

Low vitamin K nutritional status (as measured by circulating levels of vitamin K, as well as by products of its activity, such as the amount of Gla-proteins) is associated with increased risk of fracture. Standard measures of osteoporosis correlate poorly with vitamin K status.29 This observation suggests that relying entirely on standard measures of osteoporosis risk such as bone mineral density may not prove to be reliable as measures of overall vitamin K sufficiency.

Several compelling lines of evidence support the use of vitamin K in preventing and treating osteoporosis.30 In epidemiological studies, lower intake of vitamin K is associated with increased risk of osteoporosis.31,32 Both animal and human studies suggest that vitamin K may have a role in preventing and treating osteoporosis.33-35 In small studies, daily doses of vitamin K2 have prevented bone loss.30

GLA PROTEINS: SENSITIVE MEASURES OF TRUE VITAMIN K STATUS

Vitamin K’s primary function is to aid in the carboxylation of Gla-proteins.14 Once thought to be involved only in coagulation, Gla-proteins are now known to exist in many tissues. Without enough vitamin K, some Gla-proteins remain under-carboxylated and cannot function properly. Under-carboxylated osteocalcin, for example, has little activity in bone formation.39

While vitamin K deficiencies severe enough to cause defects in the blood coagulation system are rare, growing evidence suggests that less severe deficiencies affecting bone health may be quite common.39 Improvements in technology for measuring under-carboxylated Gla-proteins have led to the observation that almost everyone exhibits evidence of insufficient vitamin K activity, as indicated by under-carboxylation of at least one Gla-protein.14 This revelation was important in the recent movement to increase the recommended daily consumption of vitamin K.14,27,37,40 It is important to remember that because foods provide only about a quarter of the daily requirement, increasing one’s intake of this vitamin almost always entails supplementation.

According to a review of the recent literature published in 2004, reasonably strong evidence indicates that daily vitamin K intake of less than 100 mcg is not optimal for bone health.36 The authors recommend that family physicians stress the importance of adequate vitamin K intake to their patients, particularly those at risk for bone loss and osteoporosis. In a critical review published in 2005, Dr. Jamie Adams of Castle Medical Center in Kailua, Hawaii, noted that “numerous studies have demonstrated the importance of vitamin K in bone health.”37 Dr. Adams pointed out that the combination of vitamins K2 and D may substantially reduce bone loss, and that vitamin K2 is synergistic when used together with hormone therapy. Vitamin K is now among the mix of micronutrients considered vital for maintaining good bone health.38

The primary medical treatment for osteoporosis is a class of drugs known as bisphosphonates. These drugs reduce the activity of osteoclasts, the cells responsible for resorption of bone minerals. The bisphosphonates do not, however, increase new bone formation, so they address only part of the problem.

By increasing the production of osteocalcin, vitamin K may provide additional bone-strengthening effects. Indeed, in a rat model of osteopenia (bone loss that precedes osteoporosis), a vitamin K2 derivative at low doses increased bone mineral gain and the overall bone formation rate.33 Building on this observation, other researchers have established that the combination of the bisphosphonate etidronate and vitamin K2 is more effective than etidronate alone in preventing new fractures in patients with osteoporosis.35