© Whole Foods Magazine

January 2007

The Science of ATP: Part 4  An interview with Eliezer Rapaport, Ph.D., exploring the connection between ATP and aging.

 

By Richard A. Passwater, Ph.D.

 

We have been chatting with adenosine triphosphate (ATP) research pioneer Dr. Eli Rapaport for the past three months, discussing the basic chemistry of ATP and Dr. Rapaport’s research that has led to important health findings for ATP supplements.

We have discussed how ATP is used within cells (intracellular) to produce and store the energy that drives the countless thousands of biochemical reactions that produce “life.” The energy contained within the phosphate bonds of ATP is converted to both chemical and mechanical energies. ATP’s high energy bond can be transferred to other compounds to drive the biochemical reactions that move nutrients into cells, remove waste products, propel nerve signals, make proteins and other body compounds, move skeletal muscles, regulate blood flow, contract the heart muscle and virtually everything that involves life.

What we have learned from Dr. Rapaport’s research is that ATP also has extremely important roles outside of cells (extracellular) as well. Extracellularly, ATP and its in vivo degradation product, adenosine, activate specific ATP and adenosine receptors on cells such as in the artery linings, nerve endings and various organs, to produce beneficial health effects. As a result, extracellular ATP and adenosine are regulators of many physiological responses including vascular, heart and skeletal muscle functions. Oral ATP supplements directly increase extracellular blood plasma ATP pools to improve blood vessel tone, increase vasodilation and enhance blood flow. Not only is extracellular ATP cardioprotective and organ protective, it enhances delivery of nutrients and oxygen to the brain, heart and all tissues and organs of the body as well as stimulates removal of waste products such as lactic acid. Furthermore, extracellular ATP can increase needed intracellular ATP as it is used up and achieves it by stimulating oxygen and glucose disposal that are needed for intracellular ATP synthesis.

In this installment, as we resume—and conclude—our chat with Dr. Rapaport about his research and the many ways in which ATP supplements provide health benefits, we will consider the potential of ATP in benefiting conditions that are directly related to aging. Specifically, we will look at cardiac protection, peripheral arterial disease (PAD), arthritic diseases, type 2 diabetes and its clinical complications, cerebral circulation and mental acuity.

As you may remember, Dr. Eliezer Rapaport received his Ph.D. from the Johns Hopkins University in 1971. He served on the faculties of Harvard Medical School at the Massachusetts General Hospital, Boston University School of Medicine and the Worcester Foundation for Experimental Biology.

 

Passwater: Would you remind our readers about the basic relationships between physiological ATP pools and aging?

 

Rapaport: For the convenience of our readers, I am going to include references, which are keyed by numbers in parentheses. A list of these references is available on request. During aging (e.g. 65-75 years old), initial levels of red blood cell ATP pools drop to about half of what they are in young individuals (1). Older humans (mean age of 68.8 years) retain only 50% of muscle mitochondrial ATP synthesis as compared with adults (mean age of 38.8 years) (2). Purine (ATP and adenosine) losses, adversely affecting organ and skeletal muscle functions, were also reported in diseases and other stressful conditions (3). The reduced blood and skeletal muscle pools of ATP in the aged, lead to a variety of adverse conditions, which are primarily the result of decreased blood flow.

 

Passwater: Yes, but what can we do about it? Does oral ATP help?

 

Rapaport: Yes. Let me start at the beginning with earlier studies. Animal studies showed that low levels of ATP administered directly into the duodenum, the proximal part of the small intestine, yielded significant positive cardiovascular and pulmonary responses (4). The duodenum is the area of the small intestines where enteric or uncoated ATP pills are absorbed, followed by the incorporation of the adenosine and inorganic phosphate moieties into the liver ATP pools. The expanded liver ATP pools are the source of elevated blood plasma ATP pools, as was described in detail in our previous interviews.

To go back to the effects of ATP administered directly into the duodenum in rabbits, they included reductions in pulmonary vascular resistance, reductions in peripheral vascular resistance followed by increases in blood flow. No effects on arterial blood pressure or heart rate were observed.

An increase in left ventricular work index, which is an indication of improved cardiac output was found. Cardiac output is a value that expresses the efficiency of the heart in circulating the blood throughout the vascular bed and is expressed in units of L/min/sq m. In addition, an increase in arterial oxygen pressure (PaO2) was observed after the administration of ATP. Intraluminal ATP, at physiological concentrations, was shown to produce not only local vasodilation, but also vasodilation at sites upstream from the site of its application. Adenosine on the other hand, induced only local vasodilation.

 

Passwater: To what degree can blood flow be improved?

 

Rapaport: Low physiological levels of blood plasma ATP (less than 1 microolar), induced an 8% increase in vascular diameter, corresponding to a minimum of 17% increase in blood flow (5). Vasodilation induced by physiological levels of ATP is mediated primarily by nitric oxide (NO), which is synthesized by the enzyme NO synthetase in vascular endothelial cells in response to the interaction of ATP with P2Y receptors. The NO then diffuses into and acts in neighboring perivascular smooth muscle cells, which control vascular tone and produce relaxation and vasodilation of the blood vessel in response to NO.

 

Passwater: That’s significant and certainly important. Is extracellular ATP involved in mechanisms of vasodilation other than NO synthesis?

 

Rapaport: Yes. At higher levels of ATP, corresponding to ATP released from red blood cells containing expanded ATP pools, other mechanisms of vasodilation operate besides NO synthesis. These mechanisms include induction of vasodilatory prostaglandins synthesis, mostly prostacyclin (PGI2) as well as non-NO, non-prostacyclin induced vasodilation that is mediated by the direct interactions of ATP and adenosine with their corresponding receptors.

As importantly, endothelium-derived hyperpolarization factor (EDHF) is synthesized and released in response to intraluminal ATP. In the cerebral arteriols, elevated ATP stimulates blood flow in response to metabolic demand by inducing EDHF synthesis. Thus, circulatory ATP regulates and controls blood flow to the central nervous system as well as to peripheral sites (5).

 

Passwater: Is there a relationship between extracellular ATP and aging involving muscle mass?

 

Rapaport: The direct correlation between aging and the decline mostly in skeletal muscle mitochondrial ATP synthesis (2,6) as well as the significant decreases in blood ATP parameters upon aging in humans (1) and experimental animals (7,8) have been established. Recently however, decreases in ATP levels caused by intentionally introduced mutation into mitochondrial DNA in animals (9) and declines in skeletal muscle mitochondrial function in humans (10) were demonstrated to be a direct cause of aging. Thus, a direct relationship between significant declines in skeletal muscle and blood levels of ATP and the aging process has now been established (9,10).

 

Passwater: Can this relationship be utilized to slow aging?

 

Rapaport: The desire to slow the aging process by improving skeletal muscle strength and function has attracted a considerable degree of interest. Hormone treatments of elderly men with human growth hormone (GH) and testosterone and hormone treatment of elderly women with GH and hormone replacement therapy (HRT), was the subject of a recent large clinical trial (11). The results confirmed the apparent positive effects of growth hormone and sex steroid combinations on body composition, namely, increasing lean body mass and decreasing fat mass (11). However, the results clearly demonstrated that lean body mass did not translate into improved skeletal muscle function and as importantly, the risk of adverse effects associated with the use of these hormonal regimens was substantial (12).

 

Passwater: Let’s move to the roles of ATP and adenosine in cardiac protection. What are the basic mechanisms thought to be responsible?

 

Rapaport: Gram for gram, the heart consumes more energy than any other organ of the body. It’s no wonder, then, that recent research ties the failing heart with massive losses in cardiac ATP. For the first time ever, researchers at Johns Hopkins University used magnetic resonance spectroscopy to examine beating hearts. They discovered that people with a history of heart failure have a significant reduction in myocardial ATP (13).

 

Passwater: This is an important point that Dr. Stephen Sinatra made with us when he emphasized that “it’s all about ATP.” Most cardiologists still do not understand the concept of ATP leakage.

 

Rapaport: The creatine kinase reaction, which utilizes the phosphorylation of ADP by creatine phosphate, catalyzed by creatine kinase, to buffer against the severe losses of ATP, fails in the diseased heart. Two basic mechanisms serve in the protection of the heart by ATP and adenosine. One is the well-established role of ATP in maintaining normal blood pressure. It has been demonstrated that the increase in blood pressure upon aging is related to lower levels of blood plasma (extracellular) purines (ATP and adenosine) in the aged (7,8).

Several research groups claimed that the blood pressure lowering effects of omega-3 polyunsaturated fatty acids, such as DHA and EPA, are the result of these acids inducing the release of ATP from vascular endothelial cells (14,15).

 

Passwater: It’s interesting how the heart nutrients are entwined with ATP production: gPLC is used to carry fats into the heart cells for ATP production; coenzyme Q-10 is critical for ATP production; ribose provides a basic building block for ATP synthesis; and fish oil omega-3 fatty acids are involved with releasing ATP into the vascular network.

 

Rapaport: There is also a second mechanism in which adenosine acts as a major cardiac protector through its interaction with adenosine receptors: 1. by interacting with adenosine A1 receptors, adenosine attenuates the release of catecholamines, which by interacting with beta-adrenoceptors produce myocardial hyper-contraction and 2. by interacting with adenosine A2 receptors, adenosine stimulates coronary blood flow and inhibition of platelet and leukocyte activation. The release of catecholamines as a result of the low cardiac output in heart failure leads to a compensatory hyperadrenergic state. The increased catecholamines levels also lead to elevations in blood plasma free fatty acids, which increase the dependency of the failing heart’s energy production on beta oxidation of fatty acids, a process heavily dependent on blood flow for the delivery of oxygen. Under the poor flow conditions, a futile cycle is formed.

The stimulation of coronary blood flow in the diseased heart by ATP and adenosine operate by mechanisms of reduction in systemic vascular resistance through vasodilation as outlined earlier in this interview. These activities of adenosine described under 1 and 2, tend to synergistically inhibit the effects of ischemic (oxygen-poor) heart disease.

In addition, the most powerful cardioprotective effect of adenosine is in ischemic preconditioning. When brief periods of ischemia precede sustained ischemia, the resulting infarct size is dramatically reduced. Ischemic preconditioning operates via adenosine A1 receptor activation (16,17).

Administration of ATP, the biological precursor of adenosine, produces conditions that mimic the brief periods of ischemia without actually having ischemic conditions. These cardioprotective effects then act in significantly benefiting heart function during chronic heart failure and acute myocardial infarction (16).

 

Passwater: How do ATP and adenosine act in relief of progression and symptoms of peripheral arterial disease (PAD), which is prevalent among older members of the population.

 

Rapaport: Peripheral arterial disease (PAD) is the result of systemic atherosclerosis, which produces atherosclerotic plaques, initially in the arterial lumen of the lower extremities resulting in a progressive decline in blood flow to the lower extremities. Because of its under-diagnosis, it is often called a “silent killer.” The prevalence of PAD was found to be 4.5% in a population of American men and women over the age of 40 and is more common in people over 55.

All the symptoms of the variety of peripheral vascular diseases are caused by the narrowing of blood vessels in the legs and are therefore benefited by treatment with ATP and its physiological vasodilatory activities. The currently used drugs for the treatment of PAD are all vasodilators of one type or another; recently, these have been used along with statins. Peripheral arterial disease greatly increases the risks of heart attack or stroke and of dying within a decade.

The reason for the considerable underestimation of PAD is because only symptomatic patients (those suffering from intermittent claudication, a condition that causes pain during walking) are taken into account. Two-thirds of those afflicted with peripheral arterial disease do not know they have it because of lack of symptoms, except for a steady decline in their ability to walk intermediate distances.

As mentioned, the cause of the disease is atherosclerosis, the buildup of fatty deposits on the arterial wall. There are other common warning signs besides pain (intermittent claudication), which indicate the existence of peripheral arterial disease. These include discoloration of the legs or feet, foot ulcers that fail to heal or legs that swell easily, become numb or cold or feel tingly. However, relying only on symptoms for diagnosing PAD causes a majority of cases to go undetected.

The ratio between systolic arterial pressure in the ankle and in the brachial artery (Ankle Brachial Index, ABI) is now considered a gold standard for identifying patients with peripheral arterial disease. This ratio is decreased considerably with the progression of peripheral arterial disease. The drugs used to treat intermittent claudication are pentoxifylline (Trental) and cilostazol (Pletal). Statins, which are drugs used to lower LDL cholesterol (such as Simvastatin), in addition to antiplatelet/anticlotting agents such as low dose aspirin or clopidogrel (Plavix), which inhibit artery-blocking clots, are commonly used in the management of peripheral arterial disease.

 

Passwater: However, thanks to your research, we know that ATP can be very beneficial to PAD patients.

 

Rapaport: Well, there is research in this area even preceding mine. Since the early 1950s, adenine nucleotides such as AMP (adenosine 5’-monophosphate) and ATP have been successfully used for the treatment of symptoms of peripheral vascular diseases (18-20). AMP acts by the same mechanism as ATP, both agents undergoing degradation to adenosine and inorganic phosphate in the systemic circulation, followed by absorption and incorporation into liver ATP pools and resulting in significant stimulation of peripheral blood flow via mechanisms described earlier. At that time, ATP was used in Europe whereas AMP was used mostly in the United States.

Today, ATP is the preferred treatment for the expansion of blood plasma ATP pools because it is more effective and can commonly be produced in a purer form. AMP was approved as a drug in the United States in 1967, in a form of intramuscular injections of 25 mg once or twice daily followed by three times weekly for the treatment of stasis dermatitis or skin ulcers, which are the results of varicose or phlebitic veins. An oral formulation of 250 mg of ATP administered daily can easily achieve the intravascular levels of ATP produced by the AMP injections, which are in the milligram levels. The successful treatment of a variety of conditions resulting from venous insufficiency and chronic or acute thrombophlebitis with AMP or ATP has been documented (18-20).

 

Passwater: As I understand, the beneficial treatment of arthritic diseases and especially inflammatory arthritic conditions with AMP and ATP also dates back to the early 1950s. What caused the abandonment of the successful utilization of these natural agents?

 

Rapaport: There were two main reasons for the loss of interest in utilizing ATP or AMP in the effective treatments of peripheral vascular diseases and arthritic diseases. One reason was that adenosine did not show any efficacy in improving these dysfunctions. Yet it was known that ATP or AMP is rapidly degraded to adenosine and inorganic phosphate inside the vascular bed.

This issue has now been resolved since I demonstrated that adenosine and inorganic phosphate, but not adenosine alone, incorporate into the liver ATP pools supplying the adenosine precursor for expanded red blood cell ATP synthesis and release of ATP into the blood plasma compartment.

The second reason was lack of patent protection, which was also resolved by my issued broad patents applicable to administration of ATP or AMP for expansion of blood plasma ATP pools, rather than for specific utilities.

Osteoarthritis, a degenerative disorder where a specific joint function deteriorates rapidly, along with bursitis, tendonitis and rheumatoid arthritis, which is a systemic disease affecting all joints, all become prominent in the subpopulation over 50 years old. Osteoarthritis, a condition affecting more than 20 million Americans, was thought earlier to be a disease involving only deterioration of a joint’s cartilage but is now acknowledged to encompass tissues surrounding the ailing joint as well. Namely, muscles, bones, tendons, ligaments and bursa, which are sac-like cavities filled with synovial fluid and located at sites where joint friction occurs, all contribute to the painful inflammatory disease, the symptoms of which are treated with several types of medication along with surgical procedures.

The drugs and supplements used to treat the symptoms of osteoarthritis are over-the-counter pain-killers, nonsteroidal anti-inflammatory agents (indomethacin, ibuprofen or naproxen), cox-2 inhibitors Vioxx and Celebrex, tetracycline, hyaluronic acid, corticosteroids, and glucosamine and chondroitin sulfate. The most common surgical procedures available for relief of pressure on joints are arthroscopic surgery and joint replacement. Rheumatoid arthritis, a crippling systemic autoimmune disease of the joints, is more debilitating than the other joint diseases and afflicts 2.5 million people in the United States. Drugs that are commonly prescribed for rheumatoid arthritis include methotrexate along with the recently developed biologics ethanercept (Enbrel), infliximab (Remicade) and anakinra (Kineret), all three are designed to block the activities of inflammatory cytokines.

The etiology of osteoarthritis is unknown but is considered to be the result of interacting mechanical and biological causes. All forms of arthritic diseases involve decreases in blood flow to the afflicted joints, accumulation of undesirable agents in the vicinity of the afflicted joints such as bacteria, environmental toxins, along with waste and tissue breakdown products that contribute to the inflammatory reaction around the degenerating joints. Thus, treatments that produce increases in blood flow to and from the afflicted joints provide substantial benefits to the joints’ health. Both AMP and ATP have been used since the 1950s as effective treatments for the relief of symptoms of debilitating arthritic diseases such as osteoarthritis, bursitis and tendonitis (21-24).

An effective oral formulation of ATP, can easily repeat the early successes of intramuscular injections of AMP and ATP in the alleviation of symptoms of arthritic diseases. A mechanical breakdown of the joint’s cartilage was thought to be the overriding cause of osteoarthritis. Let me re-emphasize: It is now accepted that all the tissues surrounding the afflicted joint, which were mentioned earlier as contributors to the inflammatory disease are also important in the prevention of this disease. Muscles, bones, ligaments, tendons and bursa, all benefit from enhanced circulation, which tend to strengthen the tissues by increasing the supply of oxygen and nutrients and the removal of waste products. This process is particularly relevant to muscles (25-27), which by supporting the joint, prevent tears in tendons and ligaments. A weakness or tear in tendons or ligaments forces the joint’s cartilage to bear more weight, hastening its degradation.

 

Passwater: What are the biochemical mechanisms whereby ATP and adenosine act in benefiting the regulation of blood sugar levels?

 

Rapaport: In our last interview we discussed the increasing data demonstrating that adenosine is an important regulator of insulin’s actions in skeletal muscle cells. Adenosine was reported to increase the sensitivity of insulin receptors to the action of insulin and thus stimulate disposal of blood glucose into skeletal muscle cells. This activity of adenosine is mediated by the adenosine A1 receptor, which was shown to be linked to insulin signaling by augmenting the activity of insulin at its receptor. Therefore adenosine, which is the in vivo degradation product of ATP, has a significant role in maintaining and improving insulin sensitivity.

Once insulin sensitivity is impaired, insulin resistance gradually develops followed by Type 2 diabetes and its clinical complications. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disease resulting primarily from a variety of pancreatic beta cell disorders and insulin resistance. Beta cell dysfunction in regulating insulin secretion yields the chronic hyperglycemia with all its associated clinical complications. Blood plasma glucose levels are responsible for the stimulation of insulin secretion by beta cells.

The transport of glucose into pancreatic beta cells is followed by its glycolytic metabolism resulting in increases in beta cells’ ATP pools (28,29). A slight increase in beta cell ATP levels is sufficient to close its ATP-sensitive potassium channels, thus depolarizing beta cell membrane and opening its calcium channels. The resulting influx of extracellular calcium and an increase in recruitment of calcium from intracellular stores yield an increase in total cellular calcium levels, which then activate the granular insulin secretory machinery. Thus, intracellular beta cell ATP pools have a key role in transducing the signals of the stimulus-secretion coupling pathway.

Toxins such as alloxan or streptozotocin, which produce experimental diabetes in animals, act by interfering with mitochondrial oxidative phosphorylation, producing small decreases in cellular ATP pools. Due to the sensitivity of beta cells to ATP pools function, only beta cells, among all the animal cells, are affected by these toxins, which significantly reduce insulin secretion in response to glucose stimulation resulting in a form of diabetes.

In addition to beta cell intracellular ATP pools, a powerful effect of extracellular ATP was demonstrated more than 30 years ago on the physiological secretion of insulin by acting as insulin secretagogue. This effect of extracellular ATP is a result of its interaction with P2 receptors on beta cell membrane coupled to increases in extracellular calcium influx and recruitment of calcium from intracellular stores leading to insulin release from beta cell granules.

Detailed animal studies identified the regulation of insulin secretion and improvement in glucose tolerance by the action of ATP or its agonists on the P2Y receptors that are present on beta cells (28,29). These roles of intracellular ATP inside beta cells and extracellular ATP in blood plasma in the physiological regulation of insulin secretion, are now well-established (28,29). The aged, who suffer from chronic decline of red blood cell and blood plasma ATP pools (extracellular) and reductions in mitochondrial ATP synthesis (intracellular), are therefore particularly susceptible to defects in the stimulus-secretion coupling pathway of insulin secretion.

In addition, it has been demonstrated that low levels of ATP, similar to those present under normal physiological conditions, stimulate the expression of the glucose transporters GLUT1 and GLUT4 in the plasma membrane of skeletal muscle cells. Elevated levels of extracellular ATP increase the expression of these glucose transporters, thus promoting enhanced uptake of glucose from the blood plasma (30). The physiological regulation of glycemic levels by ATP is especially significant in view of the problems existing with the pharmacological management of type 2 diabetes. Insulin is the mainstay treatment of diabetic patients. The overwhelming adverse reaction to insulin is hypoglycemia. Hypoglycemia (excessively low blood glucose levels) is a major risk and should be weighed against the benefits of insulin treatment, especially in patients who respond to milder hypoglycemic drugs. The sulphonylureas act by stimulating insulin release from pancreatic beta cells by binding to and closing the ATP-sensitive potassium channels leading to insulin release by mechanisms described earlier.

The meglitinides are not sulphonylureas but are capable of binding to the same target on the beta cells and acting by the same mechanism. Glibenclamide, gliclazide, glipizide and glimepiride are the sulphonylureas most commonly used in treatment of type 2 diabetes. The major adverse effect of sulphonyluraes is hypoglycemia, which can lead to a coma. Metformin and thiazolidinediones affect insulin sensitivity by independent mechanisms and disaccharidase inhibitors reduce rapid carbohydrate absorption.

It is acknowledged that no single agent is capable of achieving target glucose levels in type 2 diabetes patients without major risk factors. Proper diet and nutritional supplements have a beneficial role when properly used in combinations with mild hypoglycemic agents. A major problem with the use of the synthetic non-physiological hypoglycemic drugs is that in aged diabetic patients, hepatic and renal functions are impaired, resulting in longer and sustained effects of these drugs due to their improper clearance from the circulation.

The major clinical complications prevalent in aged diabetic patients include peripheral vascular disease, diabetic neuropathy, diabetic nephropathy and eye disorders such as cataracts, glaucoma and diabetic retinopathy. The established vasoreactivity of ATP in stimulating blood flow especially to the lower extremities makes oral ATP especially attractive in providing benefits in chronic hyperglycemic induced peripheral vascular disease and diabetic neuropathy. The use of oral ATP by the aged, would provide physiological regulation of glycemic levels along with improvements in some of the major clinical complications especially prevalent in the aged patients.

 

Passwater: How do oral ATP supplements play a role in improving the cerebral circulation and benefiting mental acuity?

 

Rapaport: More than 20 years ago, Forrester et al., (31) demonstrated that ATP at physiological levels, plays a major role in the local control of cerebral blood flow in baboons. Intracarotid injections of very low levels of ATP, readily achievable by oral ATP formulations, showed a threshold vasodilatory response at 0.004 micromolar in the baboon. Starting at this level, ATP increased oxygen consumption in the baboon brain parenchyma through an increase in regional cerebral blood flow, which in turn was the result of the cerebral vessels’ pronounced vasodilation by ATP. In the central nervous system (CNS) increased flow equals improvements in metabolism, which yields enhanced function. Since skeletal muscles have been known to release ATP during exercise, the well-known aphorism mens sana in corpore sano, or a healthy mind in a healthy body seems validated.

In cerebral arteries and arterioles, ATP is the major regulator of blood flow inducing the synthesis of NO at low concentrations of ATP and EDHF (endothelium-derived hyperpolarization factor) at higher concentrations of ATP. Both NO and EDHF stimulate blood flow in the cerebral vasculature and are synthesized in response to ATP interactions with P2Y receptors. Since ATP is released from red blood cells, pathological conditions that result in the loss of red blood cells, such as cerebral hemorrhage, are expected to result in reduced vasomotor responses.

In an animal model of cerebral hemorrhage, the loss of red blood cells was shown to be crucial to the physiological regulation of the cerebral circulation. It was demonstrated that the loss of ATP and oxyhemoglobin, both of which released in large amounts during red blood cell lysis, is responsible in producing an attenuated vasoactive response during cerebral hemorrhage. Endothelial cells in both cerebral macro- and microvessels contain a substantial distribution of P2Y receptors, which suggests that under normal flow conditions, ATP released from red blood cells regulates vasodilation and enhancement of cerebral blood flow in response to metabolic demand.

The size of the cerebral arteries or arterioles determined whether the ATP-induced vasodilation was produced by NO or endothelium-derived hyperpolarizing factor (EDHF) with the role of NO declining as the vessel size is decreased and the role of EDHF becoming more prominent (32).

Because of its mechanism and the prominence of ATP in stimulating regional cerebral blood flow, oral ATP consumed in the absence of specific cerebral metabolic demand is likely to produce a significant enhancement of flow, metabolism and function in the brain. The result would be improved mental acuity in response to oral ATP formulations. There is no currently available agent that is known to improve mental acuity in the aged.

 

 

Passwater: How does oral ATP-Induced stimulation of the peripheral microcirculation benefit skin aging and removal of superfluous fat deposits?

 

Rapaport: A variety of conditions related to impaired peripheral microcirculation and chronic venous deficiency, are common in the elderly. These include skin aging, Raynaud’s disease, acrocyanosis, cold-induced vasospasm and unesthetism related to deposits of superfluous fat such as cellulite. The quest for agents that improve the microcirculation by acting as topical vasodilators, has been the holy grail of the cosmetic industry. Esculoside (U.S. Patent No. 5,679,358) or ginkgo biloba (European Patent No. 275,005) are examples of primary ingredients in cosmetic preparations of topical vasodilators utilized in these conditions.

The clinical indications of Raynaud’s disease and acrocyanosis are usually treated with pharmacological oral vasodilators such as prazosin and the Ca-channel blocker nifedipine. These vasodilators while showing some activity in Raynaud’s disease are acknowledged to be ineffective in the treatment of acrocyanosis.

It is however the conditions of cellulite and unesthetism related to the deposits of superfluous fat, mostly in females thighs, face and neck areas, that constitute a particularly large market. These conditions are thought to be the result of poor arterial and arteriolar blood flow and lack of perfused capillaries, which make these fat deposits metabolically isolated. Therefore, in cases where lipolysis is achieved due to diet or topical treatment, free fatty acids cannot be removed from the interstitial environment of the white adipose tissue and are reconstituted as fat by lipogenesis. For the reduction in aging of the skin, topically active cosmetic preparations that improve peripheral microcirculation and increase vasoactivity of the arteries and precapillary arterioles have been sought.

Oral ATP formulations are an established physiological peripheral vasodilator that has been discussed earlier in this interview as acting in the treatment of skin ulcers and stasis dermatitis due to varicose or phlebitic veins. In addition, conditions such as pruritus and pain, attributed to venous insufficiency, were resolved by AMP or ATP treatment (18-20). Oral ATP formulations have considerable potential in the treatment of skin aging and deposits of superfluous fat.

 

 

Passwater: Well, Dr. Rapaport, this has been a very enlightening chat. The health benefits to our readers are enormous. We thank you very much for taking the time to discuss your research with us. It has been a long journey since my childhood days of watching “lightning bugs” with amazement. Little did I realize then that what I was watching was the energy of a chemical bond converted to the form of light emission, in a biological reaction initiated by one of the most fascinating molecules in living organisms-ATP." WF

 

References on request. Send requests to editorial@wfcinc.com .

© 2007 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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