From the Archives
DURK PEARSON & SANDY SHAW'S®
LIFE EXTENSION NEWSLETTERTM
Life Extension Newsletter, written by Life Extension scientists Pearson & Shaw, was prescient with regard to many of the biomedical ideas it first brought to the attention of the public. Unfortunately, it is no longer available and thus, with the permission of the authors, we reproduce selected portions for your enlightenment. Please note the return of another Pearson & Shaw Newsletter, Life Extension News, the currrent issue of which is contained in this publication. The growth hormone story picks up where Sandy breaks her leg at a gerontological conference where she is initially attended to by no less than Dr. Denham Harman, M.D., Ph.D., father of the Free Radical Theory of Aging.
ISSUE #25 PAGE 2
ARGININE RELEASES GROWTH HORMONE
Having a broken foot is extremely inconvenient and sometimes dangerous. Just try going up or down stairs on crutches! We had been about to start arginine supplementation experiments on ourselves for immunostimulation, when Sandy's broken foot provided us with a golden opportunity. We had read scientific reports of arginine stimulating the healing of broken bones in experimental animals, and Sandy decided to take it.
Other nutrients have been shown to cause growth hormone release, including niacin (200 mg is a mild GH releaser) (Irie, 1967,1970), tyrosine (nutrient amino acid - releases a small amount of GH in a small percentage of subjects with 40 gram intravenous doses), and methionine (nutrient amino acid - releases GH but can cause atherosclerosis under certain conditions). The nutrient amino acid arginine and ornithine (another amino acid) are both relatively strong GH releasers. Arginine and ornithine can release enough GH to equal that found in a heavily exercising teenager.
Arginine and ornithine cause growth hormone release via your brain's cholinergic nervous system. (Casanueva, 1984) This is the system that uses acetylcholine - made in the brain from the nutrient choline with the help of the cofactor vitamin B5 - to transmit information between the nerve cells. Without adequate amounts of acetylcholine, neither arginine nor ornithine can cause growth hormone release, though we know of no evidence that choline or vitamin B5 alone can cause GH release. This is why we recommend the use of a choline + B5 supplement in conjunction with arginine or ornithine GH releasers. Note that many antihistamines, cold pills, and the non prescription sedative diphenhydramine are anticholinergics. These drugs will block the GH releasing effects of arginine and ornithine.
Contrary to what some people believe (and some fraudulent products claim), you can't develop winning muscle mass without exercise, even if you take a growth hormone releaser like arginine. But arginine is very effective at helping you maintain muscle mass you already have, even if you are not exercising. We are two 47 year-old research scientists and almost completely sedentary, but we regularly take arginine supplements, as described below, and maintain the well muscled bodies we had twenty years ago. You may have seen 5'3" Sandy bend steel horseshoes on television.
In 1982, after we reported our ideas and experiences regarding the use of growth hormone releasers such as arginine in our first book, Life Extension, A Practical Scientific Approach, there was a world-wide shortage of arginine for several months, and a world-wide shortage of ornithine for about a year! Their main prior use had been as ingredients in culture media.
We personally use arginine in either one of two different ways: we take 12-24 grams 45 minutes to one hour before exercise (to enhance the effects of the exercise) or just before bedtime (to enhance both sex and the natural pulse of growth hormone release shortly after one falls asleep). We generally recommend the following total daily quantities of arginine (free base) for healthy male adults: Weight 100 to 140 pounds, 12 grams; 140 to 200 pounds, 18 grams; over 200 pounds, 24 grams. For healthy female non-pregnant, non-lactating adults: under 120 pounds, 6 grams; 120 to 180 pounds, 12 grams; over 180 pounds, 18 grams. Women are usually more sensitive to the GH releasing effects of arginine and ornithine than men. (Merimee, 1969) Start with about 25% of your target quantity, and increase it gradually over a period of a few days to minimize the occurrence of minor side effects such as nausea. If you prefer ornithine, use half of these amounts. The dose figures given in the literature usually refer to the amount of amino acid free base used, such as arginine. Many commercial products contain an acid addition salt such as arginine hydrochloride rather than the free base arginine. Some of the product labels give the amount of the contents as the free base, other as the hydrochloride. Unless the amount of the amino acid is given as the free base (eg, 6 grams arginine), you will need to take about 20% more since the hydrochloride adds about 20% to the weight without contributing to the GH releasing activity.
Don't assume that more is always better. It is unlikely that a 60 gram dose would cause significantly more GH release that a 24 gram dose. A 30 gram injection of arginine is used to test pituitary function: this dose has been chosen to be high enough to completely saturate this GH release mechanism. (See the Cautions at the end of this article for side effects and precautions.)
It is important not to ingest certain other amino acids, either as a supplement or in foods, at the same time or shortly before taking the arginine. Some of these other amino acids, including lysine, compete with arginine to enter the brain (where the action takes place). You can take your protein supplement or high protein low glycemic index carbohydrate meal after your workout.
Casanueva, Villanueva, Cabranes, Cabezas-Cerrato, Fernandez-Cruz, "Cholinergic Mediation of Growth Hormone Secretion Elicited by Arginine, Clonidine, and Physical Exercise In Man," J. Clin. Endocr. Metab.59(3):526-530 (1984)
Christy, "Anterior Pituitary Function in Normal Subjects and in Patients with Systemic Diseases," in Obese, et al, editors Cecil Textbook of Medicine, 15th ed, pp.2085-2091, Philadelphia:Saunders (1979)
Irie, et al, "Effect of Nicotinic Acid Administration on Plasma Growth Hormone Concentrations," Proc Soc Exptl Biol Med 126:708 (1967)
Merimee, et al, "Arginine Initiated Release of Growth Hormone: Factors Modifying the Response in Normal Men," New Eng J Med. 280(26) :1434-1435 (1969)
Murad and Haynes, "Adenohypophyseal Hormones and Related Substances," in Gilman, Goodman, Gilman editors Goodman and Gilman's Pharmacological Basis of Therapeutics 6th ed, pp.1369-1396, New York:MacMillan (1980)
ISSUE #25 PAGE 7
Arginine Side Effects: Most men and some women report increased libido with arginine supplements. There may also be increased irritability. A large release of GH can also cause nausea. Remember how Arnold Schwarzenegger used to keep a barf bucket next to his workout station when he was a teen-ager? He said that if he wasn't working out hard enough to throw up, he wasn't working out hard enough to win. In his twenties, this no longer happened because the exercise no longer caused such a big GH release. You are less likely to have annoying side effects if you start out with a small amount, and gradually increase your dose over a period of couple of weeks.
Ornitine Side Effects: Arginine, but not ornithine is found in ordinary food protein. Arginine has been given to medically monitored subjects at up to 60 grams per day without reports of serious problems. Much less is known about the safety of the regular use of large amounts of ornithine. Since about half of the arginine that you ingest is normally converted to ornithine in your body, it isn't surprising that the reported side effects of ornithine are similar to those of arginine. It takes about half as much ornithine as arginine to release a given amount of GH, but ornithine costs twice as much. We generally use arginine, considering it to be more medically conservative. The immunostimulant and wound healing stimulant effects of arginine are far better established, too. Moreover, arginine but not ornithine, increases sperm count.
Choline Side Effects: Too much choline and/or vitamin B5 can cause the production of too much acetylcholine. Since acetylcholine is what makes your muscles contract, this can cause excessive muscle tone. The most common symptoms or cholinergic excess is a stiff neck, a tension headache, or gut cramps, diarrhea, or constipation. You are less likely to have annoying side effects if you start out with a small amount, and gradually increase your dose over a period of a couple of weeks. Do not use choline bitartrate; in effective doses, there is so much bitartrate in this form of choline that diarrhea is almost inevitable. Chronic diarrhea isn't just annoying; potassium loss can be so large that it may cause heart failure by ventricular fibrillation.
Niacin Side Effects: 200 milligrams of niacin will most certainly cause transitory skin flushing and a sensation or heat, burning, or itching, though this is not dangerous. Do not take more than 800 milligrams of niacin per day without medical supervision, since the livers of some individuals cannot tolerate higher doses.
Although the growth hormone releasing effects or arginine and ornithine have been stressed in this article, we do not wish to imply that all of the anabolic, wound healing, and immunostimulant effects of arginine and ornithine are due to their GH releasing activity. Arginine and ornithine also act as precursors to polyamines such as spermine and spermidine, which are growth stimulating substances, and these two amino acids have many other uses within the body, too. Nevertheless, the anabolic, wound healing, and immunostimulant effects of growth hormone itself are so similar to those of arginine and ornithine that we did not think that an exploration of this distinction would be of much interest to body builders and athletes.
ISSUE #13 PAGE 3
STIMULATION OF THE IMMUNE SYSTEM AND OF HEALING BY ARGININE
We have previously written about immune system stimulation and increased healing rate in experimental animals and humans with oral arginine supplements. Now a new clinical study reports the benefits of large (25 g) supplements of arginine in a liquid diet for postoperative recovery of major abdominal surgery for cancer.
The purpose of the study was to try to reduce the immunosuppression and catabolic response (loss of lean body tissue) that normally occurs after such a trauma. Glycine (43 g/day) was administered to other patients (who did not receive arginine) as a test of its possible utility. Although many animal studies have demonstrated the efficacy of arginine, relatively few human studies had been done. Barbul, in his excellent review, reports some of these. (For example, Dr. Barbul administered oral arginine hydrochloride (30 g/day) for one week and noted a significant increase in peripheral blood mean lymphocyte blastogenic response to con A and PHA, measures of immune system activity.)
The mean total daily caloric intake in this experiment was not significantly different between the arginine and glycine supplemented groups. However, daily nitrogen balance became positive after day 5 in the arginine group (indicating that lean body tissue was being built up faster than it was being broken down), whereas it remained negative in the glycine group throughout the seven day study period. There were increases in immune system T-lymphocyte activation in the arginine group and a slight increase in the glycine group, the difference between the two groups being significant. Only the arginine group had an increase in the CD4 (T helper cell) activity. (T helper cells are needed to help your immune system recognize and react to infections and cancer cells. AIDS patients fall prey to many infections because the AIDS virus kills the T helper cells.) Growth hormone increased in both groups, but somatomedin C (which mediates the effects of growth hormone) was significantly increased only in the arginine group on day 7.
Daly, et al, "Immune and Metabolic Effects of Arginine in the Surgical Patient," Ann. Surg. Vol. 208(4), pp. 512 523 (1988)
ISSUE #23 PAGE 93
ARGININE-DERIVED NITRIC OXIDE AND ITS EFFECTS
An entirely new and important effect of the amino acid arginine has recently been discovered.
In 1987, scientists suggested that endothelium-derived relaxing factor (EDRF), a substance with important functions in the vascular (circulatory) system, such as blood pressure regulation, was nitric oxide, a gas. Now, a mere two years later, a lot more is known about nitric oxide, with evidence indicating that it is about nitric oxide, with evidence indicating that it is EDRF and that it is derived from the amino acid L-arginine. A two-day symposium was just held at the Royal Society in London entitled "Nitric Oxide from L-Arginine."
Nitric oxide (NO) has now been found to also participate in regulation of the nervous and immune systems and is produced from arginine by the liver, adrenal, and kidney. The biological roles include control of vascular resistance and of platelet function. NO can mediate a profound vasorelaxation (reducing blood pressure) and inhibit both platelet adhesion (stickiness) and aggregation (clumping) which can lead to coronary thrombosis heart attacks and occlusive strokes. It has been hypothesized that some cardiovascular disease patients do not manufacture adequate amounts of NO. A lack of NO may play a role in vasospasm, which can lead to hypoxic tissue damage, just as occurs in a coronary or an occlusive stoke. Basal NO release is central to control of blood pressure and flow. High doses of an analog-antagonist of arginine called L-NMMA causes acute hypertension which is rapidly reversed by intravenous L-arginine. Endothelium derived relaxation is impaired by atherosclerosis and inhibited by LDL. LDL, when oxidized, is an even more effective inhibitor, which depresses NO production by endothelial cells. We would like to see a double-blind placebo controlled trial of arginine and antioxidant nutrient supplements for the control of hypertension and to inhibit abnormal clot formation.
Macrophage mediated killing of tumor cells and of some bacteria seems to involve NO. Some of the effects of L-arginine on immune functions, including increased thymic lymphopoiesis (increased T-cell production), stimulation of lymphocyte proliferation, interleukin production, promotion of tumor and graft refection and of wound healing, may involve NO derived from the arginine. Both animal experiments and double-blind placebo controlled trials in humans have shown that arginine supplements are immunostimulants and wound healing accelerators.
Griffith, Randall, "Nitric Oxide Comes of Age," The Lancet pp. 875-876, Oct. 7, 1989
Palmer, Ashton, Moncada, Nature 333: 664-666 (1988)
Feigl, "EDRF - A Protective Factor?" letter to Nature 331: 11 Feb. 1988
Jacobs, "L-Arginine is Endogenous Source Of NO," Trends in Pharmacological Sciences, Sept. 1988
Collier and Vallance, "Second Messenger Role for NO Widens to Nervous and Immune Systems," Trends in Pharmacological Sciences, Nov. 1989
ISSUE, #26 PAGE 13
L-ARGININE REDUCES BLOOD PRESSURE IN HUMANS
In issue #23 [above] we wrote about a newly-discovered natural function of arginine: it serves as the precursor to NO, nitric oxide, a gas which is now believed to be endothelium-derived relaxing factor (EDRF) that powerfully relaxes blood vessels. Doctors at the Keio University School of Medicine in Tokyo recently tested the effects on human blood pressure of an infusion of L-arginine. They administered a dose of 500 mg/kg over 30 minutes (that is quite a lot, for example, the dose would be 35 grams for a 154 pound man) to five healthy men aged 24 to 37 and to five patients (four male) with essential hypertension aged 30 to 65. The antihypertensive drugs the latter patients were taking were withdrawn 4-7 days before the experiment.
The infusion caused rapid onset of hypotension in both groups, reducing both systolic and diastolic blood pressure. Blood pressure returned to baseline levels by 20 minutes following the infusion. The researchers thought the effects were probably caused by EDRF induced vasodilation.
In animal studies, L-arginine alone has not caused hypotension, although it has reversed the pressure (blood pressure increasing) effects of NG-monomethyl-L-arginine, a competitive inhibitor of EDRF synthetase (the enzyme that converts L-arginine to NO).
We would like to see a double-blind placebo controlled study of 12-18 grams of oral L-arginine (a common growth hormone releaser dose) on blood pressure. A lower dose taken orally would deliver less L-arginine than would be delivered over a longer period of time.
Nakaki, et al, "L-Arginine-Induced Hypotension," The Lancet pg. 696, Sep. 15, 1990
ISSUE #26 PAGE 12
ARGININE AND SEX
We have found some very interesting information on arginine that suggests a mechanism for sexual enhancement (our own observations and those of others) reported anecdotally by both men and women using an arginine formulation.
On pp. 93-94 of issue #23, we discussed endothelium-derived relaxing factor (EDRF), a substance that relaxes blood vessels, and, thus, is important in the regulation of blood pressure (it has other functions, too, such as inhibiting platelet adhesion and aggregation which can lead to blood clots, occlusive strokes, and coronary thrombosis). It was recently discovered that EDRF is NO, nitric oxide, a gas, and that NO is produced from arginine by the liver, adrenal, and kidney.
Penile erection results when smooth muscle of the corpus cavernosum relaxes, which is followed by venous occlusion and engorgement of the corporal sinusoids (cavities) with blood. Four scientists now report that stimulation-induced relaxation of corporal smooth muscle is markedly inhibited by an inhibitor (NG-nitro-L-arginine) of the biosynthesis of NO from arginine, as well as by other agents that interfere with the biological actions of NO. Thus, penile erection may be mediated by NO. The chart included with their report shows that addition of L-arginine to rabbit corpus cavernosum preparations containing NG-nitro-L-arginine alone.
We have also had reports of increases in libido in women who take arginine. Although women do not have penile erection during sex, there is blood engorgement of homologous tissues: perhaps this is mediated by NO.
Ignarro, Bush, Buga, Rajfer, Nature (scientific correspondence), pp. 131-132 (13 Sept. 1990)
ISSUE #22 PAGE 84
POSSIBLE IMPROVED FERTILITY WITH ARGININE
Arginine Supplements Increase Sperm Count and Sperm Motility in Men With Low Sperm Counts/Motility
L-arginine enhanced sperm motility in vitro, with response to arginine following a dose-response curve (more L-arginine causing greater motility). Other substances tested that did not enhance sperm motility included L-ornithine, d-arginine, L-lysine, and the arginine analogs L-homoarginine and L-nitroarginine.
A daily dose of 4 grams of L-arginine was used to treat 178 men with sterility because of oligospermia (low sperm count). Sperm count increased by 100% in 42 cases (23.6%) and 15 pregnancies occurred soon after in this group. In 69 patients (38.7%), there was a marked increase in the number and motility of sperm and 13 pregnancies resulted. In 21 cases (12.3%) a moderate increase occurred in sperm count (but it was still classified as oligospermic) and in half sperm motility improved. In 46 patients (25.4%), there was no improvement in either sperm count or motility: these patients had severe oligospermia. The authors note that in some studies arginine treatment of oligospermic patients was unsuccessful probably, they propose, because of insufficient doses (1 to 2 grams daily). Other studies they cite reported significant improvement in more than 30% of patients given larger doses (10 to 20 grams daily).
Schachter, Goldman, Zukerman, "Treatment of Oligospermia with the Amino Acid Arginine," The Journal of Urology 110:311 (1973)