Arginine, contrary to popular notion, is an essential amino acid, and a …
… and thus arginine may be the
most important nutrient you can take
By Will Block
In Ken Russell’s volatile movie Mahler, about the Late-Romantic Austrian composer, the opening scene portrays Gustav Mahler’s composing hut at the end of a pier reaching out onto a lake. Except for the soothing chatter of birds, there is a pervading veil of silence. Suddenly, the hut erupts into an explosive ball of fire accompanied by the orchestral strains of the “Apocalypse” chord [a call to every body and every soul to love earth and life] from Mahler’s incomplete Tenth Symphony. Fire, water, earth, and air. From the genius of the composer—whose works have been described as hymns to nature—we are reminded that all of nature is renewed by fire [Igne Natura Renovatur Integra (INRI)] and that the energies of the creative mind have the power to disrupt what is static or degenerative (for the first part of the film, see http://www.youtube.com/watch?v=unck-eZIDOU). Induced pleuropotent stem cells may be likened to a sudden and massive explosion of creative energy. They will change everything, and put the options of self-renewal into everyone’s hands.
luripotency (from the Latin plurimus, meaning a great many, and potens, meaning possessing power) is a term used in conjunction with certain type of stem cells. Specifically, it denotes the nature of stem cells that are induced from non-pluripotent cells—typically adult somatic cells—by the “forced” expression of specific genes. Such induced pluripotent stem cells (iPSCs) are able to differentiate into virtually any type of other cells … an awesome feat when you think about it. Virtually, something can become anything. Thus, iPSCs are similar to natural pluripotent stem cells (nPSCs), such as embryonic or umbilical stem cells. But alas, these have been placed off limits for the most part by the battle between proponents—who foresee its immense scientific promise—and opponents—who proclaim that it devalues human life in its most basic form because of the sources from which they are harvested.
The Triumph of Regenerative Medicine
Nevertheless, the formidability of iPSCs to facilitate many of the same functions and properties as nPSCs has been a triumph for the applied science that will radically change the world of health in our near lifetimes, probably well within the current decade of the 21st century. Regenerative medicine is the name given to this emerging technology.
Imagine growing new tissues and organs such as liver, cartilage, and neural tissues on scaffolding, with your own genetic material, and perhaps even bio-printing it at home (see
“The Self-Manufacturing Revolution” in the August, 2011 issue). Imagine building new teeth, new eyes, or even a new heart, not the age of your old organ, but the age of your 25-year-old youthful self. This is the brave new world toward which we are rapidly moving (see graphic on page 7).
As in Mice, So in Humans
Recent research has established that the expression of just four transcription factors employed outside of a mammal’s body can reprogram its somatic cells to pluripotent states, creating iPSCs. In other exogenous (external-to-the-body) studies, scientists have demonstrated that iPSCs can be generated with fewer transcription factors, facilitated by expression of reprogramming factors and synthetic small molecules.
The formidability of induced
pluripotent stem cells to achieve the
same functions and properties as
natural pluripotent stem cells has
been a triumph for the applied
science that will radically change the
world of health in our near lifetimes.
Recently, researchers report identification of a new small molecule, a protein arginine methyltransferase inhibitor, which enabled one of the four transcription factors, Oct4,* to induce the reprogramming of mouse embryonic fibroblasts in combination with the use of a transforming growth factor inhibitor.
The Oct4-induced iPSCs were shown to be similar to mouse embryonic stem cells, with respect to typical pluripotency criteria. Of greater importance, they were shown to give rise to liveborn mice demonstrating superlative reprogramming induced by this condition. This study suggests that regulation of protein arginine methylation might be involved in the reprogramming process and accordingly that the amino acid arginine plays a role in the induction of pluripotent states.
But then, arginine possesses a great many powers, independent of the iPSCs that it may help create. Arginine has been found to strongly assist the release of growth hormone, which dramatically lessens with age. It has also been found to increase the production of nitric oxide (NO), the production of which is catalyzed from arginine from the release of an enzyme by acetylcholine called nitric oxide synthase, or NOS, of which there are four different versions. One version is endothelial nitric oxide synthase (eNOS), which is found in our blood vessels and crucial for maintaining cardiovascular health. Significant deficiencies in eNOS activity are characteristic of cardiovascular disease.
Another version of NOS is neuronal nitric oxide synthase (nNOS), which is found in neurons throughout the central and peripheral nervous systems, where NO performs a wide array of important functions. Then there is mitochondrial nitric oxide synthase (mtNOS), which is found in our cells’ mitochondria, the tiny organelles that generate almost all of our energy. Finally, there is inducible nitric oxide synthase (iNOS), which is found in cells of the immune system, where NO is generated to combat infections.
A Major Anti-Aging Breakthrough
In a paper published in Science in 2003, researchers discovered that NO from eNOS induces mitochondrial biogenesis, the creation of new mitochondria in our cells, a major finding given the energy role of mitochondria. Two years later, the same researchers found a link between that and the mechanism of caloric restriction, which extends the lifespans of many different kinds of organisms, from yeasts to mammals. The Free Radical Theory of Aging postulated by Denham Harman, M.D., Ph.D., in 1956 was not just concerned with age-related diseases but also in the aging process itself. Harman, now 96 years old, eventually pointed out that the primary hotbed of free radical activity is the mitochondria, because that’s where the oxidative reactions of cellular energy metabolism occur. So if arginine, through production of NO, can increase the number and quality of mitochondria, this constitutes a major anti-aging breakthrough.
And as we shall see in the following sections, arginine may be thought of as a pluripotent nutrient, with many arms of activities and benefits.
Arginine Helps Control Flow-Mediated Dilation
Flow-mediated dilation (FMD) is a widely used tool to investigate endothelial function. It is a measure of how an artery relaxes following a sheer stress stimulus that produced a nitric-oxide dependent response. However, FMD assessment may cause mechanical damage to the arterial endothelium.
In a new study, researchers investigated the effect of FMD assessment on endothelial function. After enrollment of 20 healthy subjects (26 ± 6 years; 12 males, 8 females), FMD was assessed by measuring brachial artery (the major blood vessel in the upper area) dilation in response to hyperemia after 5 min of forearm cuff inflation. Subjects were studied on 2 subsequent days. On day 1 they underwent two consecutive FMD measures, with the second test (FMD2) performed 15 min after the first test (FMD1). On day 2, the subjects were randomized to receive either placebo (saline) or intravenous L-arginine (10 g in 20 min).
Regulation of protein arginine
methylation might be involved in the
reprogramming process and,
accordingly, the amino acid arginine
may play a role in the induction of
At the end of the infusion, patients underwent two consecutive FMD measures following the same protocol as on day 1. On day 1, FMD2 was lower than FMD1 in both groups. However, on day 2, a significant reduction of FMD was observed during FMD2 compared to FMD1 in the placebo group, but not in the arginine group. FMD assessment induced a significant impairment of endothelial function. The researchers thought that an increase of endogenous NO synthesis inhibitors was responsible for the phenomenon that was reversed by L-arginine administration.
Arginine Enhances Exercise Tolerance and Lowers Systolic Blood Pressure
A recent report has found that dietary nitrate supplementation increases plasma nitrite concentration, a biomarker of nitric oxide (NO) availability, and that this improves exercise efficiency and exercise tolerance in healthy humans. Based on this, researchers at the School of Sport and Health Sciences, St. Luke’s Campus, University of Exeter in Exeter, United Kingdom, hypothesized that dietary supplementation with L-arginine, the substrate for NO synthase (NOS), would elicit similar responses.
In a double-blind, crossover study, nine healthy men (aged 19–38 years) consumed a beverage containing 6 g of L-arginine or a placebo beverage and completed a series of moderate- and severe-intensity exercise bouts one hour after ingestion of the arginine. Plasma NO2 (nitrate) concentration was significantly greater in the arginine than the placebo group (108% greater) and systolic blood pressure was significantly reduced (from about 131 to 123 mmHg). A systolic of 120 mmHg is considered healthy.
The steady-state O2 uptake (VO2) during moderate-intensity exercise was reduced by 7% in the arginine group. VO2 is a measurement of the maximal oxygen consumption, maximal oxygen uptake, and peak oxygen uptake or aerobic capacity. During severe-intensity exercise, the VO2 slow-component amplitude was reduced in both the arginine and placebo groups, while the time to exhaustion was extended 707 and 562 seconds in arginine and placebo, respectively, following consumption of arginine.
In conclusion, arginine supplementation reduced the O2 cost of moderate-intensity exercise and blunted the VO2 slow component. Arginine also extended the time to exhaustion during severe-intensity exercise. In other words, arginine supplementation reduced systolic blood pressure and improved exercise efficiency and exercise tolerance in healthy humans.
Arginine Battles Cardiovascular Aging
Judging from the enormous number of scientific studies done with arginine, there are many morbidities for which arginine is needed. Yet the Mayo Clinic says that most people get enough arginine, and do not need to take supplements.* They are not alone in this opinion. Yet despite this common belief, especially within the medical community, the Mayo Clinic also states that “symptoms of arginine deficiency include poor wound healing, hair loss, skin rash, constipation, and fatty liver …” and that, although “[a]rginine is considered a semi-essential amino acid … supplementation with additional amounts is sometimes needed.” That might include “people with protein malnutrition, excessive ammonia production, excessive lysine intake, burns, infections, peritoneal dialysis, rapid growth, urea synthesis disorders, or sepsis [who] may not have enough arginine.” Hmph!
Arginine, through production of NO,
can increase the number and quality
of mitochondria, and this constitutes
a major anti-aging breakthrough.
But judging from the enormous number of scientific studies done with arginine, there are many other morbidities for which arginine is needed, including the all-encompassing category of aging, an inescapable condition of “normal” life as we know it. A recent review makes this abundantly clear with regard to cardiovascular senescence. More about this down further in this article.
The Amount of Arginine in the Typical American Diet
From an analysis of the Third National Health and Nutrition Examination Survey, a public-use nutrition survey of the non-institutionalized U.S. population, it was found that the mean arginine intake for the U.S. adult population is 4.4 g/day, with 25% of the population consuming less than 2.6 g/day. Arginine consumption varied according to demographic and cardiovascular risk factors in the population. This means that the analysis gives credence to the idea that low-arginine availability may be a factor in the development of atherosclerosis and cardiovascular disease. At the very least, for 25% of the population, 2.6 g/day is not enough for many other needs. Nor is 4.4 g/day likely to be enough. Indeed, the amount that reasonably can be obtained from food may not be sufficient.
See “The Triumph of Regenerate Medicine” subhead on page 4
Reprinted by permission from David Simonds
Grave Damage When Deficient
Arginine is frequently billed as a conditionally-essential amino acid in our diets. This does not make a lot of sense. When there is a deficiency, various inflammatory and oxidative processes result, especially in the vascular endothelium, the lining of the blood vessels in our bodies. The consequences of these processes cause grave damage to the endothelium, degrading many of its properties that are crucial for proper function, the result of which may result in the development of atherosclerosis.
In the course of vascular system events, the normal functions of the endothelium are highly dependent on sufficient production of NO. Production is accomplished through the activation of an enzyme, eNOS, made and released by vascular endothelial cells, which acts on arginine to produce NO.
When excessive oxidative vascular injury occurs, caused for example by the stresses of obesity or hypertension, reactive and destructive oxygen species form, a plenitude of which can lead to the inhibition of eNOS, thereby decreasing NO production. If, at the same time, there is too little arginine present, eNOS forms a highly reactive oxide causing further vascular endothelial injury and inflammation.
NO Is the Champion of the Crusade Against Atherosclerosis
In such an arginine-deprived environment, atherosclerosis proceeds apace and the battle is lost to cardiovascular disease. NO is the champion of the crusade against this disease; it is the glorious knight in a good fight. What’s truly important to recognize is that NO can only be produced in the body from arginine, and that it is a principal agent of blood vessel relaxation (vasodilation). Without enough NO, clogged arteries (aka atherosclerosis), chest pain, coronary artery disease, heart failure, intermittent claudication/peripheral vascular disease (resulting in muscle pain), swelling of blood vessel that causes headaches (vascular headaches), and erectile dysfunction prevail. On other fronts, arginine also triggers the body to make protein and has been studied for wound healing, bodybuilding, enhancement of sperm production (spermatogenesis), and prevention of wasting in people with critical illnesses.
The mean arginine intake for the U.S.
adult population is 4.4 g/day, with
25% of the population consuming
less than 2.6 g/day.
How Much is Enough?
In a recent study, researchers enrolled 54 subjects (30 men, 24 women), otherwise healthy outpatients, who were divided based on blood pressure (BP) measurements into either a healthy control group (19 subjects) or a hypertensive treatment group (35 patients). The latter were freshly diagnosed with mild hypertension, but had received no drugs or supplements prior to classification as hypertensive. Then the subjects were randomized to either 2 or 4 g of supplemental arginine three times daily (for a total of either 6 or 12 g/day) or placebo.
Hypertension has long been thought to be one of the highest cardiovascular risk factors, because it represents a significant disturbance in the balance of vasomotor influences. It can cause disruptions that affect functional vasoconstriction, which can result in vessel closure and block microcirculation. Hypertension can also engender structural alterations that may affect the vascular endothelium so that there is decreased bioavailability of NO. Once called endothelium-derived relaxing factor, NO is responsible for establishing and maintaining resting vascular tone, regulating blood flow to meet the metabolic demands of tissue, and adapting vessel diameter to inflow volume. This has been upheld by long-term follow-up studies in the offspring of hypertensive patients. These have achieved a deeper understanding of the prognostic and genetic importance of reduced NO bioavailability in hypertension.
NO can only be produced
in the body from arginine.
The Arginine Paradox
When NO is generated in the endothelium, L-arginine is converted to L-citrulline via eNOS. However, without an adequate and continuous supply of arginine, substrates, and several cofactors (which include folate* and probably citrulline and the antioxidants vitamin C and E), the formation of NO would not occur. Even though the intracellular concentrations of arginine normally exceed the level required for the maximal enzyme kinetics of NOS by a long shot, supplementation with arginine improves endothelial function, slows atherosclerotic plaque formation, and alters autonomic function. These changes are all consistent with enhanced NO biosynthesis. This seeming paradox may be explained by the tendency of NOS to compartmentalize along with the relative, rather than absolute, deficiency of arginine. When arginine is taken as a supplement, it displaces the competitive inhibitor, improves intracellular transport of this amino acid, and restores NO production to physiological levels. But it will work better if it is served up with cofactors.
NO Discovery Stimulated Arginine Interest
The study of arginine supplementation increased dramatically after the arginine/nitric oxide pathway was discovered. Among the findings of many of these studies was the beneficial effect of arginine on NO production and for reducing systemic BP. A review of these studies found that the results were not uniform and rather inconclusive, with dosages of arginine safely administered at even 30 g in single i.v. infusions. Studies of BP utilized oral doses of arginine ranging from 5–20 g daily, with most of them within the 6–9 g range. These data determined the choice of arginine administration regimens in the aforementioned BP study.
This study was designed to investigate the effects of arginine on BP, both for the purpose of hypertensive patient qualification and arginine therapy assessment. In large trials, lowering of BP by 2–3 mmHg by antihypertensive drugs is considered significant and leads to favorable outcomes, including the recognition that reducing even mild hypertension can lower the high risk of cardiovascular events, even when compounded by the presence of other risk factors.
Hypertension was diagnosed with mean awake BP values ≥135 mmHg systolic or 85 mmHg diastolic or average night-time values of ≥120 mmHg systolic or 70 mmHg diastolic or 24-hour BP values ≥125 mmHg systolic or 80 mmHg diastolic. Physical and laboratory examinations, which included blood and urine tests, were normal.
There were no adverse reactions in the subgroups receiving arginine, which was well tolerated—all subjects completed the study. The groups of patients receiving arginine for four weeks displayed BP reductions, with statistically significant reductions in the 24-hour and daytime BP parameters of the hypertensive patients, who received 4 g of arginine three times a day (12 g/day). Arginine lowered both systolic and diastolic BP, with a stronger hypotensive effect observed during the day. According to the researchers, the reductions by arginine were comparable to those achieved by antihypertensive drugs, with a mean daytime drop of 6 mmHg systolic and 5 mmHg diastolic. These reductions have been associated with substantial reductions in cardiovascular disease mortality, risk of stroke, and risk of myocardial infarction.
Arginine Fights Cardiovascular Aging
A comprehensive review of supplemental arginine was recently published by researchers at the Molecular Cardiology Research Institute, Tufts Medical Center, Boston. In their overview, the researchers report that as age advances, arteries lose their ability to effectively dilate owing to endothelial dysfunction. The result of this senescence is the increased age-associated risk of cardiovascular disease (CVD). It is anticipated that mortality from CVD will worsen owing to the effects of aging. With more than 35 million Americans now 65 years of age or older, the sordid fact is that the majority of these individuals have some form of CVD.
Arginine has been studied for
wound healing, bodybuilding,
enhancement of sperm production
(spermatogenesis), and prevention of
wasting in people with
Thus, the researchers analyzed papers showing that arginine plays a number of valuable roles in a variety of physiological processes, including nitrogen detoxification, immunocompetence, growth hormone (GH) secretion, and insulin secretion.
The review was focused principally on the ability of arginine to protect vascular endothelial function as a novel nutritional strategy to possibly stave off the progression of vascular dysfunction with aging and cardiovascular disease. Emphasis was placed on arginine’s propensity to alter the vascular inflammatory and systemic hormonal milieu, which in turn may have a profound effect on vascular endothelial function.
The reductions by arginine were
comparable to those achieved by
Aging Advances Vascular Endothelial Dysfunction
In the absence of other risk factors, aging is an independent atherogenic inducer, increasing morbidity and mortality from CVD, myocardial infarction, and stroke. As aging advances, vascular dysfunction becomes pervasive and peripheral vasodilatory capacity is lessened due to the deterioration of endothelial dysfunction. Importantly, the vascular endothelium is responsible for numerous autocrine, paracrine, and endocrine functions. These include vascular tone regulation and inflammation, cell growth, platelet function, and thrombosis. NO, the potent vasoactive hormone released by endothelial cells, plays a key role in maintaining the vascular wall in a tranquil state in response to sheer stress via its ability to dampen inflammation, and reduce cellular proliferation, among other capabilities.
One of the factors exacerbating endothelial dysfunction with aging is reduced NO production and bioavailability. The diminishment of NO contributes to a shifting of the vascular wall toward a defense posture—with the increased expression of chemokines, cytokines, and adhesion molecules—leading to leukocyte recruitment and platelet aggregation. Thus the atherosclerotic process is initiated or furthered. Endothelial dysfunction is a precursor to atherogenesis and, because of its correlation with aging, it is a primary phenotypic expression for normal human aging. Moreover, this aspect of vascular senescence may be the principal causative agent for the increased CVD risk associated with aging.
Other age-related declines associated with endothelial dysfunction include memory loss, reduced activity competence for daily living, and an onslaught of the numerous diseases of aging. These include erectile dysfunction, renal dysfunction, hypertension, and stroke. The deterioration of endothelial dysfunction is predictive of future cardiovascular events, and constant impairment of endothelial function virtually assures adverse outcomes. Also, improving endothelial function reverses cardiovascular decline.
As described above, NO production requires substrates and cofactors. When produced and released, NO diffuses into vascular smooth muscle cells causing relaxation. As well, NO affects potassium channels, calcium levels, and the muscle protein myosin, a motor molecule. All together, these changes serve to regulate regional blood flow through flow-mediated dilation. Other substrate and cofactors required for this reaction include oxygen, NADPH, flavin, heme, and tetrahydrobiopterin (BH4). Folate is now thought to improve vascular function by mimicking BH4 activity. Aging aggravates any dysfunctionality caused by missteps in substrate and cofactor modulation. The resulting complicity reduces NO bioavailability, lessens vasodilation, and alters regional circulation and tissue perfusion. Reduced substrate activity may also be detrimental, limiting and reducing both NO formation and vasodilation.
Arginine Especially Valuable with Age
Surgery or trauma causes growth and repair to accelerate, and under these catabolic conditions arginine becomes conditionally essential, especially with age (if you want to combat the “conditions”). This is also true when, with aging, numerous organ systems deteriorate, such as with sarcopenia (i.e., lean tissue loss). Indeed, aging and CVD are synonymous with inflammation, a condition which normally leads to recovery and restoration of tissue integrity, but may not, when the inflammatory process persists.
Even in the absence of clear risk factors or clinical disease, inflammation and oxidative stress can ultimately result in pathogenesis. Consequently, aging alone can be thought of as a catabolic/inflammatory state. It is for this reason that the use of arginine as a nutritional strategy to protect the vasculature from the negative effects of aging and disease should be considered essential, and not just conditionally essential.
Emphasis was placed on arginine’s
propensity to alter the vascular
inflammatory and systemic hormonal
milieu, which in turn may have a
profound effect on vascular
Arginine Enhances Vascular Function
As already stated, arginine can help with angina, atherosclerosis, heart failure, coronary artery disease (CAD), erectile dysfunction, and intermittent claudication/peripheral vascular disease. All of these are related to its effects on vascular endothelial function.
In one study conducted in men with CAD, a dose of 7 g taken 3 times per day (21 g/day) for 3 days increased plasma levels of arginine, while improving endothelium-dependent dilation. Another study with hypercholesterolemic young adults, using the same dose over a 4 week period found that plasma arginine levels doubled, while endothelial-dependent dilation increased nearly 3½ fold.
Also, in a prospective, double-blind, randomized crossover trial, 16 g of arginine for 14 days or placebo in 12 healthy old participants (age 73.8 ± 2.7 years) found that arginine improved endothelial-dependent vasodilation (5.7% ± 1.2%), whereas placebo had no effect. Serum levels of arginine increased significantly, but placebo had no effect. In several studies with older patients with stable CAD, arginine supplementation has also been shown to improve flow-mediated dilation.
Not All Arginine Studies Agree
Also, other studies have shown that older patients with CAD and concomitant renal dysfunction may not benefit from arginine supplementation and similarly, that acute intravenous infusion of arginine has no effect on endothelial-dependent vasodilation in healthy older individuals. As well, the effects of 9 g of arginine per day for 1 month on endothelium-dependent vasodilation in healthy postmenopausal women increased plasma arginine, but without any change in flow-mediated dilation. Others have shown that lower amounts of arginine have no effect on plasma levels of arginine, forearm blood flow, or endothelial-dependent vasodilation in healthy men.
GH secretion declines with aging and
this is associated with
declines in muscle mass and
bone mineral density as well as
increases in adiposity.
From the results of a recently concluded meta-analysis, it would appear that arginine’s positive effects, at least at low levels, are dependent on initial endothelial health. Supplementation does not seem to affect endothelial-dependent flow-mediated dilation (FMD) in healthy individuals when vascular endothelial function has not already deteriorated, owing possibly to an existing sufficiency of NO activity. [But this may not be entirely true (see prior section, “Arginine Helps Control Flow-Mediated Dilation”)].This would explain the failure of low levels of arginine supplementation to increase FMD in such subjects. But in those with more endothelial dysfunction, arginine would appear to be very useful indeed.
Not for All Aging Populations?
Even though studies have shown that short-term arginine therapy improves endothelial function in older patients with peripheral artery disease, arginine may not work for all aging populations. In this cohort, there has even been a study showing detrimental effects on endothelial function. Using 3 g/day of arginine for six months, the result was reduced NO availability, FMD, and other measures. Two possible causes for these outcomes are that additional arginine may lessen the sensitivity of smooth muscle cells to NO release due to arginine tolerance and that there may be a counter-regulatory nitrate tolerance for prolonged exposure. There are other causes, but none are clear. The possibility always remains that without adequate cofactors, the bioavailability of which also diminishes with age, arginine’s benefits are thwarted.
Offsetting the above-mentioned is a study of long-term arginine administration showing a favorable effect on coronary endothelial function in those with coronary endothelial dysfunction and nonobstructive CAD. However, a highly publicized study published in JAMA found that arginine supplementation was associated with higher postinfarction mortality, but these results were probably due to inadequate analysis along with high statin use (see
“L-Arginine Therapy in Acute Myocardial Infarction: Why the Negative Results? Could It Have Been Prevented?” in the March 2006 issue). From that article, “[Durk & Sandy] do not recommend that those who have recently had heart attacks take L-arginine (even with the addition of vitamin C, folic acid, and CoQ10) until there is more knowledge about the reasons for this study’s results.” The formidable Adrian Barbul, M.D., has chimed in on this to cast added doubt.
Arginine has shown promise as a vascular prophylaxis against endothelial dysfunction induced by acute stressors. Acute cigarette smoking and consumption of a high-fat meal significantly reduce endothelial function. Thus, arginine taken prior to smoking or with a high-fat meal prevents the deleterious effect of these perturbations on endothelial function according to at least four studies.
Arginine as an Anti-Inflammatory Agent and Immune Function Enhancer
While inflammation/oxidative stress has been identified as the principal factor for endothelial dysfunction, there are other factors including inadequate arginine/BH4 ratio (probably addressed by using folate, as explained above). Another is the abundance of reactive oxygen species (ROS) generated with aging, which can uncouple NOS from arginine oxidation, resulting in superoxide production and the formation of peroxynitrite instead of NO. Superoxide may cause added BH4 oxidation and eNOS uncoupling. Antioxidants such as vitamin C and E may also be of benefit.
An often missed benefit of arginine is immune function enhancement. In fact, higher plasma concentrations may increase the activity of natural killer cells among other immune agents such as T-cells. Arginine is also noted to exercise an immune-preserving effect under conditions of protein malnutrition. Although arginine’s possible direct effects on inflammation and oxidative stress have barely been examined, animal studies show that arginine prevents upregulation of NADPH oxidase, a known generator of ROS within aging vasculature.
In patients with chronic kidney and CVD, arginine reduces several important markers of inflammation and oxidative stress ADMA (the endogenous inhibitor of NO), along with inflammatory enzymes, and homocysteine (a ROS stimulator that causes vascular damage and atherosclerosis). Arginine also reduces endothelin-1, a potent vasoconstrictor and important modulator of endothelial dysfunction with advancing age.
Arginine as a Multifaceted Nutrient
It is known that arginine stimulates the release of growth hormone (GH), along with insulin, glucagon, epinephrine, norepinephrine, and prolactin. While many amino acids stimulate insulin secretion, arginine is the most potent, and although insulin resistance is connected to endothelial dysfunction, insulin can improve endothelial-dependent vasodilation independently of NO activity. GH secretion declines with aging and this is associated with declines in muscle mass and bone mineral density as well as increases in adiposity. Decreases in GH release has also been linked to deterioration of various cardiovascular and immunological functions.
It is good to know that arginine is a powerful stimulator of GH. Numerous studies have demonstrated that patients with GH deficiency have reduced endothelial dysfunction, and augmenting GH in these patients restores endothelial function. Also, acute infusion of GH increases endothelial-dependent vasodilation. GH contributes to arginine-induced, NO-mediated vasodilation and animal models demonstrate that a deficiency induces pro-oxidative states.
GH can significantly reduce cellular mitochondria ROS generation by upregulating the expression of endogenous antoioxidants. GH has many other benefits, increasing the expression of eNOS mRNA, reducing ADMA, and increasing endothelial progenitor cells. Consequently, because arginine increases GH release, it is likely to improve endothelial function by (1) directly activating eNOS; (2) upregulating eNOS protein expression; and (3) preserving NO bioavailability via its antioxidant properties.
Arginine is far more essential than
you may have previously thought,
and is a must for
every supplement program.
A Powerhouse of a Defense Against Aging
If you are young and if you have preserved vascular endothelial function, arginine may have little effect on endothelial-dependent vasodilation. But if you are older, taking arginine will strengthen your cardiovascular system. Certainly, in select aging patient populations with overt endothelial dysfunction and reduced arginine stores, arginine by itself may very well improve vascular function via its ability to augment NO. So much the better if arginine is properly cofactored.
And don’t forget that independently, arginine may also improve endothelial function via its ancillary effects, along with anti-inflammatory/antioxidant benefits for endothelial cells. Not to mention arginine’s effects on hormonal modulation including GH release, mitochondrial benefits, and its possible use for iPSCs. Arginine is far more essential than you may have previously thought, and is a must for every supplement program.
- Park IH, Zhao R, West JA et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 2008;451:141–6.
- Li Y, Zhang Q, Yin X et al. Generation of iPSCs from mouse fibroblasts with a single gene, Oct4, and small molecules. Cell Res 2011;21:196–204.
- Yuan X, Wan H, Zhao X, Zhu S, Zhou Q, Ding S. Brief report: combined chemical treatment enables Oct4-induced reprogramming from mouse embryonic fibroblasts. Stem Cells 2011 Mar;29(3):549-53. doi: 10.1002/stem.594.
- Nisoli E, Clementi E, Paolucci C, Cozzi V, Tonello C, Sciorati C, Bracale R, Valerio A, Francolini M, Moncada S, Carruba MO. Mitochondrial biogenesis in mammals: the role of endogenous nitric oxide. Science 2003 Feb 7;299(5608):896-9.
- Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 2005 Oct 14;310(5746):314-7.
- Harman, D. A biologic clock: the mitochondria? J Am Geriatr Soc 1972 Apr;20(4):145-7.
- Nerla R, Di Monaco A, Sestito A, Lamendola P, Di Stasio E, Romitelli F, Lanza GA, Crea F. Transient endothelial dysfunction following flow-mediated dilation assessment. Heart Vessels 2011 Sep;26(5):524-9.
- Bailey SJ, Winyard PG, Vanhatalo A, Blackwell JR, DiMenna FJ, Wilkerson DP, Jones AM. Acute L-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise tolerance. J Appl Physiol 2010 Nov;109(5):1394-403.
- Heffernan KS, Fahs CA, Ranadive SM, Patvardhan EA. Arginine as a nutritional prophylaxis against vascular endothelial dysfunction with aging. J Cardiovasc Pharmacol Ther 2010 Mar;15(1):17-23.
- King DE, Mainous AG 3rd, Geesey ME. Variation in arginine intake follow demographics and lifestyle factors that may impact cardiovascular disease risk. Nutr Res 2008 Jan;28(1):21-4.
- Ast J, Jablecka A, Bogdanski P, Smolarek I, Krauss H, Chmara E. Evaluation of the antihypertensive effect of arginine supplementation in patients with mild hypertension assessed with ambulatory blood pressure monitoring. Med Sci Monit 2010 Apr 28;16(5):CR266-71.
- Heffernan KS, Fahs CA, Ranadive SM, Patvardhan EA. Arginine as a nutritional prophylaxis against vascular endothelial dysfunction with aging. J Cardiovasc Pharmacol Ther 2010 Mar;15(1):17-23.
- Moens AL, Vrints CJ, Claeys MJ, Timmermans JP, Champion HC, Kass DA. Mechanisms and potential therapeutic targets for folic acid in cardiovascular disease. Am J Physiol Heart Circ Physiol 2008 May;294(5):H1971-7.
- Adams MR, McCredie R, Jessup W, Robinson J, Sullivan D, Celermajer DS. Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis 1997; 129(2):261-9.
- Clarkson P, AdamsMR, Powe AJ, et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996;97(8):1989-94.
- Bode-Boger SM, Muke J, Surdacki A, Brabant G, Boger RH, Frolich JC. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med 2003; 8(2):77-81.
- Maxwell AJ, Zapien MP, Pearce GL, MacCallum G, Stone PH. Randomized trial of a medical food for the dietary management of chronic, stable angina. J Am Coll Cardiol 2002;39(1):37-45.
- Yin WH, Chen JW, Tsai C, Chiang MC, Young MS, Lin SJ. L-arginine improves endothelial function and reduces LDL oxidation in patients with stable coronary artery disease. Clin Nutr 2005;24(6):988-97.
- Sozykin AV, Noeva EA, Balakhonova TV, Pogorelova OA, Men’shikov M. Effect of L-arginine on platelet aggregation, endothelial function and exercise tolerance in patients with stable angina pectoris [in Russian]. Ter Arkh 2000;72(8):24-7.
- Bai Y, Sun L, Yang T, Sun K, Chen J, Hui R. Increase in fasting vascular endothelial function after short-term oral L-arginine is effective when baseline flow-mediated dilation is low: a metaanalysis of randomized controlled trials. Am J Clin Nutr 2009; 89(1):77-84.
- Boger RH, Bode-Boger SM, Thiele W, Creutzig A, Alexander K, Frolich JC. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. J Am Coll Cardiol 1998;32(5):1336-44.
- Wilson AM, Harada R, Nair N, Balasubramanian N, Cooke JP. L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation 2007;116(2):188-95.
- Lerman A, Burnett JC Jr, Higano ST, McKinley LJ, Holmes DR Jr. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation 1998;97(21):2123-8.
- Abumrad NN, Barbul A. Arginine Therapy for Acute Myocardial Infarction. JAMA 2006 May10:2138-9.
Will Block is the publisher and editorial director of Life Enhancement magazine.