Anti-aging effects of L-arginine

Abstract

l-Arginine is one of the most metabolically versatile amino acids. In addition to its role in the synthesis of nitric oxide, l-arginine serves as a precursor for the synthesis of polyamines, proline, glutamate, creatine, agmatine and urea. Several human and experimental animal studies have indicated that exogenous l-arginine intake has multiple beneficial pharmacological effects when taken in doses larger than normal dietary consumption. Such effects include reduction in the risk of vascular and heart diseases, reduction in erectile dysfunction, improvement in immune response and inhibition of gastric hyperacidity. This review summarises several positive studies and personal experiences of l-arginine. The demonstrated anti-aging benefits of l-arginine show greater potential than any pharmaceutical or nutraceutical agent ever previously discovered.

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Journal of Advanced Research (2010) 1, 169–177
Cairo University
Journal of Advanced Research
REVIEW
Anti-aging effects of l-arginine
Mohamed Z. Gad ∗
Department of Biochemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo – GUC,
Main Entrance Al Tagamoa Al Khames, New Cairo City 11835, Egypt
Received 17 June 2009; received in revised form 16 August 2009; accepted 29 September 2009
Available online 9 June 2010
KEYWORDS
l-Arginine;
Anti-aging;
Clinical pharmacology;
Metabolism;
Therapeutic use
Abstract l-Arginine is one of the most metabolically versatile amino acids. In addition to its role in the
synthesis of nitric oxide, l-arginine serves as a precursor for the synthesis of polyamines, proline, glutamate,
creatine, agmatine and urea. Several human and experimental animal studies have indicated that exogenous
l-arginine intake has multiple beneficial pharmacological effects when taken in doses larger than normal
dietary consumption. Such effects include reduction in the risk of vascular and heart diseases, reduction in
erectile dysfunction, improvement in immune response and inhibition of gastric hyperacidity. This review
summarises several positive studies and personal experiences of l-arginine. The demonstrated anti-aging
benefits of l-arginine show greater potential than any pharmaceutical or nutraceutical agent ever previously
discovered.
© 2010 Cairo University. All rights reserved.
Metabolism of l-arginine: an entrance to clinical value
l-Arginine is a basic natural amino acid. Its occurrence in mam-
malian protein was discovered by Hedin in 1895 [1].l-Arginine is
engaged in several metabolic pathways within the human body. It
serves as a precursor for the synthesis not only of proteins but also of
urea, polyamines, proline, glutamate, creatine and agmatine (Fig. 1)
[2]. As part of this, l-arginine is an essential component of the urea
cycle, the only pathway in mammals that allows the elimination
of toxic ammonia from the body. Ornithine, the by-product of this
∗Tel.: +20 2 27590717; fax: +20 2 27581041.
E-mail addresses: mohamed.gad@guc.edu.eg,drmzgad@tedata.net.eg.
2090-1232 © 2010 Cairo University. Production and hosting by Elsevier. All
rights reserved. Peer review under responsibility of Cairo University.
Production and hosting by Elsevier
reaction, is a precursor for the synthesis of polyamines, molecules
essential for cell proliferation and differentiation. l-Arginine is also
required for the synthesis of creatine, an essential energy source for
muscle contraction. Agmatine, which has a clonidine-like action on
blood pressure, is also formed from l-arginine, though its phys-
iological function is not yet fully understood. However, current
interest in l-arginine is focused mainly on its close relationship
with the important signal molecule nitric oxide (NO). l-Arginine
is the only substrate in the biosynthesis of NO, which plays critical
roles in diverse physiological processes in the human body including
neurotransmission, vasorelaxation, cytotoxicity and immunity.
It is worth mentioning that the processes described in Fig. 1
do not all occur within each cell; instead, they are differentially
expressed according to cell type, age and developmental stage, diet,
and state of health or disease. In fact, Fig. 1 is somewhat misleading
in that it summarises the metabolism of arginine at a wholebody
level; it does not represent arginine metabolism in any particular
cell type, nor does it indicate which enzymes are expressed under
different conditions, which enzymes are regulated, the presence of
various inter- and intracellular transport systems or how substrates
are divided into the different pathways.
doi:10.1016/j.jare.2010.05.001

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170 M.Z. Gad
Fig. 1 Overview of mammalian arginine metabolism. Only enzymes
that directly use or produce arginine, ornithine, or citrulline are identi-
fied, and not all reactants and products are shown. Inhibition of specific
enzymes is indicated by dashed lines and the dash within a circle.
Amino acid residues within proteins are identified by brackets. Key to
abbreviations: ADC, arginine decarboxylase; AGAT, arginine: glycine
amidinotransferase; ARG, arginase; ASL, argininosuccinate lyase;
ASS, argininosuccinate synthetase; DDAH, dimethylarginine dimethy-
laminohydrolase; Me2, dimethyl; OAT, ornithine aminotransferase;
ODC, ornithine decarboxylase; OTC, ornithine transcarbamylase; P5C,
l-D1-pyrroline-5-carboxylate; PRMT, protein–arginine methyltrans-
ferase [2].
l-Arginine requirements in humans
l-Arginine is traditionally classified as a semi-essential or condition-
ally essential amino acid; it is essential in children and non-essential
in adults. Homeostasis of plasma l-arginine concentrations is regu-
lated by dietary arginine intake, protein turnover, arginine synthesis,
and metabolism. This may explain why, under certain conditions,
l-arginine may become an essential dietary component. The main
tissue in which endogenous l-arginine synthesis occurs is the kid-
ney, where l-arginine is formed from citrulline, which is released
mainly by the small intestine [3]. The liver is also capable of
synthesising considerable amounts of l-arginine; however, this is
completely reutilised in the urea cycle so that the liver contributes
little or not at all to plasma arginine flux [4].
l-Arginine normally constitutes approximately 5–7% of the
amino acid content of a typical healthy adult diet. This accounts to
an average intake of 2.5–5 g/day, which only meets the body’s min-
imal requirements for tissue repair, protein synthesis and immune
cell maintenance. l-Arginine delivered via the gastrointestinal tract
(GIT) is absorbed in the jejunum and ileum of the small intestine. A
specific amino acid transport system (the y+transporter) facilitates
this process; this transport system is also responsible for assisting
the transport of other basic amino acids l-lysine and l-histidine
[5]. About 60% of the absorbed l-arginine is metabolised by the
GIT, and only 40% reaches the systemic circulation intact. Most
dietary proteins have a relatively balanced mixture of amino acids,
and thus the only way to selectively deliver more l-arginine to an
individual would be to supplement with the individual amino acid
itself.
There is little evidence to support an absolute dietary deficiency
as a cause of vascular dysfunction in humans. However, evidence
that supports the importance of an exogenous supply of l-arginine
for a healthy vascular system has been provided by Kamada et
al. [6]. In this study, vascular endothelial function was examined
in a lysinuric protein intolerant (LPI) patient that had a genetic
defect of dibasic amino acid transport caused by mutations in the
SLC7A7 gene. The transporter is normally expressed in intestinal
and renal epithelial cells, and deficient expression leads to impaired
dietary uptake of exogenous l-arginine and impaired renal tubular
reabsorption of filtered l-arginine. As a result, plasma l-arginine
concentration in the patient was considerably lower than normal
(reduced by 79%).
Assessment of NO-dependent endothelial function in this
patient revealed serum levels of nitrogen oxides (NOx) and
flow-mediated brachial artery vasodilator response approximately
70% lower than in controls. The patient also suffered from
reduced circulating platelet count, increased plasma levels of the
thrombin–antithrombin III complex, and elevated plasma fibrin
(ogen) degradation products. Intravenous infusion of l-arginine
reversed all these effects. The conclusion that can be derived
from these results is that the extracellular supply of l-arginine is
essential for proper endothelial nitric oxide synthase (eNOS) activ-
ity, despite the fact that intracellular l-arginine may far exceed
the Km for eNOS, a phenomenon termed in literature ‘argi-
nine paradox’. Most investigators believe that this phenomenon
is due to the colocalisation of cation arginine transporter (CAT-
1) with membrane-bound eNOS in plasmalemmal caveoli [7].
The importance of the external supply of l-arginine suggests
the definition of l-arginine as a ‘semi-essential’ amino acid in
adults.
The clinical pharmacology of l-arginine
l-Arginine and the cardiovascular system
Normal plasma arginine concentrations are ∼80–120 ␮M; intracel-
lular concentrations are even greater (up to 1 mM). The Km for
arginine as a substrate for the NOS is in the region of 1–10 ␮M;
thus there would appear to be a vast surplus of substrate. Neverthe-
less, several reports have indicated that administration of exogenous
l-arginine may enhance the generation of NO.
In the cardiovascular system, exogenous l-arginine causes a
rapid reduction in systolic and diastolic pressures when infused
into healthy humans and patients with various forms of hyper-
tension. Furthermore, oral l-arginine supplementation attenuates
platelet reactivity and improves endothelial function in ani-
mal models of hypercholesterolemia and atherosclerosis. Clinical
studies of l-arginine in humans have also been highly posi-
tive in improving endothelial dysfunction and even preventing
restenosis after balloon angioplasty. An excellent review of the
clinical pharmacology of l-arginine, particularly in the cardio-
vascular system, has been provided by Boger and Bode Boger
[8].
A summary of some of the positive results for l-arginine in
the prevention and improvement of cardiovascular disease (CVD)
include: 6.6 g/day oral in hypercholesterolemic patients with periph-
eral arterial disease (Heartbar)—at 2 weeks increased pain-free,
increased total walking distance (by 66 and 23%), and increased
quality of life [9]; 15 g/day oral in patients with congestive heart
failure—at 5 days improved glomerular filtration rate, natriuresis
and plasma endothelin levels [10];2×3.3 g/day oral in type I dia-
betic patient with debilitating exertional angina pectoris—at 7 days
completely ameliorated angina and normalised exercise capacity
[11]; 8.4 g/day oral in hypercholesterolemic humans—at 2 weeks
normalised platelet aggregation [12]; 17 g/day oral in healthy non-

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Anti-aging effects of l-arginine 171
Table 1 Clinical conditions with elevated ADMA [16].
Condition Fold increase vs. controls
Hypercholesterolemia 2–3
Hypertriglyceridemia 2
Hypertension 2
Pulmonary hypertension 2–3
Peripheral arterial disease 2–4
Chronic renal failure 2–12
Congestive heart failure 2–3
Type 2 diabetes 2
Preeclampsia 2
smoking elderly population—at 14 days decreased serum total
cholesterol (TC) and decreased low density lipoproteins cholesterol
(LDL-C), but not decreased high density lipoproteins cholesterol
(HDL-C) [13]; long-term oral l-arginine reduced restenosis after
experimental angioplasty [14]; reduced intimal thickening in vein
grafts [15].
Most reports ascribe the clinical benefits of l-arginine in CVD
to the provision of NO. l-Arginine is the only precursor for NOS
reaction. NO is produced by all tissues of the body and plays par-
ticularly important roles in cardiovascular homoeostasis. Several
studies have shown that l-arginine improves vascular function by
overcoming the deleterious effects of asymmetric dimethylarginine
(ADMA), a novel cardiovascular risk factor. ADMA is a competi-
tive inhibitor of NOS and has been found to be elevated in serum in
many diseases (Table 1)[16].
In a recent study from our lab [17], we provided evidence
that ADMA (along with other CVD risk factors malondialdehyde
(MDA), homocysteine and myeloperoxidase (MPO) activity) was
elevated in sera of 15 renal failure patients on hemodialysis. Oral
l-arginine administration (15 g/day, 5 g t.i.d. for 1 month) in these
patients caused significant reduction in these biochemical markers
(Fig. 2).
Fig. 2 Effect of oral l-arginine administration (15 g/day, 5 g t.i.d.
for 1 month) on MDA, MPO, ADMA and homocysteine levels in 15
renal failure patients on hemodialysis and suffering from CVD. CVD
events were defined as: acute myocardial infarction diagnosed by typi-
cal clinical and ECG changes, angina pectoris based on typical clinical
characteristics or transitory ischemic events verified by echocardiogra-
phy. Data are represented as mean±SD. Differences between groups
were compared using a one-way analysis of variance (ANOVA) fol-
lowed by LSD post hoc analysis. *Statistically significant from before
oral l-arginine administration at p≤0.05 [17].
Table 2 NO-dependent and -independent cardiovascular actions
of l-arginine.
NO-dependent vascular actions
↑Vasodilator tone [18]
↓Leukocyte adhesion [19]
↓Platelet aggregation [20]
↓SMC proliferation [21]
↓Superoxide production [22]
↓Endothelial dysfunction [23]
NO-independent vascular actions
↓Angiotensen-converting enzyme activity [24]
↓Thromboxane B2 formation, fibrin & platelet-fibrin complex [25]
↓Blood viscosity [26]
↓Leukocyte adhesion to non-endothelial matrix [27]
↓LDL oxidation [28]
Non-specific cardiovascular effects
Increases the synthesis of urea, creatine, proline, polyamines and
release of hormones as insulin, growth hormone, glucagon and
prolactin [8]
Thus, within the scope of NO-dependent and NO-independent
vascular actions of l-arginine (Table 2) accumulating evidence
supports the clinical use of l-arginine as an anti-atherosclerotic
supplement.
l-Arginine and sexual function
Arginine is required for normal spermatogenesis. Over 50 years
ago, researchers found that feeding an arginine-deficient diet to
adult men for 9 days decreased sperm counts by ∼90% and
increased the percentage of non-motile sperm approximately 10-
fold [29]. Oral administration of 500 mg arginine–HCl per day
to infertile men for 6–8 weeks markedly increased sperm counts
and motility in a majority of patients, and resulted in successful
pregnancies [30].
There are only very few reports on the improvement of erectile
function by l-arginine administration. A study by Chen et al. [31]
revealed a significant subjective improvement in sexual function
in men with organic erectile dysfunction (31% of cases) after oral
intake of 5 g l-arginine for 6 weeks, but only if they had decreased
NOx excretion or production. Other studies have shown that long-
term oral administration of pharmacological doses of l-arginine
improves the erectile response in the aging rat [32] as well as in
patients with erectile dysfunction [33,34]. However, Klotz et al.
[35] reported in a controlled crossover study that oral l-arginine at
3×500 mg/day was not better than a placebo as a first line treatment
for the mixed type of impotence.
In general, studies in this area are scarce and provide incon-
sistent results. Further studies, particularly of long-term usage of
l-arginine, are needed to distinguish the group of patients that can
most benefit from this supplement. The theoretical basis of these
studies is furnished by the established crucial role of NO from nerves
and possibly endothelia in initiating and maintaining intracavernous
pressure increase, penile vasodilatation, and penile erection that are
dependent on cyclic GMP synthesised with activation of soluble
guanylyl cyclase by NO in smooth muscle cells [36]. The aphro-
disiac properties of l-arginine have not been adequately studied,
despite the noticeable presence of l-arginine in most aphrodisiac
and sexual stimulation formulas commercially available in the inter-
national market.

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172 M.Z. Gad
l-Arginine and the gastrointestinal tract
NO donors have been repeatedly shown to protect gastric mucosa
against damage induced by various agents [37,38]. In addition,
reports from different laboratories have demonstrated the impor-
tance of endogenous NO in the protection of gastric mucosa.
Two studies from Pique’s laboratory [39,40] have shown that NO
plays a vasodilatory role in gastric microcirculation during acid
secretion. Other studies have accredited the role of NO as an
endogenous modulator of leukocyte adhesion [41]. In support,
Calatayud et al. [38] have shown that transdermal nitroglyc-
erine protected against indomethacin-induced gastric ulceration
through maintenance of mucosal blood flow and reduction of
leukocyte–endothelial cell rolling and adherence. Moreover, Wal-
lace [42] has stated that reduction of gastric blood flow is the
main predisposing factor in the induction of non-steroidal anti-
inflammatory drugs (NSAID) gastropathy. Other than the role
of NO in maintenance of blood flow, NO may protect against
NSAID damage by promotion of prostaglandin synthesis. A mutual
interaction has been observed between NOS and cyclooxygenase
(COX) enzymes. NO donors were shown to enhance COX activ-
ity whereas NOS inhibitors blocked prostaglandin E2 (PGE2)
production [43].
In a study from our lab [44], we demonstrated the role of NO
in protecting against indomethacin-induced gastric ulceration.
Intraperitoneal (i.p.) injection of l-arginine (300 mg/kg) 30 min
before i.p. injection of 30 mg/kg indomethacin to rats almost
completely protected the rats against indomethacin-induced gastric
ulceration by a mechanism independent of modulation of acid
secretion, mucin content or pepsin activity, but via maintenance
of mucosal NO. On the other hand, pretreatment of rats with the
NOS inhibitors l-NAME (50 mg/kg), a non-selective constitutive
nitric oxide synthase/inducible nitric oxide synthase (cNOS/iNOS)
inhibitor, or the selective iNOS inhibitor aminoguanidine (AMG)
(50 mg/kg) worsens the ulcer index (the sum of the length (mm)
of all lesions in the fundic region) (Fig. 3). In support to the
anti-ulcerogenic effect of l-arginine, reports by Lazaratos et al.
[45] and Jimenez et al. [46] have indicated the protective role
of l-arginine against the ulcerogenic action of endothelin-1 and
ibuprofen, respectively.
Reports have not restricted the role of NO to gastric protec-
tion, but also discussed the acceleration of ulcer healing. Konturek
et al. [47] have shown that glyceryl trinitrate is capable of ulcer
healing and that suppression of NO synthesis resulted in impaired
ulcer healing. It is possible that NO directly accelerates ulcer repair
by promoting the growth of smooth muscles, as suggested by
Hogaboam et al. [48].
In a recent study (in press), we have tested the effect of NO mod-
ulation on peptic ulcer healing using the NO precursor; l-arginine,
Fig. 3 Ulcer index (mm) of normal, indomethacin, l-NAME,
aminoguanidine, and l-arginine treated rats. Results are mean ±SEM of
6–10 animals. **Significantly different from indomethacin at p< 0:01.
a competitive inhibitor of NOS, l-NAME and the NO donor; nitro-
glycerine (NTG). Rats were injected with a single oral dose of
indomethacin (30 mg/kg) and then treated with l-arginine, NTG or
l-NAME, once daily for 7 days starting 4 h after the indomethacin
injection. Gross lesion examination and histological assessment
were done. Gastric tissue content of NO, PGE2 and mucin were
detected. In addition, oxidative stress markers including glutathione
(GSH) and lipid peroxides were measured. l-Arginine and NTG
were found to accelerate the healing of indomethacin-induced
ulcers, as evident in macroscopic and histological examination, to
restore normal levels of NO and GSH and to significantly attenuate
the increase in PGE2 and lipid peroxides induced by indomethacin.
On the other hand, l-NAME was found to exacerbate the mucosal
damage (Table 3).
In parallel, Brzozowski et al. [50] have shown that intragas-
tric administration of l-arginine (32.5–300 mg/kg/day) enhanced
the healing rate of acetic acid-induced ulcers in a dose-dependent
manner, while d-arginine was not effective.
l-Arginine and wound healing
Wound healing involves platelets, inflammatory cells, fibroblasts
and epithelial cells. All of these cell types are capable of producing
NO either constitutively or in response to inflammatory cytokines.
NO produced by both iNOS and eNOS plays many important roles in
wound healing, from the inflammatory phase through to scar remod-
eling. NO has cytostatic, chemotactic and vasodilatory effectsduring
early wound repair, regulates proliferation and differentiation of sev-
eral cell types, modulates collagen deposition and angiogenesis, and
affects wound contraction (Fig. 4)[51].
l-Arginine was first noted to enhance wound healing in 1978
[52]. Since then dietary l-arginine has been shown to improve colla-
Table 3 Gross examination of the effect of treatment with l-arginine, NTG or l-NAME on gastric ulcer induced by indomethacin in rats.
Groups No. of dead rats Ulcer No. Ulcer index (mm) Ulcer score
Control 0 0 – –
Indomethacin 3 13.25 ±0.75 19.0 ±1.45 3.62 ±0.26
Indomethacin + l-arginine 1 0 – –
Indomethacin + NTG 2 0 – –
Indomethacin + l-NAME 5 17.11 ±0.65 23.2 ±1.15 4.55 ±0.17
Gastric ulcer was induced by a single oral injection of indomethacin (30 mg/kg), and then 4 h later, treatment schedule was given daily for 1 week as
follows: l-arginine (200 mg/kg), NTG (1 mg/kg) and l-NAME (15 mg/kg). Measurements were done 7 days later. Values given are means of 10–15
observations ±SEM. Ulcer index = sum of lengths of all lesions in each stomach; ulcer score indicates severity of gastric lesion, where 1(ulcerated area
1–6 mm2), 2(ulcerated area 7–12 mm2), 3(ulcerated area 13–18mm2), 4(ulcerated area 19–24 mm2) and 5(ulcerated area > 24 mm2)[49].

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Anti-aging effects of l-arginine 173
Fig. 4 Schematic of the hypothesised roles of NO in wound healing.
Production of NO from eNOS or iNOS leads to modulation of cytokines
(e.g., MCP-1, RANTES, VEGF, and TGFb1), which in turn modulates
the various facets of wound healing (e.g., chemoattraction, proliferation,
collagen deposition, and angiogenesis) [51].
gen deposition and wound strength in both humans [53] and animals
[54]. This effect may be due in part to the subsequent increase in pro-
duction of ornithine by the action of arginase enzyme, a precursor
of l-proline during collagen synthesis [55]. The direct role of NO
as a cofactor in the promotion of wound healing by l-arginine has
also been reported [56].l-Arginine might improve wound immune
cell function by decreasing the inflammatory response at the wound
site [57].
The healing effect of l-arginine is also extended to
cover burn injuries. Oral dietary l-arginine supplementation of
100–400 mg/kg/day shortened re-epithelisation times, increased
amounts of hydroxyproline, and accelerated the synthesis of repara-
tive collagen in burned rats [58]. Burn injuries significantly increase
arginine oxidation and fluctuations in arginine reserves. Total par-
enteral nutrition (TPN) increases conversion of arginine to ornithine
and proportionally increases irreversible arginine oxidation. These
make arginine conditionally essential in severely burned patients
receiving TPN [59].
l-Arginine and insulin sensitivity
Diabetes is associated with reduced plasma levels of arginine [60]
and elevated levels of the NOS inhibitor ADMA [61]. Evidence
suggests that arginine supplementation may be an effective way
to improve endothelial function in individuals with diabetes mel-
litus (DM) [62]. As well, low dose IV arginine has been shown
to improve insulin sensitivity in obese, type 2 DM, and healthy
subjects [63]. Arginine may also counteract lipid peroxidation
and thereby reduce microangiopathic long-term complications of
DM [64].
A double-blind trial found oral arginine supplementation (3 g
three time/day, 1 month) significantly improved, but did not com-
pletely normalise, peripheral and hepatic insulin sensitivity in
patients with type 2 DM [65]. Moreover, l-arginine regulates insulin
release by NO-dependent [66] and NO-independent [67] pathways.
l-Arginine and CNS function
Very few articles have investigated the effects of l-arginine sup-
plementation on CNS function. However, accumulating evidence is
beginning to indicate that NO plays a part in the formation of mem-
Fig. 5 The role of nitric oxide in the long-term potentiation of neu-
ronal activity. Glutamate released from the presynaptic nerve terminal
activates different types of receptors on the dendrites of the postsynaptic
neuron. Under normal conditions the alpha-amino-3-hydroxy-5-methyl-
4-isoxazole propionate (AMPA) receptors mediate most of the effects
of glutamate. During high-frequency synaptic transmission, however,
the activation of N-methyl-d-aspartate (NMDA) receptors results in
an increase in intracellular calcium, which stimulates the constitutive
nitric oxide synthase (NOS). The nitric oxide (NO) that is produced dif-
fuses back to the presynaptic neuron, where it enhances the release of
glutamate. The increased glutamate release leads to greater activation
of postsynaptic glutamate receptors, thereby increasing the effective-
ness of that synapse. Plus signs indicate stimulation, and l-arg denotes
l-arginine [69].
ory [68].In vitro, after specific receptor stimulation, NO is released
from a postsynaptic source to act presynaptically on one or more
neurons. This leads to a further increase in the release of glutamate
and, as a result, to a stable increase in synaptic transmission, a phe-
nomenon known as long-term potentiation. This is thought to be
linked to memory function (Fig. 5)[69]. Experiments in animals
also suggest that NO is involved in memory, because inhibiting NO
synthesis in vivo impairs learning behaviour [70].
l-Arginine (1.6 g/day) in 16 elderly patients with senile demen-
tia has been found to be effective in reducing lipid peroxidation
and increasing cognitive function [71]. In their recent report, Jing
et al. [72] explored the possible role of l-arginine in Alzheimer’s
disease (AD), taking into consideration known functions for l-
arginine in atherosclerosis, redox stress and the inflammatory
process, regulation of synaptic plasticity and neurogenesis, and
modulation of glucose metabolism and insulin activity. They pro-
vided evidence that l-arginine may play a prominent role in
protection from age-related degenerative diseases such as AD.
Further investigation is still needed to cover this virgin area of
research.

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174 M.Z. Gad
l-Arginine and muscular activity
l-Arginine has been purported to have ergogenic potential [73].
Athletes have taken arginine for three main reasons: (1) its role in
the secretion of endogenous growth hormone; (2) its involvement in
the synthesis of creatine; (3) its role in augmenting nitric oxide. In
a double-blind study, the effect of a 4-week treatment with arginine
aspartate on 21 athletes was assessed [74]. The treated group showed
enhanced maximal oxygen consumption as well as a significantly
decreased plasma lactate concentration at work intensity of 200,
300 and 400 W (running workout) on the treadmill as compared
to the control group. In another study, 8 weeks of oral l-arginine
administration (3 g) to 20 male subjects on an exercise program with
weights caused a significant increase in muscle strength and mass
as compared to the non-treated group [75].
Duchenne muscular dystrophy (DMD) is a lethal, X-linked dis-
order associated with dystrophin deficiency that results in chronic
inflammation, sarcolemma damage, and severe skeletal muscle
degeneration. Recently, the use of l-arginine, the substrate of
neuronal nitric oxide synthase (nNOS), has been proposed as a phar-
macological treatment to attenuate the dystrophic pattern of DMD.
Hnia et al. [76] were able to demonstrate that l-arginine decreases
inflammation and enhances muscle regeneration in mdx mice (an
animal model of Duchenne myopathy). The inhibitory effect of
l-arginine on the NF-kappaB/Metalloproteinase cascade reduces
beta-dystroglycan cleavage and translocates utrophin and nNOS
throughout the sarcolemma. Evidence suggests that l-arginine up-
regulates utrophin in muscles, which could compensate for the lack
of dystrophin in DMD. Utrophin has over 80% homology with
dystrophin [77].
Other effects of l-arginine
Other than the benefits in the above stated conditions, l-arginine
has been demonstrated to improve peripheral circulation [78], renal
function [79], and immune function [80]. It also possesses anti-
stress and adaptogenic capabilities [81].l-Arginine stimulates the
release of growth hormone [82] as well as the release of pancreatic
insulin and glucagon and pituitary prolactin [8]. The antioxidant
property of l-arginine has been well documented in several reports
[83,64]. An interesting article by Grasemann et al. [84] has demon-
strated an acute and transient improvement of pulmonary function
in cystic fibrosis patients by a single inhalation of l-arginine.
Nebulised l-arginine significantly increased exhaled nitric oxide
concentrations.
Therapeutic use of l-arginine supplement
l-Arginine is available commercially in several countries in vari-
able dosage forms and mostly indicated as a nutritional supplement.
It is available as capsules, tablets, powder, effervescent gran-
ules, injection, infusion, and cream with a very wide range
of doses. The indications also are quite inconsistent. Amongst
the many indications provided on the commercial forms of l-
arginine are: prevention and improvement of ischemic heart disease,
improvement of microcirculation, improvement of erectile function,
improvement of physical exercise capacity, reduction of high blood
pressure, improvement of local tissue blood supply and oxygena-
tion, improvement of creatine transport, increase of energy levels,
antioxidant, stimulation of dopamine, adrenaline and noradrenaline
release, increase of growth hormone production, improvement of
wound healing, enhancing immunity, help to reverse atherosclero-
sis, management of metabolic alkalosis, aphrodisiac, enhancement
of sperm mobility and viability, and treatment of interstitial cystitis.
l-arginine is also available commercially as a vaginal lubricant and
sexual enhancer cream.
Currently,two large multinational pharmaceutical companies are
interested in marketing products of l-arginine; the first company
produces a product formed of l-arginine with vitamins C and E and
marketed as an aid in the recovery of wounds, burns and surgery. The
second company is currently recruiting participants for the phase IV
clinical trial of oral l-arginine aspartate in the muscular fatigue of
the quadriceps, expressed in terms of the fatigue resistance factor
(FRF).
Safety considerations
Of the available studies on orally administered l-arginine in humans,
few reported any adverse effects following acute or chronic treat-
ment. Doses up to 30 g/day have been generally well tolerated, with
the most common adverse effects of nausea and diarrhoea being
reported infrequently at higher doses—from 15 to 30 g [85].No
changes in liver function, blood glucose, or plasma electrolytes have
been reported. In the absence of appropriately designed safety stud-
ies, caution should be taken if l-arginine is used in infants, pregnant
Table 4 Most noticeable observations of the subjects at the end of the 4-week study.
Feature % of cases (total =21 cases)
Remarkable improvement Mild improvement No change
Mental capability
Ability to concentrate 55 35 10
Memory retrieval 55 35 10
Delay in mental exhaustion 75 15 10
Reduction in severity of anxiety and stress 60 20 20
Reduction in nervousness 72 21 7
Deepness of sleep 80 10 10
General mood 70 25 5
Muscular activity
Muscular performance 75 5 20
Delay in muscular exhaustion 60 15 25
Sexual performance in males 54 33 13
Overall feeling of well being 65 20 15

Author's personal copy
Anti-aging effects of l-arginine 175
Table 5 Additional observations at the end of the 4-week study
reported by some subjects.
1. Adjustment of blood pressure in mild hypertension.
2. High energy, especially in the morning when waking up.
3. Clear mind.
4. Stamina and resistance to depression and anxiety.
5. Increase in urine output.
6. Improvement of hair and nail growth and hardness.
7. Improvement of skin texture and appearance.
8. Increase in night dreams.
9. Improvement of circulation and temperature of extremities.
10. Reduction of hyperacidity.
11. Overall improvement of GIT system and defecation.
12. Improvement of most vital activities greatly affected in diabetics,
including: reduction of neuritis, improvement of glucose
metabolism, enhancement of libido and sexual performance and
adjustment of body weight.
or lactating individuals, and those with viral infections and serious
compromised renal or hepatic function.
l-Arginine: anti-aging pilot study
In an open-label randomised limited study conducted by the author,
5 g/day l-arginine base was administered orally once at night for 28
days in 21 subjects with age ranging between 41 and 75 years old (14
between 41 and 49 years, 4 between 50 and 59 years, 2 between 60
and 69 years, and 1 between 70 and 79 years), 16 were males and 5
females, 17 were non-smokers and 4 smokers, and 18 of the 21 sub-
jects were taking other medications to control either hypertension,
myocardial ischemia, diabetes, gastro-oesophageal reflux disease
(GERD) and hyperacidity, hypothyroidism, neuritis, or rheumatoid.
All recruited subjects gave written informed consent that complied
with the principles of the Helsinki declaration.
A questionnaire was given to the subjects to be completed weekly
for 4 weeks. The subjects were advised to write their health status
before and after taking l-arginine. The questionnaire included 30
points regarding their mental, muscular, sexual, circulatory, GIT,
and other functions during the 4-week administration. Scoring was
recorded from 1 to 5; 1 was a remarkable improvement, 2 was a mild
improvement, 3 no difference, 4 was worse than before, and 5 was
not applicable. The subjects were also advised to report any adverse
reactions developed during the administration of the supplement.
In addition, they were asked if they wanted to continue taking the
supplement after termination of the study. Tables 4 and 5 summarise
the most noteworthy information of this pilot study.
At the end of the study, none of the 21 cases experienced any side
effects or aggravation of health problems from l-arginine adminis-
tration. All the 21 cases wanted to continue taking the supplement
after termination of the study.
Conclusions
Many – if not all – of the body functions described in this text are
debilitated by aging. Studies have shown that l-arginine, through its
versatile metabolic and physiological pathways, can improve many
of these functions. To summarise some of its effects; l-arginine
is involved in the production of a variety of enzymes, hormones,
and structural proteins. It facilitates the release of growth hormone,
insulin, glucagon, and prolactin. It is a component of the hormone
vasopressin, produced by the pituitary gland. It is the physiologi-
cal precursor of diverse biological compounds such as nitric oxide,
polyamines, proline, glutamate, creatine, agmatine and urea. As a
booster of immunity, arginine stimulates the thymus and promotes
lymphocyte production. This may be an important key for arginine’s
ability to promote healing of burns and other wounds. Arginine
has a positive effect on cerebral as well as systemic circulation. It
enhances sexual performance in males. It protects from – as well as
heals – gastric ulcers induced by various agents. The demonstrated
anti-aging benefits of l-arginine show promises greater than any
pharmaceutical or nutraceutical agent ever previously discovered.
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