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Anti-aging Research > citrulline
L-citrulline
Specific Recommendations:
News & Research:
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Metformin influences nitrogen and urea metabolism - Science Daily,
9/14/16 - "metformin intake lowers the levels of the
harmful LDL cholesterol by activating the AMPK protein complex ... metformin
also modulates the body's nitrogen and urea metabolism ... the activation of
the AMPK pathway by metformin affects nitrogen and urea metabolism through a
further enzyme***, which thus lowers the citrulline levels ... Accordingly,
the scientists suspect that the additional intake of citrulline could have a
positive effect on the cardiovascular system in patients being treated with
metformin" - See
BulkSupplements Pure L-Citrulline Powder at
Amazon.com.
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Chowing down on watermelon could lower blood pressure, study suggests -
Science Daily, 4/3/14 - "the group was divided into
two. For the first six weeks, one group was given four grams of the amino
acid L-citrulline and two grams of L-arginine per day, both from watermelon
extract. The other group was given a placebo for 6 weeks ... consuming
watermelon had a positive impact on aortic blood pressure and other vascular
parameters" - See
L-citrulline at Amazon.com
and
L-arginine products at Amazon.com.
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Nitric Oxide Now -- Ask Me How - WashingtonPost.com, 10/6/03 -
"In the arteries, the innermost layer of cells
releases
nitric oxide to
signal smooth muscle cells to dilate (increase the diameter of) the
arteries. This allows blood to flow more freely, particularly during
exercise ... By the 1990s, many scientists saw nitric oxide as the next
great weapon for treating heart disease, impotence and even bacterial
infections ... Niteworks has
L-arginine and also L-citrulline, which
recycles spent L-arginine by resupplying it with atoms it lost producing
nitric oxide ... "Ninety dollars a month? That's obscene," Murad said. "You
can probably get [vitamin] C and E for pennies a day. You can probably get
arginine for about a dollar a day""
Abstracts:
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Several Supplements May Give the Heart a Boost - WebMD, 12/8/22 -
"Omega-3 fatty acids, found in fish, vegetable oils,
nuts (especially walnuts), flax seeds, flaxseed oil, and leafy vegetables ...
Omega-6 fatty acids, polyunsaturated fats found in vegetable oils, nuts, and
seeds ... L-arginine, an amino acid that helps the body build protein. It can be
found in protein-rich foods like fish, red meat, poultry, soy, whole grains,
beans, and dairy products ... L-citrulline, a nonessential amino acid found in
watermelon ... Folic acid, a form of vitamin B9 used for deficiency and to
prevent pregnancy complications. It is added to cold cereals, flour, breads,
pasta, bakery items, cookies, and crackers, as required by federal law. Foods
that are naturally high in folate include leafy vegetables, okra, asparagus,
certain fruits, beans, yeast, mushrooms, animal liver and kidney, orange juice,
and tomato juice ... Vitamin D, a fat-soluble vitamin that is naturally present
in a few foods, added to others, and available as a dietary supplement. Fatty
fish (such as trout, salmon, tuna, and mackerel) and fish liver oils are among
the best sources ... Magnesium, which keeps blood pressure normal, bones strong,
and your heart rhythm steady. In addition to supplements, magnesium can be found
in green leafy vegetables like spinach, nuts, beans, peas, and soybeans, as well
as whole-grain cereals ... Zinc, found in chicken, red meat, and fortified
breakfast cereals ... Alpha-lipoic acid, an antioxidant made naturally in the
body and also found in foods. It is in red meat, carrots, beets, spinach,
broccoli, and potatoes ... Coenzyme Q10, an antioxidant found in cold-water fish
like tuna, salmon, mackerel, and sardines; vegetable oils; and meats ...
Melatonin ... Plant-based polyphenols such as catechin, curcumin, flavanol,
genistein, and quercetin"
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Effects of L-Citrulline
Supplementation on Endothelial Function and Blood Pressure in Hypertensive
Postmenopausal Women - Nutrients 2022 Oct 20 -
"Aging and menopause are associated with decreased nitric oxide bioavailability
due to reduced L-arginine (L-ARG) levels contributing to endothelial dysfunction
(ED). ED precedes arterial stiffness and hypertension development, a major risk
factor for cardiovascular disease. This study investigated the effects of
L-citrulline (L-CIT) on endothelial function, aortic stiffness, and resting
brachial and aortic blood pressures (BP) in hypertensive postmenopausal women.
Twenty-five postmenopausal women were randomized to 4 weeks of L-CIT (10 g) or
placebo (PL). Serum L-ARG, brachial artery flow-mediated dilation (FMD), aortic
stiffness (carotid-femoral pulse wave velocity, cfPWV), and resting brachial and
aortic BP were assessed at 0 and 4 weeks. L-CIT supplementation increased L-ARG
levels (Δ13 ± 2 vs. Δ-2 ± 2 µmol/L, p < 0.01) and FMD (Δ1.4 ± 2.0% vs. Δ-0.5
± 1.7%, p = 0.03) compared to PL. Resting aortic diastolic BP (Δ-2 ± 4 vs. Δ2 ±
5 mmHg, p = 0.01) and mean arterial pressure (Δ-2 ± 4 vs. Δ2 ± 6 mmHg, p = 0.04)
were significantly decreased after 4 weeks of L-CIT compared to PL. Although not
statistically significant (p = 0.07), cfPWV decreased after L-CIT
supplementation by ~0.66 m/s. These findings suggest that L-CIT supplementation
improves endothelial function and aortic BP via increased L-ARG availability"
- See
L-citrulline at Amazon.com.
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L-citrulline prevents
heat-induced mitochondrial dysfunction and cell injury through nitric
oxide-mediated Drp1 inhibition in mouse C2C12 myoblasts - Br J Nutr 2022 Jul
6 - "Severe heat exposure causes mitochondrial
fragmentation and dysfunction, which contribute to the pathogenesis of
heat-related illness. L-citrulline is a naturally occurring amino acid and has
been suggested to influence heat shock responses. This study aimed to test
whether L-citrulline supplementation would preserve mitochondrial integrity and
attenuate heat-induced skeletal muscle injury, and elucidate the underlying
mechanisms ... Our results suggest that L-citrulline prevents heat-induced
mitochondrial dysfunction and cell injury through NO-mediated Drp1 inhibition in
C2C12 myoblasts. L-citrulline may be an effective treatment for heat-related
illnesses and other mitochondrial diseases"
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Impact of high-intensity
interval training with or without l-citrulline on physical performance, skeletal
muscle, and adipose tissue in obese older adults - J Cachexia Sarcopenia
Muscle 2022 Mar 7 - "Aging is associated with a
progressive decline in skeletal muscle mass and strength as well as an increase
in adiposity. These changes may have devastating impact on the quality of life
of older adults ... High-intensity interval training is effective in improving
functional capacities, lean mass, muscle power, and waist circumference in obese
older adults. HIIT also increases markers of mitochondrial biogenesis,
mitochondrial fusion, and mitophagy. Importantly, adding CIT to HIIT results in
a greater increase in muscle strength and a significant decrease in fat mass.
The present study therefore positions HIIT combined with CIT as an effective
intervention to improve the health status of obese older adults"
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L-citrulline ameliorates
pathophysiology in a rat model of superimposed preeclampsia - Br J Pharmacol
2021 Dec 22 - "Preeclampsia, characterized by
hypertension, proteinuria, and fetal growth restriction, is one of the leading
causes of maternal and perinatal mortality. By far, there is no effective
pharmacological therapy for preeclampsia ... This study shows that L-citrulline
supplementation reduces gestational hypertension, improves placentation and
fetal growth in a rat model of superimposed preeclampsia. L-citrulline
supplementation may represent an effective and safe therapeutic strategy for
preeclampsia that benefit both the mother and the fetus"
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Effects of L-citrulline
supplementation on nitric oxide and antioxidant markers after high-intensity
interval exercise in young men: a randomized controlled trial - Br J Nutr
2021 Jun 17 - "L-citrulline (L-Cit) is a nonessential
amino acid that stimulates nitric oxide (NO) production and improves exercise
performance by reducing muscle damage indices ... nine young men (21 ± 1 years)
participated in a double-blind crossover study in which they received 12 g of
L-Cit and placebo (PL) an hour prior to high-intensity interval exercise on two
occasions, separated by a seven-day washout period ... Our data indicate that
L-Cit supplementation (single 12 g dose pre-exercise) induces improvements in
antioxidant markers following a session of high-intensity interval exercise in
young men"
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Acute effects of
Nitrosigine® and citrulline maleate on vasodilation - J Int Soc Sports Nutr.
2020 Feb 24 - "Sports supplements such as pre-workouts
tout this benefit; however, many have not been tested under laboratory
conditions to examine the effects of commonly used supplements on vasodilation.
Two popular supplements are Nitrosigine® and citrulline malate (CM) ... Baseline
FMD measurement was obtained for each visit, followed by consumption of one
clinical dose CM (8 g), Nitrosigine (1.5 g), or dextrose placebo (8 g).
Following a 60-min digestion period, FMD was repeated. Supplementation order was
randomized controlling for potential order effects ... Nitrosigine and CM
increased FMD by 31 and 34%, respectively, compared to a decrease of 2% during
the placebo trial ... Both Nitrisigine and CM increased endothelial-dependent
vasodilation as measured by a change in FMD. Increased vasodilation leads to an
increase in skeletal muscle blood flow resulting in potential improvements in
exercise performance" - See
Nitrosigine at Amazon.com.
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Citrulline stimulates
muscle protein synthesis, by reallocating ATP consumption to muscle protein
synthesis - J Cachexia Sarcopenia Muscle. 2019 May 8 - "Animal studies and
clinical data support the interest of citrulline as a promising therapeutic for
sarcopenia ... Under certain stress conditions, citrulline increases muscle
protein synthesis by specifically reallocating mitochondrial fuel to the protein
synthesis machinery"
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Citrulline malate
supplementation does not improve German Volume Training performance or reduce
muscle soreness in moderately trained males and females - J Int Soc Sports
Nutr. 2018 Aug 10 - "We conclude that an acute dose of
CM does not significantly affect anaerobic performance using an isokinetic chair
in recreational active participants. Practical implications include precaution
in recommending CM supplementation. Coaches and athletes should be aware of the
disparity between the chemical analyses of the products reviewed in the present
investigation versus the manufacturers' claims"
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l-Citrulline
Supplementation: Impact on Cardiometabolic Health - Nutrients. 2018 Jul
19;10(7) - "Diminished bioavailability of nitric oxide
(NO), the gaseous signaling molecule involved in the regulation of numerous
vital biological functions, contributes to the development and progression of
multiple age- and lifestyle-related diseases. While l-arginine is the precursor
for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral
l-arginine supplementation is largely ineffective at increasing NO synthesis
and/or bioavailability for a variety of reasons. l-citrulline, found in high
concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in
the mitochondria that also serves as a substrate for recycling l-arginine.
Unlike l-arginine, l-citrulline is not quantitatively extracted from the
gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is
therefore more effective at increasing l-arginine levels and NO synthesis.
Supplementation with l-citrulline has shown promise as a blood pressure lowering
intervention (both resting and stress-induced) in adults with pre-/hypertension,
with pre-clinical (animal) evidence for atherogenic-endothelial protection.
Preliminary evidence is also available for l-citrulline-induced benefits to
muscle and metabolic health (via vascular and non-vascular pathways) in
susceptible/older populations"
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Citrulline decreases
hepatic endotoxin-induced injury in fructose-induced non-alcoholic liver
disease: an ex vivo study in the isolated perfused rat liver - Br J Nutr.
2017 Jun 22:1-8 - "In vivo, citrulline significantly
decreased dyslipidaemia induced by a high-fructose diet and insulin resistance.
In the isolated perfused rat livers, endotoxaemia resulted in higher cytolysis (alanine
aminotransferase release) and higher inflammation (Toll-like receptor 4) in
livers of fructose-fed rats, and it was prevented by citrulline supplementation
... In this context of mild steatosis, our results suggest that fructose-induced
NAFLD leads to an increased hepatic sensitivity to LPS-induced inflammation.
Citrulline-induced restriction of the inflammatory process may thus contribute
to the prevention of NAFLD"
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Evaluation of the Effects
and Mechanism of L-Citrulline on Anti-obesity by Appetite Suppression in
Obese/Diabetic KK-Ay Mice and High-Fat Diet Fed SD Rats - Biol Pharm Bull.
2017;40(4):524-530 - "L-Cit induced significant
reduction of food intake, body weight and fat tissue mass in obese/diabetic
KK-Ay mice ... Our study suggests that L-Cit improves metabolic syndrome through
decreased body weight by appetite suppression"
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Supplemental Citrulline
Is More Efficient than Arginine in Increasing Systemic Arginine Availability in
Mice - J Nutr. 2017 Feb 8 - "Arginine is considered
to be an essential amino acid in various (patho)physiologic conditions of high
demand. However, dietary arginine supplementation suffers from various
drawbacks, including extensive first-pass extraction. Citrulline supplementation
may be a better alternative than arginine, because its only fate in vivo is
conversion into arginine ... Citrulline supplementation is more efficient at
increasing arginine availability than is arginine supplementation itself in
mice" - See BulkSupplements Pure
L-Citrulline DL-Malate 2:1 Powder at Amazon.com and
BulkSupplements Pure L-Arginine HCL Powder at
Amazon.com.
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The effects on plasma
L-arginine levels of combined oral L-citrulline and L-arginine supplementation
in healthy males - Biosci Biotechnol Biochem. 2017 Feb;81(2):372-375 -
"Oral l-citrulline plus l-arginine supplementation more
efficiently increased plasma l-arginine levels than 2 g of l-citrulline or
l-arginine, suggesting that oral l-citrulline and l-arginine increase plasma
l-arginine levels more effectively in humans when combined" - [Nutra
USA] - See
BulkSupplements Pure L-Arginine HCL Powder
at Amazon.com and
BulkSupplements Pure L-Citrulline Powder at
Amazon.com.
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Preventive effects of
citrulline on Western diet-induced non-alcoholic fatty liver disease - Br J
Nutr. 2016 May 20:1-13 - "Cit improves Western
diet-induced liver injuries via decreased lipid deposition, increased insulin
sensitivity, lower inflammatory process and preserved antioxidant status. This
may be related in part to its protective effects at the gut level"
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l-Citrulline
supplementation attenuates blood pressure, wave reflection and arterial
stiffness responses to metaboreflex and cold stress in overweight men - Br J
Nutr. 2016 May 10:1-7 - "Combined isometric exercise or
metaboreflex activation (post-exercise muscle ischaemia (PEMI)) and cold pressor
test (CPT) increase cardiac afterload, which may lead to adverse cardiovascular
events. l-Citrulline supplementation (l-CIT) reduces systemic arterial stiffness
(brachial-ankle pulse wave velocity (baPWV)) at rest and aortic haemodynamic
responses to CPT ... placebo or l-CIT (6 g/d) for 14 d in a cross-over design.
Brachial and aortic systolic blood pressure (SBP), diastolic blood pressure
(DBP) and mean arterial pressure (MAP), aortic augmented pressure (AP),
augmentation index (AIx), baPWV, reflection timing (Tr) and heart rate (HR) were
evaluated at rest and during isometric handgrip exercise (IHG), PEMI and
PEMI+CPT at baseline and after 14 d. No significant effects were evident after
l-CIT at rest. l-CIT attenuated the increases in aortic SBP and wave reflection
(AP and AIx) during IHG, aortic DBP, MAP and AIx during PEMI, and aortic SBP,
DBP, MAP, AP, AIx and baPWV during PEMI+CPT compared with placebo. HR and Tr
were unaffected by l-CIT in all conditions. Our findings demonstrate that l-CIT
attenuates aortic blood pressure and wave reflection responses to
exercise-related metabolites. Moreover, l-CIT attenuates the exaggerated
arterial stiffness response to combined metaboreflex activation and cold
exposure, suggesting a protective effect against increased cardiac afterload
during physical stress"
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Oral
L-citrulline supplementation enhances cycling time trial performance in healthy
trained men: Double-blind randomized placebo-controlled 2-way crossover study
- Journal of the International Society of Sports Nutrition 201613:6 -
"L-Citrulline supplementation significantly increased
plasma L-arginine levels and reduced completion time by 1.5 % (p < 0.05)
compared with placebo. Moreover, L-citrulline significantly improved subjective
feelings of muscle fatigue and concentration immediately after exercise"
- [Nutra
USA]
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Arginine
behaviour after arginine or citrulline administration in older subjects - Br
J Nutr. 2015 Dec 1:1-6 - "Arginine (ARG) and its
precursor citrulline (CIT) are popular dietary supplements, especially for the
elderly. However, age-related reductions in lean body mass and alterations in
organ functions could change their bioavailability ... In conclusion, a single
CIT administration in the elderly is safe and well tolerated, and CIT proves to
be a better in vivo ARG precursor than ARG itself in healthy elderly subjects"
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Citrulline
and Nonessential Amino Acids Prevent Fructose-Induced Nonalcoholic Fatty Liver
Disease in Rats - J Nutr. 2015 Aug 5 - "nonessential
amino acids (NEAAs) ... Cit and NEAAs effectively prevented fructose-induced
NAFLD. On the basis of literature data and our findings, we propose that NEAAs
may exert their effects specifically on the liver, whereas Cit presumably acts
at both the hepatic and whole-body level, in part via improved peripheral Arg
metabolism"
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Combining
citrulline to atorvastatin preserves glucose homeostasis in a murine model of
diet-induced obesity - Br J Pharmacol. 2015 Jul 30 -
"Citrulline-atorvastatin combination prevents fat mass accumulation and
maintains glucose homeostasis in DIO fed mice. Furthermore, it potentiates
inhibition of hepatic de novo lipogenesis activity. This combination is thus
promising for preservation of glucose homeostasis in patients under statin
therapy"
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Combined
L-citrulline and glutathione supplementation increases the concentration of
markers indicative of nitric oxide synthesis - J Int Soc Sports Nutr. 2015
Jun 10;12:27 - "Nitric oxide (NO) is endogenously synthesized from L-arginine
and L-citrulline. Due to its effects on nitric oxide synthase (NOS), reduced
glutathione (GSH) may protect against the oxidative reduction of NO ... plasma
NOx with L-citrulline + GSH was significantly greater than control and
L-citrulline" - See Stimulin at Amazon.com.
I'm not so sure taking glutathione supplements will raise glutathione.
Some say you need to take NAC. See:
- How to
Boost Glutathione Levels - Dr. Murray's Newsletter, 7/30/03 -
"When healthy subjects were given a single dose of up to 3,000 mg of
glutathione researchers found there was no increase in blood glutathione
levels.11 ... In contrast, blood glutathione levels rose nearly 50% in
healthy individuals taking 500 mg of vitamin C.12 Vitamin C raises
glutathione by helping the body manufacture it. In addition, to vitamin C,
dietary sources of glutathione and several other nutritional compounds can
help increase glutathione levels including N-acetylcysteine (NAC),
alpha-lipoic acid, glutamine, methionine, and whey protein. Also, vitamin
B6, riboflavin, and selenium are required in the manufacture of glutathione"
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Citrulline
Supplementation Induces Changes in Body Composition and Limits Age-Related
Metabolic Changes in Healthy Male Rats - J Nutr. 2015 May 27 -
"nonessential amino acids (NEAAs) ... Compared with the
NEAA-treated group, citrulline supplementation was associated with lower
mortality (0% vs. 20%; P = 0.05), 9% higher lean body mass (P < 0.05), and 13%
lower fat mass (P < 0.05). Compared with the NEAA-treated group,
citrulline-treated rats had greater muscle mass (+14-48% depending on type of
muscle; P < 0.05 for tibialis, gastrocnemius, and plantaris). Susceptibility to
oxidation of lipoproteins, as measured by the maximal concentration of
7-ketocholesterol after copper-induced VLDL and LDL oxidation, was lower in
citrulline-treated rats than in NEAA-treated rats (187 ± 8 μmol/L vs. 243 ± 7
μmol/L; P = 0.0005)"
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Citrulline
induces fatty acid release selectively in visceral adipose tissue from old rats
- Mol Nutr Food Res. 2014 Jun 10 - "During aging,
increased visceral adipose tissue (AT) mass may result in impaired metabolic
status. A citrulline (CIT)-supplemented diet reduces AT mass in old rats"
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l-Citrulline,
But Not l-Arginine, Prevents Diabetes Mellitus-Induced Glomerular
Hyperfiltration and Proteinuria in Rat - Hypertension. 2014 May 27 -
"l-citrulline administered to diabetic rats increases
plasma l-arginine concentration, which prevents the diabetes mellitus-induced
glomerular hyperfiltration, filtration fraction, and proteinuria, possibly by a
vascular effect" - See
l-citrulline at Amazon.com.
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Effects of
watermelon supplementation on arterial stiffness and wave reflection amplitude
in postmenopausal women - Menopause. 2013 May;20(5):573-7 -
"In a randomized cross-over study, 12 postmenopausal
women (mean [SE] age, 57 [1] y; mean [SE] body mass index, 38.1 [2.1] kg/m; mean
[SE] SBP, 153 [4] mm Hg) were assigned to watermelon supplementation
(L-citrulline/L-arginine 6 g/d) or placebo supplementation for 6 weeks ... baPWV
(-1.2 [0.3] m/s, P < 0.001), aortic SBP (-10 [3] mm Hg, P < 0.01), and aortic
diastolic blood pressure (-7 [1] mm Hg, P < 0.001) decreased after watermelon
supplementation compared with placebo ... Watermelon supplementation reduces
arterial stiffness and aortic SBP by reducing pressure wave reflection amplitude
in obese postmenopausal women with hypertension" - Note: A -10 on the
systolic is about what you'd get with prescription medications. - See
Stimulin at Amazon.com
(1,875 mg of L-citrulline) and
L-arginine products at Amazon.com.
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Oral
L-citrulline supplementation improves erection hardness in men with mild
erectile dysfunction - Urology. 2011 Jan;77(1):119-22 -
"L-arginine supplementation improves nitric
oxide-mediated vasodilation and endothelial function; however, oral
administration has been hampered by extensive presystemic metabolism. In
contrast, L-citrulline escapes presystemic metabolism and is converted to
L-arginine, thus setting the rationale for oral L-citrulline supplementation as
a donor for the L-arginine/nitric oxide pathway of penile erection ... A total
of 24 patients, mean age 56.5 +/- 9.8 years, were entered and concluded the
study without adverse events. The improvement in the erection hardness score
from 3 (mild ED) to 4 (normal erectile function) occurred in 2 (8.3%) of the 24
men when taking placebo and 12 (50%) of the 24 men when taking L-citrulline (P <
.01). The mean number of intercourses per month increased from 1.37 +/- 0.93 at
baseline to 1.53 +/- 1.00 at the end of the placebo phase (P = .57) and 2.3 +/-
1.37 at the end of the treatment phase (P < .01). All patients reporting an
erection hardness score improvement from 3 to 4 reported being very satisfied"
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Oral
L-Citrulline Supplementation Attenuates Blood Pressure Response to Cold
Pressor Test in Young Men - Am J Hypertens. 2009 Oct 22 -
"Compared to placebo, oral L-citrulline treatment
decreased (P < 0.05) brachial SBP (-6 +/- 11 mm Hg), aortic SBP (-4 +/- 10
mm Hg), and aortic PP (-3 +/- 6 mm Hg) during CPT but not at rest. There was
an inverse correlation (r = -0.40, P < 0.05) between changes in aortic SBP
and Tr during CPT after L-citrulline supplementation"
-
Regulation of nitric oxide production in health and disease Curr Opin
Clin Nutr Metab Care. 2009 Oct 16 - "The role of the
cofactor tetrahydrobiopterin in nitric oxide production and its relation
with arginine availability is indicated as an important explanation for the
arginine paradox. This offers potential for nitric oxide regulation by
dietary factors such as arginine or its precursors and vitamin C. Because
diets with a high saturated fat content induce high plasma fatty acid
levels, endothelial nitric oxide production is often impaired due to a
reduction in nitric oxide synthase 3 phosphorylation. Increasing the
arginine availability by arginine therapy or arginase inhibition was,
therefore, proposed as a potential therapy to treat hypertension. Recent
studies in septic patients and transgenic mice models found that inadequate
de-novo arginine production from citrulline reduces nitric oxide production.
Citrulline supplementation may, therefore, be a novel therapeutic approach
in conditions of arginine deficiency" - See
L-arginine products at Amazon.com
and
l-citrulline products at iHerb.
-
Maternal Supplementation With Citrulline Increases Renal Nitric Oxide in
Young Spontaneously Hypertensive Rats and Has Long-Term Antihypertensive
Effects - Hypertension. 2007 Oct 15
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