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Home > Anti-aging Research > citrulline


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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.
  • 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.
  • 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""


  • 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.
  • 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"
  • 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"
  • 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"
  • 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"
  • 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.
  • 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"
  • 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"
  • 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"
  • 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"
  • 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"
  • 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.
  • 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.
  • 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"
  • 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"
  • 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]
  • 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"
  • 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"
  • 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"
  • 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"
  • 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)"
  • 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"
  • 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.
  • 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.
  • 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"
  • 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