Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 2 • February 2013

Why We Recommend
Supplementation with L-Arginine
(and Also Histidine)

Serum Levels of Histidine and Arginine Significantly
Lower in Obese as Compared to Non-Obese Women:

These Amino Acids Are Negatively Associated
With Inflammation and Oxidative Stress in Obese Women

A recent paper1 reports that, in a study of 235 obese women compared to 217 non-obese women controls, six amino acids (but especially histidine and arginine) were found to be significantly lower in the obese women. Importantly, both histidine and arginine were negatively associated with inflammation and oxidative stress in the obese women, while in the non-obese controls, histidine was negatively associated with oxidative stress.

We both take histidine (250 mg. three or four times a day) as an ingredient in a formulation we designed for reducing the formation of AGEs (advanced glycation endproducts).2,3 Inhibiting the formation of AGEs is a mechanism which we consider a very likely part of histidine’s anti-inflammatory and anti-oxidative stress effects. We also take arginine, 6–12 grams/day. Arginine can also provide protection against inflammation and oxidative stress via its conversion to nitric oxide, a critical factor in regulating vasodilation and blood pressure,4 as well as protecting against AGE formation.5


1. Niu et al. Histidine and arginine are associated with inflammation and oxidative stress in obese women. Brit J Nutr. 108:57-61 (2012).
2. Lee et al. Histidine and carnosine dellay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. Eur J Pharmacol. 513:145-50 (2005).
3. Hobart et al. Anti-crosslinking properties of carnosine: significance of histidine. Life Sci. 75:1379-89 (2004).
4. Giugliano et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine: evidence for reduced availability of nitric oxide during hyperglycemia. Circulation. 95:1783-90 (1997).
5. Radner et al. L-arginine reduces kidney collagen accumulation and N-epsilon-(carboxymethyl)lysine in the aging NMRI-mouse. J Gerontol. 49(2):M44-6 (1994).

Low Plasma Levels of L-Arginine in Patients with Major Depression

This recent paper6 reports on an investigation of the mechanisms that might explain why major depression (MD) is an independent cardiovascular risk factor. It was a small study involving 19 subjects with MD (34 ± 4 years) and 19 control subjects (34 ± 3 years). The researchers examined L-arginine influx, NO (nitric oxide) synthase activity and intracellular cGMP levels in platelets, as well as systemic factors including eNOS, iNOS, arginase, soluble guanylate cyclase, platelet aggregation and the systemic amino acid profile in both MD subjects and controls.

The results included: L-arginine influx in platelets was reduced in MD as compared to controls, from 46.2 ± 9.5 to 20.02 ± 2.12 pmol/10000000000 cells. NOS activity and intracellular cGMP were diminished in MD. The concentration of plasma L-arginine was reduced by 20% in the MD patients.

The reduced availability of arginine and reduced activity of the nitric oxide signaling pathway could be an important contributor to the increased risk of cardiovascular disease in MD patients. It is known that a deficiency of arginine can result in uncoupling of nitric oxide synthase and the subsequent production of superoxide radicals rather than nitric oxide.7 However, this was a small study and should, therefore, be interpreted with this limitation in mind.

6. Pinto et al. Low plasma levels of L-arginine, impaired intraplatelet nitric oxide and platelet hyperaggregability: implications for cardiovascular risk in depressive patients. J Affect Disord. 140(2):187-92 (2012).
7. van der Zwan et al. Systemic inflammation is linked to low arginine and high ADMA plasma levels resulting in an unfavourable NOS substrate-to-inhibitor ratio: the Hoorn Study. Clin Sci (London). 121:71-8 (2011).

Plasma Arginine Concentrations Reduced in Cancer Patients

Another paper8 reports an association of low plasma concentrations of L-arginine with cancer. The researchers measured plasma arginine concentrations in patients with various types of tumors, hypothesizing that L-arginine concentrations would be lower than those in age- and sex-matched control subjects. Indeed, L-arginine concentrations were found to be significantly lower than in the controls in patients with the cancers they studied: breast cancer, colonic cancer, and pancreatic cancer.

The researchers propose that disturbances of L-arginine metabolism could “contribute to the cascade of metabolic events leading to cancer cachexia.”8 In addition, they explain, “[i]t was recently shown that the high arginase activity of tumors is a mechanism of tumor-induced immunosuppression through depletion of arginine concentrations in the microenvironment of the tumor.”8

8. Vissers et al. Plasma arginine concentrations are reduced in cancer patients: evidence for arginine deficiency? Am J Clin Nutr. 81:1142-6 (2005).

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