Treatment with L-Arginine and L-Citrulline with Antioxidants Prevents High-Glucose-Induced Cellular Senescence

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 9 No. 4 • December 2006

Treatment with L-Arginine and L-Citrulline with Antioxidants Prevents High-Glucose-Induced Cellular Senescence

A very recent paper1 (whose authors included Nobel Prize winner Louis J. Ignarro, who won the prize for codiscovery of NO, nitric oxide) reported the results of experiments testing the hypothesis that increasing NO production by endothelial cells [either by genetically transfecting human umbilical venous epithelial cells with eNOS (endothelial nitric oxide synthase) or by treating the cells with NO donors or L-arginine or L-citrulline or antioxidants or a combination of the last three] could delay or prevent the endothelial cell senescence that results from exposure to high glucose levels.

The authors note in their introduction that “Senescent cells from aged animals express increased levels of proinflammatory molecules, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis.” They point out that NO “is a widespread signaling molecule in the cardiovascular system, which functions in multiple ways to protect against the initiation and progression of atherosclerosis. NO prevents the adhesion and aggregation of blood cells and inhibits vascular smooth muscle cell proliferation.”

Exposure of cells to high glucose levels for 24 hours resulted in decreased expression of eNOS, the enzyme responsible for generating NO in blood-vessel walls. “Treatment with L-arginine, L-citrulline, and antioxidants (vitamin C and E) alone or in combination showed a significant recovery of the decreased nitrite [a measure of NO] level under high glucose conditions. When L-arginine, L-citrulline, and antioxidants were given together, the recovery of nitrite production was more marked.”

Moreover, high glucose exposure for 72 hours resulted in increased cellular senescence as indicated by increased beta-galactosidase and decreased telomerase. The number of senescent cells (by the above measures) was significantly decreased when L-arginine, L-citrulline, and antioxidants were given together. The authors report an earlier paper2 in which coadministration of antioxidants with L-arginine and L-citrulline produced an enhanced antiatherosclerotic effect in advanced atherosclerosis in high-cholesterol-fed rabbits.

Treatment with the NO donor drug DETA-NO or transfecting the cells with eNOS decreased cell senescence (as indicated by reduced levels of the senescence-associated enzyme beta-galactosidase and increased levels of the senescence-reduced levels of telomerase). “Treatment with L-arginine or L-citrulline of eNOS-transfected cells partially inhibited, and combination of L-arginine and L-citrulline and antioxidants strongly prevented, high-glucose-induced cellular senescence.”

L-Arginine is converted by eNOS (and also by neuronal NOS, nNOS, and inducible NOS, iNOS) into NO and L-citrulline. This process is now believed to take place in membrane structures called caveolae, where L-arginine supplies may be limited. L-Citrulline is converted back to L-arginine in caveolae by a salvage pathway and thus supplies additional L-arginine for use by eNOS, nNOS, and iNOS.

The authors conclude, “In the present study, high-glucose-induced endothelial dysfunction, oxidative stress, and cellular senescence were reversed with the administration of L-arginine, L-citrulline, and antioxidants.”

Our InnerPower Plus™ and improved InnerPower™ contain L-arginine, L-citrulline, and antioxidants. We developed these formulations for our own daily use to help maintain healthy NO production in blood vessels and thus to help prevent atherosclerosis.


  1. Hayashi et al. Endothelial cellular senescence is inhibited by nitric oxide: implications in atherosclerosis associated with menopause and diabetes. Proc Natl Acad Sci USA 103(45):17018-23 (2006).
  2. Hayashi et al. L-Citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci USA 102:13681-6 (2005).

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