Effects of Caloric Restriction May Be Partly Due to Enhanced Expression of Endothelial Nitric Oxide Synthase

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No. 4 • October 2005

Effects of Caloric Restriction May Be Partly Due to Enhanced Expression of Endothelial Nitric Oxide Synthase

An exciting new paper1 reports that in mice calorically restricted for 3 or 12 months, there was an increase in endothelial nitric oxide synthase (eNOS) expression and 3',5'-cyclic guanosine monophosphate (cGMP, the second messenger for nitric oxide that signals downstream chemical pathways). The enhanced eNOS was accompanied by mitochondrial biogenesis (creation of new mitochondria), increased oxygen consumption and ATP production, and an enhanced expression of SIRT1 (a gene believed to regulate lifespan). In animals genetically engineered to lack eNOS (eNOS-/-), caloric restriction was unable to induce significant mitochondrial biogenesis in a number of tissues, including white adipose tissue. The CR-induced increase in oxidative metabolism and ATP production was blunted in eNOS-/- animals. SIRT1 was increased in calorically restricted eNOS-/- animals, but the increase (in white adipose tissue) was only 30% of that in calorically restricted animals with normal (wild type) eNOS gene expression.

Thus, upregulation of endothelial nitric oxide synthase may account for much of the effects of caloric restriction, at least in mice. Interestingly, in a cell-culture experiment done as part of the above study, the authors found: “SIRT1 mRNA [messenger RNA] and protein were ~threefold higher in cultured white adipocytes exposed either to NO donors . . . or to a cGMP analog . . . than in untreated cells and ~80% lower in WAT [white adipose tissue] of eNOS-/- mice when compared with wild-type animals. Thus expression of SIRT1 in WAT during CR might be partly mediated by NO acting via cGMP.”

These findings are very exciting, because it is possible through nutritional means (particularly supplementation with arginine) to increase nitric oxide. It would be interesting to see the results of lifespan studies in calorically restricted and ad libitum-fed mice given a diet enriched in arginine. Note that addition of choline and vitamin B5 to an arginine supplement provides more material for acetylcholine synthesis; acetylcholine activates eNOS to release NO derived from arginine.


  1. Nisoli et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310:314-7 (2005).

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