Caloric Restriction Stimulates Angiogenesis Through Adiponectin

Nagoya, Japan -

Caloric restriction is by far the most documented method of extending lifespan.  People have filed patents on methods of identifying compounds that induce biological effects similar to caloric restriction.  There are several theories as to how caloric restriction mediates its effects.  One interesting one is that it modulates the sirtuin pathway.  This is the same general biological pathway that the company Sirtris is working on.

In a recent paper (Kondo et al. Caloric restriction stimulates revascularization in response to ischemia via adiponectin-mediated activation of eNOS. J Biol Chem  2008 Nov 6) the effect of caloric restriction on natural angiogeneic responses after induction of critical limb ischemia was examined.  We know that even induction of angiogenesis after administration cell therapy requires activation of recipient regenerative responses such as SDF-1 secretion and mobilization of endogenous bone marrow progenitors. 

But why would caloric restriction be beneficial?  Well on the one hand we do know that endothelial reactivity is better in people who are calorically restricted (Raitakari et al. Weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler Thromb Vasc Biol 2004 Jan;24(1):124-8.) Maybe caloric restriction is beneficial for stem cells?  Well anyways, here is what Kondo et al showed, which in our opinion is pretty significant.

-  Took wild-type mice, half were allowed to eat whatever they wanted, the other half were calorically restricted. 

-  Keep the mice for 4 weeks on a diet or control.  Then induce ischemic injury by surgically ligating the femoral artery on one leg.

-  Observe the mice healed faster and had more angiogenesis if they were calorically restricted !!

So this by its self got us at StemCellPatents.com excited.  But the investigators took the study to the next level...they noticed in this and in previous studies that they conducted that caloric restriction is associate with increase levels of adiponectin, a hormone made by adipose tissues.

-  Repeated the caloric restriction/control experiment with mice that are genetically engineered to lack adiponectin.

-  Caloric restriction had no effect in the adiponectin knockouts !!! 

Also interesting points

-  Caloric restriction was associated with higher levels of endothelial nitric oxide activation

-  Caloric restriction in mice lacking endothelial nitric oxide synthase do not have increased angiogenesis after caloric restriction

-  Phosphorylation of AMP-activated protein kinase (AMPK) in muscles made ischemia was needed for angiogenesis

These data suggest a pathway whereby caloric restriction stimulates adiponectin, which stimulates eNOS and also AMPK phosphorylation.   It will be interesting to find out if these pathways work on stimulation of endothelial precursor cells that are systemic or local ones for the creation of neoangiogenesis.