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AMP-activated kinase, a target of exercise mimetics, may contribute to photoaging and cell death

Posted Sep 22 2008 10:18am

AMP-activated kinase (AMPK) agonists mimic the effects of exercise, raising the possibility of a “workout pill” that could simulate the effects of vigorous activity. The applications to human health are, to mildly understate the case, significant; it sounds almost too good to be true, and it leaves one looking for the catch.

But it turns out that AMPK is activated by certain types of genotoxic stress, and contributes to UV-induced apoptosis in the skin. From Cao et al.:

AMP-activated protein kinase contributes to UV- and H 2 O 2 -induced apoptosis in human skin keratinocytes

AMP-activated protein kinase or AMPK is an evolutionarily conserved sensor of cellular energy status, activated by a variety of cellular stresses that deplete ATP. However, the possible involvement of AMPK in UV- and H2O2-induced oxidative stresses that lead to skin aging or skin cancer has not been fully studied. We demonstrated for the first time that UV and H2O2 induce AMPK activation (Thr172 phosphorylation) in cultured human skin keratinocytes. UV and H2O2 also phosphorylate LKB1, an upstream signal of AMPK, in an EGFR dependent manner. … We also observed that AMPK serves as a negative feedback signal against UV-induced mTOR (mammalian target of rapamycin) activation in a TSC2 dependent manner. Inhibiting mTOR and positively regulating p53 and p38 might contribute to AMPK’s pro-apoptotic effect on UV- or H2O2-treated cells. Furthermore, activation of AMPK also phosphorylates acetyl-CoA carboxylase or ACC, the pivotal enzyme of fatty acid synthesis, and PFK2, the key protein of glycolysis in UV-radiated cells. Collectively, we conclude that AMPK contributes to UV- and H2O2-induced apoptosis via multiple mechanisms in human skin keratinocytes and AMPK plays important roles in UV-induced signal transduction ultimately leading to skin photoaging and even skin cancer.

Note especially that last line (emphasis mine): activation of AMPK could exacerbate the pro-aging effects that UV light exerts on the skin. Judging from the peroxide results, this also applies to endogenously generated reactive oxygen species (ROS) — which one can’t avoid by simply staying out of the sun.

Before we panic and throw the exercise mimetic baby out with its carcinogenic bathwater, I’d want to see whether AMPK agonists like AICAR do in fact synergize with stresses like UV and peroxide to increase apoptotic cell death in the skin. If they do…well, I think we found that catch.

      
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