Does caloric restriction induce hormesis?

The question of whether caloric restriction (CR) is hermetic is addressed i n terms of two common definitions of the term. In terms of the older defini tion, i.e., a growth-stimulatory effect when lower doses of a compound whic h resulted in growth inhibition at higher doses, CR is better characterized as a co-hormetic (i.e., a paradigm which at relatively "low doses," in com bination with some stimulus, will evince increased growth (proliferation) a nd at higher "doses" will inhibit this increased proliferation) rather than a hermetic agent. Mechanisms such as cellular selection of cellular subpop ulations, increases in receptor efficiency, and preservation of cellular pr oliferative potential can interact with agents and produce increased growth as long as the CR is not too severe. In terms of a broader definition, i.e., nonmonotonic dose-response behavior of a compound for any adverse response, CR appears to be hermetic, both as a result of body weight (BW) loss and other potential mechanisms. The impa ct of changes in BW, or frank CR, can be considered a component of every te st for hormesis, and is thus capable for interaction with any other agent. The changes that BW loss (or CR) induce are so profound that any aspect of an agent's action - metabolism, pharmacokinetics, pharmacodynamics - can mo dulate the response of an organism to an agent. Similarly, other effects of a chemical that induce BW loss, e.g., physical activity or temperature dys regulation, can also induce dose-response curves that appear hermetic. The interaction of the hermetic agents of BW loss and CR can influence agent te sts. Controlling these factors may make it possible to dissect the key component s of a hermetic response. In addition, the effects of CR or BW loss appear to extrapolate well across species [Colman R, Kemnitz JW. Aging experiments using nonhuman primates. In: Yu BP (Ed), Methods in Aging Research. CRC Pr ess, Boca Raton, FL, 1999, pp. 249-267]. Thus there is some reason to belie ve that these hermetic factors may be important for humans, and may already be a factor for tests of adverse agents already conducted in humans.