Toxicological Sciences, Vol 52, 3-12, Copyright © 1999 by Society of Toxicology
RW Hart, R Dixit, J Seng, A Turturro, JE Leakey, R Feuers, P Duffy, C Buffington, G Cowan, S Lewis, J Pipkin and SY Li
Carcinogenicity and aging are characterized by a set of complex endpoints,
which appear as a series of molecular events. Many of these events can be
modified by caloric intake. Since most of these processes determine an
organism's ability to cope with various environmental stressors, it is not
surprising that a relationship (in the presence of a constant nutrient
density) exists between caloric intake and time-to- tumor and/or life span.
Our studies have clearly shown that generally, the greater the caloric
intake, the greater the body weight, the higher the incidence of
spontaneous tumor occurrence, the greater the susceptibility to chemical
carcinogens, and the shorter the life span. It is also recognized that
variables other than body weight influence the life span and
carcinogenesis. We have focused our attention on the questions of how and
to what extent caloric intake modifies those homeostatic processes believed
to be critical in determining the ability of an organism to cope with
endogenous and exogenous stresses such as chemical, physical, and
biological carcinogens. The response of an organism to its environment can
be divided into four categories-- physiological, metabolic, molecular, and
cellular. We have found that, from a physiological perspective, decreasing
caloric intake causes body temperature in rodents to be decreased by 0.5 to
1.8 degrees C and water consumption to be increased by 80%, as is running
activity. However, metabolic output per gram of lean body mass is not
altered. Reproductive capacity declines, whereas the ECG waveform is
preserved as caloric intake decreases. Alterations in these and other
physiological functions suggests that energy intake serves as a signal to
up-regulate or down-regulate functions related to the flight-or- fight
response observed in placental mammals. A number of key metabolic pathways
are altered as a function of lowered caloric intake, even though the rate
of food consumption per gram of lean body mass remains steady during body
weight decreases caused by decreasing caloric intake. Pharmacological
compartmentalization, however, is altered. As caloric intake declines,
changes occur in the expression of a number of drug-metabolizing enzymes,
with the most striking effect seen in sex- specific growth hormones and
liver-dependent phase I and phase II enzymes. Additionally, oxidative
stress (free-radical and mediated damage to macromolecules) appears to
decrease as a function of reduced caloric intake. A number of molecular
processes also change with changes in energy consumption. Our studies have
shown that, regardless of the source and nature of DNA damage, DNA repair
is better preserved and/or enhanced when caloric consumption decreases. In
addition, the fidelity of DNA replication increases and oncogene expression
is stabilized, P53 gene expression is increased, and apoptosis is elevated
by up to 500% with decreased caloric intake. At the cellular level, cell
proliferation is decreased in direct proportion to lower energy intake in
some but not all tissues. Studies have also shown an enhancement in immune
capacity, changes in IGF1, and accelerated rates of wound healing
proportionate to declines in energy consumption. Our most recent findings,
however, have shown that the benefits associated with decreases in caloric
intake only occur in the presence of sufficient nutrient quality and
density. In the absence of proper nutrition, however, sensitivity to
carcinogens and toxic substances appears to be enhanced. These findings are
supported by independent studies. These observations have led us to
conclude that, in certain organisms, when caloric intake is decreased,
there is an up-regulation of those processes that modulate the responses to
a wide range of environmental stressors. This response allows for a better
survival rate and a down-regulation of reproductive activity. It is our
belief that, during periods of environmental stress, these systems may be
essential to perpetu
ARTICLES
Adaptive role of caloric intake on the degenerative disease processes
National Center for Toxicological Research, Jefferson, Arkansas 72079, USA. RHart@nctr.fda.gov
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