Toxicological Sciences, Vol 52, 3-12, Copyright © 1999 by Society of Toxicology
R Hart, R Dixit, J Seng, A Turturro, J Leakey, R Feuers, P Duffy, C Buffington, G Cowan, S Lewis, J Pipkin and S 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
1.9<IMG SRC="/math/deg.gif">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 <it>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
perpetuation of the species and the gene pool of the individual.
ARTICLES
Adaptive role of caloric intake on the degenerative disease processes
National Center for Toxicological Research, 3900 NCTR Road, Jefferson, Arkansas 72079, USA; Department of Safety Assessment, Merck Research Laboratories, West Point, PA, USA; Department of Surgery, College of Medicine, University of Tennessee, Memphis, TN 38163, USA; Corresponding author; Fax: 870 543 7332; E-mail: RHart@nctr.fda.gov
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