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2005
Department of Biostatistics, University
of Alabama, Ryals Public Health Building, Room 327, 1665
University Boulevard, Birmingham, Alabama 35294-0022.
OBJECTIVE: We used a rodent model
of dietary obesity to evaluate effects of caloric restriction-induced
weight loss on mortality rate. Research Measures and Procedures:
In a randomized parallel-groups design, 312 outbred Sprague-Dawley
rats (one-half males) were assigned at age 10 weeks to
one of three diets: low fat (LF; 18.7% calories as fat)
with caloric intake adjusted to maintain body weight 10%
below that for ad libitum (AL)-fed rat food, high fat
(HF; 45% calories as fat) fed at the same level, or HF
fed AL. At age 46 weeks, the lightest one-third of the
AL group was discarded to ensure a more obese group; the
remaining animals were randomly assigned to one of three
diets: HF-AL, HF with energy restricted to produce body
weights of animals restricted on the HF diet throughout
life, or LF with energy restricted to produce the body
weights of animals restricted on the LF diet throughout
life. Life span, body weight, and leptin levels were measured.
RESULTS: Animals restricted throughout life lived the
longest (p < 0.001). Life span was not different among
animals that had been obese and then lost weight and animals
that had been nonobese throughout life (p = 0.18). Animals
that were obese and lost weight lived substantially longer
than animals that remained obese throughout life (p =
0.002). Diet composition had no effect on life span (p
= 0.52). DISCUSSION: Weight loss after the onset of obesity
during adulthood leads to a substantial increase in longevity
in rats.
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University of Florida, Department
of Aging and Geriatric Research, College of Medicine,
P.O. Box 100107, Gainesville, FL 32608, USA.
Debate exists over the impact of
caloric restriction (CR) on the level of energy expenditure.
At the whole animal level, CR decreases metabolic rates
but in parallel body mass also declines. The question
arises whether the reduction in metabolism is greater,
smaller or not different from the expectation based on
body mass change alone. Answers to this question depend
on how metabolic rate is normalized and it has recently
been suggested that this issue can only be resolved through
detailed morphological investigation. Added to this issue
is the problem of how appropriate the resting energy expenditure
is to characterize metabolic events relating to aging
phenomena. We measured the daily energy demands of young
and old rats under ad libitum (AD) food intake or 40%
CR, using the doubly labeled water (DLW) method and made
detailed morphological examination of individuals, including
21 different body components. Whole body energy demands
of CR rats were lower than AD rats, but the extent of
this difference was much less than expected from the degree
of caloric restriction, consistent with other studies
using the DLW method on CR animals. Using multiple regression
and multivariate data reduction methods we built two empirical
predictive models of the association between daily energy
demands and body composition using the ad lib animals.
We then predicted the expected energy expenditures of
the CR animals based on their altered morphology and compared
these predictions to the observed daily energy demands.
Independent of how we constructed the prediction, young
and old rats under CR expended 30 and 50% more energy,
respectively, than the prediction from their altered body
composition. This effect is consistent with recent intra-specific
observations of positive associations between energy metabolism
and lifespan and theoretical ideas about mechanisms underpinning
the relationship between oxygen consumption and reactive
oxygen species production in mitochondria.
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Department of Otolaryngology, Chicago,
Illinois, USA.
OBJECTIVE/HYPOTHESIS: To document
age-related histologic morphometric changes of rat skin
and the effects of calorie restriction on such changes.
STUDY DESIGN: Fischer 344 rats of three age groups (young,
4 mo; adult, 1 year; old, 24+ months) were procured from
ad libitum (AL) diet and calorie-restricted (CR) colonies
of the National Institute of Aging and were used for histologic
study. Each study group consisted of six animals. METHODS:
Skin samples from the dorsum (DS) and footpad (FP) of
these animals were excised and processed for histology
with staining techniques for general morphology (hematoxylin-eosin-phloxine)
and for differentiation of collagen bundles and elastic
fibers (Verhoeff-van Gieson technique). Light microscopic
morphometric and stereologic point counting procedures
were applied manually to tissue sections to obtain quantitative
data on the depth of the epidermis, dermis, and stratum
corneum, epidermal nuclear number, and percentage fraction
of collagen, elastic fibers, capillaries, and pilosebaceous
units. Data were analyzed with two-way of analysis of
variance (ANOVA) to determine significant effects of age,
diet, and age-diet interaction on these parameters in
AL rats and their age-matched cohorts. RESULTS: Significant
effects of age, diet, or age-diet interaction were observed
in respect of the thickness of epidermis, dermis, stratum
corneum of FP, epidermal nuclear number, collagen percentage
fraction, and area fraction of capillaries. DS epidermis
showed increasing thickness in AL group, but this was
reduced in CR rats. A similar trend in DS dermal depth
was observed. Fewer capillaries were present in aging
CR rats. The DS epidermal nuclear profiles and collagen
area fraction also showed effects of diet and age-diet
interaction. Aging changes, especially the effect of CR,
was more evident in the measured parameters of dorsal
skin. No alterations were observed in the distribution
of pilosebaceous units and elastic fiber profiles of the
skin. CONCLUSIONS: The Fischer 344 rat shows many age-related
changes in the skin, some of which are different from
data reported in literature. The pattern of aging changes
in skin parameters was different in the two groups, suggesting
an in influence of CR. CR appears to modify the aging
rate of some skin components, and this may be caused by
metabolic changes imposed by diet.
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2004
Institut fuer Genetik, Forschungszentrum
Karlsruhe, 76021 Karlsruhe, Germany.
We have monitored global changes
in gene expression in mouse liver in response to fasting
and sugar-fed conditions using high-density microarrays.
From approximately 20,000 different genes, the significantly
regulated ones were grouped into specific signaling and
metabolic pathways. Striking changes in lipid signaling
cascade, insulin and dehydroepiandrosterone (DHEA) hormonal
pathways, urea cycle and S-adenosylmethionine-based methyl
transfer systems, and cell apoptosis regulators were observed.
Since these pathways have been implicated to play a role
in the aging process, and since we observe significant
overlap of genes regulated upon starvation with those
regulated upon caloric restriction, our analysis suggests
that starvation may elicit a stress response that is also
elicited during caloric restriction. Therefore, many of
the signaling and metabolic components regulated during
fasting may be the same as those which mediate caloric
restriction-dependent life-span extension.
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2001
Department of Nutrition, University
of California, Davis, CA 95616, USA.
The incidence of end-stage renal
disease (ESRD) has risen considerably in the past two
decades. This trend is partly due to the alarming rise
in the incidence of type 2 diabetes over the same period,
which in turn might be linked to the staggering increase
in overweight and obesity. If these trends continue, ESRD
can be expected not only to cause suffering of ever growing
numbers of patients, but also to become an increasing
financial as well as logistical burden on the health care
system. Therefore, it is imperative not only to gain a
better understanding of the molecular, cellular and metabolic
mechanisms involved in renal pathology, but also to uncover
treatment modalities, including lifestyle changes, that
can help prevent and/or slow the progression of kidney
pathogenesis. Insights into both of these aspects are
provided by animal models of obesity and diabetes. It
has long been known that food restriction, more so than
restriction of any particular dietary component, can greatly
enhance longevity in laboratory rodents. These findings
are being extended into a variety of other mammals, including
nonhuman primates. These studies have indicated that caloric
restriction in nonobese laboratory animals does not primarily
affect specific disease processes but rather nonspecifically
slows the aging process. In contrast, a growing body of
evidence suggests that in genetically obese animals, food
restriction can prevent or greatly delay the onset of
specific degenerative lesions, in particular glomerulonephritis
associated with obesity and diabetes.
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Department of Physiology, University
of Texas Health Science Center at San Antonio, and South
Texas Veterans Health Care System, San Antonio, TX 78284-7756,
USA.
Over 60 years ago, McCay's laboratory
showed that dietary or calorie-restriction dramatically
increased the lifespan of rats. Since then, numerous laboratories
with a variety of strains of rats and mice have confirmed
this initial observation and have shown that reducing
calorie intake (without malnutrition) significantly increases
both the mean and maximum survival of rodents. Currently,
dietary restriction is the only experimental manipulation
that has been shown to retard ageing of mammals. Although
mechanism whereby dietary restriction retards ageing is
currently unknown, much of the emerging data suggest that
the calorie-restricted rodents live longer and age more
slowly because they are more resistant to stress and have
an enhanced ability to protect cells against damaging
agents.
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| 2000
Faculty of Food Science and Biotechnology,
Pukyong National University; 599-1 Daeyeon-Dong, Nam-Gu,
Pusan 608-737, Korea.
This study was to evaluate the effect
of dietary restriction (DR) on lifespan and oxidative stress
of dementia mouse model SAMP8 with impaired learning and
memory. SAMP8 female mice were fed either ad libitum (AL)
or fed 60% of food intake of AL. Results showed that basal
metabolic rates (BMR) were significantly lower (15 to 22%)
in DR with increased median and maximum lifespans, suggesting
feed and gross efficiencies were significantly lower in
DR than in AL. Grading score of senescence resulted in a
marked improvement about 2-fold by DR compared with AL.
The amounts of lipofuscin at 12 months were significantly
lowered 16% in DR than that of AL. Median and maximal lifespans
significantly increased (28.5% and 16.4%, respectively)
by DR, and also lowered superoxide radical about 15 approximately
45% in DR compared with AL at 4, 8 and 12 months of age.
On the other hand, superoxide dismutase (SOD) activities
were higher (about 15 approximately 30%) in DR than those
in AL group of SAMP8 except for 4 months of age. Our results
suggest that 40% calorie restricted SAMP8 can effectively
suppress dementia-related abnormalities during aging.
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Department of Psychosomatic Medicine,
Graduate School of Medical Sciences, Kyushu University,
3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan.
Caloric restriction in rodents
is well known to retard the rate of aging, increase mean
and maximum life-spans, and inhibit the occurrence of
many age-associated diseases. However, little is known
about the influence of short-term repeated fasting on
longevity. In this study, female (NZB x NZW)F1 mice were
used to test the physiological effect of short-term repeated
fasting (4 consecutive days, every 2 weeks). The results
showed that fasting mice survived significantly longer
than the full-fed mice, in spite of the fasting group
having a heavier body weight than the control group. Mean
survival times for fasting and control mice were 64.0+/-15.3
and 47.9+/-9.4 weeks, respectively. Short-term repeated
fasting manipulation was also effective on the prolongation
of life-span in autoimmune-prone mice.
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School of Biological Sciences, University
of Liverpool, United Kingdom.
Calorie restriction (CR) in mammals
has been recognized as the best characterized and most
reproducible strategy for extending maximum survival,
retarding physiological aging, and delaying the onset
of age-related pathologic conditions in mammals. The overwhelming
majority of studies using CR have used short-lived rodent
species, although current work using rhesus and squirrel
monkeys will determine whether this paradigm is also relevant
to manipulating the rate of primate aging. The mechanism
by which restricted calorie intake modifies the rate of
aging and pathology has been the subject of much controversy,
although an attenuation in the lifetime accumulation of
oxidative damage appears to be a central feature. Although
the majority of studies have focused on the ability of
cells from calorie-restricted animals to scavenge free
radicals to explain the slower accrual of oxidative damage
with age, it is not established that CR has a consistent
effect to upregulate the activity of these enzymes in
all tissues. A major effect of calorie-restricted feeding
now appears to be on the rate of production or leak of
free radicals from the mitochondria. The details of the
adaptation and the signaling pathway that induces this
effect are currently unknown.
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1999
McArdle Laboratory for Cancer Research
and The Center for Environmental Toxicology, University
of Wisconsin-Madison, 53706-1599, USA.
Studies of the multistage nature
of hepatocarcinogenesis in the rat have led to the development
of models having significant potential application to
carcinogenesis in other tissues as well as other species.
Whereas the initial and final stages of carcinogenesis-initiation
and progression-involve genetic changes and are operationally
irreversible, the intermediate stage of promotion is operationally
reversible and can be modulated by a variety of environmental
factors. Numerous investigations have demonstrated that
chronic caloric restriction modifies neoplastic development,
primarily during the stage of promotion, so that fewer
lesions develop. Short-term fasting of rats, initiated
with a nonnecrogenic dose of diethylnitrosamine (DEN)
and promoted with 0.05% phenobarbital (PB) for 4 weeks,
results in loss of virtually all of the measurable altered
hepatic foci (AHF) after two 5-day periods of fasting
with an intermediate 2-day period of feeding. This change
was accompanied by a marked decrease in bromodeoxyuridine
(BrdU) labeling of hepatocytes within AHF together with
a significant increase in apoptosis of such cells measured
by nick end-labeling. Similar but lesser effects were
noted in surrounding, nonfocal hepatocytes. On refeeding,
both the numbers and volume percentage of AHF returned
within 2 weeks to values seen in nonfasted controls. Administration
of PB during the fasting period did not alter these results,
although AHF reappeared more rapidly in such animals on
refeeding. Nuclear DNA fragmentation was evident in samples
of whole liver from fasted animals. During this same period
the expression of c-myc mRNA increased 3- to 9-fold, while
levels of albumin and insulin-like growth factor I mRNAs
decreased significantly. This study demonstrates a model
system in which the reversibility of the effects of promoting
agents may be rapidly determined and the effects of chemopreventive
inhibitors of promotion may be rapidly evaluated.
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Department of Biomedical Sciences,
University of Modena and Reggio Emailia, Modena, Italy.
Connective tissue shows peculiar
and complex age-related modifications, which can be, at
least in part, responsible for altered functions and increased
susceptibility to diseases. Food restriction has long
been known to prolong life in rodents, having antiaging
effects on a variety of physiologic and pathologic processes.
Therefore, the aorta has been investigated in rats fed
normal or hypocaloric diet, from weaning to senescence.
Compared with controls, caloric-restricted animals showed
less pronounced age-dependent alterations such as elastic
fiber degradation, collagen accumulation and cellular
modifications. Immunocytochemical analyses revealed that
elastic fibers were positively labelled for biglycan,
decorin, ApoB100 (LDL), ApoA1 (HDL) and elastase and that
the intensity of the reactions was time- and diet-dependent.
With age, the major changes affecting aortic elastic fibers
were increased positivity for decorin, LDL and elastase.
Compared with age-matched normal fed rats, caloric restricted
animals revealed lower content of LDL, decorin and elastase
and higher positivity for HDL. These data suggest that
a caloric restricted diet might influence the aging process
of the arterial wall in rats, delaying the appearance
of age-related degenerative features, such as structural
alterations of cells and matrix and modified interactions
of elastin with cells and with other extracellular matrix
molecules.
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Department of Physiology and Pharmacology,
Wake Forest University, School of Medicine, Winston-Salem,
NC 27157-1083, USA.
The present study was designed
to assess the impact of moderate caloric restriction (60%
of ad libitum fed animals) on cerebral vascular density
and local cerebral blood flow. Vascular density was assessed
in male Brown-Norway rats from 7-35 months of age using
a cranial window technique. Arteriolar density, arteriole-arteriole
anastomoses, and venular density decreased with age and
these effects were attenuated by moderate caloric restriction.
Analysis of local cerebral blood using [14C]iodoantipyrine
indicated that basal blood flow decreased with age in
CA1, CA3 and dentate gyrus of hippocampus; similar trends
were evident in cingulate, retrosplenal, and motor cortex.
Basal blood flow was increased in all brain regions of
moderate caloric restricted old animals (compared to old
ad libitum fed animals) and no differences were observed
between ad libitum fed young and caloric restricted older
animals. In response to a CO2 challenge to maximally dilate
vessels, blood flow increased in young and old ad libitum
fed animals, but a similar increase was not observed in
caloric restricted old animals. We conclude that a decrease
in cerebral vasculature is an important contributing factor
in the reduction in blood flow with age. Nevertheless,
vessels from young and old animals have the capacity to
dilate in response to a CO2 challenge and, after CO2,
no differences are observed between the two age-groups.
These results are consistent with the hypothesis that
aged animals fail to adequately regulate local cerebral
blood flow in response to physiological stimuli. Moderate
caloric restriction increases microvascular density and
cerebral blood flow in aged animals but tissues exhibit
little or no increase in blood flow in response to CO2
challenge. The cause of this deficient response may indicate
that vessels are maximally dilated in aged calorically
restricted animals or that they fail to exhibit normal
regulatory control.
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2000
Institute on Aging, University of
Wisconsin, Madison 53706, USA.
Dietary manipulations to prevent
cancer and other diseases of aging have drawn broad public
and scientific attention. One indicator of this interest
is that dehydroepiandrosterone (DHEA) supplements are
widely consumed by those who hope that this hormone may
keep them "younger longer." However, key data
to support this belief are lacking. For example, the influence
of DHEA treatment on spontaneous cancer and life span
in healthy, long-lived strains of mice or rats is unknown.
This is in contrast to the situation for caloric restriction
(CR), which is known to oppose cancer development and
increase maximum life span in rodents. To address this
issue, we assigned 300 middle age (12-month-old) male
C57BL/6 mice to one of four groups (n = 75 for each group)
and evaluated them for longevity and spontaneous disease
patterns. Two groups were fed a normal diet (ND), and
two others were fed a calorie-restricted diet (RD). One
ND group and one RD group were also given 25 microg/ml
DHEA sulfate (DHEAS) in their drinking water. Although
urine samples from DHEAS-treated mice contained 10-fold
more DHEA and DHEAS than did samples from unsupplemented
mice, DHEAS administration did not affect body weight,
life span, or cancer patterns. The RD lowered body weight
by 26% and increased maximum life span by approximately
15%. The incidence of the most prevalent cancer, plasma
cell neoplasm, was higher in RD mice (66%) than in ND
mice (41%). Thus, DHEAS, as administered here, influenced
neither cancer nor longevity at two caloric intakes. In
contrast, CR from middle age increased longevity, the
age at which tumor-bearing mice died, and the percentage
of mice dying with cancers, suggesting that CR may retard
promotion and/or progression of existing lymphoid cancers.
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1998
Department of Physiology, University
of Texas Health Science Center at San Antonio, USA.
Reducing the food intake of rodents
to well below that of ad libitum fed animals increases
the life span. This action, which gerontologists often
refer to as the antiaging action of dietary restriction
(DR), is due to the slowing of the aging processes. DR
also maintains most physiological processes in a youthful
state and delays the occurrence and/or slows the progression
of age-associated disease processes. This antiaging action
of DR results from the reduced intake of calories. Reduction
of the body fat content does not play a causal role in
the antiaging action of DR, nor does reduction in the
metabolic rate. Alterations in the characteristics of
carbohydrate metabolism and of oxidative metabolism in
response to DR have been found that are of such a nature
that they could, at least in part, underlie the antiaging
action. Several theories have recently been proposed in
regard to the mechanisms responsible for the antiaging
action of DR, but none has been tested by rigorously designed
studies. Of these theories, the one that seems most promising
is based on the fact that DR protects rats and mice of
all ages against the damaging actions of acute stressors.
This protective action against stressors may play a major
role in the antiaging action of DR.
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1997
Biometry and Risk Assessment, Genetic
Toxicology, National Center for Toxicological Research,
3900 NCTR Road, Jefferson, Arkansas 72079, USA.
Little is known about the mechanisms
by which acute and chronic caloric restriction (CR) modulate
disease, longevity, and toxicity. To study these endpoints,
behavioral parameters such as food and water consumption
and physiologic parameters such as motor activity, body
temperature, metabolic output (oxygen use), and respiratory
quotient (RQ) were continuously monitored in 26-month-old
male B6C3F1 mice and Fischer 344 rats fed either ad libitum
(AL) or a CR diet (60% of AL). Different dietary regimens
were used: rodents were (1) chronically food-restricted
using daily feeding starting at 14 months of age, (2)
chronically food-restricted using alternate day feeding,
or (3) abruptly switched from CR to AL (acute CR). The
physiologic and behavioral changes seen with chronic and
acute CR were consistent across strains and species. Average
body temperature, the number of meals, and the ratio of
food/water consumption were significantly lower in CR
rodents than in AL rodents. Also, the daily range of body
temperature, oxygen metabolism, RQ, average water consumption,
and motor activity was significantly higher in CR rodents.
CR caused the onset of altered neurobehavioral functions
such as abnormal water consumption; increases in motor
activity, serum corticosterone, and stress proteins (HSP);
and decreases in the basal setpoint for body temperature
and brain metabolism. These changes strongly suggest that
many beneficial effects of CR are controlled by the hypothalamic-pituitary-adrenal
axis via hormonal regulation. This study supports the
assertion that nutritional status may be a primary factor
of consideration in development of safety standards and
assessment of risk.
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Department of Medicine, University
of Texas Health Science Center, San Antonio 78284-7874,
USA.
Life-long food restriction is known
to slow aging and reduce the rate of occurrence of age-associated
disease processes, but the mechanism by which this is
accomplished is unknown. In this study we have examined
the effect of food restriction on the proliferative response
of spleen cells to mitogens and lymphokine production
in 6-, 18-, and 30-month-old AL and FR Fischer-344 x Brown
Norway (F-344 x BNF1) female rats whose average life span
is 137 weeks on an ad libitum (AL) diet and 177 weeks
on a food-restricted (FR) diet. In addition, the ability
of food restriction to recall antigens was tested in 10-month-old
rats by immunizing them with keyhole limpet and hen's
egg albumin and measuring proliferative response of draining
lymph node cells to these antigens. Our results indicated
that the spleen-cell proliferative response to phytohemagglutinin
and concanavalin A (Con A) was equal in 6- and 18-month-old
rats but declined significantly in 30-month-old AL rats
compared to FR rats. Although flow cytometric analyses
did not reveal differences for CD4, CD8, and Ig+ cells
with age, a significant rise in memory T cells (Ox-22low)
in both CD4+ and CD8+ T-cell subset lineage was noted
in AL-fed rats at 30 months of age. In FR rats, however,
only a minimal shift of naive T cells (Ox-22high) to memory
cells was observed. In FR rats, the observed changes in
the naive and memory T-cell subsets correlate well with
the observed higher levels of the antiinflammatory interleukin-2
(IL-2) and lower levels of the proinflammatory cytokines
such as IL-6 and tumor necrosis factor-alpha. The ability
of food-restricted animals to recall antigens was lower
compared to their age-matched controls, though the proliferative
response to T-cell mitogen Con A and superantigen staphylococcal
enterotoxin B was higher. These findings indicate that
food restriction may selectively act to maintain a lower
number of antigen-induced memory T cells with age, thereby
maintaining the organism's ability to produce higher levels
of IL-2 with age. In summary, the increased cell-mediated
immune function noted in aged FR rats appears to be due
to the presence of a higher number of naive T cells, which
are known to produce elevated levels of the antiinflammatory
cytokines, which may in part be responsible for reducing
the observed age-related rise in disease.
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Department of Pathology and Laboratory
medicine, University of California School of Medicine,
Los Angeles 90095-1732, USA.
TNF-alpha and IL-6 are generally
increased in the sera of aged humans and mice. The dysregulation
of these cytokines may be critical in autoreactivity and
immune dysfunction. In earlier studies we demonstrated
that production of TNF-alpha and IL-6 following in vitro
stimulation of peritoneal macrophages by LPS was reduced
in old compared to young mice, and that dietary caloric
restriction (CR) had no effect on the induction of TNF-alpha
in this system. In the present study we examined the effects
of age and calorie restriction on the constitutive production
of both TNF-alpha and IL-6. Serum levels of both cytokines
were significantly higher in old versus young mice. However,
in old mice subjected to long term CR the serum levels
were comparable to those of young mice. The potential
involvement of normalization of TNF-alpha and IL-6 levels
in the life extension effect of CR are discussed.
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1996
Department of Medicine, University
of Wisconsin, Madison, USA.
Caloric restriction (CR), which
has been investigated by gerontologists for more than
60 yr, provides the only intervention tested to date in
mammals (typically mice and rats) that repeatedly and
strongly increases maximum life span while retarding the
appearance of age-associated pathologic and biologic changes.
Although the large majority of rodent studies have initiated
CR early in life (1-3 mo of age), CR started in midadulthood
(at 12 mo) also extends maximum life span in mice. Two
main questions now face gerontologists investigating CR.
By what mechanisms does CR retard aging and disease processes
in rodents? There is evidence to suggest that age-associated
increases in oxidative damage may represent a primary
aging process that is attenuated by CR. Will CR exert
similar actions in primates? Studies in rhesus monkeys
subjected to CR and limited human epidemiological data
support the notion of human translatability. However,
no matter what the answers are to these questions, the
prolongation of the health span and life span of rodents
by CR has major implications for many disciplines, including
toxicologic pathology, and raises important questions
about the desirability of ad libitum feeding.
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Institute of Human Ageing/Department
of Environmental and Evolutionary Biology, University of
Liverpool, Liverpool L69 3BX, UK.
Reproductive ageing in female rodents
is accompanied by changes in circulating peptide and steroid
hormones leading to irregular, lengthened oestrous cycles
prior to loss of fertility. In this study, the effect
of ageing is reported on steroid hormone synthesis within
individual ovarian follicles and its retardation by restricted
feeding for two groups of ad libitum fed animals (114
and 350 days) and two groups of diet-restricted animals
(350 and 600 days). Follicles from ad libitum fed animals
of 350 days showed a transition in follicular steroid
hormone synthesis to release elevated amounts of oestradiol-17beta
on all days of the cycle. This age-related change in follicle
steroid release was significantly delayed by maintaining
animals on a restricted feeding regime, and was not complete
even by 600 days of age. This effect of diet as a means
to manipulate ageing of the follicular steroidogenic pathways
provides a useful system for investigating the control
of reproductive ageing in rodents.
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University of Texas Health Science
Center at San Antonio 78284-7756, USA.
Restricting the food intake of
mice and rats to well below that of ad libitum-fed animals
markedly slows the aging processes. This action is reflected
in an increase in longevity, a decrease in the age-associated
increase in age-specific mortality rate, the maintenance
of the physiological processes in a youthful state even
at advanced ages, and the delaying of the onset or slowing
of the progression or both of most age-associated diseases.
The dietary factor responsible is the reduction in energy
(caloric) intake. Many hypotheses have been proposed regarding
mechanisms underlying this antiaging action. Hypotheses
relating the antiaging action to the retardation of growth
and development, the reduction of adipose mass, and the
reduction of metabolic rate have been found to be wanting.
Two of the proposed hypotheses have some evidence in their
support. One involves the altered metabolic characteristics
of glucose fuel use and of oxidative metabolism. The other
relates to the enhanced ability of the rodents restricted
in food intake to cope with challenges, which in turn
has been linked to the glucocorticoid system and to the
heat-shock protein system.
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1995
Pathology Associates, Inc., Jefferson,
Arkansas 72079, USA.
Groups of C57BL6 mice of each sex
were assigned to one of 2 dietary regimens, ad libitum
(AL) or dietary restriction (DR), to study effects of
food restriction on body weight, survival, and neoplasia.
The AL and DR groups were subdivided into a scheduled
sacrifice group for examination at 6-mo intervals, and
a lifetime group to provide longevity data. Necropsies
and microscopic examinations were conducted on 911 animals.
In the lifetime group food consumption averaged 33.6 and
34.4 g per week by AL males and AL females, respectively;
the DR counterparts were given 40% less. The diet contained
4.35 kcal/g. The average lifetime body weights were 34.8,
26.8, 22.6, and 21.6 g for AL males, AL females, DR males,
and DR females, respectively, and their age at 50% survival
was 27.5, 26.9, 31.7, and 33.5 mo. Maximal lifespan was
increased 18% in DR males and females. Lifetime incidence
of tumor-bearing mice was 89% and 86% for AL males and
females, versus 64% for each sex of DR mice. Dramatic
reduction occurred in female DR mice in lymphoma (9% vs
29%), pituitary neoplasms (1% vs 37%), and thyroid neoplasms
(0.4% vs 8%). In males, hepatocellular tumors were reduced
to 1% from 10% by DR. In contrast, the incidence of histiocytic
sarcoma was increased in DR females and unaffected in
DR males. Tumor onset was delayed in DR animals; 87% of
all neoplasms in males and 95% in females had occurred
in the AL mice by 24 mo, whereas the DR animals had only
52% and 39% of their lifetime incidence, respectively,
by that age. This study provided comparative AL and DR
data from C57BL6 mice examined randomly at 6-mo intervals
(cross-sectional group) in parallel with data from animals
in similar cohort that was unsampled and allowed to succumb
naturally (longevity group). Dietary restriction reduced
the lifetime percentage of tumor-bearing animals and the
number of tumors per animal, and delayed the age at onset
of most neoplasms.
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Department of Physiology, University
of Texas Health Science Center, San Antonio, USA.
Restriction of caloric intake increases
longevity, slows the rate of functional decline, and reduces
incidence of age-related disease in a variety of species.
Most laboratory rodent studies have initiated restriction
before puberty, whereas ongoing studies in nonhuman primates
utilize restriction in adulthood. The mechanism of action
of caloric restriction remains unknown; however, data
suggest that cellular functions are altered in such a
way that destructive by-products of metabolism are reduced,
and defense or repair systems are enhanced by this nutritional
manipulation.
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1993
Division of Genetic Toxicology, National
Center for Toxicological Research, Jefferson, AR 72079.
The basic mechanisms of aging and
its retardation by caloric restriction (CR) remain unclear.
One suggested means by which CR could retard aging is
based on production of mitochondrial free radicals, and
efficiency of their subsequent metabolism. Currently,
there is little information concerning the influences
of age and CR on the rates of in vivo mitochondrial free
radical production. However, evidence for CR-induced modulation
of free radical detoxification capacities is mounting.
The direction of the influence of CR on free radical detoxification
is tissue-specific. These effects are broad and appear
to provide positive advantage.
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1991
Institute of Human Ageing, University
of Liverpool, U.K.
Polypeptide assembly rates during
in vivo hepatic protein synthesis were studied as a function
of age and restricted feeding in male rats. With ageing
the time to assemble the average peptide in the liver
of fully-fed rats significantly increased. In young rats
maintained on a restricted feeding regime known to retard
ageing, the time to assemble the average polypeptide was
increased 2.5 times. With ageing the rate of peptide elongation
increased so that at 2 years of age the underfed animals
assembled peptides at a significantly faster rate than
their age-matched controls. The rate of elongation of
peptides during hepatic protein synthesis was shown to
be directly dependent upon circulating T3 levels rather
than the dietary status of the animal. On refeeding young
diet restricted rats, polypeptide assembly kinetics did
not immediately return to control values although the
rate of protein synthesis was significantly increased.
Total liver RNA content increased significantly in refed
animals allowing for a greater rate of chain initiation
to offset the slow rate of chain elongation. A period
of 28 days of ad libitum feeding was required before assembly
kinetics returned to control values and is probably indicative
of a persistent impaired monodeiodination of T4 to T3.
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1989
Department of Physiology, University
of Texas Health Science Center, San Antonio.
Glucose has been proposed as a
mediator of aging processes by means of glycation reactions
resulting in advanced glycosylation end-products, thereby
altering protein and DNA function. Testing this provocative
concept has a high priority in gerontologic research.
In this study, food restriction of rats--a procedure which
markedly retards aging processes--was used to test the
glycation hypothesis. Food-restricted rats were found
to have a sustained plasma glucose concentration and percentage
glycosylation of hemoglobin significantly lower than those
of ad libitum fed rats. These findings are consistent
with and provide support for the glycation hypothesis.
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1988
Department of Neurosurgery, University
of Groningen, The Netherlands.
This study was designed to determine
the effect of fasting upon cerebral hypoxic-ischemic injury.
In the first part of the study the effect of fasting was
determined for survival, brain tissue water and kation
contents, and blood-brain barrier integrity. In the second
part of the study the administration of the substrates
beta-hydroxybutyrate (BHB) and glucose has been evaluated
regarding their influence upon the effect of fasting.
The study used the Levine-Klein model of unilateral carotid
occlusion and hypoxia because it mimics clinical situations
of ischemia with hypoxia. The data show that fasting did
protect rats from developing brain infarction following
hypoxia-ischemia. Hypoglycemia seems to be involved in
the mitigation of ischemic blood-brain barrier disruption.
The plasma glucose level seems to be not the only factor
involved in the genesis of the tissue kation changes.
Starvation-induced ketosis probably does not play a role
in the protection mechanism.
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Department of Obstetrics and Gynecology,
Mount Sinai Hospital Medical Center, Chicago, Illinois.
We studied the effects of short-term
dietary restriction on the survival of 3-4-month-old tumor-free
and tumor-bearing Fisher rats. The diet-restricted food
regimen consisted of alternate day ad libitum feeding
followed by alternate day fasting. Diet-unrestricted control
rats were fed ad libitum daily. Six tumor-free rats on
the diet-restricted regimen compensated for the dietary
restriction by an increase in food consumption during
the alternate feeding days, and lost an average of only
2-3% of their weight in 13 days. Six tumor-free rats on
a daily ad libitum feeding regimen gained an average of
6.8% in 15 days. The above dietary-restricted regimen
was initiated 1 week before 24 rats were inoculated intraperitoneally
with 15 million Mat 13762 ascites tumor cells. Sixteen
of 24 (66.7%) diet-restricted tumor-bearing hosts and
5/24 (20.8%) diet-unrestricted tumor-bearing hosts survived
at 9 days after tumor inoculation (p less than 0.005).
Twelve of 24 (50%) diet-restricted tumor-bearing hosts,
and 3 of 24 (12.5%) diet-unrestricted tumor-bearing hosts,
survived at 10 days after tumor inoculation (p less than
0.025). Thus, the survival of tumor-bearing rats was enhanced
by short-term relatively mild dietary restrictions. We
suggest that relatively mild dietary restrictions should
be included in clinical trials designed to inhibit cancer
growth and enhance the survival of human cancer patients.
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Department of Child Health, St. George's
Hospital Medical School, London, U.K.
The isoenzymes carbonic anhydrase
II (CAII) and III (CAIII) have been measured by radioimmunoassay
in the livers of male and female rats aged from 21 to
800 days. No sexual dimorphism at 21 days was found, but
from 50 to 400 days both isoenzymes show sexual differences.
From 600 days onwards, these differences are less apparent.
CAIII concentrations in two 'fast' fibre muscles and one
'slow' fibre muscle have been determined. There is no
sexual dimorphism in muscle, but a wide variation between
individuals was observed. Fast muscles show maximal CAIII
levels at 800 days, whereas in slow muscle the concentration
of the isoenzyme is declining at this time.
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Department of Psychology, Princeton
University, New Jersey 08544.
Two sets of experiments describing
the effects of chronic undernutrition on sensory-motor
function and susceptibility to environmental stressors
are described. In the first, Fischer 344 rats between
10 and 12 months of age were placed on an every-other-day
feeding regimen. Behavioral tests designed to assess sensory
function (auditory and visual thresholds), somato-motor
competence (hang time from a horizontal wire, balance
on a narrow beam, descent of a wire mesh pole), and sensory-motor
integrity (auditory startle) were then conducted every
3 to 6 months. Chronic undernutrition significantly increased
life span and increased somato-motor competence but did
not affect sensory function or sensory-motor integrity.
In the second set of experiments both acute and chronic
dietary restriction impaired the ability of young adult
Sprague-Dawley rats to effectively thermoregulate in response
to a cold environment. Body temperature dropped more rapidly
and recovered at a slower rate in the dietarily restricted
animals. Fischer 344 rats maintained on a restricted diet
for 16 months were similarly impaired. The latter findings
suggest that techniques for extending life span based
on laboratory animal models may have little relevance
to either animals or humans living in their natural habitats
where a wide variety of environmental stressors are encountered.
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1987
Female C3B10RF1 mice maintained
on either a control (approximately 95 kcal/week) or restricted
(approximately 55 kcal/week) diet since weaning were tested
in a behavioral battery at 11 to 15 or 31 to 35 months
of age (middle-aged vs. aged). Age-related declines observed
among control groups in tests of motor coordination (rotorod)
and learning (complex maze) were prevented by the restriction
regime. In addition, diet restriction increased locomotor
activity in a runwheel cage among mice of both ages but
did not affect exploratory activity in a novel arena.
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Sensory and motor task performance
was assessed at 3 to 4 month intervals in chronically
underfed and ad libitum-fed control rats from maturity
into senescence. Diet-restricted rats weighed less than
controls and lived significantly longer. Diminished body
mass improved the underfed rats' abilities to hang suspended
from a wire, to maintain balance on a narrow beam, and
to descend from a wire mesh pole in a coordinated fashion.
Underfed rats, however, lost these abilities at the same
rate as did control rats. Undernutrition did not affect
the startle response to acoustic stimulation, nor did
it influence auditory or visual lead stimulus inhibition
of the startle response. Both groups of animals showed
progressive, age-related losses of sensory-motor function
which proceeded at the same rate in each group. Life-prolonging
undernutrition did not appear to retard aging of these
simple, reflexive behaviors.
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