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PERIODICAL
FASTING AND CALORIC RESTRICTION FOR LIFE EXTENSION,
DISEASE TREATMENT AND CREATIVITY.
(clinical and experimental data)
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CALORIC RESTRICTION AND FASTING EXTEND THE LIFE SPAN
AND DECREASE ALL-CAUSE MORTALITY (Evidence) |
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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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