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2005
Laboratory of Cardiovascular Science,
Gerontology Research Center, National Institute on Aging,
National Institutes of Health, 5600 Nathan Shock Drive,
Baltimore, MD 21224, USA.
Human studies have documented age-related
declines in caloric intake that are pronounced at advanced
ages. We examined caloric intake from a longitudinal study
of aging in 60 male and 60 female rhesus monkeys (Macaca
mulatta) collected for up to 10 years. Monkeys were provided
a standardized, nutritionally fortified diet during two
daily meals, and intake was measured quarterly. About
half of the monkeys were on a regimen of caloric restriction
(CR) representing about a 30% reduction in caloric intake
compared to controls (CON) of comparable age and body
weight. CR was applied to determine if this nutritional
intervention retards the rate of aging in monkeys similar
to observations in other mammalian studies. Following
reproductive maturity at 6 years of age, there was a consistent
age-related decline in caloric intake in these monkeys.
Although males had higher intake than females, and CON
had higher intake compared to CR, the sex and diet differences
converged at older ages (>20 years); thus, older CR
monkeys were no longer consuming 30% less than the CON.
When adjusted for body weight, an age-related decline
in caloric intake was still evident; however, females
had higher intake compared to males while CR monkeys still
consumed less food, and again differences converged at
older ages. Motivation for food was assessed in 65 of
the monkeys following at least 8 years in their respective
diet groups. Using an apparatus attached to the home cage,
following an overnight fast, monkeys were trained to reach
out of their cage to retrieve a biscuit of their diet
by pushing open a clear plastic door on the apparatus.
The door was then locked, and thus the biscuit was irretrievable.
The time spent trying to retrieve the biscuit was recorded
as a measure of motivation for food. We observed an age-related
decline in this measure, but found no consistent differences
in retrieval time between CR and CON groups of comparable
age and time on diet. The results demonstrate an age-related
decline in food intake and motivation for food in rhesus
monkeys paralleling findings in humans; however, we found
no evidence that monkeys on a long-term CR regimen were
more motivated for food compared to CON. Examining the
relationship of selected blood proteins to food intake
following 7-11 years on the study, we found a negative
correlation between globulin and intake among males and
females after accounting for differences in age. In addition,
a positive correlation was observed between leptin and
intake in males.
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2003
Intramural Research Program, Gerontology
Research Center, National Institute on Aging, NIH, 5600
Nathan Shock Drive, Baltimore, MD 21224, USA.
Calorie restriction (CR) extends
lifespan and reduces the incidence and age of onset of
age-related disease in several animal models. To determine
if this nutritional intervention has similar actions in
a long-lived primate species, the National Institute on
Aging (NIA) initiated a study in 1987 to investigate the
effects of a 30% CR in male and female rhesus macaques
(Macaca mulatta) of a broad age range. We have observed
physiological effects of CR that parallel rodent studies
and may be predictive of an increased lifespan. Specifically,
results from the NIA study have demonstrated that CR decreases
body weight and fat mass, improves glucoregulatory function,
decreases blood pressure and blood lipids, and decreases
body temperature. Juvenile males exhibited delayed skeletal
and sexual maturation. Adult bone mass was not affected
by CR in females nor were several reproductive hormones
or menstrual cycling. CR attenuated the age-associated
decline in both dehydroepiandrosterone (DHEA) and melatonin
in males. Although 81% of the monkeys in the study are
still alive, preliminary evidence suggests that CR will
have beneficial effects on morbidity and mortality. We
are now preparing a battery of measures to provide a thorough
and relevant analysis of the effectiveness of CR at delaying
the onset of age-related disease and maintaining function
later into life.
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2002
Laboratory of Neurosciences, National
Institute on Aging, Baltimore, Maryland 21224, USA.
Plasma levels of thyroid hormones
- triiodothyronine (T 3 ), thyroxin (T 4 ), and thyroid-stimulating
hormone (TSH) were measured in male and female rhesus
monkeys (Macaca mulatta) fed either ad libitum or a 30
% calorie-restricted (CR) diet (males for 11 years; females
for 6 years). The same hormones were measured in another
group of young male rhesus monkeys during adaptation to
the 30 % CR regimen. Both long- and shorter-term CR diet
lowered total T 3 in plasma of the monkeys. The effect
appeared to be greater in younger monkeys than in older
counterparts. No effects of CR diet were detected for
either free or total T 4, although unlike T 3, levels
of this hormone decreased with age. TSH levels also decreased
with age, and were increased by long-term CR diet in older
monkeys only. No consistent effects of shorter-term CR
diet were observed for TSH. In the light of the effects
of the thyroid axis on overall metabolism, these results
suggest a possible mechanism by which CR diets may elicit
their well-known beneficial 'anti-aging' effects in mammals.
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Laboratory of Neurosciences, National
Institute on Aging, Baltimore, Maryland 21224, USA.
For nearly 70 years it has been recognized
that reduction in caloric intake by 30-40% from ad libitum
levels leads to a significant extension of mean and maximal
lifespan in a variety of short-lived species. This effect
of caloric restriction (CR) on lifespan has been reported
in nearly all species tested and has been reproduced hundreds
of times under a variety of different laboratory conditions.
In addition to prolonging lifespan, CR also prevents or
delays the onset of age-related disease and maintains many
physiological functions at more youthful levels. Studies
in longer-lived species, specifically rhesus and squirrel
monkeys, have been underway since the late 1980s. The studies
in nonhuman primates are beginning to yield valuable information
suggesting that the effect of CR on aging is universal across
species and that this nutritional paradigm will have similar
effects in humans. Even if CR can be shown to impact upon
human aging, it is unlikely that most people will be able
to maintain the strict dietary control required for this
regimen. Thus, elucidation of the biological mechanisms
of CR and development of alternative strategies to yield
similar benefits is of primary importance. CR mimetics,
or interventions that "mimic" certain protective
effects of CR, may represent one such alternative strategy.
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Department of Communicative Disorders,
University of Wisconsin-Madison, Wisconsin Regional Primate
Center, 1975 Willow Drive, Madison, WI 53706, USA.
The present study is part of a
larger project that investigates the effect of caloric
restriction on longevity in the rhesus monkey. The purpose
of the present study was to document presbycusis and the
effect of caloric restriction on presbycusis in monkeys.
The control group had 35 monkeys allowed to eat freely
and the caloric-restricted group (CR) had 33 monkeys with
a 30% reduction in caloric intake. Monaural and binaural
auditory brainstem response (ABR) and middle latency response
(MLR) were obtained from 27 female and 41 male monkeys
that were 11-23 years of age and had been in the study
for 102, 42, or 36 months when tested. Significant findings
were the following: (1) wave I amplitudes were larger
for females and for younger monkeys, and amplitudes decreased
in aging males but not in aging females; (2) wave IV amplitudes
were larger for females than males, and amplitudes for
CR females were larger than for female controls, whereas
the amplitudes from control and CR males were not different;
(3) wave Pa latencies were shorter for females, and shorter
latencies were maintained for aging females but not for
aging males; (4) interwave interval IV-Pa was shorter
for females, and intervals lengthened for aging males
but not aging females; (5) binaural wave IV amplitude
decreased faster with age for control monkeys than for
CR monkeys, and the L+R Pa amplitude decreased with age.
Additional trends were identified for longitudinal monitoring
as monkeys enter old age.
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2001
Wisconsin Regional Primate Research
Center, Madison 53715, USA.
In a longitudinal study of the
effects of moderate (70%) dietary restriction (DR) on
aging, plasma glucose and insulin concentrations were
measured from semiannual, frequently sampled intravenous
glucose tolerance tests (FSIGTT) in 30 adult male rhesus
monkeys. FSIGTT data were analyzed with Bergman's minimal
model, and analysis of covariance revealed that restricted
(R) monkeys exhibited increased insulin sensitivity (S(I),
P < 0.001) and plasma glucose disappearance rate (K(G),
P = 0.015), and reduced fasting plasma insulin (I(b),
P < 0.001) and insulin response to glucose (AIR(G),
P = 0.023) compared with control (C; ad libitum-fed) monkeys.
DR reduced the baseline fasting hyperinsulinemia of two
R monkeys, whereas four C monkeys have maintained from
baseline, or subsequently developed, fasting hyperinsulinemia;
one has progressed to diabetes. Compared with only the
normoinsulinemic C monkeys, R monkeys exhibited similarly
improved FSIGTT and minimal-model parameters. Thus chronic
DR not only has protected against the development of insulin
resistance in aging rhesus monkeys, but has also improved
glucoregulatory parameters compared with those of otherwise
normoinsulinemic monkeys.
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Gerontology Research Center, National
Institute on Aging, Baltimore, Maryland 21224, USA.
Rhesus monkeys exhibit an age-associated
decrease in peak plasma melatonin levels analogous to
that reported for humans. This decrease is essentially
abolished in monkeys subjected to a 30% reduction in caloric
intake over a 12-yr period. The caloric restriction (CR)
effect does not seem to be a reversal, but rather a long-term
prevention, of the age-related decline in hormone concentrations.
The age effect does not seem to be due to a phase shift
in the peak of melatonin secretions, as has been observed
in some populations of aged humans. It is also extremely
unlikely that the CR effect simply reflects a phase shift,
since old monkeys on the diet have nocturnal melatonin
levels equal to or greater than adult fully fed controls.
Thus, if peak times (approximately 0200 h) were actually
shifted, maximal levels in old CR monkeys would be even
higher. These findings, coupled with previous observations
in humans, suggest that peak plasma melatonin levels may
represent a possible candidate "biomarker of aging"
in primates. Moreover, this index of age-associated physiological
decrement seems to be inhibited by dietary CR.
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Laboratory of Neurosciences, Gerontology
Research Center, National Institute on Aging, National Institutes
of Health, Baltimore, Maryland 21224, USA.
Caloric restriction (CR) remains
the only nongenetic intervention that reproducibly extends
mean and maximal life span in short-lived mammalian species.
This nutritional intervention also delays the onset, or
slows the progression, of many age-related disease processes.
The diverse effects of CR have been demonstrated many
hundreds of times in laboratory rodents and other short-lived
species, such as rotifers, water fleas, fish, spiders,
and hamsters. Until recently, the effects of CR in longer-lived
species, more closely related to humans, remained unknown.
Long-term studies of aging in nonhuman primates undergoing
CR have been underway at the National Institute on Aging
(NIA) and the University of Wisconsin-Madison (UW) for
over a decade. A number of reports from the NIA and UW
colonies have shown that monkeys on CR exhibit nearly
identical physiological responses as reported in laboratory
rodents. Studies of various markers related to age-related
diseases suggest that CR will prevent or delay the onset
of cardiovascular disease, diabetes, and perhaps cancer,
and preliminary data indicate that mortality due to these
and other age-associated diseases may also be reduced
in monkeys on CR, compared to controls. Conclusive evidence
showing that CR extends life span in primates is not presently
available; however, the emerging data from the ongoing
primate studies strengthens the possibility that the diverse
beneficial effects of CR on aging in rodents will also
apply to nonhuman primates and perhaps ultimately to humans.
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Laboratory of Neurosciences, Gerontology
Research Center, National Institute on Aging, National Institutes
of Health, Baltimore, Maryland 21224, USA.
Dietary caloric restriction (CR)
is the only intervention conclusively and reproducibly
shown to slow aging and maintain health and vitality in
mammals. Although this paradigm has been known for over
60 years, its precise biological mechanisms and applicability
to humans remain unknown. We began addressing the latter
question in 1987 with the first controlled study of CR
in primates (rhesus and squirrel monkeys, which are evolutionarily
much closer to humans than the rodents most frequently
employed in CR studies). To date, our results strongly
suggest that the same beneficial "antiaging"
and/or "antidisease" effects observed in CR
rodents also occur in primates. These include lower plasma
insulin levels and greater sensitivity; lower body temperatures;
reduced cholesterol, triglycerides, blood pressure, and
arterial stiffness; elevated HDL; and slower age-related
decline in circulating levels of DHEAS. Collectively,
these biomarkers suggest that CR primates will be less
likely to incur diabetes, cardiovascular problems, and
other age-related diseases and may in fact be aging more
slowly than fully fed counterparts. Despite these very
encouraging results, it is unlikely that most humans would
be willing to maintain a 30% reduced diet for the bulk
of their adult life span, even if it meant more healthy
years. For this reason, we have begun to explore CR mimetics,
agents that might elicit the same beneficial effects as
CR, without the necessity of dieting. Our initial studies
have focused on 2-deoxyglucose (2DG), a sugar analogue
with a limited metabolism that actually reduces glucose/energy
flux without decreasing food intake in rats. In a six-month
pilot study, 2DG lowered plasma insulin and body temperature
in a manner analagous to that of CR. Thus, metabolic effects
that mediate the CR mechanism can be attained pharmacologically.
Doses were titrated to eliminate toxicity; a long-term
longevity study is now under way. In addition, data from
other laboratories suggest that at least some of the same
physiological/metabolic end points that are associated
with the beneficial effects of underfeeding may be obtained
from other potential CR mimetic agents, some naturally
occurring in food products. Much work remains to be done,
but taken together, our successful results with CR in
primates and 2DG administration to rats suggest that it
may indeed be possible to obtain the health- and longevity-promoting
effects of the former intervention without actually decreasing
food intake.
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2000
Wisconsin Regional Primate Research
Center, University of Wisconsin, Madison, WI, USA.
Dietary restriction (DR) retards
aging and extends the maximum lifespan of laboratory mice
and rats. To determine whether DR has similar actions
in a primate species, we initiated a study in 1989 to
investigate the effects of a 30% DR in 30 adult male rhesus
monkeys. In 1994, an additional 30 females and 16 males
were added to the study. Although the animals are still
middle-aged, a few differences have developed between
the control and DR animals suggesting that DR may induce
physiologic changes in the rhesus monkey similar to those
observed in rodents. Fasting basal insulin and glucose
concentrations are lower in DR compared to control animals
while insulin sensitivity is higher in the restricted
animals. DR has also altered circulating LDL in a manner
that may inhibit atherogenesis. These results suggest
that DR may be slowing some age-related physiologic changes.
In addition to measures of glucose and lipid metabolism,
the animals are evaluated annually for body composition,
energy expenditure, physical activity, hematologic indices,
and blood or urinary hormone concentrations. In the next
few years, the first animals will reach the average lifespan
( approximately 26 years) of captive rhesus monkeys and
it will become possible to determine if DR retards the
aging process and extends the lifespan in a primate species.
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Intramural Research Program, Gerontology
Research Center, National Institute on Aging, NIH, Baltimore,
MD 21224, USA.
Calorie restriction (CR) is widely
known for its effects on life span, physiological aging
and age-related disease in laboratory rats and mice. Emerging
data from CR studies in rhesus monkeys suggest that this
nutritional intervention paradigm may also have beneficial
effects in long-lived mammals. Studies from our laboratory
and others have suggested that young- or adult-onset CR
might have beneficial effects on cardiovascular disease
and diabetes. For example, long-term CR reduced body fat
and serum triglycerides, and increased a subfraction of
HDL cholesterol associated with decreased cardiovascular
disease risk. These studies suggested that long-term CR
begun in young or adult animals might have important effects
on markers relevant to age-related disease. Few studies
have examined the effects of CR initiated in older animals
(rodents or monkeys), and the temporal nature of some potentially
beneficial effects of CR is unknown. The present study examined
several markers related to diabetes and cardiovascular disease
in thirteen older adult (> 18 year) non-obese (body fat
< 22%), male rhesus monkeys during a short-term CR paradigm.
Specifically, we collected these data at baseline (ad libitum
feeding), 10, 20, and 30% CR, and at 6 and 12 months on
30% CR. Fasting and peak insulin were significantly reduced
as were the acute and second-phase insulin responses. CR
also marginally reduced triglycerides (50% reduction), but
had no effect on total serum cholesterol or blood pressure.
Interestingly, the observed glucoregulatory changes emerged
prior to any evidence of a change in body composition suggesting
that certain effects of CR may not be wholly dependent on
changes in body composition in older monkeys.
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National Institute on Aging, Baltimore,
MD 21224, USA.
Dietary energy restriction is the
only proven method for extending lifespan and slowing
aging in mammals, while maintaining health and vitality.
Although the first experiments in this area were conducted
over 60 y ago in rodents, possible applicability to primates
has only been examined in controlled studies since 1987.
Our project at the National Institute on Aging began with
3-0 male rhesus and 30 male squirrel monkeys of various
ages over their respective life spans. Subsequently, it
has been expanded to include female rhesus monkeys, and
several other laboratories have initiated related studies.
Experimental animals are generally fed 30% less than controls,
and diets are supplemented with micronutrients to achieve
undernutrition without malnutrition. These calorically
restricted (CR) monkeys are lighter, with less fat and
lean mass than controls. Bone mass is also slightly reduced,
but in approximate proportion to the smaller body size.
CR animals mature more slowly and achieve shorter stature
than controls as well. Metabolically, CR monkeys have
slightly lower body temperature and initial energy expenditure
following onset of restriction, and better glucose tolerance
and insulin sensitivity. The latter suggest a reduced
predisposition towards diabetes as the animals age. Other
potential anti-disease effects include biomarkers suggestive
of lessened risk of cardiovascular disease and possibly
cancer. Candidate biomarkers of aging, including the age-related
decrease in plasma dehydroepiandrosterone sulfate (DHEAS),
suggest that the CR animals may be aging more slowly than
controls in some respects, although sufficient survival
data will require more time to accumulate. In summary,
nearly all CR effects detected in rodents, which have
thus far been examined in primates, exhibit similar phenomenology.
Potential applicability of these beneficial effects to
humans is discussed.
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ROW Sciences, Gaithersburg, Maryland,
USA.
As a component of a long-term,
longitudinal study of aging in this primate model, the
objective of the current experiment was to assess age
and diet effects on locomotor activity in a cross-sectional
analysis. By attaching a motion detection device to the
home cage, locomotor activity was monitored over a week
in a group (N = 47) of female rhesus monkeys (Macaca mulatta)
6-26 yrs of age. About half these monkeys composed a control
group fed a nutritionally fortified diet near ad libitum
levels, whereas an experimental group had been fed the
same diet at levels 30% less than comparable control levels
for approximately 5 yrs prior to testing. Among control
monkeys, a marked age-related decline in activity was
noted when total activity was considered and also when
diurnal and nocturnal periods of activity were analyzed
separately. When comparing activity levels between control
and experimental groups, only one significant diet effect
was noted, which was in the youngest group of monkeys
(6-8 yrs of age) during the diurnal period. Monkeys in
the experimental group exhibited reduced activity compared
to controls. Body weight was not consistently correlated
to activity levels. In some older groups, heavier monkeys
tended to show greater activity, but in younger groups
the opposite pattern was observed.
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1999
Intramural Research Program, Gerontology
Research Center, National Institute on Aging, NIH Baltimore,
Maryland 21224, USA.
The effects of calorie restriction
(CR) on life span, disease, and aging in physiological
systems have been documented extensively in rodent models.
However, whether CR has similar effects in longer-lived
species more closely related to humans remains unknown.
Studies of CR and aging using nonhuman primates (rhesus
monkeys) have been ongoing for several years at the National
Institute on Aging and the University of Wisconsin-Madison.
The majority of data published from these studies are
consistent with the extensive findings reported in rodents.
For example, monkeys on CR weigh less and have less body
fat. Monkeys on CR also exhibit lower body temperature,
fasting blood glucose and insulin, and serum lipids. In
addition, insulin sensitivity is increased in monkeys
on CR. Recent efforts in the NIA study have focused on
the effect of this intervention on risk factors for various
age-related diseases, in particular for diabetes and cardiovascular
disease. We have shown that monkeys on CR have lower blood
pressure, reduced body fat, and a reduced trunk:leg fat
ratio. Also, monkeys on CR have reduced triglycerides
and cholesterol and have increased levels of HDL2B. Low
levels of this HDL subfraction have been associated with
increased cardiovascular disease in humans. In short-term
studies, older (> 18 years) monkeys on CR exhibit reductions
in insulin and triglycerides before changes in body composition
and fat distribution became evident. These and other findings
have suggested that CR might have beneficial effects on
certain disease risk factors independent of reductions
in body weight or prevention of obesity.
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Integrated M.D./Ph.D. Program, University
of Wisconsin, Madison 53705, USA.
Caloric restriction (CR) increases
maximum life span in rodents while attenuating the development
of age-associated pathological and biological changes.
Although nearly all of the rodent studies have initiated
CR early in life (1-3 months of age), CR, when started
at 12 months of age, also extends maximum life span in
mice. Two main questions face investigators of CR. One
concerns the mechanisms by which CR retards aging and
diseases in rodents. There is evidence that CR may act,
at least in part, by reducing oxidative stress. A CR-induced
decrease in oxidative stress appears to be most profound
in post-mitotic tissues and may derive from lower mitochondrial
production of free radicals. The second issue is whether
CR will exert similar effects in primates. Studies on
CR in rhesus monkeys (maximum life span approximately
40 years) support the notion of human translatability.
We describe the University of Wisconsin Study of rhesus
monkeys subjected to a 30% reduction of caloric intake
starting at either 1989 or 1994 when they were approximately
10 years old. The data from our study and from other trials
suggest that CR can be safely carried out in monkeys and
that certain physiological effects of CR that occur in
rodents (e.g., decreased blood glucose and insulin levels,
improved insulin sensitivity, and lowering of body temperature)
also occur in monkeys. Whether oxidative stress in monkeys
is reduced by CR will be known by the year 2000, while
effects on longevity and diseases should be clearly seen
by, appropriately, 2020.
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Pennington Biomedical Research Center,
Baton Rouge, Louisiana, USA.
Calorie restriction to produce
stable long-term adult body weight for approximately 10
years prevents obesity and diabetes in middle-aged rhesus
monkeys. To determine whether this dietary regimen also
alters energy metabolism, the doubly labeled water method
was used to measure total daily energy expenditure. Six
adult male rhesus monkeys, which had been calorie-restricted
for more than 10 years, were compared to 8 control adult
monkeys, which had been fed ad libitum for their entire
lives. The calorie-restricted monkeys weighed less than
the ad-libitum fed monkeys and had a lower lean body mass
and lower fat mass. Total daily energy expenditure was
lower in the calorie-restricted than in the ad-libitum
fed monkeys, even when corrected for differences in body
size using body weight (563 +/- 64 vs 780 +/- 53 kcal/d;
p < .04), surface area (547 +/- 67 vs 793 +/- 56 kcal/d;
p < .05), or lean body mass (535 +/- 66 vs 801 +/-
54 kcal/d; p < .02) as covariates. Thyroxine (T4) was
reduced and the free thyroxine index was suggestively
lower in the calorie-restricted monkeys whereas triiodothyronine
(T3) was not significantly different. Activity in calorie-restricted
monkeys was similar to that of a weight-matched younger
adult comparison group. We conclude that the process of
preventing obesity by long-term caloric restriction causes
a significant and sustained long-term reduction in energy
expenditure, even when corrected for lean body mass.
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Department of Medicine, University
of Vermont College of Medicine, Burlington 05405, USA.
Caloric restriction (CR) has been
observed to retard aging processes and extend the maximum
life span in rodents. In an effort to evaluate the effect
of this nutritional intervention on physiologic variables
in higher species, several nonhuman primate trials are
ongoing. In particular, a study evaluating the independent
effect of CR on the extent of atherosclerosis was initiated
in 1993 in 32 adult cynomolgus monkeys. Therefore, the
trial was designed to achieve identical cholesterol intake
after animals were randomized to a control group or a
calorie-restricted group (30% reduction from baseline
caloric intake). The animals were routinely evaluated
for glycated proteins, plasma insulin and glucose levels,
insulin sensitivity, and specific measures for abdominal
fat distribution by CT scans over a 4-year interval. The
results from 4 years of intervention demonstrate that
CR improves cardiovascular risk factors (such as visceral
fat accumulation) and improves insulin sensitivity. In
contrast to other primate studies with normolipidemic
animals, CR had no independent effects on plasma lipid
levels and composition in the presence of equivalent amounts
of dietary cholesterol intake. Preliminary analysis of
atherosclerotic lesion extent in the abdominal aorta has
failed to demonstrate differences between control animals
and CR animals. Follow-up studies are being conducted
to determine the effect of CR on atherosclerosis extent
in coronary and carotid arteries.
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Intramural Research Program, Gerontology
Research Center, National Institute on Aging, NIH, Baltimore,
MD 21224, USA.
Caloric restriction (CR), undernutrition
without malnutrition, remains the only experimental paradigm
that has been shown consistently to extend lifespan and
slow aging in short-lived species. Decades of research,
mostly in laboratory rodents, have shown that CR consistently
extends lifespan, reduces or delays the onset of many age-related
diseases and slows aging in many physiological systems.
In recent years gerontologists interested in CR have focused
on two unanswered questions. 1) What is the relevance of
this nutritional paradigm to human aging? and 2) What biological
mechanism(s) underlie the diverse effects of CR leading
to a retardation of aging and disease?. To address the question
of human relevance, researchers in the Intramural Research
Program of the National Institute on Aging began a study
of CR in nonhuman primates in the late 1980s. In addition
to assessing the effects of CR on aging in primates, a major
focus of this work relates to possible metabolic mechanisms
of CR. A subsequent study at the University of Wisconsin
Madison was initiated in the early 1990s. Certain aspects
of experimental design differ between these two important
ongoing investigations, but generally these studies compliment
each other in many ways and have begun to provide much important
data regarding the effects of CR in primates. Emerging data
from these studies strongly support that physiological responses
to CR in monkeys parallel the extensive findings reported
in rodents. Lifespan data will not be available for several
years, however, the remarkable consistency with rodent studies,
in which lifespan extension is documented extensively, strengthens
the possibility that CR will also extend lifespan in primates,
perhaps including humans. This review summarizes the major
findings from the primate CR studies after over a decade
of research in this model.
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1997
Brain Imaging Center, Intramural
Research Program, National Institute on Drug Abuse, National
Institutes of Health, Johns Hopkins Bayview Medical Center,
Baltimore, MD, USA.
Calorie restriction (CR), undernutrition
without malnutrition, extends the mean and maximal lifespan
of several ecologically diverse species. Rodents on CR
demonstrate increased activity measured as spontaneous
locomotion, wheel running, open field behavior or movement.
Activity measures were recorded from 19 male rhesus monkeys
(Macaca mulatta) as either controls (C) which were fed
a nutritious diet to approximate ad libitum levels, or
as experimentals (E) which were fed 30% less than age-
and weight-matched controls. Within each diet group, some
monkeys (n = 10) began CR at 2.3 years of age (range 2.2-2.4
yrs, J Group) while another group (n = 9) began CR at
approximately 4.6 years of age (range 4-5.25, A group).
Beginning about 6 years after initiation of the study,
behavioral activity was measured via ultrasonic motion
detectors and recorded on videotape. Diurnal and circadian
activity was clearly discernible. Peaks in activity were
associated with mealtime and colony husbandry. Compared
to Group A, Group J monkeys exhibited higher overall activity
as measured by sensors, and also significantly more circling.
Compared to AC monkeys, group AE monkeys demonstrated
higher rates of gross motor behavior, pacing, stereotypies
and grooming. The increases in motor activity observed
in one group of monkeys were consistent with results obtained
from rodent studies of CR and aging. CR did not significantly
inhibit or negatively influence the display of behavior
of rhesus monkeys in the laboratory environment. We report
here, for the first time, increases in activity due to
CR in a model other than the rodent.
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Gerontology Research Center, Nathan
W. Shock Laboratories, National Institutes of Health, Johns
Hopkins University Bayview Campus, Baltimore, Maryland 21224,
USA.
The adrenal steroids, dehydroepiandrosterone
(DHEA) and its sulfate (DHEAS), have attracted attention
for their possible antiaging effects. DHEAS levels in
humans decline markedly with age, suggesting the potential
importance of this parameter as a biomarker of aging.
Here we report that, as seen in humans, male and female
rhesus monkeys exhibit a steady, age-related decline in
serum DHEAS. This decline meets several criteria for a
biomarker of aging, including cross-sectional and longitudinal
linear decreases with age and significant stability of
individual differences over time. In addition, the proportional
age-related loss of DHEAS in rhesus monkeys is over twice
the rate of decline observed in humans. Most important
is the finding that, in rhesus monkeys, calorie restriction,
which extends life span and retards aging in laboratory
rodents, slows the postmaturational decline in serum DHEAS
levels. This represents the first evidence that this nutritional
intervention has the potential to alter aspects of postmaturational
aging in a long-lived species.
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1996
Molecular Physiology and Genetics
Section, Nathan W. Shock Laboratories, National Institute
on Aging, National Institutes of Health, Hopkins Bayview
Medical Center, Baltimore, MD 21224, USA.
Many studies of caloric restriction
(CR) in rodents and lower animals indicate that this nutritional
manipulation retards aging processes, as evidenced by
increased longevity, reduced pathology, and maintenance
of physiological function in a more youthful state. The
anti-aging effects of CR are believed to relate, at least
in part, to changes in energy metabolism. We are attempting
to determine whether similar effects occur in response
to CR in nonhuman primates. Core (rectal) body temperature
decreased progressively with age from 2 to 30 years in
rhesus monkeys fed ad lib (controls) and is reduced by
approximately 0.5 degrees C in age-matched monkeys subjected
to 6 years of a 30% reduction in caloric intake. A short-term
(1 month) 30% restriction of 2.5-year-old monkeys lowered
subcutaneous body temperature by 1.0 degrees C. Indirect
calorimetry showed that 24-hr energy expenditure was reduced
by approximately 24% during short-term CR. The temporal
association between reduced body temperature and energy
expenditure suggests that reductions in body temperature
relate to the induction of an energy conservation mechanism
during CR. These reductions in body temperature and energy
expenditure are consistent with findings in rodent studies
in which aging rate was retarded by CR, now strengthening
the possibility that CR may exert beneficial effects in
primates analogous to those observed in rodents.
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1995
Molecular Physiology and Genetics
Section, Nathan Shock Laboratories, National Institute
on Aging, National Institutes of Health, Baltimore 21224,
USA.
Male rhesus monkeys (Macaca mulatta)
of different age groups representing the species life
span were fed ad libitum or a 30% reduced calorie diet
over a 7-yr period. During the first 2-3 yr of this longitudinal
study, glucose and insulin levels were not altered by
diet restriction (DR). However, reductions in fasting
blood glucose became apparent in DR animals after 3-4
yr. At the end of the 6th yr of study, glycated hemoglobin
was measured, and intravenous glucose tolerance tests
(IVGTTs) were conducted. Maximum glucose levels reached
during IVGTTs increased with age but were lower in DR
animals compared with controls. Several measures of the
insulin response (baseline, maximum, and integrated areas
under curve) increased with age and were lower in DR monkeys.
With the exception of glycated hemoglobin, which was not
different in monkeys subjected to DR, these findings confirm
previous studies in rodents demonstrating that DR alters
glucose metabolism and may be related to the antiaging
action of this intervention.
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1993
Wisconsin Regional Primate Research
Center, University of Wisconsin-Madison.
Dietary restriction (DR) retards
aging processes and extends maximum life span in rodents
and in simpler animals. We initiated a study in 30 adults
(8-14 years old) male rhesus monkeys to determine whether
or not aging processes are retarded by adult-onset DR
in a primate species and herein report results from the
experiment's first year. Following a 3-6 month period
when baseline data were obtained, 15 animals were assigned
to a control group and given free access to a semipurified
diet for 6-8 hours per day. The other 15 monkeys were
fed the same diet but at 70% of their baseline intake
levels predetermined individually. The animals are being
evaluated semi-annually for body size and composition,
physical activity, metabolic rate, glucose tolerance and
insulin sensitivity, hematologic indices, immunologic
function, and fingernail growth. Ocular function is assessed
annually. The preliminary observations after one year
are: (a) all monkeys appear to be in excellent health;
(b) average body weights for controls increased by 9%
while monkeys on DR did not gain weight; (c) monkeys on
DR have less body fat than do control monkeys, whereas
the amount of lean body mass has not been significantly
influenced by DR; (d) there was a small but statistically
significant reduction in physical activity for monkeys
on DR relative to controls; and (e) DR has not overtly
influenced the other measures. Control monkeys gradually
reduced their voluntary levels of food intake during the
first year of study, and food allotments to DR monkeys
are being adjusted accordingly in order to reinstate the
intended 30% difference between groups. These early data
indicate that DR can be safely instituted in adult monkeys,
but that longer term and/or more severe DR is required
to determine if it is capable of influencing age-sensitive
indices in long-lived primates.
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1992
Molecular Physiology and Genetics
Section, National Institute on Aging, National Institutes
of Health, Francis Scott Key Medical Center, Baltimore,
Maryland 21224.
Rhesus and squirrel monkeys have
been fed a semisynthetic diet at approximately ad libitum
or 30% reduced levels for 3.5 (rhesus group 2) to 4.5
(rhesus group 1 and squirrel) years. Animals have maintained
excellent health status as determined by physical examinations,
hematology, and blood chemistry. While relative rates
of body weight gain in restricted group 1 rhesus and squirrel
monkeys have been markedly reduced, DR effects on crown-rump
length (body height) have been variable. In addition,
numerous physiological and biochemical parameters have
been measured, and several exhibit significant cross-sectional
age effects. Interestingly, several of these also exhibit
possible species and genotype (group 1 and 2 rhesus) differences.
A number of physiological parameters are emerging that
might be altered by DR; however, further explanation of
these effects awaits more extensive and detailed analyses.
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1990
Molecular Physiology and Genetics
Section, Gerontology Research Center, NIA, NIH, Baltimore,
MD.
Juvenile (1 yr) and adult (3-5
yr) male rhesus monkeys (Macaca mulatta) and juvenile
(1-4 yr) and adult (5-10 yr) male squirrel monkeys (Saimiri
sciureus) were fed a diet at or near ad libitum levels
based on recommended caloric intake for age and body weight
or fed 30% less of the same diet with this restriction
gradually introduced over a 3-mo period. Analysis of body
weights among these respective control and experimental
groups from the first year of the study indicated that
the monkeys undergoing dietary restriction were gaining
weight at a markedly slower rate compared to control values.
Actual food intake among diet-restricted groups had been
reduced 22-24% below control levels. Periodic analysis
of hematology and blood chemistry measurements over the
first year of the study detected few significant differences
between control and experimental groups to indicate that
diet restriction was not detrimental to general health.
When values obtained from hematology and blood chemistry
measurements of juvenile and adult groups (control and
experimental groups combined) were compared to ad libitum
fed old monkeys from each species (greater than 18 yr
for rhesus; greater than 10 yr for squirrel monkeys),
many significant age differences were noted. Among the
largest and most consistent findings in both species were
age-related decreases in concentrations of lymphocytes,
serum glutamic oxalacetic transaminase, serum glutamic
pyruvic transaminase, alkaline phosphatase, and phosphates
as well as the albumin/globulin ratio and the blood urea
nitrogen/creatinine ratio. Age-related increases in serum
globulin and creatinine concentrations were also found.
These parameters as well as many others being implemented
in the study will be monitored further to determine if
diet restriction affects the rate of development as well
as aging as observed in numerous rodent studies applying
such nutritional manipulations.
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