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*
Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center, Baltimore, Maryland 21224;
ROW Sciences, Rockville, Maryland 20850 and
**
Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8525
1To whom correspondence should be addressed at Laboratory of Neuroscience, National Institute on Aging, National Institutes of Health, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224. E-mail: MLANE{at}vms.grc.nia.nih.gov
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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0.04). The number of total menstrual cycles over 2 y, as
well as the percentage of normal-length cycles (24–31 d), was
lower in older than in younger monkeys (P 0.05).
Older monkeys also had lower estradiol (P = 0.02)
and higher follicle-stimulating hormone (P = 0.02) concentrations than did younger monkeys. We conclude that ER does
not negatively affect these indices of skeletal or reproductive health
and does not alter age-associated changes in the same variables.
KEY WORDS: • aging • bone loss • primate • reproduction • energy restriction
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,2)
. This paradigm has been studied most extensively in
mice, rats and other short-lived species: however, investigations
in nonhuman primates (3
,4)
are beginning to yield
promising data demonstrating that physiological responses of rhesus
monkeys to ER closely parallel existing rodent literature
(5)
and that ER reduces many risk factors associated with
diabetes and cardiovascular disease (6
,7)
and may even
reduce mortality rates related to these diseases (8)
.
With few exceptions, ER is thought to retard many of the physiological
changes that occur with aging. Bone loss and reproductive aging are
among the most important public health issues for older individuals,
but little information is available regarding the possible effects of
ER on these aspects of aging. The initial reports that this regimen
extended the life span in rodents also recognized the potential for a
negative influence on bone mass (9)
. In this study, it was
noted that femurs removed from severely ER rats were extremely fragile
and reportedly crumbled on dissection. Subsequent studies have used
less severe levels of ER (60% of ad libitum, or 40% ER) and have
reported reductions in several indices of skeletal mass such as bone
mineral density, bone mineral content, calcium content and bone
strength (10
11
12
13)
. Only two studies have examined the
effect of ER (40%) on bone loss with aging in rats
(14
,15)
, and they reported that unlike their counterparts
who were fed ad libitum, ER rats did not experience significant
reductions in bone mass between 24 and 27 mo of age.
Data regarding the effects of chronic ER on reproductive indices are
similarly limited. ER, such that the body weight of restricted rats
remained at 50% of that of controls, delayed the onset of puberty
(16
,17)
and retarded the loss of ovarian function
(acyclicity) that occurs during aging (16
,18)
. The onset
of persistent estrus was delayed in ER (40%) female rats
(19)
. ER (20–40%) mice become acyclic
(20
,21)
, but on refeeding, they continue to cycle at ages
beyond which control mice that are fed ad libitum had ceased normal
estrous cycling. Although limited, studies of reproductive hormones
during ER demonstrate that in young female rats, ER reduced serum
follicle-stimulating hormone (FSH) and progesterone concentrations
while increasing 17ß-estradiol concentrations measured during the
first estrous cycle (17)
. In older rats (220 d), ER
reduced the estradiol peak and levels of progesterone, but FSH
concentrations reportedly increased (18)
. Sampling in
these studies was synchronized to the phase of estrous, which was
determined through vaginal smears.
Several studies have demonstrated the possible use of nonhuman primate
models for studies of skeletal and reproductive aging. For example,
nonhuman primate models of both estrogen depletion
(22
23
24
25
26
27
28
29)
and age-related bone loss
(30
31
32
33
34
35
36
37)
have been described. In addition, many nonhuman
primate species, rhesus monkeys in particular (38
,39)
,
exhibit a natural menopause that includes oligomenorrhea followed by a
complete cessation of menstrual cycling and changes in reproductive
hormones that parallel findings in humans. However, studies of the
effect of ER, which retards many aging processes, on skeletal and
reproductive indices in longer-lived species are limited to male
rhesus monkeys. We reported that ER delayed both sexual
(40)
and skeletal (41)
maturation in young
male rhesus monkeys. A more recent study (42)
from our
laboratory reported that male rhesus monkeys on longer-term ER
(>11 y) exhibited a slight reduction in bone mass at some (mid and
distal radius), but not all (total body and lumbar spine), skeletal
sites and that the effects of ER were mostly due to changes in body
composition. A study of adult-onset ER at the University of
Wisconsin (4)
reported that after 12 mo of ER, there was
no significant reduction in bone mass in male monkeys compared with
control (CON) monkeys. No studies have reported the effects of ER on
skeletal health and reproductive function in female rhesus monkeys.
The present study was designed to assess skeletal mass, reproductive cycling and related biochemical markers in young, adult and perimenopausal female rhesus monkeys after 6 y of ER. We used dual-energy x-ray absorptiometry (DEXA) to assess bone mineral density (BMD) and bone mineral content (BMC) at several skeletal sites, including total body, lumbar spine and the mid and distal radius. Several indices of skeletal metabolism and reproductive function obtained from serum samples were also studied, including bone turnover, calcium homeostasis and reproductive cycling and hormones.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A total of 40 female rhesus monkeys (Macaca mulatta)
ranging in age from 7 to 27 y were used in this study. All monkeys
consumed the same semisynthetic, pelletized feed (NIA open formula;
Ralston Purina) offered in two meals each day at 0700 and 1400 h.
Daily food allotments for CON monkeys followed established primate
nutrition guidelines (43)
for monkeys of a given age and
weight. ER monkeys were offered 30% less food per day than CON monkeys
of a comparable age and body weight. ER was begun 6 y before the
collection of data for the present study. At the time ER was initiated,
monkeys ranged in age from 1 to 21 y. Regular measurements of food
consumption during the study have shown that the specified allotments
offered to CON monkeys approximated the amount eaten by providing free
access to food.
To ensure adequate micronutrient intake in the monkeys eating 30% less
food per day, the diet was formulated to exceed National Research
Council guidelines (43)
for vitamins, minerals and trace
elements by 
30–40%. Therefore, because the diet composition was
the same for the CON and ER groups, the experimental manipulation was a
reduction in total intake (including all nutrients) and not an
alteration in or a deficiency of a specific dietary component. The
nutrient content of the diet was 173 g protein/kg, 50 g
fat/kg, 65 g fiber/kg and 16.32 kJ/g gross energy. Calcium,
phosphorus and vitamin D concentrations of the diet were 12.2 g/kg, 6.1
g/kg and 3.5 IU/g, respectively. Because the daily food allotments were
greater in CON monkeys, the absolute intakes of calcium, phosphorus,
vitamin D and all other nutrients were higher (P < 0.0001) in CON than in ER monkeys (1.8 ± 0.07 versus 1.3 ± 0.04 g/d, 0.19 ± 0.04 versus 0.08 ± 0.02 g/d and 491.6
± 20.2 versus 363.8 ± 9.8 IU/d, respectively). Additional
details on diet composition and food allotments and consumption can be
found in previous reports (3
,41)
.
Female rhesus monkeys reach puberty at 2.5–3.5 y of age, have a mean
life span of 24 y (44)
and experience reproductive
changes similar to human menopause in their mid-20s (39)
.
Thus, monkeys in the present study began ER at various life stages,
including prepubertal, adult and old adult. At the onset of this study,
the monkeys were matched for age and body weight and divided into two
groups: CON (n = 21) and ER (n
= 19). Age ranges at which data where collected in the present
study and means for the two groups are presented in Table 1
. The monkeys included in this study were acquired in 1991 from two
sources (a military testing program at Aberdeen Proving Ground,
Maryland, and Labs of Virginia, Yemassee, SC). Monkeys were born in
captivity and thus had known birth dates and well-documented
histories. No monkey had been involved in invasive experimentation
before entering the study. These animals are part of an ongoing
longitudinal investigation of ER and aging at the National Institute on
Aging (NIA) (3
,45)
. No monkey in the present study had
been acyclic for >6 mo, and therefore all were considered to be
premenopausal during the period of data collection.
|
Housing and feeding conditions were identical to those described in our
longitudinal study of aging in male rhesus monkeys (3
,45)
.
Briefly, monkey rooms were maintained on a 12-h light/dark cycle
(lights on 0600–1800 h) with room temperature of 22–28°C and
50–60% humidity. All animals have been housed at the Primate Unit of
the National Institutes of Health Animal Center since the beginning of
the study. The Primate Unit is fully accredited by the Association for
Assessment and Accreditation of Laboratory Animal Care International,
and all procedures described herein received full approval of the
Animal Care and Use Committee of the Gerontology Research Center,
National Institute on Aging, National Institutes of Health.
Data collection and laboratory determinations.
All procedures were conducted in food-deprived (overnight),
anesthetized with tilotamine HCl/zolazepam HCl (Telazol 3.5–4.0 mg/kg
intramuscular) monkeys. If additional chemical restraint was required
for DEXA scans, an inhalable anesthetic (isofluorane) was used and
titrated to reduce all extraneous skeletal muscle movement. Total body,
lumbar spine (lumbar vertebrae 2–4) and forearm (mid and distal
radius) bone mineral density and content were determined by DEXA scans
after 6 y of ER. All DEXA scans were performed with a Lunar
DPX-
scanner (Lunar, Madison, WI) using Lunar Pediatric Software
(Version 1.3 E) for total body and spine scans and Lunar Small Animal
Software (Version 1.0C) for forearm scans. For scans of the radius, a
forearm positioning board supplied by the manufacturer was used (Lunar,
Madison, WI) to place the monkey’s left arm (palm down, open fist) on
the scan table. The scanned image of the radius was divided into three
equal portions, and bone mass in the middle and distal thirds were
determined. Precision values for the five DEXA sites are summarized in
Table 2
.
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Monkeys were observed daily for signs of menstrual bleeding. The first
observation of bleeding was counted as d 1 of the cycle, and blood
samples were then collected in anesthetized monkeys on d 5. Serum was
separated by centrifugation and stored at -80°C for future analyses
of biochemical parameters. Menstrual cycling was observed daily in two
12-mo periods before and after DEXA scans and blood sampling. The
rhesus menstrual cycling is normally 24–31 d long (38)
.
Frozen serum samples were analyzed for osteocalcin [RIA (radioimmunoassay); Diagnostic Systems Laboratories, Webster, TX); parathyroid hormone (PTH) (IRMA; Diagnostic Products Corporation, Los Angeles, CA);1,25-dihydroxyvitamin D [1,25(OH)2-D] (double antibody RIA; DiaSorin, Stillwater, MN) and 25-hydroxyvitamin D [25(OH)D] (RIA; DiaSorin). Estradiol, progesterone, FSH and luteinizing hormone (LH) concentrations were analyzed at Wisconsin Regional Primate Research Center (Madison, WI) with in-house RIA. Serum concentrations of calcium (colorimetric assay, Hitachi 747) and phosphorus (kinetic) were measured at Antech Diagnostics (Farmingdale, NY).
Mid-morning voided urinary samples were collected and assayed for pyridinoline (PYD) and deoxypyridinoline (DPD), markers of bone resorption. Both were measured with HPLC. Peaks were detected by fluorescence, quantified by external standards (courtesy of S. Robins Rowett Research Institute, Aberdeen, Scotland) and expressed per mmol of urinary creatinine (No. 555; Sigma Chemical Co., St. Louis, MO).
Statistical analyses.
Cross-sectional effects of aging on BMC and BMD in CON monkeys
were assessed through simple linear regression. A Student’s nonpaired
t test was initially used to determine the effects of ER
on the same measures. ANCOVA was used to assess the independent effects
of ER, age and body weight on bone mass. For all data, normality of
residuals was tested. Most data met normality assumptions. In those
isolated cases when data did not satisfy these assumptions, data were
transformed using a Box-Cox procedure (46)
. In the
cases where data were transformed to approximate normality, a linear
transformation was subsequently applied to return the data to original
scale to simplify interpretation. All analyses were conducted with NCSS
Statistical Software (Kaysville, UT) with P 0.05
accepted as significant. Homogeneity of regression (parallelism of
slopes) was tested across the CON and ER conditions to evaluate the
validity of using ANCOVA-based inferences regarding ER effects.
Identical techniques were used to explore relationships between bone
mass (dependent variables BMD and BMC) and measures of body composition
(independent variables lean mass and fat mass) as well as the effects
of age and ER on various biochemical variables, hormones and menstrual
cycling.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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summarizes various subject characteristics, including age
ranges for CON and ER groups, and energy intake and the effects of ER
on body weight and composition. Group size and the age range studied
did not differ between CON and ER groups. As expected, female monkeys
in the ER group consumed fewer calories, weighed less and had less fat
mass than CON monkeys (P < 0.05).
BMC and BMD tended to be lower in ER monkeys than in CON monkeys
(Table 3
). Although linear regression did not detect any cross-sectional age
effects on BMC or BMD (Figs. 1
,
2), when ANCOVA was used to assess the independent effects of ER, age and
body weight on bone mass, a significant independent effect of age on
BMD, but not BMC, was observed at all skeletal sites (Table 4
; P < 0.05). There also was an independent effect of
body weight on all measures of bone mass. These data confirm those in
Table 3
in that, with one exception (total body BMD, P
< 0.05), there were no independent effects of ER on bone mass
with control for age and weight.
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). Lean body mass was a significant predictor of bone mass at all sites
(P < 0.05). Fat mass was correlated only with mid and
distal radius BMC (P 0.03, respectively).
|
. Serum concentrations of parathyroid hormone and
1,25(OH)2-D were unaltered by age. Serum 25(OH)-D
concentrations were lower in older female monkeys (P<
0.05). No effects of ER were observed for any biochemical variable.
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summarizes the effects of age and ER on serum estradiol, FSH,
progesterone and LH. Only estradiol and FSH showed significant
cross-sectional changes with age, with lower estradiol and higher
FSH concentrations in older monkeys relative to younger monkeys. No
significant effects of chronic ER on reproductive hormone
concentrations were observed.
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) and the percentage of normal length (24–31 d) cycles
(Fig. 4B
) showed a significant cross-sectional decline
with age in CON monkeys (P< 0.05). There were no effects of
ER on either of these cycling variables.
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|
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,12
,14
,15)
and strength (9
,13)
and an
alteration in menstrual cycling (17
,20
,21)
. The present
study is the first to assess markers of skeletal and reproductive
health in female rhesus monkeys. We report here that chronic (6 y) ER
initiated at various ages and life stages does not significantly alter
bone mass (BMC and BMD) in female monkeys at any of the four skeletal
sites examined. In addition, ER did not alter biochemical measures of
skeletal metabolism and did not disrupt menstrual cycling or
reproductive hormone levels. These findings suggest that ER has no
significant negative impact on skeletal or reproductive health in
sexually mature, premenopausal or perimenopausal female rhesus monkeys.
In addition, ER did not appear to retard or reverse certain
age-associated changes in reproductive indices.
We observed a significant effect of age (P < 0.05) on
BMD at the lumbar spine and radius sites, suggesting that bone mass at
these sites was reduced in older females. We also observed significant
age effects on serum estradiol (decrease, P < 0.05)
and FSH (increase, P < 0.02). These findings are
consistent with previous studies in female rhesus monkeys. For example,
Colman et al. (37)
reported an age-related loss of
bone mass concomitant with reduced serum estradiol and increased FSH
concentrations in a study of 15 aged female rhesus monkeys. Similar
hormonal changes in aged females have been reported in other studies
(38
,39)
. Last, the observed reduction in the total number
and proportion of normal cycles is consistent with previous reports
(38
,39
,47
,48)
and, when combined with bone mass and
hormonal data, suggest that monkeys in the present study exhibited
age-appropriate changes in bone mass and reproductive hormones.
In contrast to previous reports in rats on 40% ER
(11
,12
,14
,15)
and male rhesus monkeys on 30% ER
(42)
, measures of bone mass were not reduced in female
monkeys on 30% ER compared with CON monkeys. Several possibilities may
explain this lack of agreement. Differences in nutrient intake among
the studies seem an unlikely explanation because the diet used in the
study of male rhesus monkeys was identical to the diet used in this
study. It is also unlikely that differences in nutrient intake
influenced the current findings. If indeed differences in nutrient
intake between CON and ER monkeys were physiologically relevant, we
would have expected significant differences in bone mass to be
apparent. Instead, we observed no effect of ER on bone mass. It is
possible that this lack of agreement is due to either the duration of
ER or the age of the animals. Monkeys in the present study were studied
after 6 y of ER compared with 11 y in the study of male
monkeys (42)
. In addition, both the mean and maximum ages
of the male monkeys were greater than those of the females in this
study. It is also possible that there is a gender-specific response
to ER. Although ER studies have been conducted in female rats
and mice and are under way in rhesus monkeys (44)
, studies
specifically designed to examine differences in male and female
responsiveness to ER have not been conducted. Some have suggested that
males and females may respond differently to nutritional stress
(49
,50)
. As such, possible gender differences in the
response to the type of ER regimen used in this study may have
contributed to our observation that unlike males, there were no
significant effects of ER on bone mass in females. The ongoing
longitudinal studies in our laboratory involving both male and female
rhesus monkeys offer a unique opportunity to more fully examine this
question.
In agreement with previous rat and primate studies
(5)
, we observed that female monkeys on ER exhibited
significant changes in body composition compared with CON monkeys.
Specifically, ER significantly lowered both body weight and body fat.
ANCOVA revealed that body weight was a strong predictor of bone mass at
all skeletal sites measured. Among the major body compartments, lean
body mass, which was not altered by ER in these monkeys, emerged as the
strongest predictor of bone mass. This is in agreement with studies in
premenopausal women (51
52
53
54
55)
as well as findings from our
study in male rhesus monkeys (42)
. The lack of an effect
of ER on lean and bone mass in the present study suggests that these
variables may indeed be related. However, Sanderson et al.
(11)
reported that reductions in bone mass observed in
40% ER rats were related to changes in body weight in those animals.
Clearly, additional studies are needed to further explore the
relationship between ER-induced changes in body composition and
bone mass.
Because chronic ER had been shown to reduce bone mass in rats and in
male rhesus monkeys, we believed it important to assess the effect of
ER on biochemical markers of calcium homeostasis and skeletal
metabolism. We did not observe an effect of 30% ER on serum levels of
PTH, 25(OH)D or 1,25(OH)2-D. These findings are
in agreement with our studies in male rhesus monkeys (42)
and some rat studies (11)
. The work of Kalu et al.
(10
,14
,15)
showed that 40% ER prevented an
age-related development of renal disease and resulting
hyperparathyroidism but that vitamin D concentrations were unaffected
by ER. Serum phosphorous and calcium concentrations were also unaltered
in the present study (data not shown). Markers of bone formation
(osteocalcin) and resorption (PYD and DPD) were likewise unaltered by
the diet. A short-term (6–9 wk) ER (40%) regimen in rats
reportedly increased bone turnover but did not alter PTH or calcium
levels (12)
. The present findings and previous reports in
male monkeys (42)
suggest that chronic ER does not alter
calcium homeostasis or bone turnover in rhesus monkeys.
We observed that older monkeys in both the CON and ER groups exhibited
reductions in the number of menstrual cycles and the number of normal
length (24–31d) cycles. This suggests that older monkeys in both
groups were beginning to experience menstrual difficulty, as has been
reported before menopause in both humans and rhesus monkeys
(38
,39)
. The finding that ER monkeys did not differ
significantly from CON monkeys at any age suggests that this level of
restriction (30%) did not alter menstrual cycling. In contrast,
rat studies have reported that moderate ER delayed the onset of
persistent estrous and reduced serum levels of progesterone
(16
17
18
19)
. The effects of ER on FSH and estradiol levels in
rats differ depending on the age at which hormone levels were measured
(17
,18)
. Two possible explanations for the lack of
agreement between rat and monkey findings are readily apparent. First,
the ER paradigm used in monkeys uses a more moderate degree of
restriction (30%) than that typically used in rats (40%).
Another possible explanation relates to species differences in
reproductive cycles. Rhesus monkeys exhibit a prolonged (24–31 d)
menstrual cycle that is very similar to the cycle in humans. In
contrast, the rat estrous cycle is much shorter (4–5 d) and is
characterized by more frequent peaks in estradiol.
This study is the first to examine the effects of chronic ER (30%), a nutritional intervention that extends the life span and slows aging in many physiological systems in rodents, on skeletal and reproductive health in female rhesus monkeys. In contrast to previous studies in rats and in male rhesus monkeys, ER does not have a negative impact on bone mass, biochemical indices of skeletal metabolism, menstrual cycling or reproductive hormones in premenopausal monkeys. Furthermore, ER did not retard age-related changes in skeletal or reproductive indices. An assessment of the impact of ER on menopausal and postmenopausal changes must await future studies.
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FOOTNOTES |
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Manuscript received June 16, 2000. Initial review completed August 21, 2000. Revision accepted December 12, 2000.
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