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Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, MD 21224
1To whom correspondence should be addressed. E-mail: mattsonm{at}grc.nia.nih.gov.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • energy restriction • cardiovascular disease • glucose metabolism • hypertension • sympathetic nervous system
Dietary and behavioral factors appear to have major influences on the risk of cardiovascular disease (1,2). The rising tide of obesity and a metabolic syndrome characterized by insulin resistance and hypertension in many countries throughout the world are attributed to overeating and decreased amounts of exercise (3). Accordingly, two interventions that have been reported to reduce blood pressure (BP) and improve glucose metabolism in obese humans and in laboratory animals are low energy diets and physical exercise (4–6). However, the mechanism(s) by which low energy diets reduce the risk of cardiovascular disease are not clear. Dietary restriction [reduced energy intake or intermittent food deprivation (IF), with maintenance of micronutrients] can increase life span and reduce the incidence of age-related diseases including cancer, diabetes and kidney disease (7). The cellular and molecular mechanisms underlying the beneficial effects of dietary restriction regimens are beginning to be revealed and appear to involve diminished free-radical production and a mild cellular stress response, which induces the expression of genes that enhance the ability of cells to cope with more severe stress (8). Physiological changes associated with dietary restriction that might benefit the cardiovascular system include increased insulin sensitivity and reductions in BP and triglycerides (5, 6,9, 10).
An impaired ability to adapt to physiological and psychological stress may contribute to the pathogenesis of several different disorders including cardiovascular disease (2). Accordingly, there has been intense interest in identifying ways of reducing exposure to stress or enhancing adaptation to stress. Data suggest that improved stress adaptation can be accomplished by physical exercise (11) and behavioral training methods such as biofeedback and meditation (12). Diet-restricted rats and mice have increased resistance to high temperature (13) and to a number of different toxins (14,15). However, the effects of dietary restriction on cardiovascular responses to stress are unknown.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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All animal procedures were approved by National Institute on Aging Animal Care and Use Committee. Male Sprague-Dawley rats were maintained on a 12 h light/dark cycle, with lights on at 0600 h and off at 1800 h daily, and were provided continuous access to water throughout the study. Rats were individually housed after surgical implantation with a telemetric transmitter, and were given ad libitum (AL) access to food until the experimental diets were initiated. A telemetry system (Data Sciences International, St. Paul, MN) was used to monitor behavioral and physiological variables: a TA11PA-C40 (C40) transmitter for monitoring general activity, heart rate (HR), and diastolic, systolic and mean BP; and a TA10ETA-F20 (F20) transmitter for monitoring general activity, HR, and core body temperature. Surgical implantations of transmitters were performed in 3-mo-old rats under isofluorane anesthesia using a six-station anesthesia system (SurgiVet, Waukesha, WI), which combines in one system the delivery of isofluorane anesthesia mixed with therapeutic oxygen and an optional evacuation system. For a C40 implant, the catheter tip was inserted upstream into the descending aorta between the renal arteries and iliac bifurcation. The catheter was secured with tissue adhesive at the insertion point. The body of the implant was inserted into the peritoneal cavity and sutured to the abdominal musculature at the incision site. For an F20 implant, the body of the implant was inserted into the peritoneal cavity and secured to the abdominal musculature at the incision site. The two biopotential leads were routed subcutaneously to the desired placement sites located lateral to midline of the chest. The tips of leads were placed within muscle tissue and secured with a suture. Rats were allowed to recover for at least 1 mo before initiation of the experimental diets.
Diets and experimental design.
A total of 16 rats were divided into two groups (eight rats per group): one group was given AL access to a standard NIH-07 rat diet (Harlan Teklad, Indianapolis, IN), and the second group was fed the same food every other day, an IF regimen that lengthens the life span of rats and mice by 
30% (16). The study design involved analyses before diet initiation and during the 6-mo period after diet initiation (Fig. 1A). Before initiating the experimental diets, physiological variables were recorded for 72 h, and rats were then randomly assigned to one of the two diet groups. Physiological variables were recorded in rats under basal (nonstress) conditions and during and after stress sessions at designated times during the 6-mo study (Fig. 1A). Basal physiological variables were recorded continuously during a 72-h period. To examine responses to a stressor, the basal condition was recorded overnight before the treatment. On the day of the stress test, the rat was subjected to a restraint or cold-water swim at the indicated times before and after the initiation of the diet as outlined (Fig. 1A). All stress treatments were performed between 0900 and 1500 h. Blood samples were obtained immediately after the stress session.
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The immobilization stress was performed using a modified plastic DecapiCone restrainer (Braintree Scientific, Braintree, MA). Physiological variables were recorded for 10–20 min before the stress session, during the 1-h stress period, and for 1–2 h poststress. The rat was immediately returned to its cage, and the poststress physiological variables were recorded. In the test of the responses to a single immobilization stress, all rats were deprived of food overnight, and the stress sessions were performed between 0900 and 1300 h. During the 5-d period when responses to the immobilization stress sessions were tested, the feeding schedules were maintained as usual. For the IF group the first stress day was a feeding day, and accordingly, the last stress day (d 5) was also a feeding day. Blood samples were obtained immediately after the 1-h immobilization stress session. The swim stress was administered by placing the rat in a 170-cm diameter tank containing cold water (21–22°C) for up to 15 min. A video system (Videomex; Columbus Instruments, Columbus, OH) was used to determine total swimming time, distance and speed. Immediately after removal of the rat from the tank, a blood sample was taken from the tail vein, the rat was returned to its cage and physiological variables were recorded for 2 h. In the cold-swim stress test, both the IF and AL rats were tested after they had eaten.
Analyses of blood samples.
To eliminate possible effects of differences in food consumption status at the time of blood sampling, rats in both the IF and AL groups were deprived of food overnight before blood sampling. A volume of 2 mL of blood was drawn from the tail vein of each rat under anesthesia with isofluorane. The plasma was isolated and stored at -80°C. Plasma insulin (#008-10-1137-01; ALPCO Diagnostics, Windham, NH) and insulin-like growth factor 1 [(IGF-1) #DSL-10-2900; Diagnostic Systems Laboratories, Webster, TX] concentrations were measured by ELISA. Plasma glucose levels were measured using a Beckman glucose analyzer (Beckman Instruments, Fullerton, CA). The levels of adrenocorticotropic hormone (ACTH) and corticosterone in plasma were measured using radioimmunoassay kits (#07-106101 and #07-120102, respectively; ICN Diagnostics, Costa Mesa, CA). The concentrations of epinephrine and norepinephrine in plasma were measured using a catecholamine assay kit (#074-114602; ICN Diagnostics, Orangeburg, NY).
Statistical analyses.
Data for physiological variables were analyzed using repeated-measures ANOVA followed by post hoc assessments with the Student-Newman-Keul’s (SNK) test. One-way ANOVA followed by the SNK test or Student’s t test was used for comparing hormone levels. A value of P < 0.05 was considered significant. Values in the text are means ± SEM.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Body weights of rats in the IF group were significantly less than those in rats that were given AL access to food (Fig. 1b). IF rats consumed 30% less food over time than did AL rats (data not shown). There were no significant changes in activity, HR or body temperature in AL rats during the 6-mo period of the study (Fig. 2). However, BP was significantly greater at the 6-mo time point than at baseline in both IF and AL rats (P < 0.05).
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Cardiovascular and neuroendocrine responses to stress.
The increases in both diastolic and systolic BP during 1 h of immobilization stress were less in IF rats compared with their own responses before diet initiation and with the AL rats (Table 1). IF rats also exhibited a significantly reduced HR response to immobilization stress. Rats that had been on the IF regimen exhibited a reduced magnitude of responses of BP and HR after release from immobilization. Body temperature increased during immobilization stress, and the magnitude of the increase was lower in the IF rats compared with that of the AL rats (Table 1). After release from stress, the body temperature in IF rats was less than in AL rats. There were no significant differences between the groups in activity after release from the immobilization stress.
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Plasma concentrations of glucose and insulin were significantly lower in IF rats compared with those of AL rats at 3 mo after diet initiation (Table 4). The IF and AL groups did not differ in their plasma concentrations of IGF-1. The concentrations of glucose and insulin were significantly increased to similar levels after a single immobilization stress in both IF and AL rats (Table 4). Plasma glucose and insulin concentrations were also increased to similar levels after the last day in a series of daily immobilization stress sessions, and after a cold-water swim stress in rats in both the IF and AL groups (Table 4). Collectively, these data demonstrate that IF reduces plasma glucose and insulin levels under nonstress conditions suggesting improved insulin sensitivity, while metabolic responses to different types of stress are maintained in IF rats.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Excessive exposure to uncontrollable stressors and/or the inability to adapt to stress are implicated in the pathogenesis of several different disorders including hypertension and atherosclerotic vascular disease (2,25). Moreover, acute stressors can trigger myocardial infarctions and strokes (26). Energy restriction has been reported to increase the resistance of organisms ranging from yeast and flies to rodents to several different stressors including heat and exposure to chemical toxins (14,15,27–29). Our findings showed that IF rats exhibited a marked improvement in cardiovascular stress adaptation as indicated by decreased BP and HR responses to immobilization stress. Interestingly, responses of the sympathetic nervous system to the stress were maintained or even enhanced in the IF rats. The ability of rats to mobilize glucose in response to stress, a critical mechanism for increasing energy availability to muscle cells, was also fully intact in IF rats. The reduction in the blood glucose level after repeated immobilization stress sessions in this study was most likely attributable to a general reduction of the stress response in the IF rats. However, it is certainly possible that the IF rats could have reduced levels of glycogen in their livers. Thus, it appears that IF greatly improves cardiovascular risk factors (reduced BP, and glucose and insulin levels) under nonstress conditions, reduces the hypertensive effects of acute and repeated stressors, while allowing normal activation of sympathetic and energy-mobilizing responses to stress. This conclusion is supported by a recent study showing that the decreased body weight, adrenal hypertrophy and thymic involution normally caused during an 8-wk period of daily immobilization stress (2 h/d) did not occur in rats that had been on a energy-restriction regimen before the stress period (30).
IF resulted in an intriguing complement of changes in stress-related hormones under basal and stress conditions. Basal (nonstress) levels of ACTH and corticosterone were increased in rats on the IF diet, indicating that IF results in a tonic activation of the HPA stress axis. In contrast, rats on the IF diet exhibited reduced ACTH and corticosterone responses to immobilization stress, particularly after repeated daily bouts of immobilization. These findings suggest that, as with other dietary restriction regimens (7), IF causes a tonic activation of the HPA axis. Other studies have shown that a similar IF regimen induces stress responses in cells that appear to account for the beneficial effects of IF in those tissues. For example, IF induces the expression of protein chaperones such as glucose-regulated protein-78 (GRP-78) and heat shock protein-70 (HSP-70) and neurotrophic factors such as brain-derived neurotrophic factor in brain cells, which play important roles in several beneficial effects of IF on the brain including increased resistance of neurons to oxidative and metabolic stress, and stimulation of neurogenesis (the production of new nerve cells from neural stem cells) (28,31). It is not known whether IF induces similar changes in cells of the cardiovascular system. However, it has been reported that aging results in a failure of ischemic-preconditioning effects on the heart, and food restriction preserves the ischemic-preconditioning response in rats (32), and a recent gene-profiling study is consistent with up-regulation of cytoprotective genes in animals on a energy-restricted diet (33).
The enhanced ACTH response to the swim stress in the IF rats compared with that of the AL rats shows that IF did not compromise the ability of the rats to respond to the stress. However, the fact that the levels of corticosterone in the same blood samples were not increased in the IF rats suggests that the adrenal cortex in IF rats may have a reduced sensitivity to ACTH. There was also an enhanced norepinephrine response to swim stress in the IF rats compared with that of the AL rats. Consistent with ACTH response data, the increased norepinephrine response showed that IF did compromise the ability of the rats to respond to the stress and suggests that IF enhances the responsiveness of the sympathetic nervous system.
Although this study was not intended to be a comparison of IF with low energy diets, such a comparison may prove interesting. Several previous studies, including our own, have shown that some biochemical and physiological effects induced by IF are similar to those induced by conventional energy restriction. For example, both IF and energy restriction decrease blood glucose and insulin levels, and increase corticosterone levels (7,34,35). However, differences have also been documented. For example, IF increases levels of ketone bodies (3-hydroxybutyrate), whereas energy restriction does not, and energy restriction decreases IGF-1 levels, whereas IF does not (34). With respect to the effects of IF and energy restriction on cardiovascular function, it was previously reported that energy restriction lowers resting BP and HR in rats (5), and our data document similar effects of IF on BP and HR in rats. Future direct comparisons of the two different dietary restriction regimens may provide novel insight into the mechanisms by which such diets benefit the cardiovascular and other organ systems.
Two cellular mechanisms that may play major roles in the anti-aging effects of dietary restriction are reduced free-radical production (7) and activation of signaling pathways that increase the resistance of cells to stress (8). Reduced levels of reactive oxygen species in many different tissues including liver, brain and heart have been documented in studies of rodents on energy-restricted diets (36,37). Increased oxidative stress in blood vessels and the heart occur in association with hypertension (38) and diabetes (39). Several observations suggest that an enhanced cellular stress resistance may also contribute to beneficial effects of IF on the cardiovascular system including studies showing that dietary restriction increases levels of cytoprotective stress proteins such as HSP-70 and GRP-78 in various tissues including the heart (33), and the fact that physical exercise stresses vascular and heart cells (40) and exerts similar effects to those of IF on BP and glucose metabolism (41,42 and the present study). Although future studies will be required to establish the underlying cellular and molecular mechanisms, the present data provide the first evidence that IF can improve cardiovascular stress adaptation, findings with important implications for preventing cardiovascular and cerebrovascular disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 16 January 2003. Initial review completed 21 February 2003. Revision accepted 21 March 2003.
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