Calorie restriction at increasing levels leads to augmented concentrations of corticosterone and decreasing concentrations of testosterone in rats
Introduction
The influence of calorie restriction (CR) on increasing life span, enhancing immunocompetence, and reducing the incidence of age-related diseases is well established [1], [2], [3], [4], [5]. Calorie restriction–induced alterations are numerous, affecting virtually every physiologic system. The potential mechanisms involved in the antiaging action of CR are correspondingly multifaceted and, as a consequence, are still not well understood. The majority of research interest in this area has been directed toward significant alterations in oxidative damage (free radical damage), insulin sensitivity, and systemic changes in the sympathetic nervous and neuroendocrine systems (for a recent review, see Masoro [6]). It is likely, however, that because of the central role played by neuroendocrine systems in the regulation and integration of physiologic processes, they orchestrate the diverse molecular and cellular changes that ultimately prolong life in the CR state [7]. Indeed, it is unlikely that these coordinated cellular and molecular changes could be achieved directly and independently without systemic control by neuroendocrine factors [8].
Particular attention has been directed toward the involvement of the hypothalamic-pituitary-adrenal (HPA) axis, and specifically the glucocorticoid corticosterone (CORT), in the life-prolonging capacity of CR. Food availability has been demonstrated to influence both the overall activity and rhythmicity of the HPA axis in animal studies [9]. A commonly observed effect of CR is the elevation of total and free CORT concentrations [10], [11], [12], [13], [14], an expected characteristic given the need to meet ongoing energy demands. Despite the elevated levels of CORT, however, earlier constituents of the HPA axis, such as corticotropic-releasing factor and adrenocorticotropic hormone (ACTH), are down-regulated [15], [16], [17] or unaffected by CR [10].
It is theorized that the hyperadrenocorticism reported as a result of CR chronically enhances the same protective mechanisms mobilized during acute stress [18], [19], [20]. These prophylactic mechanisms are proposed to protect the organism not against the stressor per se but by preventing the normal first line of defense to stress (against hemorrhage, metabolic disturbances, infection, inflammation, etc) from overshooting and potentially threatening homeostasis [21].
Marked modulations are also reported in the hypothalamic-pituitary-gonadal axis as a result of CR. Overall, a down-regulation of this axis is reported with levels of testosterone (TEST) being suppressed in response to CR [22], [23]. It has been suggested from an evolutionary perspective that food shortage results in an adaptive redirection of resources from reproduction to somatic maintenance [24]. In this way, the survival of the individual organism is favored over that of species propagation.
The sympathoadrenal axis and its potential role in the life-prolonging capacity of CR have been largely unexplored. The small amount of research that has been conducted, however, suggests that CR elevates circulating levels of noradrenalin (NA) and adrenalin (A) in the short term (14 days) at substantial (≈CR50%) and severe (≈CR75%) doses and decreases NA in the long term (28 days) at a substantial dose in rats [25]. Furthermore, cardiac concentrations of NA and A are elevated in both the short term for substantial and severe CR [26] and the long term as a result of substantial CR [25]. Interestingly, longer-term (1 year) CR has been demonstrated to have no effect on basal NA and A [27], suggesting an adaptation to the dietary manipulation.
The sympathetic nervous system is a critical integrative component of an organism, particularly in its regulation of the cardiovascular system [28], [29]. Given that age-related structural and functional alterations of the cardiovascular system are attenuated as a consequence of CR (for a review, see Herlihy and Kim [30]), further investigation of the sympathoadrenal axis is warranted.
In the interest of contributing to the growing body of literature on the neuroendocrinologic characteristics of CR and their potential role in life prolongation, the aim of the current research was to further investigate the effects of adult-initiated CR on a number of neuroendocrine end points within the same animal. Further characterization of neuroendocrine alterations in an animal model of CR will serve the direct purpose of addressing current hypotheses concerning the prophylactic capacity of CR and the ultimate aim: the eventual development of CR mimetics. With the rise of obesity in Western cultures and the associated increase in preventable chronic diseases such as cardiovascular disease, stroke, obstructive pulmonary disease, and diabetes mellitus, these developments may alleviate the impact on not only individuals but the health care system. Similarly, age-associated diseases such as Alzheimer's may be postponed or alleviated.
We hypothesized, based on the research literature for CR, that there would be no effect or a significant decrease in ACTH, an increase in CORT, a significant decrease in TEST, and an alteration to sympathoadrenal hormones. To test these hypotheses, CR was started in early adulthood and maintained for a period of 3 weeks, as less than this period has been shown to be adequate to instigate changes to neuroendocrinologic axes [14], [17], [25]. Following the CR period, animals were decapitated; and trunk blood was collected to assay for serum or plasma concentrations of the above-mentioned hormones using enzyme-linked immunosorbent assays (ELISAs). To date, no single study has investigated a potential dose-response on hormones of the above-mentioned axes; and thus, the second aim was to use a number of restriction regimens of varying doses and determine whether these affect the neuroendocrine end points differentially. The ultimate purpose of the latter aim was to determine if lower levels of restriction are adequate to induce neuroendocrinologic alterations.
Section snippets
Animals
Forty 4-month-old, specific pathogen-free, male Hooded Wistar rats weighing an average of 413 ± 13 g before CR onset were procured from the University of Adelaide (Adelaide, Australia) and allowed to acclimate to the animal facility for 1 week before the commencement of experimentation. Rats were housed in individual plastic cages (38 × 27 × 15 cm) in the same room, maintained at 22°C ± 1°C on a 12:12-hour light/dark cycle with lights on at 4:00 am. Water and standard rodent chow (Barastoc,
Effect of CR on body weight
No differences were observed between groups for body weight before the onset of CR (F4,39 = 0.01, P = 1.000). Following CR onset, body weights were measured between 3:00 pm and 4:00 pm, 3 times a week, immediately before feeding for the CR animals throughout the experimental period (Table 2). Over the 3-week period of CR, the control animals gained 5% of their baseline body weight; the CR12.5% maintained their baseline weight; and the CR25%, 37.5%, and 50% lost 5%, 11%, and 16%, respectively.
Discussion
A number of hormonal alterations were observed to result from the various doses of CR used in this study that were in support of the study hypothesis. Fig. 5 illustrates these findings relative to the current research literature. Hypothalamic-pituitary-adrenal activity, with regard to ACTH, was unaffected by any dose. However, basal concentrations of serum CORT were increased by CR12.5% (55%), CR25% (50%), CR37.5% (89%), and CR50% (94%) relative to controls; and a dose-response was observed.
Acknowledgment
We would like to thank the Australian Research Council (LP 0775284) and Jim's Group Pty Ltd for generously supporting this research financially. We would also like to thank Sarah McBride for her technical assistance with the animals and Antonina Govic for her assistance with the editing of this paper.
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