Organisms have evolved neuroendocrine and metabolic response systems to enhance survival during periods of food shortage, which occur frequently in nature.
The anti-aging effect of caloric restriction (CR) might derive from these adaptive responses to maximize organism survival.
Caloric restriction (CR) is an important paradigm in biomedical gerontology.
Because the anti-aging effect of CR is robust and reproducible in many laboratory organisms, ongoing projects have been extended to nonhuman primates.
The effects of CR have been explained from the evolutionary view that organisms have evolved neuroendocrine and metabolic response systems to maximize survival during periods of food shortage.
When environmental energy resources are plentiful, organisms grow, reproduce, and store excess energy as triacyglycerol (TG) in adipocytes for later use as fuel.
In this sense, adipocytes have also evolved.
Once organisms encounter a period of food shortage, seasonally or hazardously occurring in nature, they suspend growth and reproduction, induce defense molecules such as glucocorticoids and heat shock proteins, and shift whole-body fuel utilization from both carbohydrate and fat to almost exclusively fat.
The effects of CR might derive from these adaptive responses.
These views predict the presence of adipocyte-associated signaling molecules that regulate the neuroendocrine system and fuel utilization.
Role for leptin in the neuroendocrine system
The evolutionary view predicts the presence of neuroendocrine signal(s) that halt growth and reproduction while enhancing the stress response system.
An increase in plasma glucocorticoids, catecholamines, and glucagons, and a decrease in insulin, growth hormone, gonadotropins, and thyroid hormones profile the classic hormonal response to fasting.
Although long-term CR could differ in several aspects of physiology from fasting, the hormonal profile of CR is similar to that of fasting.
Leptin, a peptide hormone secreted principally from adipocytes, was first identified as a molecule that regulates appetite and energy expenditure via the CNS; dysfunction of its signaling results in hyperphagia and obesity.
Subsequent studies have revealed another important role for leptin under life-threatening conditions, i.e., its role as a stress-related hormone.
Fasting reduces the plasma leptin concentration and concomitantly suppresses gonadal, somatotropic, and thyroid hormones; however, fasting also increases plasma glucocorticoid levels.
Administration of exogenous leptin in fasting rats and mice reverses the fasting-induced hormonal state.
In rodents, secretion of leptin from adipocytes appears to be dually regulated.
Leptin secretion is primarily related to body adipose levels; leptin gene expression and fasting plasma leptin concentrations are positively correlated with the percentage of body fat.
Another type of leptin regulation is unrelated to body weight and fat.
Plasma leptin levels decline precipitously within 24 h after food deprivation, while feeding stimulates leptin secretion within a few hours.
The effects of leptin are mediated through direct interaction of leptin with its receptors in the CNS and peripheral tissues.
Only the long form of the leptin receptor (Ob-Rb) has a cytoplasmic region containing several motifs required for signal transduction.
The other forms lack some or all of these motifs.
Ob-Rb, the predominant signaling receptor, is expressed most prominently in the arcuate nucleus of the hypothalamus (ARH), ventromedial hypothalamic nucleus (VMH), paraventricular hypothalamic nucleus (PVH), and lateral hypothalamus (LH).
These nuclei regulate appetite and energy expenditure.
As shown in Fig. 1, there are two distinct leptin-sensitive neuronal populations in the ARH, both of which exhibit mutually antagonistic effects on energy homeostasis.
Physiologic concentrations of plasma leptin tonically inhibit a population of neuropeptide Y (NPY)/agouti-related peptide (AGRP) neurons, but activate proopiomelanocortin (POMC)/ cocaine- and amphetamine regulated transcript (CART) neurons.
Fasting releases NPY/AGRP neurons from leptin's inhibitory tone, and attenuates the stimulatory tone of leptin on POMC/CART neurons.
A survey of the literature of signal pathways from the ARH revealed that these leptin-sensitive ARH-neurons, which are primarily involved in regulation of appetite and energy expenditure, also control the gonadal, somatotropic, thyroidal, and adrenal glucocorticoid systems.
There is both functional and anatomic evidence that a reduction in the plasma leptin concentration elicites hypothalamic changes in response to fasting.
Hypothetic role of leptin signaling in neuroendocrine alterations by caloric restriction; diagram.
The reduced plasma concentration of leptin affects two distinct neuronal populations in the hypothalamic arcuate nucleus via the long-form of the leptin receptor (Ob-Rb);
(1) neuropeptide Y (NPY)/agouti-related peptide (AGRP)-neurons;
(2) proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART)-neurons.
Subsequently, NPY/AGRP-neurons are activated, whereas POMC/CART-neurons are attenuated.
NPY-neurons, which exert an inhibitory tone, project to gonadotropin-releasing hormone (GnRH)-, growth hormone-releasing hormone (GHRH)-, and thyrotropin-releasing hormone (TRH)-neurons in the hypothalamus; in contrast, NPY-neurons stimulate corticotropin-releasing hormone (CRH)-neurons.
AGRP, mostly coexpressed in NPY-neurons, is an endogenous antagonist at the melanocortin type 4 receptor (MC4-R).
AGRP-neurons suppress TRH-neurons by antagonizing the actions of α-melanocyte stimulating hormone (α-MSH), a cleavage product of POMC.
The reduced plasma leptin attenuates the POMC–α–MSH pathway, resulting in activation of CRH-neurons, but attenuation of TRH-neurons.
The stimulatory signal from CART-neurons is also decreased.
The hypothalamic changes reflect alterations in secretion of pituitary hormones, and thus, target organs or hormones.
Most of the changes depicted are documented, except for CRH and ACTH (Shimokawa and Higami, 2001).
CR-induced alterations in the neuroendocrine system
In CR rats, the plasma leptin concentration is persistently lower than control rats fed ad libitum over 24 hours.
Data regarding the CR effects on the hypothalamic peptides are limited.
Most of the published data, however, indicate that NPY is augmented and POMC declines during CR.
A preliminary study also indicated that there is reduced GHRH-mRNA expression in the ARH in CR rats.
To I. Shimokawa, and Y. Higami knowledge, there are no data published on the CR effects on thyrotropin-releasing hormone (TRH) and growth hormone-releasing hormone (GnRH).
Unexpectedly, the expression of corticotropin releasing hormone (CRH)-mRNA decreases following relatively long-term CR, although acute food deprivation upregulates CRH-mRNA expression.
Plasma ACTH is not increased in CR rats; thus, CR might act on the level of the adrenal gland.
Indeed, leptin directly reduces cortisol synthesis; therefore, the adrenal gland might be a main site of leptin's action in CR.
Possible involvement of leptin in signal transduction efficiency during CR
The hormonal profile in CR rodents is almost the same as that in fasting rodents.
This profile, however, might not reflect the characteristics of CR.
For example, plasma glucose and insulin levels are consistently lower in CR rodents throughout the day and night.
CR, however, maintains the glucose uptake by tissues including the skeletal muscle and cerebellum in vivo.
In vitro studies indicate that leptin has no effect on the sensitivity or responsiveness of the glucose transport system to insulin in adipose and muscular cells.
Further studies are needed, however, because efficient signal transduction under life-threatening conditions would be evolutionarily adaptive.
Role for leptin in metabolic adaptation
The anti-aging effect of CR might occur in the process of metabolic adaptation to reduced caloric intake.
After a day of fasting, whole-body fuel utilization shifts from carbohydrate and fat in the fed state to almost exclusively fat.
Fatty acids and glycerols released from the adipose tissue are converted into energy substrates such as ketone bodies and glucose mostly in the liver, a principal organ in the adaptive response to fasting.
Transcription factors that regulate the expression of metabolic enzymes are also changed.
Energy intake and utilization in CR rodents are similar to those of fasting animals.
Studies of the respiratory quotient in male Fischer 344 rats, in which a CR group was fed a small (60%) daily meal, suggest a metabolic shift in CR rats depending on food availability, while there is little change in control rats fed ad libitum.
CR rats predominantly metabolize protein and lipid before feeding when glycogen reserves are depleted, and metabolize carbohydrate immediately after feeding.
In contrast, control rats fed ad libitum metabolize a constant ratio of protein, lipid, and carbohydrate over 24h.
In contrast to its control of the neuroendocrine system during starvation, the role for leptin in the metabolic shift is yet to be determined.
There are, however, several lines of evidence suggesting that leptin has an important role in metabolic adaptation during CR.
When leptin is administered intraventricularly in fasting Sprague-Dawley rats, the reduced respiratory quotient is reversed almost completely to the control level in rats fed ad libitum.
The results indicate that a decline in leptin signaling contributes to the shift to the fat-based metabolism.
To date, exact signals that regulate the transcription factors for the expression of lipid synthesis and fatty acids oxidation in the liver remain obscure.
Some scientists might be oversimplifying the role of leptin in the effect of CR.
The hormonal profile of CR includes a decrease in insulin and an increase in glucocorticoids, both of which interact with leptin in peripheral tissues.
Molecular dissection of the mechanisms of CR, however, provides an insight into regulation of the aging process in organisms, leading to extension of a healthy lifespan in humans.