Defense Mechanisms and the Shape of Dose-Response Relationships
Environmental Health Perspectives 106, Supplement 1, February 1998
1University of Texas Technical University, Lubbock, Texas; 2National Center for Toxicological Research, Jefferson, Arkansas
Key words: caloric restriction, dietary restriction, aging, calories, cancer, diet, carcinogenesis, glucocorticoids, life span, longevity, body mass index, adaptation, evolution
This paper is based on a presentation at The Third BELLE Conference on Toxicological Defense Mechanisms and the Shape of Dose-Response Relationships held 12-14 November 1996 in Research Triangle Park, NC. Manuscript received at EHP 29 May 1997; accepted 21 August 1997.
The authors wish to thank A. Turturro for many thoughtful discussions. This work was sponsored in part by National Institute on Aging-National Center for Toxicological Research (NCTR) contract 224-86-0001 and the NCTR.
Address correspondence to Dr. J.E.A. Leakey, HFT-020, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079. Telephone: (501) 543-7916. Fax: (501) 543-7332. E-mail: email@example.com
Abbreviations used: ACTH, adronocorticotrophic hormone; AVP, arginine vasopressin; BMI, body mass index; COX-2, cyclooxygenase isoform 2; CRF, corticotropin-releasing factor; CYP2C11, cytochrome P450 2C11; DHEA, dehydroepiandrosterone; EGF, epidermal growth factor; FSH, follicle-stimulating hormone; HPA, hypothalamo-pituitary-adrenal axis; HSP70, heat shock protein 70; IGF-1, insulinlike growth factor 1; LH, luteinizing hormone; NOSi, inducible form of nitric oxide synthase; PLAc, cytosolic phospholipase A2; PDGF, platelet-derived growth factor; TGF-ß, transforming growth factor beta.
The dose-response relationship between caloric intake and life span is not simple. In rodent models, for example, animals are at an increased risk of dying from protein-calorie malnutrition if dietary intake is extremely low. Interestingly, among survivors, caloric restriction is associated with a significant reduction in cancer incidence compared to that in ad libitum-fed controls. With moderate caloric restriction an optimal range may be found that generally supports reproduction, disease resistance, and longevity. The highest levels of caloric intake enhance growth and reproductive capacity but also significantly increase risk of morbidity, primarily because of development of specific cancers (7). These effects are reflected in the relationship between body weight and mortality, which is essentially J-shaped in rodent models (8,9) and the human population (10-13).
Under the usual experimental paradigms, calorically restricted animals receive a balanced reduction of the protein, carbohydrate, and fat content of the diet without a reduction of micronutrient content. Within a defined range of caloric restriction (typically 30-50% of ad libitum consumption), they show a decrease in the incidence and proliferative rate of spontaneous and chemically induced neoplasia. They also demonstrate a significant increase in maximum achievable life span compared to ad libitum-fed controls (6,14). Many biochemical and physiologic changes occur coincident with these effects but are difficult to distinguish from age-related pathologies (15). Therefore, for a mechanistic understanding, it is important to characterize and distinguish between the immediate adaptive response to reduced caloric intake and the resultant long-term effects on pathologic end points (7).
Nutrient stress such as fasting, starvation, or insulin-induced hypoglycemia results in elevated glucocorticoid levels, but unlike classic stress, hypothalamic release of corticotropin-releasing factor (CRF) does not appear to play a major role in initiating the glucocorticoid response (25-27). Rather, arginine vasopressin (AVP) plays the major role in the hypothalamus and the adrenal response to adrenocorticotropic hormone (ACTH) appears amplified by pancreatic polypeptide, which is secreted by the pancreas during periods of hypoglycemic stress (28,29). In addition, adrenal corticosterone secretion may be increased further by neural stimulation via the adrenal medulla (30,31). This results in elevated corticosterone concentrations in the absence of elevated ACTH (and by inference CRF) in both starved (25) and calorically restricted (27,32) rats. Under normal physiologic conditions, once the hypoglycemic crisis has been rectified, insulin levels will rise and, as suggested by in vitro experiments (33), may downregulate adrenal corticosterone secretion in favor of dehydroepiandrosterone (DHEA) secretion. Like insulin, DHEA is generally anabolic in function and reportedly antagonizes many of the effects of glucocorticoids (34-37).
However, during pathologic conditions such as Cushing's syndrome or prolonged excessive glucocorticoid therapy, natural feedback regulation is bypassed and a pathologic hyperglycemia develops, which is characterized by concurrent elevated insulin and glucocorticoid levels. Such conditions of hypercorticism concurrent with hyperinsulinemia, if prolonged, would be expected to result in pathologic conditions such as atherosclerosis and mature-onset diabetes (38). Classic stress appears to be controlled primarily by the hypothalamo-pituitary-adrenal axis (HPA). CRF and AVP secretion from the hypothalamus increase in response to interleukins or neuropeptides and stimulate ACTH secretion by the pituitary (39). Thus, plasma concentrations of both CRF and ACTH are increased in addition to serum corticosterone levels. CRF decreases hyperphagia (40) and is pyrogenic and an inflammatory mediator (41).
Apoptosis recently has been proposed to play an important role in inhibiting tumor development by eliminating damaged and genetically transformed cells from tumor-susceptible tissues (55-60). Apoptosis is characterized as differing from tissue necrosis in that only selected cells are eliminated and the resulting cell debris is immediately phagocytized by adjacent cells so that an inflammatory response is not initiated (61,62). Glucocorticoids induce apoptosis in lymphatic tissues (56) and fibroblasts (63) and possibly in mammary epithelium (61,64). Glucocorticoids may also selectively mediate the effects of transforming growth factor beta (TGF-ß) in stimulating apoptosis in preneoplastic hepatocytes (42,50).
Lipocortin 1 recently has been proposed to be a mediator of glucocorticoid-induced apoptosis. It is induced in apoptotic cells where it has been proposed to inhibit recognition of the dying cells by macrophages (61). Lipocortin 1 is also a substrate for transglutaminase, and covalently linked lipocortin dimers and polymers with other proteins may be produced in apoptopic cells (61,82,83). Recently, lipocortin 1 was shown to protect cultured rat thymocytes from H2O2-elicited necrosis. Glucocorticoid treatment, which induced lipocortin 1, stimulated apoptosis, whereas treatment with an antilipocortin 1 antibody enhanced necrosis (84).
Despite their global antiinflammatory effects, glucocorticoids have been shown to potentiate certain aspects of the host defense system. For example, they reportedly induce expression of both heat shock protein 70 (HSP70) (85) and the DNA repair enzyme O6-methylguarnine-DNA methyltransferase (86) in certain tissues. They also potentiate the effects of interleukin-6 and hepatocyte-stimulating factor in inducing hepatic acute phase proteins such as Mn-superoxide dismutase and 2-macroglobulin (87-91). Although both glucocorticoids and lymphocyte stimulatory agents that are mediated via intracellular Ca2+ or protein kinase C (e.g., calcium ionophors/phorbol esters, antibodies to the T-cell antigen receptor) initiate apoptosis in maturing lymphocytes, they are mutually antagonistic to the extent that glucocorticoids protect lymphocytes from activation-induced apoptosis (92,93). Thus, the effects of glucocorticoids on the inflammatory and immune systems are modulatory rather than simply suppressive.
Inflammation, necrosis, oxidative damage, and regenerative hyperplasia all play significant roles in chemically induced tumor promotion, and glucocorticoids have been shown to inhibit hyperplasia and neoplasia in a number of systems. For example, glucocorticoids are used therapeutically as antineoplastic agents in treating several types of leukemia and lymphoma (36,94) and suppress growth of certain lung or mammary adenocarcinomas (64,95-97). Dexamethasone inhibits both peroxisome-proliferator-induced and lead-nitrate-induced proliferative hyperplasia in rat liver (98,99). Glucocorticoids also induce connexin expression and stimulate gap junction formation in cultured hepatocytes and embryonic cells (100-102). Inflammatory agents such as phorbol esters promote, and glucocorticoids inhibit, papilloma formation in mouse skin (103).
Exposing adult rats to stress, hypercorticism, or glucocorticoid therapy reduces reproductive hormone levels in both sexes (7). In males, for example, glucocorticoids appear to inhibit LH-mediated testosterone synthesis by cultured rat Leydig cells (115) and dexamethasone treatment decreases (whereas adrenalectomy increases) serum testosterone levels in vivo (116,117). In females, glucocorticoids decrease follicle-stimulating hormone (FSH)-stimulated aromatase activity and estrogen production by ovarian granulosa cells (118), suppress ovulation, and inhibit ovarian prostaglandin metabolism (119). They also inhibit the preovulatory pituitary LH surge in female rats (120) and estradiol- and gonadotropin-releasing hormone-induced LH production in cultured rat pituitary cells (121). In male rats glucocorticoids inhibit pituitary secretion of prolactin (122) but not mean LH levels (123). However, CRF and stress inhibit pituitary LH secretion in both sexes (124,125).
Several factors differentiate the nutrient stress produced by caloric restriction from other stress situations or glucocorticoid therapy (7). First, unlike treatment with pharmacologic doses of synthetic glucocorticoids, hypercorticism resulting from nutrient stress involves the natural glucocorticoids corticosterone or cortisol. The effects of these natural glucocorticoids are mediated by serum transcortin and 11ß-hydroxysteroid dehydrogenase, which may protect tissues from extreme hypercorticism (7). Furthermore, unlike synthetic steroids such as dexamethasone, corticosterone and cortisol bind to both Type I and Type II glucocorticoid receptors, so the Type I receptor response is not inhibited concurrent with an excessive Type II receptor response (136).
Second, the hypercorticism exhibited by calorically restricted rodents differs from the continuously elevated serum corticosterone levels exhibited by starved or chronically stressed rodents in that corticosterone levels are increased above those of their ad libitum-fed counterparts only during a limited circadian period prior to and coincident with feeding activity (137). This type of intermittent hypercorticism appears less damaging to mitogenic processes than continuously elevated glucocorticoid levels (7).
Third, because the hypercorticism is a response to caloric deficit and potential hypoglycemia and occurs in conjunction with normal feedback regulatory systems, it is not associated with chronic hyperglycemia or hyperinsulinemia (16,127,138). Thus, insulin resistance and protein glycation, which are the usual pathologic consequences of glucocorticoid-induced hyperglycemia, should not occur. Instead, rates of intracellular glycation and oxidation of protein would be expected to decrease in peripheral tissues because of reduced glucose incorporation. Reduced collagen glycoxidation has been observed in skin from calorically restricted rats (139), and accumulative oxidative damage to both protein and DNA is reduced by caloric restriction in a number of tissues (43,140-142).
Fourth, under the usual conditions for caloric restriction experiments, significant hypercorticism only occurs during the early stages of restricted feeding (143,144). In most strains of rodent used in caloric restriction experiments, body weight gain is reduced in the restricted animals to an extent where the body weight difference between the restricted and ad libitum-fed animals equals or exceeds the caloric deficit (Figure 1). Thus, during the latter half of a calorically restricted rat's life span, its caloric consumption per gram body weight is equal to or greater than that of its ad libitum-fed counterpart. Under these conditions significant hypercorticism would not be required to protect the animal from potential hypoglycemia. As a consequence, during senescence, when rodents are most susceptible to tissue degeneration because of reduced capacity for cellular proliferation and reduced output of mitogenic hormones (131,146), serum corticosterone levels normally are no longer significantly increased in chronically calorically restricted animals (7,143,144).
Figure 1. Influence of body weight on caloric consumption in calorically restricted Fischer 344 rats. Male F344 rats housed in a specific pathogen-free barrier facility at the National Center for Toxicological Research (Jefferson, AR) were placed on a vitamin-fortified NIH-31 diet at 40% of ad libitum food consumption, as described by Duffy et al. (147). (A) Body relative weight curves. (B) Relative food consumption (expressed as food consumed per gram body weight by the calorically restricted rats as a percentage of that consumed per gram body weight by the ad libitum-fed rats) as a function of age. By 50 weeks of age the calorically restricted rats consume equivalent amounts of food per gram body weight as their ad libitum-fed counterparts.
The effects of caloric restriction on biomarkers of mitogenesis are generally consistent with the occurrence of hypercorticism during the early but not the late stages of caloric restriction. For example, caloric restriction from 16 weeks of age abolishes growth hormone pulsatility in 6-month-old male Brown Norway rats, but pulsatility is restored in older animals (148). In male rats pulsatile growth hormone controls hepatic expression of both IGF-1 and sex-specific drug metabolizing enzymes such as cytochrome P450 2C11 (CYP2C11) (149,150). As expected from its effects on pulsatile growth hormone, caloric restriction decreases hepatic expression of both IGF-1 and CYP2C11 in young male rats (151,152). However, as the rats age hepatic IGF-1 and CYP2C11 expression decreases in the ad libitum-fed rats but is maintained by caloric restriction so that in old rats hepatic IGF-1 and CYP2C11 expression is greater in the calorically restricted animals (151,152). This age-dependent biphasic effect of caloric restriction is illustrated in Figure 2 and is a common feature of several of the reported effects of caloric restriction in rodents. These include cell proliferation rates in kidney, pancreas, and possibly liver from B6D2F1 mice (131), serum DHEA levels in Fischer 344 rats (153), and reproductive function in both rats and mice.
Figure 2. Age-dependent effects of caloric restriction. (A) Schematic representation of the effects of caloric restriction on mitogenic end points and reproductive function. Reduction in the early burst of activity delays the degradation of these systems in old age. Examples include cell proliferation in kidney tubule cells from B6D2F1 mice, as measured by in vivo labeling with BrdU (BRDU) (131); expression of hepatic CYP2C11 and its dependent activity, testosterone 16-hydroxylase in male F344 rats (CYP) (152); and expression of hepatic IGF-1 mRNA in male F344 rats (IGF-1) (151). Caloric restriction decreases these parameters (B) in young rodents but maintains them (C) in older rodents.
Effects on female reproductive funct-ion include delayed puberty (154,155), inhibition of LH pulsatility concurrent with hypercorticism (156), inhibition of ovulation (157), decreased litter size (158,159), increased lactational diestrus (160), and reduced milk production (161) during the initial period of caloric restriction and delayed reproductive senescence during the latter stage (135,158). In males the initial effects of caloric restriction include decreased LH pulsatility (162), reduced ratios of serum testosterone to estradiol (163), decreased sperm motility in rats (164,165), decreased prostrate weight, testicular sperm density, and fertility in mice (159). Long-term caloric restriction reduces testicular hyperplasia and delays Leydig cell adenoma formation in old male rats (163,166), whereas chronic feeding of a high-calorie diet reduced reproductive performance in old male CF-1 mice (167).
The antiinflammatory effects of caloric restriction are also generally consistent with effects resulting from hypercorticism. For example, caloric restriction reportedly induces lipocortin 1 immunoreactive proteins in rat liver (16), inhibits carrageenan-induced inflammation in mice (168), decreases 12-lipooxygenase activity in rat liver and testes (7), delays the onset of autoimmunity in autoimmune-prone mice (169), and inhibits promotion of mouse skin papillomas by phorbol esters (170,171). In the latter case adrenalectomy reversed the effect of caloric restriction. Interestingly, caloric restriction both potentiates regenerative hepatocyte proliferation in partially hepatectomized rats (172) and reduces cell proliferation while stimulating apoptosis in preneoplastic liver (173,174). Such an effect is consistent with the reported dual synergistic and antagonistic effects of glucocorticoids on TGF-ß in neoplastic and nonneoplastic hepatocytes (7,50).
Although older caloric-restricted mice exhibited improved cognitive function, motor performance, and reduced oxidative damage in the brain (132,133), caloric restriction did not inhibit hippocampal aging in rats, although it did not appear to be overtly detrimental to the hippocampus (109,175). However, dieting and dietary restriction reportedly impair cognitive function in humans (176). Despite potential endangerment to the hippocampus, moderate hypercorticism during nutrient stress would be expected to be beneficial because the alternative, hypoglycemia in conjunction with increased inflammatory activity, would pose a greater threat to the entire central nervous system.
Taken together, these effects suggest that caloric restriction in rodents produces a series of pleiotropic biochemical and physiologic effects consistent with a hypercorticism condition that is more severe in the early stages of caloric restriction than in the later stages and that occurs without concurrent hyperglycemia. The overall effect of this condition is to conserve energy by minimizing metabolism, proliferation, and nonessential functions in peripheral tissues. This in turn appears to minimize damage to the affected tissues so the progression of degenerative or neoplastic lesions is delayed.
The recent finding that the body weight of rodents used in cancer bioassays directly correlates with terminal incidence of background tumors (8,177) is also consistent with effects on growth and cell proliferation, which play a major role in mediating the antineoplastic effects of caloric restriction. These body weight-tumor correlations were demonstrated from analysis of the control animals from cancer bioassays conducted by the U.S. National Toxicology Program. In B6C3F1 mice terminal lung tumor incidence exhibited a positive correlation with body weight at 9 months on test, whereas terminal liver tumor incidence correlated optimally with body weight at 12 months on test (8,178). In Fischer 344 rats terminal pituitary tumor incidence exhibited a positive correlation with body weight at 13 months on test, whereas terminal leukemia incidence exhibited a positive correlation with body weight at 14 weeks (179). Interestingly, caloric restriction initiated at 6 weeks of age inhibited leukemia to a much greater extent than restriction initiated at 14 weeks, whereas pituitary adenoma formation was affected equally by both caloric restriction paradigms (179). This suggests that critical periods exist when rodents are most susceptible to subsequent development of specific cancer end points. This effect can also be demonstrated for background liver tumors in B6C3F1 mice (7).
It would appear, therefore, that the rate of growth during the early adult period of an organism's life determines its subsequent susceptibility to neoplastic or degenerative diseases, and rates of growth in part depend on glucocorticoid status and caloric intake. As stated above, glucocorticoids are a major component of the stress and inflammatory responses, where their primary functions appear to be: a) to globally reduce energy consumption so that energy is channeled to the site of trauma or inflammation, and b) to prevent excessive tissue damage due to overexpression of the inflammatory response. During severe nutrient stress hypercorticism allows an organism to conserve energy so that it may survive, but in the process growth and reproductive, immune, and cognitive functions may be compromised. However, caloric excess may be equally detrimental and result in overstimulated growth, uncontrolled cell proliferation, autoimmunity, inflammatory diseases, and neoplasia. Between these two extremes lies a physiologic window in which health and longevity are maximized (Figure 3). Hypercorticism as a hormonal response to nutrient stress appears common to most mammalian species and probably evolved as a mechanism to ensure survival of the species through periods of famine (180-183). In times of abundant food supply, rapid growth and fecundity are favored over endurance and longevity. Conversely, when food becomes scarce reproductive performance and growth are sacrificed in favor of extended total and reproductive life spans, thus increasing the probability that sufficient individuals will survive to restore the population when conditions improve.
Figure 3. Relationship between caloric consumption and morbidity/mortality rates. Evidence from epidemiologicl and mechanistic studies suggests that the relationship between caloric consumption and morbidity/mortality is essentially J-shaped. High caloric consumption increases the risk of increased body growth, obesity, and associated pathologies, whereas extreme nutrient stress resulting from fasting, starvation, or excessive caloric restriction may increase the risk of tissue degeneration and associated pathologies.
Over the past 30 years the animal husbandry conditions used by commercial breeders and rodent-testing houses have been significantly modified to favor growth and fecundity (184,185). This has resulted in rodent strains that characteristically suffer from caloric excess and exhibit reduced life expectancy and many of the symptoms listed on the left side of Figure 3. When used in toxicity studies these animals are highly sensitive not only to chemically induced carcinogenesis but also to the acute effects of toxic chemicals (186). When used in moderation with these animals, dietary restriction decreases the incidence of both spontaneous and chemically induced carcinogenesis and also reportedly decreases the acute toxicity of several chemicals (186,187). Such effects are consistent with the antiinflammatory and antineoplastic effects of hypercorticism because a heightened inflammatory response amplifies the toxicity of carcinogens such as carbon tetrachloride (188-191). Although moderate dietary restriction is recommended for increasing life span and standardizing background tumor incidence between studies (192), excessive dietary restriction, whether a result of reduced food allocation or anorectic effects of the test chemical, should be avoided in cancer bioassays, as such conditions would render the bioassay insensitive for the detection of chemically induced tumors and reduce life expectancy because of the pathologic conditions listed on the right-hand side of Figure 3.
Although the relationship between body weight and morbidity is readily apparent in laboratory animals raised from similar genetic stock under controlled laboratory environments (177,178,197), establishing similar trends in the human population is considerably more difficult. It is now well established that genetic factors play a significant role in determining risk for both cancer and coronary heart disease (198,199) and behavioral factors such as cigarette smoking and heavy consumption of alcohol also influence susceptibility to these diseases (199-201). Nevertheless, when these factors are taken into consideration, dietary caloric consumption may be one of the most important risk factors for a spectrum of human degenerative diseases (4,202), and human epidemiology studies have established that increased body weight--or body mass index (BMI)--is positively correlated to a number of morbidity/mortality indices. These include overall mortality in both men and women (13,203); cardiovascular disease (10,13,204); breast, renal, and endometrial cancer in women (205-207); and colon cancer in men (208). As in animal studies (8) the relationship between BMI, weight, and morbidity/mortality risk is not always linear in human studies; J-curve profiles are frequently produced instead. Whereas some of the risk for low-body-weight individuals can be attributed to smoking (13), the studies quoted above used Western populations, which include relatively few individuals on low-calorie diets. Including populations from developing countries would be expected to produce mortality curves resembling that shown in Figure 3. Indeed it frequently has been noted that as caloric consumption relative to caloric demand increased in developed countries, disease susceptibilities changed from those characteristic of caloric deficit to those characteristic of caloric excess (209).
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Last Update: March 11, 1998