0192-0561/92 $5.00 + .00 Pergamon Press plc. International Society for lmmunopharmacology.
lnt. J. lmmunopharmac., Vol. 14, No. 3, pp. 3 6 1 - 366, 1992. Printed in Great Britain.
NUTRITION AND CELLULAR IMMUNITY ROBERT A. GOOD a n d ELLEN LORENZ Department of Pediatrics, All Children's Hospital, University of South Florida, St. Petersburg, Florida, U.S.A.
Abstract - - We have investigated the influence of nutrition on immune function in animals and man over the past two decades. The profound impairment of immune function that had not been observed in children in developing countries could not consistently be reproduced in the laboratory setting; paradoxically, moderate nutritional restriction could even enhance T-cell-based cell-mediated immune responses in experimental animals. Studies of the crucial role of the element zinc in maintenance of vigorous cellular immunity provided at least a partial explanation of this paradox. Zinc, shown to be absolutely crucial for development and expression of both T- and B-cell functions, was commonly deficient as were other micronutrients under many conditions of protein-calorie malnutrition. Indeed, administration of adequate zinc alone could correct some of the T-cell-mediated immune functions in children with protein-calorie malnutrition. In later investigations we found that as long as all essential nutrients were supplied in adequate amounts, 40°7o chronic energy (calorie) restriction will regularly extend lifespan and maintain vigorous immunologic function while preventing numerous cancers and immunologically based diseases of aging, such as profound and destructive autoimmune diseases in genetically short-lived mice strains, as it was known to do for moderately long-lived rats and long-lived strains of mice. Such undernutrition without malnutrition appears to influence a wide range of critical metabolic and physiologic processes in both short-lived and long-lived animals. One of the most challenging of these influences was a down-regulation of cellular proliferation and cell turnover in each of the rapidly replicating tissues studied. It also regularly was possible to inhibit gene expression of certain oncogenic retroviruses, such as the mammary adenocarcinoma retrovirus, in highly susceptible strains of mice.
O u r l o n g s t a n d i n g interest in the influence o f n u t r i t i o n o n cellular i m m u n i t y b e g a n m o r e t h a n two decades ago. A t t h a t time, I h a d the occasion to visit P r o f e s s o r Galal A r e f in Egypt in 1969 to see first h a n d the ravages caused by m a l n u t r i t i o n a m o n g children o f P a l e s t i n i a n refugees. Such children were o f t e n a g a m m a g l o b u l i n e m i c , were deficient in b o t h humoral and cell-mediated immunities, and s u c c u m b e d to n u m e r o u s bacterial a n d viral infections (Abassy et al., 1974). M a n y other studies have d o c u m e n t e d similar links between m a l n u t r i t i o n a n d severe i m m u n o d e f i c i e n c y . However, our interest was piqued especially by a r e p o r t f r o m David Jose a n d his colleagues in Australia. These investigators r e p o r t e d t h a t Aborigines, w h o b e c a m e m a l n o u r i s h e d u p o n weaning a n d regularly developed a decreased ability to p r o d u c e antibodies, unexpectedly showed increased proliferative responses of T-lymphocytes u p o n s t i m u l a t i o n with certain p h y t o m i t o g e n s (Jose & Welch, 1969; Jose, W e l c h & D o h e r t y , 1970). W h e n David Jose j o i n e d my l a b o r a t o r y at the University o f M i n n e s o t a , we s o u g h t to investigate this p a r a d o x in a controlled, e x p e r i m e n t a l setting. W e s h o w e d t h a t m o d e r a t e or severe protein a n d
protein-calorie restriction in mice inhibited d e v e l o p m e n t of a n t i b o d y p r o d u c i n g cells a n d p r o d u c t i o n o f circulating antibodies, regardless of the specific c o m p o s i t i o n of the diets used (Jose & G o o d , 1971). In contrast, cellular i m m u n i t y , or the thymus-dependent immune functions, was undiminished in protein or protein-calorie m a l n o u r i s h e d mice a n d rats, but, in some cases, was even e n h a n c e d (Jose, C o o p e r & G o o d , 1971). P r o t e i n or protein-calorie d e p r i v a t i o n quickened the pace of allograft rejection, increased proliferative responses to p h y t o m i t o g e n s a n d facilitated or e n h a n c e d delayed allergic responses (Jose & G o o d , 1972; F e r n a n d e s , Yunis, Jose & G o o d , 1973; Jose & G o o d , 1973; Jose, S t u t m a n & G o o d , 1973; work reviewed in G o o d et al., 1976). K r a m e r & G o o d (1978) f o u n d t h a t delayed allergic reactions r e m a i n e d intact in guinea-pigs whose diets were restricted in protein to 6 - 9 % . W h e n protein was restricted to as d a n g e r o u s l y low a level as 3-5%, thereby a b r o g a t i n g delayed allergic skin reactivity, cell-mediated i m m u n i t y r e m a i n e d intact a n d in some cases a p p e a r e d to be greatly increased, as in the d e v e l o p m e n t o f cell-mediated respon361
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siveness to stimulation with minute doses of antigen. What defects in T-cell immune responsiveness did occur were consequent to defective inflammatory expression of cellular immunity rather than to defects of T-lymphocyte-mediated immune responses. Furthermore, we noted that protein or proteincalorie restriction augmented delayed allergic reactions, increased the capacity for lymphoid cells to initiate graft-vs-host reactions, up-regulated cellular immune responses against syngeneic and allogeneic tumor cells, and even increased the capacity to resist certain types of viral infections (Good, Jose, Cooper, Fernandes, Kramer & Yunis, 1977; Good, West & Fernandes, 1980). The divergent influences of protein or proteincalorie restriction on cellular and humoral immune responses stood in stark contrast to the great majority of reports from the field, in which almost all aspects of immunity were grossly impaired as a consequence of malnutrition. We reasoned that differences in the consumption of adequate levels of micronutrients might be at work in this dichotomy - the laboratory animals we had studied had been provided with all essential nutrients and trace elements, but protein-calorie malnourished children in the Third World obviously were deficient in many of these micronutrients as well as in protein and calories. For instance, the divergent effects of proteincalorie nutrition might be partly explained by findings concerning the important role the trace metal zinc plays in immune function. It became clear that this element was essential to numerous T-lymphocyte responses. Prasad, Halstead & Nadimi (1961) described a zinc deficiency that produced a syndrome of growth failure, male hypogonadism, neurosensory defects and increased susceptibility to infection. These symptoms were completely reversed once adequate zinc intake was established. After this initial description of zinc deficiency in humans, Brummerstedt, Hagstad, Basse & Andresen (1971) described a genetic disorder in F r i e s i a n - H o l s t e i n cattle in which defective intestinal absorption of zinc was accompanied by thymic aplasia, hypoplastic Peyer's patches and deficiencies of cell-mediated responses to bacterial antigens. These deficiencies could all be reversed or normalized by zinc supplementation. Moynahan & Barnes (1973) reported similar findings in the human disorder called acrodermatitis enteropathica, that was featured by thymic hypoplasia, poorly developed lymph nodes, plasmacytosis within the spleen, deficiency of IgA and deficiency of delayed skin
reactions to numerous bacterial and fungal antigens. Here again, administration of oral zinc promptly resolved the immunodeficiency syndrome. These descriptions of the notable immunological consequences of zinc deficiency in these two crucial experiments of nature were followed by laboratory analyses of the role of zinc in imnmnity (Fraker, Haas & Leuke 1977; Leuke, Simonel & Fraker, 1978). Similarly, Tanaka, Fernandes, Tsao, Pih & Good (1978) and Fernandes, Nair, Ono4, Tanaka, Floyd & Good (1979) established that zinc deficiency caused thymic involution and diminished antibody responses in A / J a x mice and showed that nutritional deficiency produced profound immunodeficiency long before manifestation of acrodermatitis enteropathica appeared in the deprived animals. These immune defects could be normalized in part by transfer of thymocytes from zinc-sufficient mice. We later showed that a zinc deficiency could account for the profound deficiencies in T-lymphocyte-mediated immunities in protein-calorie malnourished children but not in protein-calorie deprived laboratory animals (Fernandes et al,, 1979). In addition, we demonstrated that in the A / J a x mice zinc deficiency impaired both primary and secondary antibody responses. In subsequent investigations (Iwata et al., 1979; Rao, Schwartz & Good, 1979; CunninghamRundles, Cunningham-Rundles, Dupont & Good, 1980; Schloen, Fernandes, Garofalo & Good, 1979; Cunningham-Rundles et al., 1981) we showed that dietary zinc deficiency could suppress a wide range of immune responses and parameters, particularly those of the T-lymphocyte arm of the immune system. These multiple effects of dietary zinc deficiency included thymic involution, depletion of thymocyte populations, depression of thymulin levels, depression of delayed type hypersensitivity, lowering of total T-cell counts, reduction in primary and secondary antibody responses, diminished natural killer cell function, impaired T-suppressor cell function, decreased interleukin-2 activity, and expansion of the immature, undifferentiated lymphocyte population referred to as the putative "null cell" phenotype. That zinc plays an important role in cell-mediated immunity has become even more readily apparent in view of the recently defined role of thymulin in regulating T-cell differentiation both within and outside the thymus. Thymulin binds zinc with greater efficiency than it does any other metal (Bach & Dardenne, 1989), and Prasad, Dardenne, Abdallah, Meftah, Brev.er & Bach (1987) have shown that serum thymulit~ activity, along with T4 : T8 ratios and IL-2 production and responsiveness, are dec-
Nutrition and Cellular Immunity reased in patients with zinc deficiency. Oral zinc remediates these deficiencies. Zinc supplementation has also been shown to correct significant defects of cellular immunity associated with Down's syndrome (Franceschi et al., 1990) and zinc deficiency that may be associated with normal aging (Kaplan, Hess & Prasad, 1988). Thus, the profound influences of zinc on immune function pointed us toward an explanation for the divergent immunological outcomes of proteincalorie malnutrition that occurred in undeveloped or developing nations versus the often beneficial effects of protein-calorie restriction that was induced in mice, rats or guinea-pigs. Zinc appeared to be a nutrient essential to normal immune response and parameters. Gershwin, Beach & Hurley (1985) reviewed many of the important roles for other micronutrients, including copper, manganese and magnesium; and Chandra (1991) has also discussed the importance of various vitamins and trace minerals in immunity. Dietary nucleotides also appear to play an important role in achieving and maintaining optimal immune responsiveness (Carver, Pimentel, Cox & Barness, 1991). Thus, at least in experimental settings, if zinc and other essential nutrients were supplemented in adequate amounts, macronutrients such as protein, carbohydrates, fats and total calories might be variously manipulated and their influence on immunity systems observed. Indeed, over the past 15 years we have studied the influence of dietary energy (calorie) restriction in various genetically short-lived strains of mice (Fernandes, Yunis & Good, 1976a, b; Fernandes, Friend, Yunis & Good, 1978a; Fernandes, Yunis, Miranda, Smith & Good, 1978b; Kubo, Day & Good, 1984). In each of these strains, we showed that chronic energy intake restriction (CEIR; imposed by means of a 40% reduction in the caloric intake of full-fed animals) could double, triple or even further extend lifespan in these inbred, short-lived mice. Moreover, CEIR delayed or, in some instances, completely inhibited development of autoimmunity diseases to which these mice succumb, particularly progressive immunologically based hyalinizing renal disease, vascular lesions, lymphoproliferative disease and even certain malignancies (Fernandes et al., 1976a, b; Fernandes et al., 1978a,b; Sarkar, Fernandes, Telang, Kourides & Good, 1982; Fernandes, Alonso, Tanaka, Thaler, Yunis & Good, 1983; Fernandes & Good, 1984). To determine whether total calorie intake was a more critical variable than calorie source, we employed diets that varied in composition from very high fat/nocarbohydrate to be very low fat/high
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carbohydrate, along with moderate intakes of both. No significant difference was observed in the influence of the different macronutrients p e r se on lifespan (Kubo, Johnson, Gajjar & Good, 1987; Gajjar, Kubo, Johnson & Good, 1987). However, when each of the experimental diets was fed at a restricted calorie level, the median and maximal longevity of mice of each strain studied increased markedly. The most dramatic shift in longevity curves occurred with a diet relatively low in fat and relatively high in carbohydrate that was fed at the CEIR level (restriction of 40% in total calories). Restriction can be imposed as late as midlife and still succeed at forestalling disease onset and greatly extending lifespan. However, for most powerful regulation of lifespan and health, CEIR is best imposed at time of weaning. The cellular and molecular bases that underlie the impressive effects of CEIR on lifespan and disease have yet to be elucidated. We have demonstrated that CEIR decelerates the pace of the immunological involution that accompanies aging. CEIR reduces the formation of circulating immune complexes and deposition of g p 7 0 - anti-gp70 immune complexes in a capillary distribution within the glomeruli (Izui et al., 1981), inhibits the age-related decrease of IL-2 responsiveness and IL-2 production (Jung, Palladino, Calvano, Mark, Good & Fernandes, 1982). CEIR can also restrain the potentially destructive influences of oxidative stress that occur in aging by selective enhancement of the activity of radical scavenging enzymes such as superoxide dismutase (Kubo, Johnson, Misra, Dao & Good, 1987). Hollander, Dadufalza, Weindruch & Walford (1986) studied mice and rats of long-lived strains and observed that CEIR increased absorption by the gastrointestinal tract of vitamin A, presumably enhancing that vitamin's anti-oxidative actions. Koizumi, Weindruch & Walford (1987) reported that CEIR increases catalase activity. In addition, Licastro & Walford (1985) reported that CEIR slows the age-related decline of lymphocytes' capacity for DNA repair. In a series of investigations we have shown that CEIR also down-regulates the rate of cellular proliferation at a number of important sites. Ogura, Ogura, Dao, Ikehara & Good (1989) showed that CEIR dramatically decreased the rate of cellular proliferation, as determined by incorporation of 3Hthymidine, within lymphoid tissues such as the thymus, liver and spleen and also within the epithelial layer of the entire gastrointestinal tract. Albanes & Winnick (1988) reported a similar inhibitory effect of CEIR on the proliferative rate of
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cells of the colonic mucosa, and these findings have been confirmed and extended (Lok et al., 1990; Bruce, 1990). We also showed that CEIR reduces the proliferative rate of CD5 B-lymphocytes, a specific B-lineage subset with a tendency toward oligoclonal or neoplastic expansion (Ogura, Ogura, Lorenz, Ikehara & Good, 1990) that may be of special importance in the development and expression of autoimmunity. In studies of mice which develop mammary adenocarcinoma consequent to endogenous infection with the mouse mammary tumor virus (MMTV), we have found that CEIR significantly inhibits the formation of hyperplastic alveolar nodules (Sarkar et al., 1982; Hamada et al., 1990). Moreover, we found that CEIR significantly reduced proviral DNA transcription of MMTV, suppressed MMTV messages in the mammary gland, liver, kidney, lung and small intestine, and reduced the expression of the protooncogenes int-1, int-2 and ras (Chen et al., 1990; Hamada et al., 1990). Thus, CEIR not only appears to slow the rate of cellular proliferation but also to reduce the frequency of genetic and oncogenetic expression that may give rise to tumorigenesis. Other potential mechanisms that may underlie the disease-inhibiting actions of CEIR include regulation of the levels of insulin and/or glucose. Ruggieri, Klurfeld, Kritchevsky & Furlanetto (1989) demonstrated that CEIR decreases serum insulin levels as well as production of insulin-like growth factors. Cerami, Vlassara & Brownlee (1987) proposed that glucose is an important regulator of the aging process through its role in the glycation of nonenzymation protein and the formation of endstage glycosylation products. Moreover, Masoro (1991) reported that plasma glucose is reduced by the CEIR regimen. Thus, control of both plasma glucose and serum insulin may well be among the critical influences of CEIR in maintaining immunologic vigor and preventing diseases associated with aging.
One attractive explanation for the beneficial effects of CEIR has been formulated by Walford & Crew (1990). Their integrative hypothesis suggests that CEIR brings about the redirection of energy from a number of biological processes, most notably reproduction and the p i t u i t a r y - hormonal axis, and thereby allows an organism to channel greater amounts of energy into critical maintainance and repair processes which occur at the molecular and cellular levels. The reduction in the rate of basal or unstimulated levels of cellular proliferation that we have observed in recent experiments appears to be one important reflection of this aspect of CEIR, as does the maintenance of vigorous cellular immunity in the aging process with a concomitant reduction in autoimmune phenomena (e.g. reduced formation of circulating immune complexes) that we have observed. Walford & Crew also suggest that an intensification of DNA repair processes and the free radical scavenging capacity occurs through regulation of trans-acting factors which bind to homologous sequences on specific genes which are involved in maintenance/repair work. CEIR may, thus, represent a type of cellular engineering by which immunological responsiveness may be sustained through old age, permitting diseases of aging, and even expression of neoplastic disease, to be controlled or greatly delayed. The promising experimental data point to a great potentiality for CEIR to foster longevity and, even more importantly, promote immunologic vigor and good health later in life. Admittedly, CEIR may be difficult to apply to humans. On the other hand, continued research on the mechanisms underlying the maximal life-prolonging actions of CEIR may lead to much simpler means of controlling the very gene expressions which seem so crucial in influencing prolongation of median lifespan, extending the span of vigorous good health and extending greatly even maximum lifespan. No other experimental influence thus far studied carries such incredible promise.
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Int., 35, 1185-1194. LICASTRO, F., SAVORANI, G., SARTI, G., SALSI, A., CAVAZZUTI,C., ZANICHELLI, L., TUCCI, G., MOCCHEGIAN1, E. & FABRIS, N. (1990). Zinc and thymic hormone-dependent immunity in normal ageing in patients with senile dementia of the Alzheimer type. J. Neuroimmun., 27, 201-208. L1CASTRO, F. & WALFORD, R. L. (1985). Aging, proliferative potential and DNA repair capacity in short-lived and longlived mice. Mech. Ageing Dev., 31, 171. LOK, E., SCOTT, F. W., MONGEAU, R., NERA, E. A., MALCOLM, S. & CLAYSON, D. B. (1990). Calorie restriction and cellular proliferation in various tissues of the female Swiss Webster mouse. Cancer Left., 51, 67-73. LUEKE, R. W., S1MONEL,C. E. & FRANKER,P. J. (1978). The effect of restricted dietary intake on the antibody mediated response of the zinc deficient A/J mouse. J. Nutr., 108, 881 -887. MASORO, E. J. (1991). Physiological consequences of dietary restriction: an overview. In Biological Effects o f Dietary Restriction (ed. Fishbein, L.), pp. 115- 122. Springer, New York. MOYNAHAN, E. J. & BARNES, P. M. (1973). Zinc deficiency and a synthetic diet for lactose intolerance. Lancet, I, 676 - 677. OGURA, M., OGURA, H., DAO, M. L., IKEHARA,S. & GOOD, R. A. (1989). Decrease by chronic energy intake restriction of cellular proliferation in the intestinal epithelium and lymphoid organs in autoimmune-prone mice. Proc. ham. Acad. Sci. U.S.A., 86, 5089-5093. OGURA, M., OGURA, H., LORENZ, E., 1KEHARA,S. & GOOD, R. A. (1990). Undernutrition without malnutrition restricts the numbers and proportions of Ly-I B lymphocytes in autoimmune (MRL/I and BXSB) mice. Proc. Soc. exp. Biol. Med., 193, 6 - 12. PRASAD, A. S., DARDENNE, M., ABDALLAH,J., MEFTAH,S., BREWER,G. J. & BACH, J. F. (1987). Serum thymulin and zinc deficiency in humans. Trans. Assoc. A m . Phys., C, 222-231. PRASAD, A. S., HALSTEAD, J. A. & NADIMI, M. 0961). Syndrome of iron-deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism, and geophagia. A m . J. Med., 31, 532-546. RAO, K. M. K., SCHWARTZ,S. A. & GOOD, R. A. (1979). Age-dependent effects of zinc on the transformation response of hyman lymphocytes to mitogens. Cell. Immun., 42, 270-278. RUGGIERI, B. A., KEURFELD, D. M., KRITCHEVSKY, D. & FURLANETTO, R. W. (1989). Caloric restriction and 7,12dimethylbenz[a]anthracene-induced mammary tumor growth in rats: alterations in circulating insulin, insulin-like growth factors I and II, and epidermal growth factor. Cancer Res., 49, 4130-4134. SARKAR, N. H., FERNANDES,G., TELANG, N. T., KOURIDES, I. A. & GOOD, R. A. (1982). Low-calorie diet prevents the development of mammary tumors in C3H mice and reduces circulating prolactin level, murine mammary tumor virus expression, and proliferation of mammary alveolar cells. Proc. natn. Acad. Sci. U.S.A., 79, 7758-7762. SCHLOEN, L. H., FERNANDES,G., GAROFALO,J. A. & GOOD, R. A. (1979). Nutrition immunity and cancer - - a review. 11: zinc, immune function and cancer. Clin. Bull. MSKCC, 9, 6 3 - 75. TANAKA,T., FERNANDES,G., TSAO, C., PIH, K. & GOOD, R. A. (1978). Effects of zinc deficiency on lymphoid tissues and immune function of A/Jax mice. Fedn. Proc., 37, 931. WALFORD, R. L. & CREW, M. (1989). How dietary restriction retards aging: an integrative hypothesis (Editorial). Growth Dev. Aging, 53, 139-140.
lnt. J. lmmunopharmac., Vol. 14, No. 3, pp. 3 6 1 - 366, 1992. Printed in Great Britain.
NUTRITION AND CELLULAR IMMUNITY ROBERT A. GOOD a n d ELLEN LORENZ Department of Pediatrics, All Children's Hospital, University of South Florida, St. Petersburg, Florida, U.S.A.
Abstract - - We have investigated the influence of nutrition on immune function in animals and man over the past two decades. The profound impairment of immune function that had not been observed in children in developing countries could not consistently be reproduced in the laboratory setting; paradoxically, moderate nutritional restriction could even enhance T-cell-based cell-mediated immune responses in experimental animals. Studies of the crucial role of the element zinc in maintenance of vigorous cellular immunity provided at least a partial explanation of this paradox. Zinc, shown to be absolutely crucial for development and expression of both T- and B-cell functions, was commonly deficient as were other micronutrients under many conditions of protein-calorie malnutrition. Indeed, administration of adequate zinc alone could correct some of the T-cell-mediated immune functions in children with protein-calorie malnutrition. In later investigations we found that as long as all essential nutrients were supplied in adequate amounts, 40°7o chronic energy (calorie) restriction will regularly extend lifespan and maintain vigorous immunologic function while preventing numerous cancers and immunologically based diseases of aging, such as profound and destructive autoimmune diseases in genetically short-lived mice strains, as it was known to do for moderately long-lived rats and long-lived strains of mice. Such undernutrition without malnutrition appears to influence a wide range of critical metabolic and physiologic processes in both short-lived and long-lived animals. One of the most challenging of these influences was a down-regulation of cellular proliferation and cell turnover in each of the rapidly replicating tissues studied. It also regularly was possible to inhibit gene expression of certain oncogenic retroviruses, such as the mammary adenocarcinoma retrovirus, in highly susceptible strains of mice.
O u r l o n g s t a n d i n g interest in the influence o f n u t r i t i o n o n cellular i m m u n i t y b e g a n m o r e t h a n two decades ago. A t t h a t time, I h a d the occasion to visit P r o f e s s o r Galal A r e f in Egypt in 1969 to see first h a n d the ravages caused by m a l n u t r i t i o n a m o n g children o f P a l e s t i n i a n refugees. Such children were o f t e n a g a m m a g l o b u l i n e m i c , were deficient in b o t h humoral and cell-mediated immunities, and s u c c u m b e d to n u m e r o u s bacterial a n d viral infections (Abassy et al., 1974). M a n y other studies have d o c u m e n t e d similar links between m a l n u t r i t i o n a n d severe i m m u n o d e f i c i e n c y . However, our interest was piqued especially by a r e p o r t f r o m David Jose a n d his colleagues in Australia. These investigators r e p o r t e d t h a t Aborigines, w h o b e c a m e m a l n o u r i s h e d u p o n weaning a n d regularly developed a decreased ability to p r o d u c e antibodies, unexpectedly showed increased proliferative responses of T-lymphocytes u p o n s t i m u l a t i o n with certain p h y t o m i t o g e n s (Jose & Welch, 1969; Jose, W e l c h & D o h e r t y , 1970). W h e n David Jose j o i n e d my l a b o r a t o r y at the University o f M i n n e s o t a , we s o u g h t to investigate this p a r a d o x in a controlled, e x p e r i m e n t a l setting. W e s h o w e d t h a t m o d e r a t e or severe protein a n d
protein-calorie restriction in mice inhibited d e v e l o p m e n t of a n t i b o d y p r o d u c i n g cells a n d p r o d u c t i o n o f circulating antibodies, regardless of the specific c o m p o s i t i o n of the diets used (Jose & G o o d , 1971). In contrast, cellular i m m u n i t y , or the thymus-dependent immune functions, was undiminished in protein or protein-calorie m a l n o u r i s h e d mice a n d rats, but, in some cases, was even e n h a n c e d (Jose, C o o p e r & G o o d , 1971). P r o t e i n or protein-calorie d e p r i v a t i o n quickened the pace of allograft rejection, increased proliferative responses to p h y t o m i t o g e n s a n d facilitated or e n h a n c e d delayed allergic responses (Jose & G o o d , 1972; F e r n a n d e s , Yunis, Jose & G o o d , 1973; Jose & G o o d , 1973; Jose, S t u t m a n & G o o d , 1973; work reviewed in G o o d et al., 1976). K r a m e r & G o o d (1978) f o u n d t h a t delayed allergic reactions r e m a i n e d intact in guinea-pigs whose diets were restricted in protein to 6 - 9 % . W h e n protein was restricted to as d a n g e r o u s l y low a level as 3-5%, thereby a b r o g a t i n g delayed allergic skin reactivity, cell-mediated i m m u n i t y r e m a i n e d intact a n d in some cases a p p e a r e d to be greatly increased, as in the d e v e l o p m e n t o f cell-mediated respon361
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siveness to stimulation with minute doses of antigen. What defects in T-cell immune responsiveness did occur were consequent to defective inflammatory expression of cellular immunity rather than to defects of T-lymphocyte-mediated immune responses. Furthermore, we noted that protein or proteincalorie restriction augmented delayed allergic reactions, increased the capacity for lymphoid cells to initiate graft-vs-host reactions, up-regulated cellular immune responses against syngeneic and allogeneic tumor cells, and even increased the capacity to resist certain types of viral infections (Good, Jose, Cooper, Fernandes, Kramer & Yunis, 1977; Good, West & Fernandes, 1980). The divergent influences of protein or proteincalorie restriction on cellular and humoral immune responses stood in stark contrast to the great majority of reports from the field, in which almost all aspects of immunity were grossly impaired as a consequence of malnutrition. We reasoned that differences in the consumption of adequate levels of micronutrients might be at work in this dichotomy - the laboratory animals we had studied had been provided with all essential nutrients and trace elements, but protein-calorie malnourished children in the Third World obviously were deficient in many of these micronutrients as well as in protein and calories. For instance, the divergent effects of proteincalorie nutrition might be partly explained by findings concerning the important role the trace metal zinc plays in immune function. It became clear that this element was essential to numerous T-lymphocyte responses. Prasad, Halstead & Nadimi (1961) described a zinc deficiency that produced a syndrome of growth failure, male hypogonadism, neurosensory defects and increased susceptibility to infection. These symptoms were completely reversed once adequate zinc intake was established. After this initial description of zinc deficiency in humans, Brummerstedt, Hagstad, Basse & Andresen (1971) described a genetic disorder in F r i e s i a n - H o l s t e i n cattle in which defective intestinal absorption of zinc was accompanied by thymic aplasia, hypoplastic Peyer's patches and deficiencies of cell-mediated responses to bacterial antigens. These deficiencies could all be reversed or normalized by zinc supplementation. Moynahan & Barnes (1973) reported similar findings in the human disorder called acrodermatitis enteropathica, that was featured by thymic hypoplasia, poorly developed lymph nodes, plasmacytosis within the spleen, deficiency of IgA and deficiency of delayed skin
reactions to numerous bacterial and fungal antigens. Here again, administration of oral zinc promptly resolved the immunodeficiency syndrome. These descriptions of the notable immunological consequences of zinc deficiency in these two crucial experiments of nature were followed by laboratory analyses of the role of zinc in imnmnity (Fraker, Haas & Leuke 1977; Leuke, Simonel & Fraker, 1978). Similarly, Tanaka, Fernandes, Tsao, Pih & Good (1978) and Fernandes, Nair, Ono4, Tanaka, Floyd & Good (1979) established that zinc deficiency caused thymic involution and diminished antibody responses in A / J a x mice and showed that nutritional deficiency produced profound immunodeficiency long before manifestation of acrodermatitis enteropathica appeared in the deprived animals. These immune defects could be normalized in part by transfer of thymocytes from zinc-sufficient mice. We later showed that a zinc deficiency could account for the profound deficiencies in T-lymphocyte-mediated immunities in protein-calorie malnourished children but not in protein-calorie deprived laboratory animals (Fernandes et al,, 1979). In addition, we demonstrated that in the A / J a x mice zinc deficiency impaired both primary and secondary antibody responses. In subsequent investigations (Iwata et al., 1979; Rao, Schwartz & Good, 1979; CunninghamRundles, Cunningham-Rundles, Dupont & Good, 1980; Schloen, Fernandes, Garofalo & Good, 1979; Cunningham-Rundles et al., 1981) we showed that dietary zinc deficiency could suppress a wide range of immune responses and parameters, particularly those of the T-lymphocyte arm of the immune system. These multiple effects of dietary zinc deficiency included thymic involution, depletion of thymocyte populations, depression of thymulin levels, depression of delayed type hypersensitivity, lowering of total T-cell counts, reduction in primary and secondary antibody responses, diminished natural killer cell function, impaired T-suppressor cell function, decreased interleukin-2 activity, and expansion of the immature, undifferentiated lymphocyte population referred to as the putative "null cell" phenotype. That zinc plays an important role in cell-mediated immunity has become even more readily apparent in view of the recently defined role of thymulin in regulating T-cell differentiation both within and outside the thymus. Thymulin binds zinc with greater efficiency than it does any other metal (Bach & Dardenne, 1989), and Prasad, Dardenne, Abdallah, Meftah, Brev.er & Bach (1987) have shown that serum thymulit~ activity, along with T4 : T8 ratios and IL-2 production and responsiveness, are dec-
Nutrition and Cellular Immunity reased in patients with zinc deficiency. Oral zinc remediates these deficiencies. Zinc supplementation has also been shown to correct significant defects of cellular immunity associated with Down's syndrome (Franceschi et al., 1990) and zinc deficiency that may be associated with normal aging (Kaplan, Hess & Prasad, 1988). Thus, the profound influences of zinc on immune function pointed us toward an explanation for the divergent immunological outcomes of proteincalorie malnutrition that occurred in undeveloped or developing nations versus the often beneficial effects of protein-calorie restriction that was induced in mice, rats or guinea-pigs. Zinc appeared to be a nutrient essential to normal immune response and parameters. Gershwin, Beach & Hurley (1985) reviewed many of the important roles for other micronutrients, including copper, manganese and magnesium; and Chandra (1991) has also discussed the importance of various vitamins and trace minerals in immunity. Dietary nucleotides also appear to play an important role in achieving and maintaining optimal immune responsiveness (Carver, Pimentel, Cox & Barness, 1991). Thus, at least in experimental settings, if zinc and other essential nutrients were supplemented in adequate amounts, macronutrients such as protein, carbohydrates, fats and total calories might be variously manipulated and their influence on immunity systems observed. Indeed, over the past 15 years we have studied the influence of dietary energy (calorie) restriction in various genetically short-lived strains of mice (Fernandes, Yunis & Good, 1976a, b; Fernandes, Friend, Yunis & Good, 1978a; Fernandes, Yunis, Miranda, Smith & Good, 1978b; Kubo, Day & Good, 1984). In each of these strains, we showed that chronic energy intake restriction (CEIR; imposed by means of a 40% reduction in the caloric intake of full-fed animals) could double, triple or even further extend lifespan in these inbred, short-lived mice. Moreover, CEIR delayed or, in some instances, completely inhibited development of autoimmunity diseases to which these mice succumb, particularly progressive immunologically based hyalinizing renal disease, vascular lesions, lymphoproliferative disease and even certain malignancies (Fernandes et al., 1976a, b; Fernandes et al., 1978a,b; Sarkar, Fernandes, Telang, Kourides & Good, 1982; Fernandes, Alonso, Tanaka, Thaler, Yunis & Good, 1983; Fernandes & Good, 1984). To determine whether total calorie intake was a more critical variable than calorie source, we employed diets that varied in composition from very high fat/nocarbohydrate to be very low fat/high
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carbohydrate, along with moderate intakes of both. No significant difference was observed in the influence of the different macronutrients p e r se on lifespan (Kubo, Johnson, Gajjar & Good, 1987; Gajjar, Kubo, Johnson & Good, 1987). However, when each of the experimental diets was fed at a restricted calorie level, the median and maximal longevity of mice of each strain studied increased markedly. The most dramatic shift in longevity curves occurred with a diet relatively low in fat and relatively high in carbohydrate that was fed at the CEIR level (restriction of 40% in total calories). Restriction can be imposed as late as midlife and still succeed at forestalling disease onset and greatly extending lifespan. However, for most powerful regulation of lifespan and health, CEIR is best imposed at time of weaning. The cellular and molecular bases that underlie the impressive effects of CEIR on lifespan and disease have yet to be elucidated. We have demonstrated that CEIR decelerates the pace of the immunological involution that accompanies aging. CEIR reduces the formation of circulating immune complexes and deposition of g p 7 0 - anti-gp70 immune complexes in a capillary distribution within the glomeruli (Izui et al., 1981), inhibits the age-related decrease of IL-2 responsiveness and IL-2 production (Jung, Palladino, Calvano, Mark, Good & Fernandes, 1982). CEIR can also restrain the potentially destructive influences of oxidative stress that occur in aging by selective enhancement of the activity of radical scavenging enzymes such as superoxide dismutase (Kubo, Johnson, Misra, Dao & Good, 1987). Hollander, Dadufalza, Weindruch & Walford (1986) studied mice and rats of long-lived strains and observed that CEIR increased absorption by the gastrointestinal tract of vitamin A, presumably enhancing that vitamin's anti-oxidative actions. Koizumi, Weindruch & Walford (1987) reported that CEIR increases catalase activity. In addition, Licastro & Walford (1985) reported that CEIR slows the age-related decline of lymphocytes' capacity for DNA repair. In a series of investigations we have shown that CEIR also down-regulates the rate of cellular proliferation at a number of important sites. Ogura, Ogura, Dao, Ikehara & Good (1989) showed that CEIR dramatically decreased the rate of cellular proliferation, as determined by incorporation of 3Hthymidine, within lymphoid tissues such as the thymus, liver and spleen and also within the epithelial layer of the entire gastrointestinal tract. Albanes & Winnick (1988) reported a similar inhibitory effect of CEIR on the proliferative rate of
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cells of the colonic mucosa, and these findings have been confirmed and extended (Lok et al., 1990; Bruce, 1990). We also showed that CEIR reduces the proliferative rate of CD5 B-lymphocytes, a specific B-lineage subset with a tendency toward oligoclonal or neoplastic expansion (Ogura, Ogura, Lorenz, Ikehara & Good, 1990) that may be of special importance in the development and expression of autoimmunity. In studies of mice which develop mammary adenocarcinoma consequent to endogenous infection with the mouse mammary tumor virus (MMTV), we have found that CEIR significantly inhibits the formation of hyperplastic alveolar nodules (Sarkar et al., 1982; Hamada et al., 1990). Moreover, we found that CEIR significantly reduced proviral DNA transcription of MMTV, suppressed MMTV messages in the mammary gland, liver, kidney, lung and small intestine, and reduced the expression of the protooncogenes int-1, int-2 and ras (Chen et al., 1990; Hamada et al., 1990). Thus, CEIR not only appears to slow the rate of cellular proliferation but also to reduce the frequency of genetic and oncogenetic expression that may give rise to tumorigenesis. Other potential mechanisms that may underlie the disease-inhibiting actions of CEIR include regulation of the levels of insulin and/or glucose. Ruggieri, Klurfeld, Kritchevsky & Furlanetto (1989) demonstrated that CEIR decreases serum insulin levels as well as production of insulin-like growth factors. Cerami, Vlassara & Brownlee (1987) proposed that glucose is an important regulator of the aging process through its role in the glycation of nonenzymation protein and the formation of endstage glycosylation products. Moreover, Masoro (1991) reported that plasma glucose is reduced by the CEIR regimen. Thus, control of both plasma glucose and serum insulin may well be among the critical influences of CEIR in maintaining immunologic vigor and preventing diseases associated with aging.
One attractive explanation for the beneficial effects of CEIR has been formulated by Walford & Crew (1990). Their integrative hypothesis suggests that CEIR brings about the redirection of energy from a number of biological processes, most notably reproduction and the p i t u i t a r y - hormonal axis, and thereby allows an organism to channel greater amounts of energy into critical maintainance and repair processes which occur at the molecular and cellular levels. The reduction in the rate of basal or unstimulated levels of cellular proliferation that we have observed in recent experiments appears to be one important reflection of this aspect of CEIR, as does the maintenance of vigorous cellular immunity in the aging process with a concomitant reduction in autoimmune phenomena (e.g. reduced formation of circulating immune complexes) that we have observed. Walford & Crew also suggest that an intensification of DNA repair processes and the free radical scavenging capacity occurs through regulation of trans-acting factors which bind to homologous sequences on specific genes which are involved in maintenance/repair work. CEIR may, thus, represent a type of cellular engineering by which immunological responsiveness may be sustained through old age, permitting diseases of aging, and even expression of neoplastic disease, to be controlled or greatly delayed. The promising experimental data point to a great potentiality for CEIR to foster longevity and, even more importantly, promote immunologic vigor and good health later in life. Admittedly, CEIR may be difficult to apply to humans. On the other hand, continued research on the mechanisms underlying the maximal life-prolonging actions of CEIR may lead to much simpler means of controlling the very gene expressions which seem so crucial in influencing prolongation of median lifespan, extending the span of vigorous good health and extending greatly even maximum lifespan. No other experimental influence thus far studied carries such incredible promise.
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Impaired interleukin-2 production in the elderly. Association with mild zinc deficiency. J. Trace Elements exp. Med., 1, 3 - 8. KOJZUMI, A., WHNDRUCH, R. & WALFORD,R. L. (1987). Influences of dietary restriction and age on liver enzyme activities and lipid peroxidation in mice. J. Nutr., 117, 361- 367. KRAMER, T. R. & GOOD, R. A. (1978). Increased in vitro cell-mediated immunity in protein-malnourished guinea pigs. Clin. Immun. lmmunopath., 11, 212-228. KUBO, C., DAY, N. K. & GOOD, R. A. (1984). Influence of early or late dietary restriction on life span and immunological parameters in M R L / M r - l p r / l p r mice. Proc. natn. Acad. Sci. U.S.A., 81, 5831-5835. KUBO, C., JOHNSON, B. C., GAJJAR, A. & GOOD, R. A. (1987). Crucial dietary factors in maximizing life span and longevity in autoimmune-prone mice. J. Nutr., 117, 1129- 1135. KUBO, C., JOHNSON, B. C., MISRA, H. P., DAO, M. L. & GOOD, R. A. (1987). Nutrition, longevity and hepatic enzyme activities in mice. Nutr. Rep. Int., 35, 1185-1194. LICASTRO, F., SAVORANI, G., SARTI, G., SALSI, A., CAVAZZUTI,C., ZANICHELLI, L., TUCCI, G., MOCCHEGIAN1, E. & FABRIS, N. (1990). Zinc and thymic hormone-dependent immunity in normal ageing in patients with senile dementia of the Alzheimer type. J. Neuroimmun., 27, 201-208. L1CASTRO, F. & WALFORD, R. L. (1985). Aging, proliferative potential and DNA repair capacity in short-lived and longlived mice. Mech. Ageing Dev., 31, 171. LOK, E., SCOTT, F. W., MONGEAU, R., NERA, E. A., MALCOLM, S. & CLAYSON, D. B. (1990). Calorie restriction and cellular proliferation in various tissues of the female Swiss Webster mouse. Cancer Left., 51, 67-73. LUEKE, R. W., S1MONEL,C. E. & FRANKER,P. J. (1978). The effect of restricted dietary intake on the antibody mediated response of the zinc deficient A/J mouse. J. Nutr., 108, 881 -887. MASORO, E. J. (1991). Physiological consequences of dietary restriction: an overview. In Biological Effects o f Dietary Restriction (ed. Fishbein, L.), pp. 115- 122. Springer, New York. MOYNAHAN, E. J. & BARNES, P. M. (1973). Zinc deficiency and a synthetic diet for lactose intolerance. Lancet, I, 676 - 677. OGURA, M., OGURA, H., DAO, M. L., IKEHARA,S. & GOOD, R. A. (1989). Decrease by chronic energy intake restriction of cellular proliferation in the intestinal epithelium and lymphoid organs in autoimmune-prone mice. Proc. ham. Acad. Sci. U.S.A., 86, 5089-5093. OGURA, M., OGURA, H., LORENZ, E., 1KEHARA,S. & GOOD, R. A. (1990). Undernutrition without malnutrition restricts the numbers and proportions of Ly-I B lymphocytes in autoimmune (MRL/I and BXSB) mice. Proc. Soc. exp. Biol. Med., 193, 6 - 12. PRASAD, A. S., DARDENNE, M., ABDALLAH,J., MEFTAH,S., BREWER,G. J. & BACH, J. F. (1987). Serum thymulin and zinc deficiency in humans. Trans. Assoc. A m . Phys., C, 222-231. PRASAD, A. S., HALSTEAD, J. A. & NADIMI, M. 0961). Syndrome of iron-deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism, and geophagia. A m . J. Med., 31, 532-546. RAO, K. M. K., SCHWARTZ,S. A. & GOOD, R. A. (1979). Age-dependent effects of zinc on the transformation response of hyman lymphocytes to mitogens. Cell. Immun., 42, 270-278. RUGGIERI, B. A., KEURFELD, D. M., KRITCHEVSKY, D. & FURLANETTO, R. W. (1989). Caloric restriction and 7,12dimethylbenz[a]anthracene-induced mammary tumor growth in rats: alterations in circulating insulin, insulin-like growth factors I and II, and epidermal growth factor. Cancer Res., 49, 4130-4134. SARKAR, N. H., FERNANDES,G., TELANG, N. T., KOURIDES, I. A. & GOOD, R. A. (1982). Low-calorie diet prevents the development of mammary tumors in C3H mice and reduces circulating prolactin level, murine mammary tumor virus expression, and proliferation of mammary alveolar cells. Proc. natn. Acad. Sci. U.S.A., 79, 7758-7762. SCHLOEN, L. H., FERNANDES,G., GAROFALO,J. A. & GOOD, R. A. (1979). Nutrition immunity and cancer - - a review. 11: zinc, immune function and cancer. Clin. Bull. MSKCC, 9, 6 3 - 75. TANAKA,T., FERNANDES,G., TSAO, C., PIH, K. & GOOD, R. A. (1978). Effects of zinc deficiency on lymphoid tissues and immune function of A/Jax mice. Fedn. Proc., 37, 931. WALFORD, R. L. & CREW, M. (1989). How dietary restriction retards aging: an integrative hypothesis (Editorial). Growth Dev. Aging, 53, 139-140.
