Exercise and the Immune System - Influence of ... - Semantic Scholar

Exercise and t h e I m m u n e System - Influence of N u t r i t i o n and Ageing Bente Klarlund Pedersen, Helle Bruunsgaard, Marianne Jensen, Anders D. Toft, Henriette Hansen & Kenneth Ostrowski The Copenhagen Muscle Research Centre and Department of Infectious Diseases, Rigshospitalet, Unviersity of Copenhagen, Denmark

Pedersen, B. K., Bruunsgaard, H., Jensen, M., Toft, A. D., Hansen, H., & Ostrowski, K. (1999). Exercise and the immune system - Influence of nutrition and ageing. Journal of Science and Medicine in Sport 2 (3): 234-252. In essence, the immune system is enhanced during moderate and severe exercise, and only intense long-duration exercise is followed by impairment of the immune system. The latter includes suppressed concentration of lymphocytes, suppressed natural killer cell activity, lymphocyte proliferation and secretory IgA in saliva. During the time of immune impairment, referred to as "the open window', microbial agents, especially viruses may invade the host and infections may be established. One reason for the "overtraining effect" seen in elite athletes could be that this window of opportunism for pathogens is longer and the degree of immnnosuppression more pronounced. Alterations in metabolism and metabolic factors may contribute to exercise-associated changes in immune function. Reductions in plasma-glutamine concentrations, altered plasmaglucose level, free oxygen radicals and prostaglandins (PG) released by the elevated number of neutrophfls and monocytes may influence the function of lymphocytes and contribute to the impaired function of the later cells. Thus, nutritional supplementation with glutamine, carbohydrate, anti-oxidants or PG-inhibitors may, in principle, influence exercise-associated immune function. Although several intervention studies have been performed, it is premature to make recommendations regarding nutritional supplementation to avoid post-exercise impairment of the immune system.

Introduction Exercise h a s significant effects on t h e i m m u n e s y s t e m . In essence, a b o u t of exercise i n d u c e s m o b i l i z a t i o n of i m m u n o c o m p e t e n t cells to t h e circulation. Following s t r e n u o u s exercise, b u t n o t m o d e r a t e exercise, t h e function of t h e i m m u n e s y s t e m is i m p a i r e d for u p to 72 h o u r s (Hoffman-Goetz & Pedersen, 1994; P e d e r s e n a n d Nieman, 1998; B r i n e s et al. 1996). Epidemiological evidence exists w h i c h s u p p o r t s t h e a n e c d o t a l i m p r e s s i o n (Nieman & H e n s o n , 1994) t h a t r e g u l a r exercise i n c r e a s e s r e s i s t a n c e to infections s u c h a s t h e c o m m o n cold (Fitzgerald, 1988; Nash, 1987), w h e r e a s h a r d t r a i n i n g is a s s o c i a t e d w i t h i n c r e a s e d r e s p i r a t o r y t r a c t infections (Fitzgerald, 1988). T h e r e l a t i o n s h i p b e t w e e n n u t r i t i o n a l factors a n d r e s i s t a n c e to infections h a s g e n e r a t e d c o n s i d e r a b l e i n t e r e s t over t h e p a s t several d e c a d e s . In i n d u s t r i a l i z e d c o u n t r i e s t h e r e l a t i o n s h i p b e t w e e n n u t r i t i o n a n d i m m u n i t y is of special i n t e r e s t in elderly s u b j e c t s , s i n c e it is k n o w n t h a t a g e - r e l a t e d i m m u n o d e f i c i e n c y is a g g r a v a t e d in m a l n o u r i s h e d s u b j e c t s . In theory, it is p o s s i b l e t h a t t h e exercisei n d u c e d i m m u n o l o g i c a l c h a n g e s c a n b e m o d u l a t e d b y n u t r i t i o n a l factors, a n d t h a t

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dietary factors influence resting levels of the i m m u n e s y s t e m in athletes. Furthermore, ageing is associated with a suppression in the n o r m a l function of the i m m u n e system which m a y influence the ability to respond to physical stress. Nutritional supplementation m a y in theory partly revert this i m m u n e senescence. On this background a short review will be given on exercise, nutrition, ageing and i m m u n e function. Exercise and A c u t e Exercise

Immune

Function

In relation to acute exercise, there are several consistent patterns that emerge regarding leukocyte subpopulations in the blood. The neutrophil concentration increases during exercise and continues to increase post-exercise (McCarthy & Dale, 1988). The lymphocyte concentration increases dm~_ng exercise and falls below pre-exercise values following intense long-duration exercise, b u t is not suppressed after moderate exercise (McCarthy & Dale, 1988). The increased lymphocyte concentration is due to recruitment of all lymphocyte subpopulations to the blood. Thus, both the CD4 ÷ T cells, CD8 ÷ T cells, CD19 ÷ B cells, CD16 ÷ natural killer (NK) cells, and CD56 ÷ NK cells increase in n u m b e r during exercise and decline following intense exercise lasting at least one hour. Furthermore, following intense long-duration exercise the function of NK a n d B cells is suppressed. Thus, the NK cell activity (the ability of NK cells to lyse a certain n u m b e r of t u m o r target cells) is inhibited. Furthermore, antibody production in the circulation is inhibited and the local production of secretory IgA in m u c o s a is inhibited (Figure 1; Pedersen, 1997; Pedersen & Nieman, 1998).

"The open window" - theory

-- rest

- - -

Figure 1: An acute bout of exercise induces mobilization of lymphocytes to the circulation. Following intense exercise the lymphocyte concentration decreasesand the ability of the cells to proliferate, mediate cytotoxic activity and produce immunoglobulins is impaired. During this temporary post.exercise immune impairment, microorganisms may invade the body and establish as infections.

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S t r e n u o u s exercise also induces increased circulating levels of several cytokines. Initial studies described increased levels of IL-1 in plasma obtained after exercise (Cannon & Kluger, 1983; Cannon et al., 1986; Evans et al., 1986), but the possibility exists that other cytokines were m e a s u r e d as the latter studies were conducted prior to the availability of recombinant IL- 1 proteins. As pointed out by Bagby et al. (1996), there have been a n u m b e r of studies which failed to detect elevated levels of IL-1 in p l a s m a (Northoff & Berg, 1991; Ullum et al., 1994; Sprenger et al., 1992; Cannon et al., 1991). However, IL-6 has been found to be enhanced in several studies (Northoff & Berg, 1991; Ullum et al., 1994; Sprenger et al., 1992; Bruunsgaard et al., 1997; Ostrowski et al., 1998; Rohde et al., 1997; Ostrowski et al., 1998; Ostrowski et al., 1998; Ostrowski et al., 1999) and is followed by an increase in the concentration of the IL-1 receptor antagonist (ILlra), a natural occurring inhibitor ofIL-1 (Ostrowstd et al., 1998; Ostrowski et al., 1998; Ostrowski et al., 1999). Recent data from our group described that the soluble TNF-~ receptors (sTNF-aR) 1 and 2 a n d the chemokines IL-8 and MIP-lb are also increased in r e s p o n s e to s t r e n u o u s exercise (Ostrowski et al., unpublished data). Bruunsgaard et al (1997) compared concentric and eccentric exercise and found an association between increased IL-6 level and muscle damage as visualized by the increase in creatine kinase. Thus, the study supports the hypothesis that the post-exercise cytokine production is related to skeletal muscle damage. Recently, we have found IL-6-mRNA in skeletal muscle biopsies obtained from runners after a m a r a t h o n r u n (Ostrowski et al. 1998). The latter data thus indicate t h a t IL-6 is locally produced in response to strenuous exercise or exercise-induced muscle damage. IL-lra-mRNA was not present in the skeletal muscle, b u t expressed by blood mononuclear cells (BMNC) obtained after, b u t not before the marathon, indicating that locally produced IL-6 induces a systemic anti-inflalnmatoly response. The cytokine cascade in response to exercise resembles that seen in response to trauma, and exercise thus m a y be considered a model of trauma. Chronic Exercise The i m m u n e function (resting levels) in athletes versus non-athletes h a s more similarities t h a n disparities, reviewed in (Nieman, 1996). Natural immunity m a y be slightly increased, whereas neutrophil function h a s been described to be slightly suppressed. The adaptive i m m u n e system (resting state) in general seems to be largely unaffected by intensive and prolonged exercise training (Baj et al., 1994; Tvede et al., 1991; Nieman et al., 1995). The innate i m m u n e system appears to respond differentially to the chronic stress of intensive exercise, with NK cell activity tending to be enhanced while neutrophil function is suppressed (Hack et al., 1994; Nieman et al., 1993; Pedersen et al., 1989; Pyne et al., 1995). Based on anecdotal information, a general feeling has been that while regular training promotes resistance to u p p e r respiratoly tract infections (URTI) severe exertion, especially when coupled with mental stress, places athletes at increased risk tbr URTI (Fitzgerald, 1991; Nieman, 1994). Based on the above mentioned epidemiological studies a relationship between exercise and URTI h a s been modelled in the form of a "J" curve (Figure 2}. This model suggests that while the risk of URTI m a y decrease below that of a sedentary individual when one engages in moderate exercise training, the risk m a y rise above average during periods of

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The "J" Form Curve RISk Of URTI Above Average

Average

Below Average Sedentary

Moderate

High

Amount and Intensity of Exercise Figure 2: T-shaped model of relationship between varying amounts of exercise and risk of upper respiratory tract infection (URTI).Thismodel suggests that moderate exercise may lower risk of infections while excessive amount may increase risk.

excessive high-intensity exercise (Nieman, 1994). The link between exerciseassociated immune changes and sensitivity to infections may be explained by the so called "open window" of altered immunity (which m a y last between 3 and 72 hours, depending on the immune measure as well as the type, duration and intensity of exercise). We have previously hypothesized that viruses and bacteria may gain a foothold, increasing the risk of subclinical and clinical infection. However, it remains to be demonstrated if athletes showing the most extreme immunosuppression following heavy exertion are those that contract an infection within the following 1-2 weeks.

Exercise; N u t r i t i o n and I m m u n e Function The m e c h a n i s m s underlying exercise-associated i m m u n e changes are multifactorial and include neuroendocrinological factors such as adrenaline, noradrenaline, growth hormone, cortisol and beta-endorphin (Pedersen et al., 1997). Physiological factors such as increased body temperature during the exercise (Kappel et al., 1991) or oxygen desaturation (Klokker et al. 1995) may also have an impact. Altered protein metabolism, such as reduced plasmaglutamine concentrations, as a result of muscular activity has been suggested to influence lymphocyte function (Newsholme & Parry Billings, 1990), and reduced plasma-glucose has been suggested to increase stress-hormone levels and thereby alter immune function (Nieman & Pedersen, 1999). Furthermore, as a consequence of the acute catecholamine- and growth hormone-induced changes in leukocyte subsets, the relative proportion of these subsets change and activated leukocyte subpopulations may be mobilized to the blood. Free oxygen radicals and prostaglandins (PG) released by the elevated n u m b e r of neutrophfls and monocytes may influence the function of lymphocytes and contribute to the 237


impaired function of the later cells. Thus, nutritional supplementation with glutamine, carbohydrate, anti-oxidants or PG-inhibitors may, in principle, influence exercise-associated immune function.

Glutamlne It has generally been accepted that cells of the immune system obtain their energy by metabolism of glucose. However, it has been established that glutamine is also an important fuel for lymphocytes and macrophages. Several lines of evidence suggest that glutamine is used at a very high rate by these cells, even when they are quiescent (Newsholme, 1994). It has been proposed that the glutamine pathway in lymphocytes may be under external regulation, due partly to the supply of glutamine itself (Ardawi & Newsholme, 1984). In vitro, glutamine stimulates lymphocyte proliferation, lymphokine activated killer cell activity and cytokine production (Rohde et al., 1995; Rohde et al., 1996). Skeletal muscle is the major tissue involved in glutamine production and is known to release glutamine into the blood stream at a high rate. It has been suggested that the skeletal muscle plays a vital role in maintenance of the key process of glutamine utilization in the immune cells. Consequently, the activity of skeletal muscle may directly influence the immune system. It has been hypothesized (the so called "gtutamine-hypothesis") that u n d e r intense physical exercise, or in relation to surgery, trauma, b u r n and sepsis, the demands on muscle and other organs for glutamine are such that the lymphoid system may be forced into a glutamine debt, which temporarily affects its function. Thus, factors that directly or indirectly influence glutamine synthesis or release, could theoretically influence the function oflymphocytes and monocytes (Newsholme, 1994; Newsholme, 1990; Wallace & Keast, 1992). Following intense long-term exercise and other physical stress, the glutamine concentration in plasma declines (Parry Billings et al., 1992; Keast et al., 1995; Essen et al., 1992; Lehmann et al., 1995; Keast, 1996; Rohde et al., 1996). Furthermore, low glutamine levels have been described in athletes with the "overtraining syndrome" (Rowbottom et al., 1997; Rowbottom et al., 1996; Keast, 1996; Keast &Morton, 1992). Clearly, optimal lymphocyte proliferation is dependent on the presence of glutamine, b u t there are no published data showing that glutamine supplementation restores impaired immune function post-exercise. The critical question therefore is not whether concomitant decreased plasma glutamine concentration and lymphocyte function occur following intense exercise, but whether a causal relationship exists. In two recent placebo-controlled glutamine intervention studies (Rohde et al., 1998; Rohde et al., 1998), it was found that glutamine abolished the post-exercise decline in plasma glutamine, without influencing post-exercise immunosuppression. Thus, the latter study did not support the hypothesis that the post-exercise decline in immune function is caused by a decrease in the plasma glutamine concentration.

Carbohydrate Earlier research had established that a reduction in blood glucose levels is linked to hypothalamic-pituitary-adrenal activation, an increased release of adrenocorticotrophic hormone and cortisol, increased plasma growth hormone, decreased insulin, and a variable effect on blood adrenaline levels (Nieman & Pedersen, 1999). Given the link between stress hormones and immune responses to prolonged and intensive exercise (Pedersen et al., 1997), carbohydrate 258


compared with placebo ingestion should maintain p l a s m a glucose concentrations, attenuate increases in stress hormones, and thereby diminish changes in immunity. This hypothesis has been tested in a n u m b e r of studies by Nieman and colleagues (Nehlsen-Canarella et al., 1997; Nieman et al., 1997; Nieman et al., 1997) using double-blind, placebo-controlled randomized designs. Carbohydrate beverage ingestion before, during (about 1 liter/hour), and after 2.5 hours of exercise was associated with higher plasma glucose levels, a n attenuated cortisol and growth hormone response, fewer perturbations in blood immune cell counts, lower granulocyte and monocyte phagocytosis and oxidative burst activity, and a diminished pro- and anti-inflammatory cytokine response. Overall, the hormonal and immune responses to carbohydrate compared with placebo ingestion were diminished. Some immune variables were affected slightly by carbohydrates ingestion (eg. granulocyte and monocyte function), while others were strongly influenced (eg. plasma cytokine concentrations, and blood cell counts). The clinical significance of these carbohydrate-induced effects on the endocrine and immune systems awaits further research. At this point, the data indicate that athletes ingesting carbohydrate beverages before, during, and after prolonged and intensive exercise should experience lowered physiologic stress. Research to determine whether carbohydrate ingestion will improve host protection against viruses in endurance athletes during periods of intensified training or following competitive endurance events is warranted.

Lipids It has been suggested that if the n - 6 / n - 3 ratio is shifted in favour of n-6, this will result in increased production of prostaglandin PGE 2 and suppress cellular immune system. During stress conditions n-3 fatty acids may counteract latent immunosuppression mediated by increasing PGE2 production which in contrast appears to be further enhanced by intake of n-6 fatty acids. The hypermetabolism n-3 fatty acids potentially acts to reduce the incidence of new infections. In animal experiments it was shown that the stress response following application of endotoxin, IL-1 or TNF was reduced when the animals were pretreated with n-3 fatty acids (fish off). The diet rich in n-3 fatty acids caused reduced catabolism, reduced febrile reaction, decreased eicosanoid production and improved survival rate.(Johnson, 3d et al., 1993) The possible interaction between intense acute exercise, known to suppress the immune system (Hoffman-Goetz & Pedersen, 1994), and polyunsaturated fatty acids (PUFA) was examined in inbred female C57BI/6 mice.(Benquet et al., 1994). The animals received either a natural ingredient diet or a diet supplemented with various oils such as beef tallow, safflower, fish oil or linseed oil for an eight week period. In the group receiving 18:3 (n-3) linseed oil it was shown that linseed oil abolished post-exercise immunosuppression of the immunoglobulin M plaque forming cell response. The mechanism underlying the absence of exerciseinduced immunosuppression in animals fed linseed oil may be that linseed oil diminishes the n - 6 / n - 3 ratio and thereby diminishes the PGE2 level after intense exercise. Thus, the effect of linseed off may be ascribed to a link between a diet rich in n-3 PUFA and abolition of prostaglandin-related immunosuppression. In support of this hypothesis, it has been shown that when the PGE 2 production was inhibited by the PG-inhibitor indomethacin, exercise-induced suppression of the NK cell activity and B cell function was attenuated (Tvede et al., 1989; Pedersen et al., 1990). The possibility that n-3 fatty acids may diminish the exercise239


induced cytokine response h a s not been investigated and there are no published h u m a n exercise studies evaluating the role of lipids in abolishing post-exercise immunosuppression. Anti-Oxidants Anti-oxidants m a y in theory neutralize the reactive species which are produced by neutrophih'c leukocytes during phagocytosis.(Babior, 1984; Hemila, 1992). Using a double blind placebo design, Peters (Peters et al., 1993) evaluated the effect of vitamin C on the incidence of URTI during the two week period follomng the 90k m Comrades ultramarathon. The URTI incidence was 68% in the placebo group, w h e r e a s only 33% reported URTI w h e n taking a 600 mg v i t a m i n C supplementation daily for 3 weeks prior to the race. In another study Peters et al (1992) found that vitamin A supplementation had no effect on the incidence of URTI in marathoners. Only one study (Nieman et al., 1997) h a s evaluated the effect of vitamin C on lymphocyte function and stress h o r m o n e levels. Supplementation with vitamin C did not influence leukocyte subsets, NK cell activity, lymphocyte proliferative responses, granulocyte phagocytosis and activated burst, catecholamines and cortisol.

Ageing and Immune Function Ageing is characterized by a decline in the ability of individuals to a d a p t to environmental stress (Makinodan & Marguerite, 1980; Miller, 1989; Miller, 1996). Ageing is associated with a functional decline in several components of the i m m u n e system. As a result, the elderly are more vulnerable, and are at increased risk of obtaining infectious diseases, tumorigenesis, and a u t o i m m u n e disorder (Armstrong, 1990). T Cells One of the most strfldng features of immunosenescence is t h y m u s involution. In h u m a n s , the thymus begins to involute at early stage of life, and the process is completed b y mid life. Many age-related changes in the i m m u n e system can be related to the loss of thymic and T cell function. The involuted t h y m u s h a s only a limited capacity to provide the circulation with "naive" T cells. There is t h u s a significant decrease in "naive" T cells relative to "memory" T cells. Positive and negative intrathymic T cell selection is compromised in the elderly and consequently leads to the appearance of anti-self-reactive T cells and T cells that do not express self-major histo compatibility (MHC)-restricted antigen recognition (Shinkai et al., 1996). The n u m b e r of cells that arrive in the periphery from the thymus is, however, m u c h too low to account for peripheral turnover and essentially nothing is known about the effects of aging on the very substantial self-renewal process in the peripheral i m m u n e system. Peripheral T cells are capable , in the abscence of thymic influence, of at least a 105 -fold expansion in vivo (Miller, 1996). The elderly have been shown to have a low total lymphocyte count. Within the T cell subsets, both CD4 ÷ and CD8 ÷ cells decrease with age, b u t is more pronounced regarding CD8 +T cells showing an age-related increase of CD4÷/CD8 + ratio (Utsuyama et al., 1992). Moreover ageing leads to a n increase in "memory" cells CD45R0 ÷ T cells at the expense of "naive" CD45RA ÷ (i.e., virgin, previously unstiinulated) T cells. This change h a s been documented in circulating CD4 ÷ and CD8 ÷ T cells (Shinkai et al., 1996). The age associated shift in T cell phenotype

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m a y largely be responsible for the age-related decline in responsiveness to mitogens in vitro and new antigens in vivo (Miller, 1996). The T cell functions decline with age, as shown in vivo by tests of cutaneous delayed type hypersensitivity (DTH) and in vitro by mitogen-stimulated proliferation. The T cells show a decreased proliferation w h e n stimulated with mitogens (Miller, 1996). The production of IL-2 and the expression of the high-affinity receptor decreases with age and, as a consequence, the T cells show a decreased ability to proliferate. The activity of cytotoxic T lymphocyte (CTL) declines with age. This can be attributed not only to the reduced n u m b e r and proliferative capability of CD8 ÷ T cells, b u t also to the reduced expression with age of genes coding for perforin and two CTL-associated serine esterases (Shinkai et al. 1996). Effros et al. (1994) compared T lymphocytes of centenarians and younger controls for the cell surface expression of CD28 ÷, a costimulatory molecule t h a t is required for optimal activation and proliferation following engagement of the T cell. They found a significant decrease in the expression of CD28 ÷ in the elderly compared to the younger controls. B Cells The data on h u m a n blood B cell n u m b e r s are in conflict, with one group finding no evidence for any effect of age (Utsuyama et al., 1992) and a second (Paganelli et al., 1992) reporting a 4-fold decline in adult life. A third group (Hoffkes et al., 1996) showed that the CD19+CD5 ÷ B cell subset was decreased in the elderly patients. It is generally reported that B cell function is only marginally affected by the ageing process (Ben-Yehuda & Weksler, 1992; Ennist et al., 1986). As T cell function and activity are adversely affected with age, regulation of B cell flmction by dysfunctional T cell m e c h a n i s m s likely contribute to this observation. An optimal h u m o r a l i m m u n e response requires the cooperation of b o t h B cells and T cells. Many of the cofactors that are needed b y the B cells to secrete immunoglobulins are produced by T cells and as a consequence m a n y of the changes seen in B cells are related to the loss in T cell flmction (Miller, 1996; Miller, 1991). Although there is a clear loss with age in the ability to produce antibody in response to new encountered antigens, it is uncertain to what extent this decline reflects intrinsic changes in B cell function (Miller, 1996). Much of the decline in h u m o r a l immunity is associated with changes in the activities o f T cells, including T cell expression of CD40L, a key factor in contact-dependent B cell activation through the cell surface CD40 ÷ protein. The elderly have shown a n increase in the s e r u m concentrations of autoantibodies, but these are typically of low titre (Miller, 1996). NK Cells

When looking at NK cell n u m b e r and activity in the spleen from both mice and rats, there is a clear and consistent age-associated decline in NK cell n u m b e r and activity (Nasrullah & Mazzeo, 1992; Saxena et al., 1984; Weindruch et al., 1983). However, w h e n examining peripheral blood NK cell activity in h u m a n s , it is frequently reported that no age-associated change is found (Ferguson et al., 1995; Ligthart et al., 1986; Murasko et al., 1986) and in some cases a n increase in NK cell n u m b e r and activity have been observed (Xu et al., 1993; Sansoni et al., 1993; Batory et al., 1981; Krishnaraj & Blandford, 1988; Krishnaraj & Blandford, 1987). One study (Facchini et al., 1987) described that the activity af NK cells (expressed per cell basis) decreases with age. 241


The Acute Phase Response in the Elderly Ageing is associated with immune activation and changes in the balance of cytokine secretion patterns (Miller, 1996; Fagiolo et al., 1992; Hobbs et al., 1993; Bruunsgaard et al., 1999). The s e r u m / p l a s m a concentrations of IL-6 (Wei et al., 1992; J a m e s et al., 1997; Hager et al., 1994; Kania et al., 1995; Ershler et al., 1993; Bruunsgaard et al., 1999) and TNF-c( (Bruunsgaard et al., 1999) have been reported to increase with age whereas others have found unaltered or undetectable IL-6 (Peterson et al., 1994), TNF-a (Fagiolo et al., 1992; Peterson et al., 1994; Catania et al., 1997; Mooradian et al., 1990) and IL-1 (Catania et al., 1997; Mooradian et al., 1990).

Nutrition and Ageing Given the fact that many of the protective immune responses are impaired in old age (De Weck, 1992; Pawelec et al., 1995), that nutritional deficiencies occur commonly in the elderly (Chandra, 1989) and that nutrition is a critical determinant of immunocompetence, it has been questioned whether a causal relationship exists between nutrition, immunity and infection in old age. Supplementation with selected nutrients may improve the immune system. Thus, Meydani (1995) showed t h a t both short- and long-term vitamin E supplementation enhanced the lymphocyte proliferative response, delayed type hypersensitivity and IL-2 production in healthy elderly subjects. However, the use of a single nutrient in large doses may lead to secondary alterations in requirements, to malabsorbtion of other nutrients, and in some instances, to impaired immune responses. Thus excessive intake of zinc (Chandra, 1984) or vitamins E and D (Payette et al.. 1990) were associated with impairment of the cellular immune response. Watson et al (1991) showed that supplementation with varying levels of B-carotene increased the n u m b e r of CD4 ÷ cells, NK cells and IL2 receptor expression on BMNC when the level of ~-carotene supplementation was greater than 30 m g / d a y for 2 months. The increase in NK cells and IL-2 receptor was dose dependent and the immunomodulation coincided with an increased level of plasma ~-carotene, b u t not plasma retinol. Recently, Chandra (1992) tested the hypothesis that an optimum intake of all essential micronutrients in physiological a m o u n t s would result in an improvement in immune response and reduce the frequency of infection in old age. Ninety-six healthy elderly subjects were randomly assigned to receive nutrient supplementation or placebo. The subjects were followed for 12 months. It was found that the subjects in the supplementation group had higher numbers of certain T cell subsets and NK cells, enhanced proliferative response to mitogens, increased IL-2 production, higher antibody response and increased NK activity. Furthermore, the groups receiving supplementation were less likely to have illness due to infections than those in the placebo group (23 versus 48 days). Regarding the immune system and lipid metabolism, indirect evidence exists that the natural immunity m a y be enhanced by n-3 fatty acids and suppressed by n-6 fatty acids. Several reports indicate that formation of PGE2 increases with ageing, and an increase in the sensitivity of the lymphoeytes from elderly subjects to the inhibitory effects on proliferation by PGE 2 has been shown. (Goodwin & Messner, 1979). Therefore, PGE2-induced suppression of cell-mediated immunity by administration of n-6 fatty acids may be of special relevance to the elderly subjects a n d in theory, diets rich in n-3 fatty acids may enhance the immune

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system in elderly subjects.

Exercise; Ageing and Immune Function Given that a n u m b e r of age-related changes occur in m a n y s y s t e m s (e.g. neuroendocnne) known to alter i m m u n e function b o t h at rest and during exercise, it would be of value to learn the extent to which both acute and chronic exercise influence i m m u n e function in the elderly (Mazzeo, 1994). Acute Exercise While few studies have been performed to date, recent evidence suggests that the ability of the i m m u n e system in older individuals to respond to the stress imposed from a single b o u t of exercise is maintained with age. Mazzeo et al. (1996) have investigated the effect of a single b o u t of exercise on i m m u n e function in young (23 _+2 years) and elderly (69 _+4 years) subjects. The subjects were studied before and immediately after 20 min of supine cycle exercise performed at 60% of peak capacity. The results from his study showed that in response to exercise the young subjects showed a significant decrease in PHA proliferative capacity, demonstrating that the acute b o u t of exercise, at that intensity and duration, was immunosuppressive. The PHA responsiveness was significantly lower for the elderly before performing the exercise test compared with the young subjects, b u t did not decline significantly as a result of exercise. This study indicates that immunoresponsiveness to a single b o u t of exercise differed across age groups. Fiatarone et al. (1989) examined the effect of age on the responsiveness of NK cells to in vivo stimulation with exercise in 8 young (30 _+ 1 years) a n d 9 old (71 _+ 1 years) subjects. The old subjects were not found to have NK cell n u m b e r s and function that were significantly different from the young subjects at baseline. In response to maximal bicycle exercise, both groups showed a n increase in the NK activity. A similar result was found by Solomon (1991) who examined the effect of a maximal ergometry exercise test on NK activity and found an increase in NK activity and n u m b e r s in both the young and the old group. Crist et al. (1989) have also examined the effect of a single b o u t of treadmill exercise in elderly women on NK cells. One group of the elderly participated in 16 weeks of aerobic training, while the other group of elderly subjects was age-matched sedentary controls. Women participating in the training showed increases in NK activity at rest when compared with the sedentary controls. An acute b o u t of treadmill exercise produced a n increase in NK activty in both groups; however, the increase was more significant in the trained group compared with controls. Chronic Exercise A limited n u m b e r of studies has addressed the effect of endurance training adaptations on i m m u n e function in older individuals. Nieman et al. (1993) examined the effect of 12 weeks of walking (5 d / w e e k at 60% heart rate reserve) and found no effect on basal NK activity and T cell function in previously sedentary elderly women (73 +_ 1 years). T cell fimction and NK activity were significantly greater in a group of highly conditioned female endurance competitors (73 _+2 years) when compared with age-matched sedentary controls, but remained below the level for the young, sedentary women. These data show a difference in i m m u n e function between m o d e r a t e l y trained a n d highly conditioned women. The m e c h a n i s m s responsible for this difference are uncertain, b u t m a y be related to differences in the training intensity, duration, 243

Exercise and the immune System

-and frequency. Alternatively, the age at which the training is initiated could be an important factor because the highly conditioned women had begun exercising at a younger age (Mazzeo, 1996). Shinkai et al. (1996) have examined the effect of exercise on immunosenescence in men. A cross-sectional survey examined whether habitual endurance exercisers retained a higher level of T cell function t h a n sedentary persons in old age. Compared with the young subjects, b o t h groups of elderly had lower circulating CD3 + and CD8 ÷ cell counts, higher CD4+/CD8 + ratio and higher percentages of activated CD3 ÷ and "memory" CD4 ÷ and CD8 ÷ cells. Moreover, a comparison between the active and sedentary elderly groups showed no differences in circulating counts of i m m u n o c o m p e t e n t cells. However, the active elderly subjects demonstrated significantly greater proliferative responses to phytohemagglutinin and to pokeweed mitogen. These results indicate that endurance training in later life is associated with a lesser age-related decline in certain aspects of circulating T cell function. Rail et al. (Rail et al. 1996) did not fred any changes in BMNC subsets, production of IL-113, TNF-a, IL6, IL2 or PGE2 production, lymphocyte proliferation or delayed type hypersensitivity response after 12 weeks of high intensity training progressive resistance training in 8 healthy young (22-30 yr) and 8 healthy elderly (65-80 yr) subjects. Rincon et al. (Rincon et al., 1996) investigated the effect of an exericse intervention program of 60 min, 3 times a week for three months in 6 frail 70 years ~ males at risk for falling, but not suffering from serious medical problems compared with 7 controls h a ~ n g no intervention. Cytotoxic activity of NK cells significantly decreased during the course of the study suggesting that exercise had an adverse effect on NK activity in the very frail elderly. Another type of exercise was performed by Xusheng et al. (1989). They investigated the effect of practicing Taichiquan (style 88) exercise, a traditional Chinese keep-fit exercise. 30 (15 female 60 + 1 and 15 male 64 _+ 1 years) elderly participated in the Taichiquan exercise and 30 age-matched subjects served as controls. At rest, the total n u m b e r of T lymphocytes and the n u m b e r of active T lymphocytes were increased significantly in the exercise group when compared with controls. Immediately after a bout of Taichiquan exercise, a marked increase of active T lymphocytes occurred. Xusheng et al. (1990) also determined the percentage and counts of zymosan-complement complex rosette forming (B) cells and found at rest t h a t the percentage in the Taichiquan exercise group was significantly lower than that of the age-matched controls. There was no significant difference observed between exercise group and control group for the n u m b e r of ZC rosettes at rest. Immediately following a set of Taichiquan exercise the percentage and the counts were significantly increased. Animal Studies While results from animal studies can be more extensive, there are very few studies available. Ferrba-adez and De la Fuente (1996) m e a s u r e d antibodydependent cellular cytotoxicity (ADDC) and NK cell activity in leucocytes from 20 young (12 weeks) and 20 old (60 weeks) BALB/c mice which had performed moderate swimming until exhaustion (Facchini et al., 1987). Acute exercise produced a significant stimulation of ADCC capacity only in aged animals whereas there was no difference in NK cell activity with regard to both young and old animals. In the s a m e study 20 old and 20 young mice performed 90 minutes 244


daffy moderate swimming for 20 days resulting in higher ADCC in both age groups. There was no difference in cytotoxic activities at baseline between the groups. Thus, ageing did not seem to induce a decrease in cytotoxic activities during acute or chronic exercise. In a study by Barnes et al. (1991), old Fischer344 rats were given endurance training for a 10-week period. Old rats had a poorer antibody response t h a n young animals; however, exercise training did not influence the antibody production to specific antigen. Pahlavani et al. (1987) investigated the role of exercise training on immunosenescence in male Fischer344 rats. Rats of four different age groups were examined (1,6,12 a n d 18 months of age, initially) after a 6 m o n t h s training program. An age-related decline was found in both unstimulated, mitogen-stimulated proliferation and IL-2 synthesis. It was concluded that exercise training prevented neither the age-related decline in lymphocyte proliferation nor the IL-2 production. Furthermore, training had an adverse effect on mitogen-induced proliferation and for IL-2 production b u t only in the younger animals. In another study Nasrulla and Mazzeo (1992) measured mitogen-stimulated lymphocyte proliferation, IL-2 production and NK cell cytotoxicity in splenocytes from 1-, 17- and 27-month old Fischer-344 male rats. Mitogen-induced proliferation a n d IL-2 production were found to decrease significantly with age in both trained a n d untrained animals. Training significantly reduced proliferation and IL-2 production in younger animals. This is in accordance with the findings by Lin et al. (1993). However, the proliferative response and the IL-2 production were found to increase in response to training in the old animals compared with the age-matched controls. The NK cell activity declined significantly with age and training did not alter this response. The latter finding is in contrast to several other animal studies in young animals, which have shown increased resting levels of NK cell activity in response to training. (MacNefl & Hoffman-Goetz, 1993; MacNefl & Hoffinan-Goetz, 1993; MacNefl & Hoffman-Goetz, 1993; HoffmanGoetz et al., 1994; Hoffman-Goetz et al., 1992).

Exercise; Nutrition and Ageing In a study of the age-related response of neutrophils and muscle damage to eccentric exercise Cannon et al. (1990) examined 55 year old subjects. The subject groups were further divided in a double-blind placebo-controlled protocol, which examined the influence of 48 days of dietary vitamin E supplementation before the exercise. All subjects were monitored for 12 days after exercise. Dietary supplementation with vitamin E tended to eliminate the differences between the two age groups, primarily b y increasing the responses of the older subjects. In another study Cannon et al., (1995) attempted to test if dietary modification of fatty acids influenced neutrophil and monocyte secretion after an in vivo inflammatory stress in older h u m a n subjects. In vivo neutrophil degranulation was assessed by p l a s m a elastase concentrations and monocyte function was assessed by IL-I~ secretion in vitro. In response to eccentric exercise, older subjects (>60 yr) taking placebo had no apparent elastase response whereas those taking fish oil supplements responded with a significant increase (142%) increase in plasma elastase similar to responses of younger reference subjects. The s a m e group investigated the influence of da_maging eccentric exercise on in vitro production and plasma concentrations of cytokines and their relationship to 245


muscle breakdown. In a double-blind placebo-controlled study they examined the Effect of vitamin E supplementation for 48 h o u r s on the exercise-induced acute phase response. The volunteers were either young (25 years) or elderly (65 years) sedentary men. They performed 45 min of eccentric exercise (downhill treadmill running). Twenty-four hours after this single session of eccentric exercise, endotoxin-induced secretion of IL-1[~ was augmented in cells obtained from the placebo subjects, b u t no significant effect was observed in cells from the vitamin E-supplemented subjects (Cannon et al. 1991). The finding by Cannon et al. (1991) that IL-l[3 and TNFa secretion was increased the morning after exercise without any current changes in mononuclear cell n u m b e r s indicate that the monocytes are activated in relation to eccentric exercise. The effect of vitamin E on IL-l[3 and IL-6 could not be ascribed to changes in prostaglandin (PGE2) (Cannon et al., 1991). Oxygen radicals enhance endotoxin-induced IL-l[3 production. (Kasama et al., 1989). Furthermore, the concentration of these reactants increases with exercise (Davies et al., 1982). Thus, the effects of vitamin E on the secretion of IL-113 are consistent with a m e c h a n i s m involving oxygen radicals. No studies have m e a s u r e d the influence of anti-oxidants on p l a s m a cytokines, which m a y be a better reflection of the in vivo situation.

Conclusion I m m u n o c o m p e t e n t cells are mobilized to the circulation during an acute b o u t of exercise. The ability of the i m m u n e system to respond to a single bout of exercise seems to be maintained in the elderly, but there is little information about the function of the cells that are mobilized in response to exercise in old versus young individuals. It is not possible to conclude whether an endurance training program alters the age-related decline in i m m u n e function. The major reason for this uncertainty is related to the scarcity of data addressing the issue of exercise and i m m u n e function in elderly. There is especially a lack of h u m a n studies. The available data suggest that although age-related decline in i m m u n e function can be retarded, the greatest effect will be seen only in very highly conditioned subjects. Several studies suggest that there is a link between nutrition and i m m u n e function. Supplementation studies indicate that age-related immunodeficiency is partly due to undernutrition or malnutrition. The immunodeficiency has been shown to be partly abolished by refeeding and by small doses of vitamins. In theory n-3 fatty acids m a y enhance age-related i m m u n e flmction and improve resistance to infections. Few studies have addressed the potential protective role of dietary s u p p l e m e n t a t i o n in exercise-induced i m m u n o suppression and muscle pain. Exercise-related i m m u n o s u p p r e s s i o n in animals was attenuated by a diet rich in n-3-fatty acids. Conflicting results exist regarding the ability of anti-oxidant supplementation to decrease the incidence of post-race URTI symptoms. However, vitamin E m a y inhibit the acute phase response in eccentric exercise. Glutamine supplementation h a s not been effective in abolishing post-exercise suppression of the i m m u n e system. Carbohydrate loading diminished the hormonal and i m m u n e responses to exercise, b u t did not abolish post-exercise suppression. The effect of carbohydrate supplementation on the risk of obtaining post-exercise infections awaits further research. Even though it is difficult to evaluate the individual health b e n e f t s of attenuating age- and exercise-related immunodeficiency by nutritional supplementation, the total benefit to the health of the population m a y be substantial.

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References Ardawi, M.S. & Newsholme, E.A. {1984) Intracellular localization and properties of phosphatedependent glutaminase in rat mesenteric lymph nodes. Biochem. J, 217, 289-296. Armstrong, R.B. (1990) Initial events in exercise-induced muscular injury. Med. Sci. Sports Exerc. 22, 429-435. Babior, B.M. (1984) Oxidants from phagocytes: agents of defense and destruction. Blood 64, 959-966. Bagby, G.J., Crouch, L.D., & Shepherd, R.E. (1996) Exercise and cytokines: spontaneous and elicited responses. In: Hoffman-Goetz, L. (Ed.) Exercise and Immune Function, pp.55-78. New York: CRC Press. Baj, Z., Kantorski, J., Majewska, E., Zeman, K., Pokoca, L., Fomalczyk, E., Tchorzewski, H., Sulowska, Z., & Lewicki, R. (1994) Immunological status of competitive cyclists before and after the training season. Int. J. Sports Med. 15, 319-324. Barnes, C.A., Forster, M.J., Fleshner, M., Ahanotu, E.N., Laudenslager, M.L., Mazzeo, R.S., Maier, S.F., & Lal, H. (1991) Exercise does not modify spatial memory, brain autoimmunity, or antibody response in aged F-344 rats. Neurobiol. Aging 12, 47-53. Batory, G., Benczur, M., Varga, M., Garam, T., Onody, C., & Petranyi, G.G. (1981) Increased killer cell activity in aged humans. Immunobiology.158, 393. Ben-Yehuda, A., & Weksler, M.E. (1992) Immune senescence: mechanisms and clinical implications. Cancer Invest 10, 525-531. Benquet, C., Krzystyniak, K., Savard, R., & Guertin, F. (1994) Modulation of exercise-induced immunosuppression by dietary polyunsaturated fatty acids in mice. J. Tox. Environm. Health 43, 225-237. Brines, R., Hoffman-Goetz, L., & Pedersen, B.K. (1996) Can you exercise to make your immune system fitter? Immunol. Today 17, 252-254. Bruunsgaard, H., Andersen-Ranberg, K., Jeune, B., Pedersen, A.N., Skinhj, P., & Pedersen, B.K. (1999) A high plasma concentration of TNFalpha is associated with dementia in centenarians. J. Gerontology (In Press). Bruunsgaard, H., Galbo, H., Halkjaer-Kristensen, J., Johansen, T.L., MacLean, D.A., & Pedersen, B.K. (1997) Exercise-induced increase in interleukin-6 is related to muscle damage. J. Physiol. Lond. 499, 833-841. Cannon, J.G., Evans, W.J., Hughes, V.A., Meredith, C.N., & Dinarello, C.A. (1986) Physiological mechanisms contributing to increased interleukin-1 secretion. J. Appl. Physiol. 61, 1869-1874. Cannon, J.G., Fiatarone, M.A., Meydani, M., Gong, J., Scott, L., Blumberg, J.B., & Evans, W.J. (1995) Aging and dietary modulation of elstase and interleukin-1 beta secretion. Am. J. Physiol. 268, R208-R213. Cannon, J.G., & Kluger, M.J. (1983) Endogenous pyrogen activity in human plasma after exercise. Science 220, 617-619. Cannon, J.G., Meydani, S.N., Fielding, R.A., Fiatarone, M.A., Meydani, M., Farhangmehr, M., Orencole, S.F., Blumberg, J.B., & Evans, W.J. (1991) Acute phase response in exercise. II. Associations between vitamin E, cytokines, and muscle proteolysis. Am. J. Physiol. 260, R1235-R12340. Cannon, J.G., Orencole, S.F., Fielding, R.A., Meydani, M., Meydani, S.N., Fiatarone, M.A., Blumberg, J.B., & Evans, W.J. (1990) Acute phase response in exercise: interaction of age and vitamin E on neutrophfls and muscle enzyme release. Am. J. Physiol. 259, R1214-R1219. Catania, A., Airagi, L., Motta, P., Manfredi, M.G., Annoni, G., Pettenati, C., Brambilla, F., & Lipton, J.M. (1997) Cytokine antagonists in aged subjects and their relation with cellular immunity. J. Gerontol. A. Biol. Sci. Med. Sci 52, B93-B97. Chandra, R.K. (1984) Excessive intake of zinc impairs immune responses. JAMA 252, 1443-1446. Chandra, R.K. (1989) Nutritional regulation of immunity and risk of infection in old age. Immunology 67, 141-147. Chandra, R.K. (1992) Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subject. Lancet 1124-1127. Crist, D.M., Mackinnon, L.T., Thompson, R.F., Atterbom, H.A., & Egan, P.A. (1989) Physical exercise increases natural cellular-mediated tumor cytotoxity in elderly women. Gerontology 35, 66-71. Davies, K.J.A., Packer, L., & Brooks, G.A. (1982) Free radicals and tissue produced by exercise. Biochem. Biophys. Res. Commun. 107, 1198-1205. De Weck, A.L. (1992) Immune response and aging. In: Munro, H. & Schlierf, G. (Eds.) Constitutive and environmental aspects, pp. 89-95. New York: Raven Press. Effros, R.B., Boucher, N., Porter, V., Zhu, X., Spauling, C., Walford, R.L., Kronenberg, M., Cohen, D., & Sch~ichter, F. (1994) Decline in CD28+ T cells in cenenarians and in long-term T cell cultures: A possible cause for both in vivo and in vitro immunosenescence. Exp. Gerontol. 29, 601-609.

247

Exercise and the Immune System -Ennist, D.L., Jones, K.H., & St.Pierre, R.L. (1986) Functional analysis of the immunosenescence of the h u m a n B cell system: Dissociation of normal activation and proliferation from impaired terminal differentiation into IgM immunoglobulin-seerei~g cells, d immunol 136, 99-105. Ershler, W.B., Sun, W.H., Binkley, N., Gravenstein, S., Volk, M.J., Kamoske, G., Klopp, R.G., Roecker, E.B., Daynes, R.A., & Weindruch, R. (1993) Interleukin-6 and aging: blood levels and mononuclear cell production increase with with advancing age and in vitro production in modifiable by dietary restriction. Lymphokine Cytokine Res 12, 225-230. Essen, P., Wernerman, J., Sonnenfeld, T., Thunel], S., & Vinnars, E. {1992} Free amino acids in plasma and muscle during 24 hours post- operatively - a descriptive study. Clin. Physiol. 12, 163-177. Evans, W.J., Meredith, C.N., Cannon, J.G., Dinarello, C.A., Frontera, W.R., Hughes, V.A., Jones, B.H., & Knuttgen, H.G. {1986) Metabolic changes following eccentric exercise in trained and untrained men. J. Appl. Physiol, 61, 1864-1868. Facchini, A., Mariani, E., Mariani, A.R., Papa, S., Vitale, M., & Manzoli, F.A. (1987) Increased number of circulating Leu 11+ (CD16) large granular lymphocytes and decreased NK activity dunng h u m a n ageing. Clin Exp Immunol 68, 340-347. Fagiolo, U., Cossarizza, A., Santacaterina, S., Ortolani, C., Monti, D., Paganelli, R., & Franceschi, C. (1992) Increased cytokine production by peripheral blood mononuclear cells from healthy elderly people. Ann. N. Y. Acad. Sci. 663, 490-493. Ferguson, F.G., Wikby, A., Maxson, P., Olsson, J., & Johansson, B. (1995) Immune parameters in a longitudinal study of a very old population of swedish people: a comparison between survivors and nonsurvivors, d, Gerontol. 50A, B378-B382. Ferrandez, M.D., & De-la, F.M. (1996) Changes with aging, sex and physical exercise in munne natural killer activity and antibody-dependent cellular cytotoxicity. Mech. Ageing Dev. 86, 83-94. Fiatarone, M.A., Morley, J.E., Bloom, E.T., Benton, D., Solomon, G.F., & Makinodan, T. (1989) The effect of exercise on natural killer cell activity in young and old subjects. J. Gerontol. 44, M37 Fitzgerald, L. (1988) Exercise and the immune system. Immunol. Today 9, 337-339. Fitzgerald, L. (1991) Overtraining increases the susceptibility to infection. Int. d. Sports Med. 12, $58. Goodwin, J.S., & Messner, R.P. (1979) Sensitivity of lymphocytes to prostaglandin E2 increases in subjects over age 70. J. Olin. Invest. 64, 434-439. Hack, V., Strobel, G., Weiss, M., & Weicker, H. (1994) PMN cell counts and phagocytic activity of highly trained athletes depend on training period. J. Appl. Physiol. 77, 1731-1735. Hager, K., Machein, U., Krieger, S., Platt, D., Seefreind, G., & Bauer, J. (1994) Interleukin 6 and seleeted plasma proteins in healthy persons of different ages. Neurobiol. Aging 15, 771-772. Hemila, H. (1992) Vitamin C and the common cold. Br. d. Nutr. 67, 3-16. Hobbs, M.V., Weigle, W.O., Noonan, D.J., Torbett, B.E., McEvilly, R.J., Koch, R.J., Cardenas, G.J., & Ernst, D.N. (1993) Patterns of cytokine gene expression by CD4 + T cells from young and old mice. J Immunol. 150, 3602-3614. Hofikes, H.G., Schmidtke, G., Uppenkamp, M., & Schmucker, U. (1996) Multiparametric immunophenotyping of B ceils in peripheral blood of healthy adults by flow cytometry. Clin. Diag. Lab. Immunol. 3, 30-36. Hoffman-Goetz, L., Arumugam, Y., & Sweeny, L. (1994) Lymphokine activated killer cell activity following voluntary physical activity in mice. J. Sports Med. Phys. Fit. 34, 83-90. Hoffman-Goetz, L., MacNeil, B., Arumugam, Y., & Randall Simpson, J. (1992) Differential effects of exercise and housing condition on murine natural killer cell activity and tumor growth. Int. J. Sports Med. 13, 167-171. Hoffman-Goetz, L., & Pedersen, B.K. (1994} Exercise and the immune system: a model of the stress response? Immunol. Today 15, 382-387. James, K., Premchand, N., Skibinska, A., Skibinski, G., Nicol, M., & Mason, J.I. (1997) I1-6, DHEA and the ageing proces. Mech Ageing Dev 93, 15-24. Johnson, J.A., 3d, Griswold, J.A., & Muakkassa, F.F. (1993) Essential fatty acids influence survival in sepsis. J. Trauma. 35, 128-131. Kania, D.M., Binkley, N., Checovich, M., Havighurst, T., Schilling, M., & Ershler, W.B. (1995) Elevated plasma levels of interleukin-6 in postmenopausal women do not correlate with bone density. J. Am. Gerlattr. Soc. 43, 236-239. Kappel, M., Stadeager, C., Tvede, N., Galbo, H., & Pedersen, B.K. (1991) Effects of in vivo hyperthermia on natural killer ceil activity, in vitro proliferative responses and blood mononuclear cell subpopulations. Clin. Exp. Immunol. 84, 175-180. Kasama, T.K., Kobayashi, T., Fukushima, M., Tabata, M., Ohno, I., Negishi, M., Ide, H., Takahashi, T., & Niwa, Y. (1989) Production of interleukin I-like factor from h u m a n peripheral blood monocytes

248

Exerciseand the Immune System and polymorphonuclear leukocytes by superoxide anion: the role of interleukin 1 and reactive oxygen species in inflamed sites. Immunol, Immunopathol. 53, 439-448. Keast, D. (1996) Immune responses to overtraining and fatigue. In: Hoffman-Goetz, L. (Ed.) Exercise and immune function, pp. 121-142. CRC Press] Keast, D., Arstein, D., Harper, W., Fry, R.W., & Morton, A.R. (1995) Depression of plasma glutamine concentration after exercise stress and its possible influence on the immune system. Med. J. Aust. 162, 15-18. Keast, D., & Morton, A.R. (1992) Long-term exercise and immune functions. In: Watson, Eisinger. (Eds). pp. 89-120. Klokker, M., Kjaer, M., Secher, N.H., Hand, B., Worm, L., Kappel, M., & Pedersen, B.K. (1995) Natural killer cell response to exercise in humans: effect of hypoxia and epidural anesthesia. J. Appl. Physiol. 78, 709-16. Krishnaraj, R., & Blandford, G. (1987) Age-associated alterations in human natural killer cells. 1. increased activity as per conventional and kinetic analysis. Clin. Inununol. Immunopathol. 45, 268-285. Krishnaraj, R., & Blandford, G. (1988} Age-associated alterations in human natural killer cells. Cell Immunol. 114, 137-148. Lehmann, M., Huonker, M., Dimeo, F., Heinz, N., Gastmann, U., Treis, N., Steinacker, J.M., Keul, d., Kajewski, R., & Hanssinger, D. (1995) Serum amino acid concentrations in nine athletes before and after the 1993 Colmar ultra triathlon. Int. J. Sports Meal. 16, 155-159. Ligthart, G.J., van Volkhoven, P.C., Schuit, H.R.E., & Hijmans, W. (1986) The expanded null cell compartment in ageing: increase in the number of natural killer cells and changes in T-cells and NK-cell subsets in h u m a n blood. Immunology 59, 353-357. Lin, Y.S., Jan, M.S., &Chen, H.I. (1993) The effect of chronic and acute exercise on immunity in rats. Int. J. Sports Med. 14, 86-92. MacNell, B., & Hoffman-Goetz, L. (1993) Chronic exercise enhances in vivo and in vitro cytotoxic mechanisms of natural immunity in mice. J. Appl. Physiol. 74, 388-395. MacNefl, B., & Hoffman-Goetz, L. (1993) Effect of exercise on natural cytotoxicity and pulmonary tumor metastases in mice. Med. Sci. Sports Exerc. 25, 922-928. MacNefl, B., & Hoffman-Goetz, L. (1993) Exercise training and tumor metastasis in mice: influence of time of exercise onset. Anticancer Res. 13, 2085-2088. Makinodan, T., & Marguerite, M.B.K. (i980) Age influence on the immune system. Adv Immunol 29, 287-330. Mazzeo, R.S. (1994) The influence of exercise and aging on immune function. Med. Sci. Sports Exerc. 26, 586-92. Mazzeo, R.S. (1996) Exercise, immunity, and aging. In: Hoffman-Goetz, L. (Ed.) Exercise and immune function, CRC Press, pp. 199-214. McCarthy, D.A., & Dale, M.M. (1988) The leucocytosis of exercise. A review and model. Sports Med. 6, 333-363. Meydani, S.N. (1995) Vitamin E enhancement of T cell-mediated function in healthy elderly: Mechanisms of action. Nutr. Rev, 53, $52-$56. Miller, R.A. (1989) The cell biology of aging: immunological models. J. Gerontol. 44, B4-B8. Miller, R.A. (1991) Aging and immune function. Int Rev Cytol 124, 187-215. Miller, R.A. (1996) The aging immune system: primer and prospectus. Science 273, 70-74. Mooradian, A.D., Reed, R.L., Osterweil, D., Clements, N., & Scuderi, P. (1990) Lack of an association between the presence of tumor necrosis factor or interleukin- 1 alpha in the blood and weight loss among elderly patients. J. Am. Geriattr. Soc. 38, 397-401. Murasko, D.M., Nelson, B.J., Silver, R., Matour, D., & Kay, D. (1986) Immunologic response in an elderly population with a mean age of 85. Am. J. Med. 81,612-618. Nash, H.L. (1987) Can exercise make us immune to disease? Phys. Sportsmed. 250-253. Nasrullah, I., & Mazzeo, R.S. (1992) Age-related immuno senescence in Fischer 344 rats: influence of exercise training. J. Appl. Physiol. 73, 1932-1938. Nehlsen-Canarella, S.L., Fagoaga, O.R., & Nieman, D.C. (1997) Carbohydrate and the cytokine response to 2.5 hours of running. J Appl Phystol 82, 1662-1667. Newsholme, E.A. (1990) Psychoimmunology and cellular nutrition: a n alternative hypothesis [editorial). Biol. Psychiatry 27, 1-3. Newsholme, E.A. (1994) Biochemical mechanisms to explain immunosuppression in well-trained and overtrained athletes. Int. J. Sports Meal, 15, S142-7. Newsholme, E.A., & Parry Billings, M. (1990) Properties of glutamine release from muscle and its importance for the immune system. J. Parenter. EnteraL Nutr. 14, 63S-67S.

249

Exerciseand the Immune System Nieman, D.C. (1994) Exercise, upper respiratory tract infection, and the immune system. Med. Sci. Sports Exerc. 26, 128-39. Nieman, D.C. (1994) Exercise, infection, and immunity. Int. J. Sports Med. 15 (Suppl 3), S131-S141. Nieman, D.C. (1996) Prolonged aerobic exercise, immune response, and risk of infection. In: HoffmanGoetz, L. {Ed.) Exercise and immune function, CRC Press, pp. 143-162. Nieman, D.C., Buckley, K.S., Henson, D.A., Warren, B.J., Sutfles, d., Able, J.C., Simandle, S., Fagoaga, O.R., & Nehlsen CannareUa, S.L (1995} Immune function in marathon runners versus sedentary controls. Med. Sci. Sports Exerc. 27, 986-992. Nieman, D.C., Fagoaga, O.R., Butterworth, D.E., Warren, B.J., Utter, A., Davis, J.M., Henson, D.A., & Nehlsen-Canarella, S.L. (1997) Carbohydrate supplementation affects blood granulocyte and monocyte trafficking but not function after 2.5 hours of running. J Appl Physiol 82, 1385-1394. Nieman, D.C., & Henson, D.A. (1994) Role of endurance exercise in immune senescence. Med. Sci.

Sports Exerc. 26, 172-181. Nieman, D.C., Henson, D.A., Butterwo~h, D.E., Warren, B.J., Davis, J.M., Fagoaga, O.R., & Neb_lsenCanarella, S.L. (1997) Vitamin C supplementation does not alter the immune response to 2.5 hours of running. Int J Sports Nutr 7, 173-184 Nieman, D.C., Henson, D.A., Garner, E.B., Butterworth, D.E., Warren, B.J., Utter, A., Davis, J.M., Fagoaga, O.R., & Nehlsen-Cannarella, S.L. [1997) Carbohydrate affects natural killer cell redistribution but not activity after running. Med Sci Sports Exerc 29, 1318-1324. Nieman, D.C., Henson, D.A., Gusewitch, G., Warren, B.J., Dotson, R.C., Butterworth, D.E., & Nehlsen Cannarella, S.L. (1993} Physical activity and immune function in elderly women. Med. Sci. Sports Exerc. 25, 823-831. Nieman, D.C., & Pedersen, B.K. (1999) Exercise and immune function: recent development. Sports Medicine 27, 73-80. Northoff, H., & Berg, A. (1991) Immunologic mediators as parameters of the reaction to strenuous exercise. Int. J. Sports Meal. 12, $9-15. Ostrowski, K., Hermann, C., Bangash, A., Schjerling, P., Nielsen, J.N., & Pedersen, B.K. (1998) A trauma-like elevation in plasma cytokines in humans in response to treadmill running. J. Physiol. (London) 508, 949-953. Ostrowski, K., Rohde, T., Asp, S., Schjerling, P., & Pedersen, B.K. (1999) The cytokine balance and strenuous exercise: TNF-alpha, IL-2beta, IL-6, IL-lra, sTNF-rl, sTNF-r2, and IL-10. J. Physiol. (London) 515, 287-291. Ostrowski, K., Rohde, T., Zacho, M., Asp, S., & Pedersen, B.K. (1998) Evidence that IL-6 is produced in skeletal muscle during intense long-term muscle activity. J. Physiol. (London) 508, 949-953. Paganelli, R., Quinti, I., Fagiolo, U., Cossarizza, A., Ortolani, C., Guerra, E., Sansoni, P., Puciilo, L.P., Scala, E., & Cozzi, E. (1992) Clin Exp Immunol 90, 351-354. Pahlavani, M.A., Cheung, T.H., Cheskey, J.A., & Richardson, A. (1987) Influence of exercise on the immune function of rats at various ages. J. Appl. Physiol. 1997-2001. Parry Billings, M., Budgett, R., Koutedakis, Y., Blomstrand, E., Brooks, S., Williams, C., Calder, P.C., Pilling, S., Baigrie, R., & Newsholme, E.A. (1992) Plasma amino acid concentrations in the overtraining syndrome: possible effects on the immune system. Meal. Sci. Sports Exerc. 24, 13531358. Pawelec, G., Adibzadeh, M., Pohla, H., & Schaudt, K. (1995) Immunosenescence: Ageing of the immune system. Immunol. Today 16, 420-422. Payette, H., Rola Pleszczynski, M., & Ghadirian, P. (1990) Nutrition factors in relation to cellular and regulatory immune variables in a free-living elderly population [see comments]. Am. J. Clin. Nutr. 52, 927-932. Pedersen, B.K. (Ed.) Exercise Immunology, pp. 1-206. Austin,Texas, U.S.A.R.G.Landes Bioscience. Pedersen, B.K., Bmunsgaard, H., Klokker, M., Kappel, M., MacLean, D.A., Nielsen, H.B., Rohde, T., Ullum, H., & Zacho, M. (1997) Exercise-induced immunomodulation - possible roles of neuroendocrine factors and metabolic factors. Int. J. Sports Med. 18, $2-$7. Pedersen, B.K., & Nieman, D.C. (1998) Exercise Immunology: Regulation and integration. Immunol. Today (In Press). Pedersen, B.K., Tvede, N., Christensen, L.D., Klarlund, K., Kragbak, S., & Halkjaer Kristensen, J. (1989) Natural killer cell activity in peripheral blood of highly trained and untrained persons. Int. J. Sports Med. 10, 129-131. Pedersen, B.K., Tvede, N., Klarlund, K., Christensen, L.D., Hansen, F.R., Galbo, H., Kharazmi, A., & Halkjaer Kristensen, J. (1990) Indomethacin in vitro and in vivo abolishes post-exercise suppression of natural killer cell activity in peripheral blood. Int. J. Sports Med. 11, 127-131. Peters, E.M., Cambell, A., & Pawley, L. (1992) Vitamin A fails to increase resistance to upper respiratory in distance runners. S. Afr. J. Sports. Med. 3-7.

25O

Exercise and the Immune System Peters, E.M., Goetzsche, J.M., Grobbelaar, B., & Noakes, T.D. (1993) Vitamin C supplementation reduces the incidence of postrace symptoms of upper-respiratory4ract infection in ultramarathon nmners. Am. J. Clin. Nutr. 57, 170-174. Peterson, P.K., Chao, C.C., Carson, P., Hu, S., Nichol, K., & Janoff, E.N. (1994) Levels of tumor necrosis factor alpha, interleukin 6, interleukin 10, and transforming ~owth factor beta are normal in tile serum of the healthy elderly. CIin. Infect, Dis. 19, 1158-1159. Pyne, D.B., Baker, M.S., Fricker, P.A., McDonald, W.A., Telford, R.D., & Weidemann, M.J. (1995) Effects of an intensive 12-wk training program by elite swimmers on neutrophtl oxidative activity. Meal. Sci. Sports Exerc. 27, 536-542. Rail, L.C., Roubenoff, R., Cannon, J.G., Abad, L.W., Dinarello, C.A., & Meydani, S.N. (1996) Effects of progressive resistance training on immune response in aging and chronic inflammation. Med Sci Sports Exerc 28, 1356-1365. Rincon, H.G., Solomon, G.F., Benton, D., & Rubenstein, L.Z. (1996) Exercise in frail elderly men decreases natural killer cell activity. Rohde, T., Asp, S., MaeLean, D.A., & Pedersen, B.K. (1998) Competitive sustained exercise in humans, lymphokine activated killer cell activity, and glutamine - an intervention study. Ettt J Appl. Physiol. 78, 448-453. Rohde, T., MacLean, D., & Pedersen, B.K. (1998) Effect of glutamine on changes in the immune system induced by repeated exercise. Med Sci Sports Exerc 30, 856-862. Rohde, T., MacLean, D.A.. Hartkopp, A., & Pedersen, B.K. (1996) The immune system and serum glutamine during a triathlon. Eur. J. Appl. Physiol. 74, 428-434. Rohde, T., MacLean, D.A., & Pedersen, B.K. (1999) Glutamine, lymphocyte proliferation and cytokine production. Scan& J. Immtmol. (In Press) Rohde, T., MacLean, D.A., Richter, E.A., Kiens, B., & Pedersen, B.K. (1997) Prolonged submauximal eccentric exercise is associated with increased levels of plasma IL-6. Am. J. Physiol. 9.73, E85E91. Rohde, T., Ullum, H., Palmo, J., Halkjaer Kristensen, J., Newsholme, E.A., & Pedersen, B.K. (1995) Effects of glutamine on the immune system- influence of muscular exercise and H1V infection. J. Appl. Physiol. 79, 146-150. Rowbottom, D.G., Keast, D., Garcia-Webb, P., & Morton, A.R. (1997) Training adaptation and biological changes among well-trained male triathletes. Med. Sci. Sports Exerc, 29, 1233-1239. Rowbottom, D.G., Keast, D., & Morton, A.R. (1996) The emerging role of glutamine as an indicator of exercise stress and overtraining. Sports Med. 21, 80-97. Sansoni, P., Cossarizza, A., Brianti, V., Fagnoni, F., Snelli, G., Monti, D., Mareato, A., Passeri, G., Ortolani, C., & Forti, E. (1993) Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 82, 2767-2773. Saxena, R.K., Saxena, Q.B., & Aider, W.H. (1984) Interleukin-2-induced activation of natural killer cell activity in spleen cells from old and young mice. Immunology 51, 719-726. Shinkai, S., Konishi, M., & Shephard, R.J. (1996) Aging, exercise, training and the immune system. Exerc Imm Rev 3, 68-95. Solomon, G.F. (1991) Psychosocial factors, exercise, and immunity: Athletes, elderly persons, and AIDS patients. Int J Sports Med 12, $50-$52, Sprenger, H., Jacobs, C., Nain, M., Gressner, A.M., Prinz, H., Wesemann, W., & Gemsa, D. (1992) Enhanced release of cytokines, interleukin-2 receptors, and neopterin after long-distance running. Clin. InununoL Immunopathol. 63, 188-95. Tvede, N., Hellmann, C., Halkjaer Kristensen, J., & Pedersen, B.K. (1989) Mechanisms of Blymphocyte suppression induced by acute physical exercise. J. Clin. Lab. Inununol. 30, 169-173. Tvede, N,, Steensberg, J., Baslund, B., Halkjaer Kristensen, J., & Pedersen, B.K. (1991) Cellular immunity in highly trained elite racing cyclists during periods of training with high and low intensity. Scan& J. Med. Sci. Sports 1, 163-166. Ullum, H., Haahr, P.M., Diamant, M., Palmo, J., Halkjaer Kristensen, J., & Pedersen, B.K. (1994) Bicycle exercise enhances plasma IL-6 but does not change IL-lalpha, IL-lbeta, IL-6, or TNFalpha pre-mRNA in BMNC. J. Appl, Physiol. 77, 93-97. Utsuyama, M., Hirokawa, K., Kurashima, C., Fukayama, M., Inamatsu, T., Suzuki, K., Hashimoto, W., & Sato, K. (1992) Differential age-change in the numbers of CD4+CD45RA+ and CD4+CD29+ T cell subsets in human peripheral blood. Mech Ageing Dev 63, 57-68. Wallace, C., & Keast, D. (1992) Glutamine and macmphage function. Metabolism 41, 1016-1020. Watson, R., Prabhala, R., Plezia, P., & Alberts, D. (1991) Effect of beta -carotene on lymphocyte subpopulation in elderly humans: evidene for a dose response relationship. Am. J. Clin. Nutr 53, 90-94.

251

Exerciseand the Immune System Wei, J., Xu, H., Davies, J.L., & Hemmings, G.P. (1992) Increase of plasma IL-6 concentration wKh age in healthy subjects. Life S¢i. 51, 1953-1956. Weindruch, R., Devens, B.H., & Raft, H.V. (1983) Influence of dietary restriction and ageing on natural killer cell activity in mice. J. Immmlol. 130, 993-996. Xu, X., Beckman, I., Ahem, M., & Bradley, J. (1993) A comprehensive analysis of peripheral blood lymphocytes in healthy aged humans by flow cytometry. Immlmology mad Cell Biology 71, 549557. Xusheng, S., Yugi, X., & Ronggang, Z. (1990) Detection of ZC rosette forming lymphocytes in healthy aged with Taichiquan (88 style) exercise. J. Sports IVied. Phys. Fit. 30, 401-405. Xusheng, S., Yugi, X., & Yunjian, X. (1989) Determination of E-rosette-forming lymphocytes in aged subjects with Taichiquan exercise. Int. J Sports Med. 10, 217-219.

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