![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Department of Bioscience and Biotechnology, Drexel University, Philadelphia, PA 19104
2 To whom correspondence should be addressed. E-mail: eg25{at}drexel.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT LITERATURE CITED |
|---|
KEY WORDS: • protein-energy malnutrition • caloric restriction • influenza • underweight • aging
The observed interaction between nutrition and immunity predates both nutrition science and immunology as fields of study. Interest in the influence of undernutrition on the susceptibility to viral infection emerged >200 y ago with the observation that malnutrition appeared to lead to increased infection in some instances and increased resistance to infection in others (1). In time, it was generally accepted that nutritional adequacy in the host could fuel viral replication, whereas any nutritional limitation to the host would interfere with the metabolism of the virus itself (1). More recent studies further explored this host-pathogen interaction, confirming that host nutritional status not only influences host immunity and viral replication, but in doing so also directs the viral genome, thus potentially influencing selective virulence (2). Attention to nutritional status, therefore, is relevant to all aspects of infectious disease, i.e., from infection, through the course of disease and recovery, and on to subsequent infections.
Fifty years ago, Sprunt and Flanigan concluded that "...the effect of malnutrition on the resistance of an animal is dependent upon the state of the animal's nutritional reserves at the time of infection." (1) According to their data, increases in the duration and severity of nutritional depletion, as well as a decrease in fat stores, were correlated with an increase in the susceptibility of mice to influenza infection. Indeed, nearly any experimental deficiency, if severe enough, will result in impaired immunity and an increased incidence of infection (3).
The focus here is on the role of reduced energy intake on immunocompetence, which is a poorly understood process due in part to inconsistent definitions. Table 1 provides a list of relevant terms, typically applied to both the nutritional disturbance and the physiologic condition that results. Although protein-energy malnutrition (PEM)3 and starvation are generally associated with a decrease in immunity and an increased incidence of infectious disease, moderate undernutrition may have less or even an opposite effect on certain aspects of immune function. For example, energy restriction (ER) without malnutrition reduces body weight, extends the lifespan in animals, and retards the age-related decline in a number of general indices of immune function (6), including the antibody response to influenza vaccination (7).
|
Aging. A proper examination of the effects of PEM and ER on the immune response to viral infection first requires a brief review of the changes in immunity that are associated with aging (10–12) because aging has been the focus of the most consistent and extensive studies on immune dysfunction, and because studies of PEM and ER must be considered in the context of age-matched controls (Table 2). Studied extensively in our laboratory, aged humans exhibit a decrease in antibody titers to influenza vaccination (13). Aging is associated with a slight decrease in total lymphocyte number and an age-associated shift from naïve (CD45RA+) to memory (CD45RO+) CD4+ and CD8+ T cells, likely to limit the inducible T-cell response (10,11,14). In mice, basal natural killer (NK) cell function appears to remain intact with advanced age, whereas the inducible NK response decreases (15). This effect is not observed consistently in humans (11). It was postulated that decreased immunity is the reason for the observed increase in morbidity and mortality resulting from infectious agents in the elderly (9,11). However, the effects of aging on immunity are highly heterogeneous among humans, including the healthy elderly, and nutritional status was proposed as one variable that may explain differences in the incidence and pathology of infection (10,11).
|
Protein restriction can lead to compromised immunity, decreased viral clearance from the lungs, and increased mortality in influenza-infected mice (22). PEM often results in wasting (involuntary weight, muscle, and tissue losses), which is associated with a decrease in NK activity in both humans and mice (18). However, NK activity appears to be somewhat resistant to PEM if wasting is avoided (18). Similarly, in a study of experimental PEM without wasting, mice exhibited normal lymphocyte proliferation and antigen presentation (17). These observations suggest the possibility that weight loss is a critical aspect in PEM-related immune dysfunction. Refeeding, with an emphasis on protein and/or micronutrients, produced favorable results in terms of T cell proliferation, IL-2 production, delayed-type hypersensitivity, antibody response, NK activity, and most important, a decreased rate of infection (9,10,19).
Energy restriction (ER).
ER, the phenomenon described as "undernutrition without malnutrition," (23) retards aging and extends average and maximal lifespan, as first demonstrated in rats by McCay et al. in 1935 (24). Although this extension in lifespan is correlated with total energy intake regardless of nutritional composition (25), it is important to note that ER diets are nutritionally enhanced to avoid malnutrition or deficiency. An ER diet (typically 40% restricted in mice) is gradually achieved by underfeeding an isocaloric diet supplemented with protein, vitamins, minerals, and salts, usually at the expense of carbohydrate. Lifelong ER was shown to increase the mean and maximal lifespan of mice by up to 
65 and 50%, respectively, compared with a diet consumed ad libitum (AL) (26). Ongoing studies of nonhuman primates predict a comparable decrease in morbidity and mortality rates (27,28), although it is premature to determine the effects on long-term disease outcome and lifespan.
The extension of lifespan and a reduced incidence of spontaneous tumors in ER rodents promulgated early interest in the potential preservation of immune function by ER (29). ER is generally acknowledged to delay the development of immunity and maintain its function later in life (6). Most studies suggest that ER rodents maintain mitogen-stimulated T-cell proliferation, cytokine production, antibody response, and inducible NK cell activity at an advanced age (6,28) (Table 2). Certain outcomes, such as the lymphopenia and enhanced antibody response to vaccination, which are observed in mice subjected to ER (7,14), have not been confirmed in nonhuman primates (28). ER results in a consistent increase in naïve:memory T-cell subpopulations, possibly related to an increased proportion of functional T cells (14,21,28,30).
ER has produced the most convincing evidence of an increased immune response to influenza (9,31); until recently, however, studies were limited to challenge by influenza vaccine (7). We discovered an anomaly in which aged ER mice are unable to withstand primary influenza infection and die within 4–7 d postinfection (8) (Fig. 1). Due to the early time course and an observed decrease in NK activity in aged ER mice when infected with influenza (8), we suspect that ER mice do not possess the innate immunity to control primary infection while mounting a specific CD8+ T-cell response, a possible effect of ER masked by the limitations of vaccine studies. Previously, ER was shown to diminish basal splenic NK cell activity in mice by 50%, although NK response to Poly I:C injection was increased to a percentage of cytotoxicity comparable to that in young controls (32).
|
Influenza infection results in an anorexia that is believed to be mediated, at least in part, by the cytokine and chemokine milieu (35). As such, weight loss and recovery serve as useful indicators of the severity and course of infection. Our observations suggest that young and aged mice can lose up to 35% of baseline body weight and still recover from influenza infection. Any additional weight loss is not compatible with recovery. Kinetic analyses of weight loss during sublethal influenza infection indicate that the recovery of weight is concomitant with a maximal CD8+ T-cell response and viral clearance (12).
There are clearly stated health risks associated with underweight in humans (BMI < 18.5 kg/m2), including compromised immunity (36). Indeed, a history of weight loss is associated with a poor clinical prognosis in hospitalized elderly and may lead to increased infections (37). Prospective and retrospective studies suggest that low or even normal body weight predicts mortality in the elderly, whereas increased weight may have a protective effect (23). If underweight is present at the time of infection with influenza virus, energy stores might not be sufficient to withstand the combined reduction in energy intake and increased energy demand associated with the infection. Aged ER mice are underweight compared with AL mice, such that weight loss during the first 4 d of influenza infection resulted in an average body weight equal to the critical weight that predicts mortality in aged AL mice (8) (Fig. 1). Voluntary ER in humans also results in underweight in some cases (38), although the potential influence of ER on the immune response to viral infection in humans remains entirely unknown.
Summary. Aging and PEM with wasting are associated with similar and cumulative defects in innate and cell-mediated immunity and an increased incidence of infection. Although the preponderance of evidence suggests that ER maintains immune function at an advanced age, including in response to immunization, more recent data clearly indicate impairment in the immune function of aged ER mice after primary influenza infection. This observation supports the notion that immunization can no longer serve as the sole indicator of the immune response to viruses (12). Further, if applicable to the human circumstance, these data have clear implications for elderly individuals at high risk for reduced energy intake resulting from social, physical, economic, and emotional obstacles to eating (39). Infection is associated with both an increase in energy demands and an anorexia that decreases energy intake. Underweight, therefore, may contribute to a poor prognosis in infection by exacerbating this energy deficit, thus negating the spectrum of health benefits attributed to ER and the maintenance of a low body weight. The potential consequences of underweight in response to infection must be addressed in future proposals on the therapeutic benefits of ER in humans (37,40) and in consideration of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE), a series of human clinical trials initiated by the National Institute on Aging in 2002. Immediate action is warranted to determine the metabolic, physiologic, and immune changes associated with ER that may affect the outcome to primary viral infection. Future studies should evaluate the kinetics of innate and cell-mediated immunity, viral clearance, and recovery in ER mice and investigate the effects of refeeding before infection to delineate the roles of weight and energy status on the immune response to primary viral infection.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
3 Abbreviations used: AL, ad libitum; CTL, cytotoxic T lymphocyte; ER, energy restriction; NK, natural killer; PEM, protein-energy malnutrition.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTLITERATURE CITED |
|---|
1. Sprunt DH, Flanigan CC. The effect of malnutrition on the susceptibility of the host to viral infection. J Exp Med. 1956;104:687–706.
2. Beck MA, Handy J, Levander OA. Host nutritional status: the neglected virulence factor. Trends Microbiol. 2004;12:417–23.[Medline]
3. Scrimshaw NS, SanGiovanni JP. Synergism of nutrition, infection, and immunity: an overview. Am J Clin Nutr. 1997;66:464S–77.
4. Insel P, Turner RE, Ross D, editors. Nutrition. Sudbury, MA: Jones & Bartlett; 2002
5. Shils ME, Olsen JA, Shike M, Ross AC, editors. Modern nutrition in health and disease. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2005
6. Pahlavani MA. Energy restriction and immunosenescence: a current perspective. Front Biosci. 2000;5:d580–7.
7. Effros RB, Walford RL, Weindruch R, Mitcheltree C. Influences of dietary restriction on immunity to influenza in aged mice. J Gerontol. 1991;46:B142–7.
8. Gardner EM. Energy restriction decreases survival of aged mice in response to primary influenza infection. J Gerontol A Biol Sci Med Sci. 2005;60:688–94.
9. Meyer KC. The role of immunity in susceptibility to respiratory infection in the aging lung. Respir Physiol. 2001;128:23–31.[Medline]
10. Lesourd B. Nutrition: a major factor influencing immunity in the elderly. J Nutr Health Aging. 2004;8:28–37.[Medline]
11. Murasko D, Gardner EM. Immunology of Aging. In: Principles of geriatric medicine and gerontology. 5th ed. Hazzard WR, Blass JP, Halter JB, Ouslander JG, Tinetti ME, editors. New York: McGraw-Hill; 2003; 35–51.
12. Murasko D, Jiang J. Response of aged mice to primary virus infections. Immunol Rev. 2005;205:285–96.[Medline]
13. Gardner EM, Bernstein ED, Dran S, Munk G, Gross P, Abrutyn E, Murasko D. Characterization of antibody responses to annual influenza vaccination over four years in a healthy elderly population. Vaccine. 2001;19:4610–7.[Medline]
14. Miller R. Age-related changes in T cell surface markers: a longitudinal analysis in genetically heterogeneous mice. Mech Ageing Dev. 1997;96:181–96.[Medline]
15. Plett PA, Gardner EM, Murasko DM. Age-related changes in interferon- alpha/beta receptor expression, binding, and induction of apoptosis in natural killer cells from C57BL/6 mice. Mech Ageing Dev. 2000;118:129–44.[Medline]
16. Gavazzi G, Herrmann F, Krause K. Aging and infectious diseases in the developing world. Clin Infect Dis. 2004;39:83–91.[Medline]
17. Redmond HP, Gallagher HJ, Shou J, Daly JM. Antigen presentation in protein-energy malnutrition. Cell Immunol. 1995;163:80–7.[Medline]
18. Ingram KG, Croy BA, Woodward BD. Splenic natural killer cell activity in wasted, protein-energy malnourished weanling mice. Nutr Res. 1995;15:231–43.
19. Lesourd B. Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments. Am J Clin Nutr. 1997;66:478S–84.
20. Zhang X, Hillyer LM, Woodward BD. The capacity of non-inflammatory (steady-state) dendritic cells to present antigen in the primary response is preserved in acutely protein- or energy-deficient weanling mice. J Nutr. 2002;132:2748–56.
21. Woodward B, Hillyer L, Hunt K. T cells with a quiescent phenotype (CD45RA+) are overabundant in the blood and involuted lymphoid tissues in wasting protein and energy deficiencies. Immunology. 1999;96:246–53.[Medline]
22. Jakab GJ, Warr GA, Astry CL. Alterations of pulmonary defense mechanisms by protein depletion diet. Infect Immun. 1981;34:610–22.
23. Mendoza-Nunez VM, Sanchez-Rodriguez MA, Retana-Ugalde R, Vargas-Guadarrama LA, Altamirano-Lozano MA. Undernutrition without malnutrition as a protective factor to prevent DNA damage in the elderly. Nutr Res. 2005;25:271–80.
24. McCay CM, Cromwell MF, Maynard LA. The effect of retarded growth upon the length of the lifespan and ultimate body size. J Nutr. 1935;10:63–79.
25. Masoro EJ. Overview of energy restriction and ageing. Mech Ageing Dev. 2005;126:913–22.[Medline]
26. Barger JL, Walford RL, Weindruch R. The retardation of aging by energy restriction: its significance in the transgenic era. Exp Gerontol. 2003;38:1343–51.[Medline]
27. Lane MA, Mattison J, Ingram DK, Roth GS. Energy restriction and aging in primates: relevance to humans and possible CR mimetics. Microsc Res Tech. 2002;59:335–8.[Medline]
28. Nikolich-Zugich J, Messaoudi I. Mice and flies and monkeys too: energy restriction rejuvenates the aging immune system of non-human primates. Exp Gerontol. 2005;40:884–93.[Medline]
29. Weindruch R. Dietary restriction, tumors, and aging in rodents. J Gerontol. 1989;44:67–71.
30. Spaulding CC, Walford RL, Effros RB. The accumulation of non-replicative non-functional, senescent T cells with age is avoided in calorically restricted mice by an enhancement of T cell apoptosis. Mech Ageing Dev. 1997;93:25–33.[Medline]
31. Webster RG. Immunity to influenza in the elderly. Vaccine. 2000;18:1686–9.[Medline]
32. Weindruch R, Devens BH, Raff HV, Walford RL. Influence of dietary restrictions and aging on natural killer cell activity in mice. J Immunol. 1983;130:993–6.[Abstract]
33. Matarese G, La Cava A. The intricate interface between immune system and metabolism. Trends Immunol. 2004;25:193–200.[Medline]
34. Yamaza H, Chiba T, Higami Y, Shimokawa I. Lifespan extension by energy restriction: an aspect of energy metabolism. Microsc Res Tech. 2002;59:325–30.[Medline]
35. Van Reeth K. Cytokines in the pathogenesis of influenza. Vet Microbiol. 2000;74:109–16.[Medline]
36. Dirks AJ, Leeuwenburgh C. Energy restriction in humans: potential pitfalls and health concerns. Mech Ageing Dev. 2006;127:1–7.[Medline]
37. Sullivan DH, Patch GA, Walls RC, Lipschitz DA. Impact of nutrition status on morbidity and mortality in a select population of geriatric rehabilitation patients. Am J Clin Nutr. 1990;51:749–58.
38. Fontana L, Meyer TE, Klein S, Hollaszy JO. Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans. Proc Natl Acad Sci U S A. 2004;101:6659–63.
39. Pirlich M, Lochs H. Nutrition in the elderly. Best Pract Res Clin Gastroenterol. 2001;15:869–84.[Medline]
40. Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr. 2003;78:361–9.
This article has been cited by other articles:
|
|
 |
|
  B. W. Ritz, I. Aktan, S. Nogusa, and E. M. Gardner Energy Restriction Impairs Natural Killer Cell Function and Increases the Severity of Influenza Infection in Young Adult Male C57BL/6 Mice J. Nutr., November 1, 2008; 138(11): 2269 - 2275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Niiya, Sk. Md. F. Akbar, O. Yoshida, T. Miyake, B. Matsuura, H. Murakami, M. Abe, Y. Hiasa, and M. Onji Impaired Dendritic Cell Function Resulting from Chronic Undernutrition Disrupts the Antigen-Specific Immune Response in Mice J. Nutr., March 1, 2007; 137(3): 671 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Duff and M. L. Galyean BOARD-INVITED REVIEW: Recent advances in management of highly stressed, newly received feedlot cattle J Anim Sci, March 1, 2007; 85(3): 823 - 840. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
