Typically, calorie restriction (CR) refers to a 30 to 40% reduction in food intake. CR feeding is important in aging research because CR is the only known experimental regimen to increase life span in all experimental models tested including yeast, nematodes, flies, and rodents (Jolly, 2004). The models examined are not malnourished because the CR diets have enriched vitamin and mineral content to compensate for the decreased food intake. CR is also potent at delaying the onset of diseases like autoimmune disease and certain types of cancer. Therefore, it appears that CR may be a dietary regimen that not only increases life span by altering the biological process of aging, but also improves the quality of life by decreasing the severity of age-related diseases.
The primary immune cell studied examining the impact of CR feeding on immune function in aging and age-associated disease has focused on the T cell. The main reason for this is that the T cell is critical in determining both the type and extent of an immune response. Two of the most consistent effects of CR on aged T cell function in rodents are maintenance of T cell IL-2 production and subsequent proliferation while maintaining a naive T cell phenotype (Pahlavani, 2000). Maintaining an optimal immune response in aging is especially critical because the leading causes of death in geriatric hospitals are infectious diseases (Hirokawa and Utsuyama, 2002). An important feature of CR feeding is that its most dramatic impact on aging is observed when the dietary regimen is started in young rodents and maintained throughout life. This is not completely surprising because dietary regimens are normally the most beneficial when used as a prophylactic treatment as opposed to a therapeutic one.
The most well-studied autoimmune-prone model examining the impact of CR on immune function is the autoimmune-prone (NZBxNZW)F1 (B/W) mouse. This model is especially valuable since multiple organs have been examined, such as spleen, kidney, mesenteric lymph nodes, peripheral blood, and submandibular glands. The B/W mouse is a good model to study the human disease Systemic Lupus Erythematosis. As in humans, autoantibodies can be found in young adult B/W mice prior to the detection of clinical disease. The B/W mice die from autoimmune renal disease (i.e., nephritis), which can be monitored by measuring proteinurea, at approximately 10 to 12 months of age. Feeding the B/W mouse a 40% CR diet beginning at six weeks of age delayed autoimmune kidney disease by 30% (Jolly, 2004). The life span of the B/W mice could be doubled when the corn oil (CO) based CR diet was substituted with fish oil (FO) (Jolly et al., 2001). It is equally important to note that CR typically does not impact T cell function in young mice even though they have been on the CR diet for a significant amount of time (Jolly, 2004). This is significant because it suggests that CR feeding alone may not cause the T cell to be immunocompromised.
In the kidney, CR prevented the disease-associated rises in the proinflammatory cytokines IFN-y, IL-12, IL-10, and tumor necrosis factor-a (TNF-a), and the proinflammatory transcription factor nuclear factor kappa B (NF-kB) activation (Jolly, 2004). In peripheral blood, CR blunted the disease-induced increases in IL-2 and IFN-y production by both CD4 and CD8 T cell subsets as well as IL-5 production in CD4 T cells (Jolly, 2004). In contrast, CR reduced the disease-associated increase in IFN-y and IL-10 production in splenic CD4 T cells and increased the loss of IL-2 and IFN-y production in CD8 T cells (Jolly, 2004). Clearly the effect of CR on immune function is dependent on the immune compartment examined, but the consistent effect is that CR appears to normalize the immune alterations caused by autoimmune disease. The majority of the rodent studies have focused on the splenic T cell since the spleen is the largest source of easily accessible T cells in rodents. It has been shown that CR feeding in B/W mice delays the disease-associated rise in memory T cells, similar to that seen in long-lived strains, and increased expression of the CD69 receptor activation marker in vivo. Autoimmune disease caused an increase in T cell activation induced cell death, decreased proliferation, also as seen in long-lived aged mice, and increased Fas expression following ex vivo stimulation of splenic lymphocytes in B/W mice. The CR dietary regimen prevented the disease-associated increase in activation-induced cell death and restored NF-kB activation to predisease levels (Jolly, 2004). These results are similar to those seen for CR's effects in aged long-lived mice. Furthermore, CR prevented disease-associated decreases in splenic lymphocyte proliferation and blunted the rise in Fas-induced apoptosis and Fas ligand expression (Jolly, 2004). Both CO- and FO-based CR diets were equally effective in the peripheral blood and splenic T cells at restoring CD4 and CD8 T cell populations to predisease levels (Jolly, 2004). Overall, the FO CR diet appeared to be the most effective in mesenteric lymph nodes at restoring CD4 and CD8 T cell populations to predisease levels and blunting disease-associated increases in cytokine (IFN-y, IL-4, IL-5, IL-10) and immunoglobulin (IgM and IgG) production3 (Jolly, 2004). It remains to be determined whether the beneficial influence of CR on immunoglobu-lin secretion was due indirectly to altered T cell cytokine production or to direct modulation of B cell function. Similar results were seen in submandibular gland cultures from B/W mice where it was found that CR decreased disease-associated increases in IL-12, IL-10, and IFN-y messenger RNA levels (Muthukumar et al., 2000). Also notable was the reduction of IgA, IgM, and IgG2a production by CR since the B/W mice also have active autoimmune disease in their salivary glands (Muthukumar et al., 2000). It is important to note that the autoimmune disease in the salivary glands is normally not life threatening. The results in B/W salivary glands are supported by observations in long-lived mice fed a CR diet in that the age-dependent increase in both IgA and IgM secretion was associated with reduced polymeric immunoglobulin receptor gene expression (Jolly, 2004).
The impact of CR feeding on T cell function in the B/W mouse is clearly unique to different anatomical sites; however, the common feature of CR is that it maintains a predisease T cell phenotype.
A major potential mechanism that may explain the beneficial effects of CR feeding in autoimmune-prone mice is change in oxidative status. First, CR may increase the protection of T cells from oxidative damage by increasing antioxidant enzyme activity. This is supported by data showing that CR increased renal superoxide dismutase (SOD), catalase (CAT), and glutathione pero-xidase (GSH-Px) activity. Interestingly, the FO-based CR diet was more effective than the CO-based CR diet, which may protect the kidney from oxidative damage. CR also blocked the disease-associated increase in cellular peroxide levels in splenic lymphocytes (Jolly, 2004). This data is similar to observations made in long-lived mice where CR prevented age-associated increases in cellular peroxides in splenic lymphocytes and age-associated susceptibility of lymphocytes to hydrogen peroxide-induced apoptosis was blunted (Avula and Fernandes, 2002). In summary, these observations suggest that CR may improve T cell function (i.e., increase proliferation ex vivo) by reducing the increased susceptibility to age-dependent increases in apoptosis and decreasing free radical damage.
In addition to delaying the onset of autoimmune disease, CR or FO CR may also alter the development of other diseases like atherosclerosis in autoimmune-prone mice. Autoimmune disease in these mice increases the expression of key adhesion receptors like intercellular adhesion molecule-1 (ICAM-1), CD28, CD80, and Mac-1, autoantibody production and LDL-cholesterol, which are known to be reduced by CR feeding (Muthukumar et al., 2004) (Muthukumar et al., 2003). Their importance in heart disease may be in recruiting and activating immune cells in the coronary arteries since chronic inflammation is now considered to be an important risk factor in the etiology of heart disease. It is important to note that the beneficial effects of the FO CR diet on lipid profiles were seen early in the initiation of the dietary regimen, which was prior to the onset of active disease (Muthukumar et al., 2003). Once again the beneficial effects of the combination of FO CR feeding may be due to decreases in free radical damage and increased antioxidant enzyme activity, which has been shown in response to the induction of oxidative stress by cyclophosphamide injection (Bhattacharya et al., 2003). Overall, these data suggest that combining two different dietary regimens known to delay the onset of inflammatory diseases may have additive benefit and relevance to multiple diseases.
The concern with the CR dietary regimen is that it may not be realistic for the human population at large. The majority of the studies discussed administer CR at a 40 to 60% reduction in food intake, and this would be quite dramatic for most people. However, simply eating the recommended daily allowances could have similar beneficial effects. The National Institute on Aging/NIH started a study in 2002 called CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) in humans. It will be interesting see how well, and how long, this population of people follows this dietary regimen and what types of results are obtained from this long-term study in humans. The true benefit of these studies may be in identifying immune-associated biomarkers, which could then be targeted in dietary supplementation and pharmacologic studies to prevent or treat various immune-mediated diseases. This would be of enormous importance to overall human health because the immune system is involved in the etiology of multiple diseases and most of the major diseases in humans.
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