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J Leukoc Biol. Oct 2008; 84(4): 900–914.
Published online Jul 2, 2008. doi:  10.1189/jlb.0108023
PMCID: PMC2538592

Age-associated changes in immune and inflammatory responses: impact of vitamin E intervention

Abstract

Aging is associated with dysregulated immune and inflammatory responses. Declining T cell function is the most significant and best-characterized feature of immunosenescence. Intrinsic changes within T cells and extrinsic factors contribute to the age-associated decline in T cell function. T cell defect seen in aging involves multiple stages from early receptor activation events to clonal expansion. Among extrinsic factors, increased production of T cell-suppressive factor PGE2 by macrophages (M[var phi]) is most recognized. Vitamin E reverses an age-associated defect in T cells, particularly naïve T cells. This effect of vitamin E is also reflected in a reduced rate of upper respiratory tract infection in the elderly and enhanced clearance of influenza infection in a rodent model. The T cell-enhancing effect of vitamin E is accomplished via its direct effect on T cells and indirectly by inhibiting PGE2 production in M[var phi]. Up-regulated inflammation with aging has attracted increasing attention as a result of its implications in the pathogenesis of diseases. Increased PGE2 production in old M[var phi] is a result of increased cyclooxygenase 2 (COX-2) expression, leading to higher COX enzyme activity, which in turn, is associated with the ceramide-induced up-regulation of NF-κB. Similar to M[var phi], adipocytes from old mice have a higher expression of COX-2 as well as inflammatory cytokines IL-1β, IL-6, and TNF-α, which might also be related to elevated levels of ceramide and NF-κB activation. This review will discuss the above age-related immune and inflammatory changes and the effect of vitamin E as nutritional intervention with a focus on the work conducted in our laboratory.

Keywords: aging, immune function, macrophage, prostaglandin, cyclooxygenase

INTRODUCTION

A variety of physiological functions, including those of the immune system, exhibits age-related changes. The age-related alterations in the immune response are referred to as immunosenescence [1,2,3,4,5]. Normal immune functions are critical for the host’s surviving in an environment full of pathogens and foreign organisms as well as dealing with the internal risk factors such as neoplasia and autoimmune diseases. A majority of age-associated changes is undesirable and often subject the aged to a higher risk of developing diseases. Dysregulated immune and inflammatory responses have been well documented in humans and animals. It is well recognized that the age-associated decline in immunologic vigor directly or indirectly contributes to increased susceptibility to infectious diseases and to a poor response to immunization [6,7,8,9]. Limited data also suggest that the status of the immune response could predict mortality in the elderly [10,11,12] and mice [13]. On the other hand, an increasing body of information has suggested that aging may be associated with an up-regulated inflammatory response [14,15,16]. Inflammation has been suggested to be one of the mechanisms underlying the pathogenesis of several age-associated diseases such as cardiovascular disease (reviewed in refs. [17, 18]), type 2 diabetes (T2D; reviewed in refs. [19, 20]), Alzheimer’s disease (AD; reviewed in ref. [21]), Parkinson’s disease (reviewed in ref. [22]), rheumatoid arthritis (RA; reviewed in refs. [23, 24]), and osteoporosis (reviewed in refs. [25, 26]). Thus, further understanding of the cellular origins and the molecular mechanisms of age-related inflammation could advance our ability to develop strategies in improving quality of health in the elderly. Several approaches have been used to change the trajectory of immunosenescense, including lifestyle (diet, exercise) and medical therapy (drugs, hormones/cytokines, cell transfer). This review will provide an overview of the work that has been done mainly in the authors’ laboratory related to age-associated changes in immune and inflammatory responses and their reversal by vitamin E. Although many other investigators’ works are cited to provide adequate background and to facilitate discussion, this review does not intend to serve as an extensive review of the literature on this subject.

ALTERED T CELL FUNCTION WITH AGE AND THE UNDERLYING MECHANISMS

T cell function declines with age

Almost all of the cell types in the immune system experience change to a certain extent with advancing age; however, the most prominent change occurs in T cells. A decline in T cell function is believed to be the central defect in immunosenescence in animal models and humans [27,28,29,30]. Age-associated impairment in T cells involves T cell development in the thymus and T cell functionality in peripheral lymphoid tissues. It has long been recognized that T cell differentiation and maturation in the thymus demonstrate a clear, age-related decline and are thus often viewed as the immunological clock of aging [31]. Thymus involution is a hallmark of advancing age [32]. As a consequence, there is a significant decline in the output of new T cells [31, 33], which partially explains the lower numbers of naïve T cells in aged animals and humans compared with those of their young counterparts. As progenitors continually leave the bone marrow and seed the thymus to maintain thymopoiesis, investigators, using mostly mouse models, have furthered their studies in this area to learn if age affects development of T cells from their hematopoietic stem cells (HSCs) in the bone marrow. These HSCs are multipotent and have lineage potential for all blood cell types. Although the number of HSCs is shown to increase with age [34, 35], aged HSCs are less efficient in developing into lymphoid- and T-lineage cells according to recent studies [35,36,37]. However, the impact of this change on the age-associated defect in T cell function is not clear. Some investigators have suggested that the thymic microenvironment and not T cell progenitors in bone marrow is a major factor contributing to an age-associated defect in T cell development [5, 38,39,40]. Despite the drastic thymic involution and low output with aging, however, the number of peripheral T cells is well maintained except for a moderate reduction in the population of naïve T cells. Work from Swain’s laboratory [41, 42] suggests that a lack of drastic change in the number of T cells indicates that naïve T cells in the aged must live longer, and as a result, they may accumulate defects that impact their function. Additionally, TCR diversity declines with aging, as its generation depends entirely on the production of new T cells in the thymus [43].

Age-associated defects in T cell function have been demonstrated repeatedly, whether measured in vitro as proliferative responses to stimulation with mitogens, antigens, or anti-CD3 antibody or in vivo as T cell proliferation responding to immunization in adoptive transfer animal models, delayed-type hypersensitivity (DTH) responses, antibody production to T cell-dependent antigens, or increased incidence of infectious disease. In mice and humans, IL-2 production as well as its receptor expression decline with age, resulting in diminished proliferation of T cells [13, 44, 45]. It has been argued that an altered ratio of memory/naïve T cell subsets contributes to this, as IL-2 is secreted preferentially by naïve T cells. However, it is now clear that in addition to the decline in the number of naïve cells, the amount of IL-2 produced per naïve cell in the aged is less than that of young mice [44] or humans [46]. Except for IL-2, the effect of aging on other cytokines produced by Th1 and Th2 cells remains a controversial issue in the literature.

Mechanisms for an age-associated decline in T cell function

Intrinsic Change in T Cells

Aging leads to a decline in T cell function, which has been attributed to intrinsic changes in T cells, as well as higher production of PGE2 by macrophages (M[var phi]; to be discussed later). Although an age-related decrease in T cell function has been observed in memory [44, 47, 48] and naïve [49,50,51] T cells, one of the hallmarks of age-related changes is a shift toward greater proportions of antigen-experienced memory T cells and a smaller proportion of naïve T cells [3, 52, 53]. In addition, naïve T cells in the aged have consistently been shown to have a declined function, as exemplified by a reduced ability to proliferate and produce IL-2 when stimulated by specific antigens [51] or anti-CD3 antibody [44]. Effective immune response to novel antigens depends on functional naïve T cells. Thus, an age-related decline in the number and function of naïve T cells is believed to contribute to the compromised response to new or infrequently encountered antigens in the aged. T cell clonal expansion is required for successful immune response, and IL-2, a T cell growth factor, is perhaps the most important molecule in T cell expansion. T cell activation induces IL-2 production and subsequently, the IL-2R expression on T cells. Binding of IL-2 to its high-affinity receptor triggers a cascade of signaling events leading to the progression of T cells through cell cycle and consequent division. Meanwhile, naïve T cells develop to gain effector functions. The age-related defect in IL-2 production is a major contributing factor that has been shown to be responsible for declined T cell function in aged mice [45, 54, 55].

To study the underlying mechanisms for age-related reduction in T cell functions, Adolfsson et al. [44], using young (6-month) and old (26-month) C57BL/6 mice, isolated T cells from spleens and showed that T cells from old mice stimulated with anti-CD3 had fewer division cycles and IL-2 production compared with those from young mice. The defect in proliferation and IL-2 production was specific to naïve T cells and was not observed in memory T cells. Furthermore, they found an age-related decline in the percent of IL-2-secreting, naïve T cells and the amount of IL-2 produced per naïve T cell.

T cell proliferation in response to stimuli is a result of up- and down-regulation of numerous signaling events with complex interactions. To further construct a comprehensive picture of molecular changes, which may contribute to an age-associated decline in T cell functions, Han et al. [56] conducted a study to characterize the gene expression profile of T cell activation-related molecules in T cells from young and old mice. In that study, they identified several significant differences in the pattern of gene expression between young and old T cells. One interesting finding is that T cells of old mice express significantly higher levels of suppressors of cytokine signaling 3 (SOCS3) and lower levels of growth factor independence-1 (Gfi-1) compared with those of young mice. In response to anti-CD3/CD28 stimulation, SOCS3 in old T cells elevated 2.7-fold compared with only 1.2-fold in young T cells; a reversed pattern was observed for Gfi-1 with an induction of 2.1-fold in old and 4.7-fold in young T cells. SOCS3 is a member of the SOCS family of intracellular, cytokine-inducible, negative feedback, which has been shown to play an important role in Th cell activation [57]. Using transgenic mice or transfected primary Th cells to obtain altered levels of SOCS3 expression, investigators have found that anti-CD3/CD28-induced Th cell-proliferative response and IL-2 production are correlated inversely with SOCS3 expression [58, 59]. Gfi-1 is a transcriptional repressor, and the SOCS3 gene contains multiple Gfi-1-binding sites in its promoter region [60]. Gfi-1 is thus believed to be a mediator responsible for the down-regulation of SOCS3 during T cell activation. Indeed, down-regulation of SOCS3 has been shown to correlate with up-regulation of Gfi-1 [59]. Together, this study suggests that relative to young T cells, less of an increase in activation-induced Gfi-1 expression in old T cells may release its check on SOCS3 expression, resulting in suppressed T cell proliferation.

Recent studies suggest that changes in the signal transduction machinery with aging might be responsible for impaired T cell function [4, 29]. As illustrated in Figure 1, activation of T cells is initiated by engagement of the TCR with peptide antigen presented by the MHC on APC or antireceptor antibodies. Occupancy of the TCR triggers activation of Src family protein tyrosine kinase Lck, which mediates the phosphorylation of immunoreceptor tyrosine-based activation motifs on CD3-ζ. This leads to the recruitment and activation of ZAP70, which subsequently phosphorylates adaptor proteins, such as the LAT. These LAT in turn mobilize other adaptor proteins or enzymes to amplify and transmit signals downstream through different stages and ultimately lead to the activation of different nuclear transcription factors necessary for cytokine gene transcription.

Fig. 1.
Immune synapse formation and intracellular signaling pathways involved in T cell activation. TCR engagement triggers the expansion and rearrangement of nascent T cell-APC contacts, leading to the formation of immune synapse. The image picture on the upper ...

Several investigators have shown that T cells from healthy old mice and human subjects display multiple defects at the early stages of the T cell signaling pathway, including tyrosine and serine/threonine phosphorylation [62,63,64], calcium mobilization [63, 64], MAPK activity [65, 66], and nuclear transcription factor NFAT, AP-1, and NF-κB activation [50, 67]. Antigen engagement with T cells through formation of an immune synapse between APC and T cells triggers redistribution of several signaling molecules to TCR. An impaired immune synapse formation as well as reduced redistribution of the key signaling molecules for T cell activation in immune synapse have been reported in T cells from aged mice compared with those of young mice (Fig. 1) [50, 61, 68]. Using an anti-CD3 hybridoma (145-2C11) as APC, Marko et al. [61] found that CD4+ T cells from old mice were less likely to form effective immune synapses than those from young mice, as observed with lower (average of 46%) redistribution of key signaling molecules Zap70, LAT, Vav, and PLCγ to the immune synapse. They did not observe such a difference in the redistribution of the tyrosine kinases Fyn and Lck, the adaptor protein SLP-76, and the serine/threonine kinase protein kinase C (PKC)θ. Although naïve and memory T cells have an age-related reduction in the formation of effective immune synapse, the change is more dramatic in naïve than in memory populations. Garcia and Miller [50] reported that naïve T cells isolated from old mice were unable to translocate signaling proteins to the immune synapse and that those that did form a synapse had less cytoplasmic migration of NFAT, a transcription factor essential for IL-2 transcription. The reported impact of aging on the signaling molecules and the prevention by vitamin E are presented in Figure 1. Further studies are needed to determine the underlying causes of impaired immune synapse formation in the aged T cells.

Increased PGE2 Production in M[var phi]: Additional Contributing Factor to the Age-related Decline in T Cell Function

In addition to age-associated changes within T cells, other non-T cell factors that also demonstrate age-associated changes, particularly suppressive factors produced by M[var phi], are thought to indirectly contribute to the decline of T cell function with aging. Among the T cell-suppressive factors produced by M[var phi], PGE2 has been studied most intensively.

Although PGE2 is necessary for T cell function, at higher concentrations, it has been shown to inhibit T cell proliferation, including CD4+ and CD8+ T cells, and CD4+ T cells are the most affected and thus, the focus of a majority of the studies. This effect of PGE2 on T cell function is the consequence of altered early signaling events in T cell activation [69] and results in an altered cytokine profile of T cells. PGE2 has been shown consistently to inhibit Th1 cytokine IL-2 and IFN-γ production as well as IL-2 receptor expression [70,71,72].

We and others [73,74,75,76] have shown that M[var phi] and spleen cells from old mice and PBMC from elderly human subjects synthesize significantly more PGE2 than their young counterparts. In a study by Franklin et al. [77], the addition of peritoneal M[var phi] from old rats to splenocytes from young rats significantly inhibited Con A-stimulated splenocyte proliferation; this inhibitory effect was also observed when PGE2 was added. These findings were further confirmed and extended by Beharka et al. [78], who showed that cocultures of M[var phi] isolated from old mice with T cells from young mice exhibited lower T cell proliferation and IL-2 production compared with those of young M[var phi] with young T cells. The addition of exogenous PGE2 at the concentrations produced by old M[var phi] decreased T cell proliferation and IL-2 production by young T cells, and the addition of cyclooxygenase (COX) inhibitor indomethacin or antioxidant nutrient vitamin E inhibited PGE2 production and improved T cell proliferation and IL-2 production [78]. The association between PGE2 and an age-associated decrease in T cell-mediated immune response was supported further by in vivo studies [75, 76], which showed that dietary vitamin E supplementation to old mice and human subjects improved their T cell proliferation, IL-2 production, and DTH response. In these studies, improved T cell-mediated immune response was accompanied by a reduced PGE2 production. Taken together, these results suggest a key role for PGE2 in T cell immunosenescence. The underlying mechanisms of an age-associated increase in PGE2 production will be discussed later in the review.

Effect of vitamin E on an age-associated decline in T cell functions

Nutritional intervention is a practical approach for modulating immune function. Vitamin E is considered one of the most effective nutrients for its effect on immune cell functions. Although vitamin E deficiency is rare, its supplementation to the diet above the recommended levels has been shown to be beneficial for T cell-mediated functions, particularly in the aged, as demonstrated in several animal studies and human clinical trials (Table 1) [75, 76, 79].

TABLE 1.
Vitamin E Supplementation and Immune Response in the Aged Animals and Humans

In animals, dietary vitamin E supplementation has been shown to enhance T cell differentiation in rat thymus, enhance lymphocyte proliferation in mice, rats, and pigs, and increase Th cell activity in mice. Meydani et al. [76] showed that increasing the level of dietary vitamin E from 30 to 500 ppm significantly increases plasma vitamin E levels, DTH, lymphocyte-proliferative response to T cell mitogen Con A, and IL-2 production in old mice; this effect of vitamin E was associated with a decrease in PGE2 production. Results in another animal study by Sakai and Moriguchi [86] supported these findings by showing that vitamin E supplementation (585 mg/kg diet) for 12 months significantly improved T cell-mediated function compared with rats fed a control diet containing 50 mg vitamin E/kg.

The immunoenhancing effect of vitamin E has been confirmed further in a number of human studies. Meydani et al. [75] reported that supplementation with vitamin E (800 mg/day) in healthy elderly over 60 years old resulted in a significant increase in DTH response, ex vivo T cell proliferation, and IL-2 production and a significant decrease in plasma lipid peroxide concentration and production of the T cell-suppressive PGE2. In a subsequent study [79], the same group investigated the effect of 4.5 months of vitamin E supplementation on in vivo indices of immune function in healthy elderly over 65 years old. In that study, 88 subjects were supplemented with placebo and 60, 200, or 800 mg dl-α-tocopherol, and all three vitamin E-supplemented groups showed a significant increase in DTH response compared with baseline. Subjects in the 200 mg/day group showed a significantly greater increase in median percent change of DTH compared with those in the placebo group and a significant increase in antibody titers to hepatitis B and tetanus vaccines. A recent study by De la Fuente et al. [85] confirmed these results and showed further a positive effect of vitamin E on innate immune function. In that study, the elderly subjects, who were given 200 mg/day vitamin E for 3 months, exhibited an increased lymphocyte-proliferative response to T cell mitogen PHA, Con A-stimulated IL-2 production, NK activity, and neutrophil chemotaxis and phagocytosis but showed decreased neutrophil adherence and superoxide anion production. Although the study was not placebo-controlled, the subjects were tested again after a 6-month washout period, and the majority of the results was close to the baseline levels, which somewhat resolved the doubt about its comparability with other studies. Similarly, Lee and Wan [87] reported a significant increase in the lymphocyte proliferative response to PHA and a significant decrease in plasma malondialdehyde and urinary DNA adduct 8-hydroxy-2′-deoxyguanosine levels after short-term supplementation with vitamin E (400 IU dl-α-tocopherol/day for 28 days) in Chinese adults.

Failure to observe the immunoenhancing effect of vitamin E has also been reported in some clinical studies. For example, De Waart et al. [83] observed no significant changes in mitogenic response to Con A and PHA or levels of IgG and IgA against Penicillium after a 3-month supplementation with vitamin E at 100 mg/day. The lower dose of vitamin E as well as the use of previously frozen lymphocytes for determination of mitogenic response and evaluation of antibody levels without previous specific vaccination may have contributed to the discrepancy observed between the results of De Waart et al. [83] and those of Meydani et al. [75, 79] and Lee and Wan [87].

Pallast et al. [84] supplemented healthy, elderly subjects (65–80 years old) with 50 or 100 mg/day vitamin E for 6 months. Subjects in the vitamin E-supplemented group showed a significant increase in DTH (induration diameter and number of positive responses) compared with their own baseline values. Overall, the only change observed is that the number of positive DTH responses tended to be larger in the 100-mg-supplemented group than that in the placebo group (P=0.06). However, a significantly greater improvement in cumulative DTH score and the number of positive DTH responses was observed in a subgroup of subjects who received 100 mg vitamin E and had a low baseline DTH reactivity. There was no significant difference in PHA-stimulated IL-2 production between the vitamin E-treated groups and the placebo group. The difference in vitamin E status at baseline and supplementation dose resulting in varied levels of changes in plasma vitamin E levels and the methodology used may have contributed to the discrepancy in reported results. Considering the results from the study by Meydani et al. [79], in which subjects in the upper tertile of serum vitamin E concentration (>48.4 μmol/L) after supplementation had a higher antibody response to hepatitis B as well as higher DTH responses than those in the lower tertile of serum vitamin E (19.9–34.7 μmol/L), the amount of increase in vitamin E levels achieved in the studies by others [83, 84] might not have been adequate to observe a highly significant effect. It is also noteworthy that Lee and Wan [87] observed a significant increase in cell-mediated immune response with a 13.4-μmol/L increase in plasma vitamin E level—a level of increase comparable with those observed by De Waart et al. [83] and Pallast et al. [84] with 100 mg supplementation. A difference in baseline vitamin E status may explain the varied results observed in these latter studies, as subjects in the study by Lee and Wan [87] had significantly lower plasma vitamin E levels at baseline (14 μmol/L) compared with those in the studies by De Waart et al. [83] (33 μmol/L) and Pallast et al. [84] (31 μmol/L). Meydani et al. [88] showed that an increase in plasma concentration of vitamin E up to 25 μmol/L is linearly associated with a change in DTH and further increase in plasma vitamin E level, however, does not seem to be associated with further improvement in DTH. A 25-μmol/L increase in plasma vitamin E can be achieved by consuming 200 mg/day vitamin E.

Mechanistic studies for the direct effect of vitamin E on T cells

The vitamin E-induced enhancement of T cell function in the aged is shown to be a result of a direct effect on T cells as well as an indirect effect of suppressing M[var phi] PGE2 production [78]. To assess the direct effect of vitamin E on T cell response, T cells purified from the spleens of young and old mice were preincubated with vitamin E or vehicle control [44]. As mentioned above, activation-induced T cell division and their IL-2 production were less in old than in young mice, and this defect was specific to naïve T cells. Vitamin E increased cell-dividing capability, total IL-2 production, as well as the number of IL-2+ T cells and the amount of IL-2 produced per naïve T cell in old but not in young mice. Furthermore, these effects were not observed in memory T cells. The differential effect of vitamin E on naïve and memory T cells may be a result of an underlying difference in the susceptibility of these cells to oxidative stress-induced damage [89].

How vitamin E enhances naïve T cell division and IL-2 production is not well understood and is thus a topic under current investigation. This effect of vitamin E may be related to its potential effect on cell-cycle progression, which in turn reflects an altered activation status of cell-cycle-related proteins as well as their interaction with IL-2. To accomplish an adaptive immune response, naïve T cells must be induced to proliferate and differentiate into effector cells. Naïve T cells can live for several months up to nearly 1 year without dividing. Upon activation, these resting cells re-enter the cell cycle and divide rapidly to produce large numbers of progeny that will differentiate to effector T cells. After resting T cells are activated by antigenic stimulation of the TCR/CD3 complex, activated T cells are driven from their quiescent state (G0) into the G1-phase of the cell cycle [90, 91]. Activated T cells produce large amounts of IL-2, and the binding of IL-2 to its high-affinity receptor triggers the G1- to S-phase transition and thus a division of T cells [92]. Traverse of G0/G1 and entry of S-phase are controlled by the ordered activation of cyclin-dependent kinases (CDKs) [93], and CDK activity is up-regulated by cyclins and down-regulated by CDK inhibitors, such as p27kip1, which is a powerful CDK inhibitor and is the primary modulator of proliferative status. IL-2 plays a significant role in inducing the cell-cycle progression of T cells through down-regulation of p27kip1 [90, 94].

Currently, there is no direct evidence for a direct effect of vitamin E on these cell-cycle-related proteins; however, a recent study reported by Han et al. [56] has provided support for this possibility. Han et al. [56] conducted a microarray analysis of gene expression profiles in the purified T cells from the mice fed a 30 (control)- or 500-ppm (supplementation) vitamin E-supplemented diet. They found that vitamin E supplementation in old mice increased expression of the genes for cell-cycle-related proteins including cyclin B, Cdc2 (Cdk1), and Cdc6 [56]. Cyclin B and Cdc2 are important for entry of cells into M-phase of the cell cycle, and Cdc6 is a key regulator in an early step of DNA replication [95, 96]. Thus, these results suggest that altered cell-cycle-related proteins might underlie the effect of vitamin E in promoting cell division cycle and IL-2 production.

As mentioned above, several groups have shown that the early events in T cell activation, including formation of effective immune synapses, are impaired in aged animals and humans. Marko et al. [61] reported that vitamin E improved effective immune synapse formation in CD4+ T cells from old mice. In that study, the authors incubated CD4+ T cells supplemented in vitro with vitamin E, together with anti-CD3 hybridoma cells (serving as APC), and found that vitamin E restored defective redistribution of signaling molecules Zap70, LAT, Vav, and PLCγ in immune synapse formed between APC and CD4+ T cells from old mice (Fig. 1). They further showed that the age-related defects as well as the vitamin E-induced effects were mainly found in old, naïve CD4+ T cells and not old memory or young memory and naïve CD4+ T cells. These authors [61] reported similar findings following in vivo supplementation of old mice with vitamin E. Further studies are underway to determine the mechanism of a vitamin E-induced increase in effective immune synapse formation.

Implications of declined T cell function in higher risk of infections on the aged and the benefit of vitamin E supplementation

Infections, particularly respiratory infections, are common in the elderly, resulting in decreased daily activity, prolonged recovery times, increased health-care service use, and more frequent complications including death [97,98,99]. The increased incidence of infection with age is believed to be in part a result of age-related changes in immune response [100,101,102]. Thus, it is anticipated that strategies to improve immune function will enhance a host’s resistance to infection. This was tested in relation to vitamin E supplementation in the elderly. Several animal and human studies have reported a protective effect of vitamin E against infection, despite variations in the dose and duration of the supplementation, infectious organisms involved, and route of administration (Table 2).

TABLE 2.
Effect of Vitamin E Supplementation on Infectious Diseases in Animals and Humans

Host resistance to influenza infection has been used as a relevant outcome to test the changes in host immunity by nutrient intervention, especially those nutrients that affect T cell functions. Influenza virus is immunogenic and induces a strong humoral and cellular immune response [110]. Many components in the immune system, including cytotoxic T lymphocytes, CD4+ and CD8+ T cells, NK cells, and B cells, as well as the cytokines produced by these cells, are involved in the response to and the eventual clearance of influenza. Cytotoxic CD8+ T cells play a major role in the clearance of influenza via a MHC-I mechanism involving perforin and Fas [111]. CD4+ T cells are also important in providing help for CD8+ T cells to maintain cytotoxic response and for B cells to produce antibody, and this function of CD4+ T cells is mainly accomplished via cytokines IL-2, IFN-γ, and TNF-α produced by Th1 cells [112]. IFN-γ is a major effector molecule mainly produced by Th1 cells but also derived from cytotoxic T cells and NK cells. IFN-γ not only has a direct, antiviral effect but also enhances functions of an antiviral network through stimulating the activity of M[var phi] and NK cells, promoting antigen presentation, and facilitating Ig class switching [113,114,115]. IL-2 is also critical in antiviral defense, as although it does not kill viruses directly, it can stimulate clonal expansion of CD4+ and CD8+ T cells, NK cells, and cytolytic T lymphocytes [116,117,118]. Particularly, IL-2 is needed to induce IFN-γ production [119, 120].

Vitamin E supplementation in old mice resulted in significantly lower viral titers on 2, 5, and 7 days postinfection, and a significant inverse correlation was observed between hepatic vitamin E levels and lung viral titers [107, 121]. Han et al. [108] showed that vitamin E supplementation of old mice infected with influenza significantly increased production of IL-2 and IFN-γ but had no effect on IL-4 production. The change in IFN-γ production correlated significantly with the decrease in viral titer. Because of the significant role of IL-2 and IFN-γ in defense against viral infections, the authors suggested that the protective effect of vitamin E against influenza infection in old mice is a result, in part, of higher levels of IFF-γ and IL-2 in the vitamin E-supplemented old mice.

With few exceptions, a majority of the human studies has investigated the effect of nutritional intervention, including vitamin E, on measures of the immune response rather than infection. Meydani et al. [75, 79] showed that vitamin E supplementation improved immune response, including DTH and response to vaccines in the healthy elderly. Furthermore, they reported a nonsignificant (P<0.09), 30% lower incidence of self-reported infections among the groups supplemented with vitamin E (60, 200, or 800 mg/day for 235 days) compared with the placebo group [79]. As infection was not the primary outcome, the study did not have enough power to detect significant differences in the incidence of infections. To overcome these limitations, they conducted a larger, double-blind, placebo-controlled trial to determine the effect of 1-year supplementation with vitamin E on objectively recorded respiratory infections in elderly nursing-home residents [103]. In that study, 617 nursing-home residents, aged over 65 years, received a capsule containing half of the recommended daily allowance of essential vitamins and minerals plus a placebo or 200 IU vitamin E (dl-α-tocopherol) daily for 1 year. The main outcomes of the study were incidence of respiratory tract infections, number of persons and number of days with respiratory infections (upper and lower), and number of new antibiotic prescriptions for respiratory infections among all randomized participants and those who completed the study. Results showed significantly fewer incidences of one or more respiratory infections [65% vs. 74%, relative risk (RR)=0.87, confidence interval (CI)=0.73–0.99, P=0.035] or upper-respiratory infections (50% vs. 62%, RR=0.81, CI=0.65–0.96, P=0.015) in vitamin E-supplemented versus the placebo-treated subjects. However, supplementation with vitamin E had no significant effect on the incidence or duration of all respiratory infection taken together or on upper or lower respiratory-tract infections measured separately. Further analysis about the foremost respiratory infection, the common cold, indicated that the vitamin E group had a lower incidence of common colds (0.66 vs. 0.83 per-subject year, RR=0.80, CI=0.64–1.00, P=0.046), and fewer subjects in the vitamin E group acquired one or more common colds (46% vs. 57%, RR=0.79, CI=0.63–0.96, P=0.016) [103]. The vitamin E-treated group also had fewer days with the common cold per-person year compared with the placebo group, but the difference did not reach statistical significance (22% less, P=0.11). These studies suggest that the immunostimulatory effect of vitamin E is associated with improved resistance to respiratory infections in the aged.

DYSREGULATED INFLAMMATORY RESPONSE WITH AGE, RELEVANCE TO DISEASES, AND EFFECT OF VITAMIN E

Age-associated increase in inflammation

Inflammation is a protective response of the body to actual injury, such as infection or trauma, or sometimes just perceived injury. Inflammation can help the host eliminate the cause of injury, such as invading microorganisms and their products, as well as the consequences of injury, such as dead cells and tissues. However, excessive, long-lasting, and inappropriately directed inflammatory response can itself become harmful, leading to damage and destruction of targeted cells, tissues, and organs. The cause of chronic inflammation is complicated and multifactorial with no clear answer in most cases; however, combined genetic and environmental factors have been indicated as contributing factors.

Chronic, low-grade inflammation has drawn increasing attention as a result of the fact that it is implicated in the pathogenesis of many common and disabling diseases involving a variety of body systems. It is worth noting that most of these diseases are degenerative and have a clear association with advancing age including atherosclerosis, T2D, AD, Parkinson’s disease, osteoporosis, and RA. A hypothesis has evolved suggesting that aging is accompanied by an inflammation state, although a consensus has yet to be reached. This hypothesis is mainly based on peripheral levels of inflammatory cytokines and liver acute-phase reaction proteins [122,123,124,125,126,127]. It has been estimated that the aged have a two- to fourfold increase in serum levels of these inflammatory mediators, which predicts mortality, independent of pre-existing morbidity [16]. Here, we are giving an overview of the work conducted in our laboratory related to age-associated up-regulation of inflammatory products in mouse M[var phi] and adipose tissue.

Age-associated increase in M[var phi] PGE2 production and the underlying mechanisms

Like other eicosanoids, biosynthesis of PGE2 is accomplished in a metabolic cascade starting from its precursor fatty acid, arachidonic acid (AA), which is present in membrane phospholipids, and released by the hydrolytic action of PLA2. Released AA is metabolized to the unstable intermediate prostanoids by COX, also called PGH2 synthase. COX has bifunctional, catalytic properties. It oxygenates and cyclizes AA to form PGG2 via its COX function, and this is followed by the reduction of PGG2 to PGH2 via its peroxidase function. PGH2 is then converted to PGE2 by the terminal synthase, PGE2 synthase, and PGE2 synthesis is determined mainly by the availability of the substrate AA and the activity of enzyme COX. As AA in total cellular fatty acid or in phospholipid fractions has been shown to remain unchanged or to decrease with age, the rate-limiting enzyme COX became the focus of the study. There are different isoenzymes of COX, a constitutive form (COX-1) and an inducible form (COX-2). COX-1 is constitutively expressed and is believed to be responsible for producing prostanoids to maintain physiological functions such as gastric protection and renal function. In contrast, COX-2 is regulated by growth factors, tumor promoters, cytokines, mitogens, glucocorticoids, and bacterial endotoxin and is implicated in inflammatory responses and pathological changes in numerous disorders.

Hayek et al. [128] examined the role of COX in the age-related increase in PGE2 synthesis in peritoneal M[var phi] from young (6-month) and old (24-month) C57BL/6 mice. They found that LPS-stimulated M[var phi] from old mice produced more PGE2 compared with those from young mice and further showed that this increased PGE2 production in the old M[var phi] mainly resulted from increased COX activity, which was, in turn, a result of increased COX-2 protein synthesis preceded by an elevated COX-2 mRNA expression [128]. In a subsequent study, we showed that this age-associated elevation in COX-2 mRNA expression is a result of a higher rate of transcription and not a change in the stability of COX-2 mRNA [129]. Neither induction by LPS nor an age-related difference in COX-1 protein or mRNA expression was observed [128]. This age-associated increase in COX-2 expression is not limited to M[var phi] or LPS stimulation. IL-1β-stimulated, peritoneal M[var phi] from old mice also produce more PGE2 than those from young mice [130]. Furthermore, calcium ionophore or T cell mitogens stimulate more PGE2 production in the splenocytes of old mice or PBMC of humans compared with their young counterparts [73,74,75,76]. In addition, an age-related increase in COX products has been observed in mouse lungs [131], human platelets [132], and human urine [133]. It is worth noting that a growing body of evidence indicates that overexpression of COX-2 is involved in the pathogenesis of a number of age-associated diseases.

In search of the mechanisms underlying the age-related up-regulation of COX-2, ceramide has emerged as a candidate fitting in the picture. Ceramide is a sphingolipid second messenger generated from the hydrolysis of membrane sphingomyelin under the action of sphingomyelinase (SMase) or by de novo synthesis. Figure 2 shows the sphingolipid metabolism pathway and the inhibitors currently used to study the impact of change in its different metabolites on biological functions. Ceramide is involved in the regulation of cell differentiation, proliferation, and apoptosis through multiple signaling pathways (for review, see refs. [134,135,136]). Studies have suggested that aging impacts on ceramide synthesis, at least in some tissues. For example, an age-related increase in brain and liver ceramide and neutral SMase levels has been reported [137,138,139]. In a senescence model of WI-38 human diploid fibroblasts, Venable et al. [140] found that endogenous levels of ceramide and neutral SMase activity elevated significantly as the cells entered the senescent phase. Furthermore, ceramide was shown to up-regulate COX expression [141,142,143,144]. Taken together, it can be hypothesized that ceramide might mediate the age-associated increase in COX-2 expression and thus, PGE2 production. This hypothesis was supported by the work of Claycombe et al. [129], which showed that M[var phi] from old mice generate significantly more intracellular ceramide than those from young mice within 30–60 min of LPS stimulation. The addition of exogenous ceramide to the M[var phi] from young mice dose-dependently increased PGE2 production and COX activity. Ceramide also further enhanced LPS-stimulated PGE2 production and COX-2 protein expression. This effect of ceramide was shown to be a result of its stimulatory effect on COX-2 mRNA transcription [129].

Fig. 2.
Sphingolipid metabolism and ceramide synthesis. Ceramide lies in the center of the sphingolipid metabolism network. Ceramide can be generated via breakdown of sphingomyelin by SMase, including neutral, acid, and alkaline SMase, or synthesized de novo ...

Subsequently Wu et al. [130] showed that the ceramide-induced up-regulation of COX-2 was a result of its induction of NF-κB activation, a key transcription factor in COX-2 regulation. Further studies showed that higher NF-κB activation was associated with increased IκB degradation in old M[var phi]. Given that other investigators have reported an age-related up-regulation of NF-κB activation in rat gastric mucosa, kidney, liver, heart, and brain [145, 146], altered NF-κB activation could contribute to a higher COX-2 expression with aging in these tissues as well. Further studies are needed to determine the regulatory mechanism upstream of IκB phosphorylation and degradation, which lead to higher NF-κB activation and COX-2 expression with aging.

Effect of vitamin E on PGE2 production and its underlying mechanism

As discussed above, in addition to its direct effect on T cells, vitamin E exerts its immunoenhancing effect by reducing PGE2 production by M[var phi]. To determine the mechanism of a vitamin E-induced decrease in PGE2 production, Wu et al. [147] conducted a study in which young (6-month) and old (24-month) C57BL/6 mice were fed 30 ppm (control) or 500 ppm (supplementation) vitamin E for 30 days, and then the peritoneal M[var phi] were isolated to determine PGE2 production. They found that LPS-stimulated M[var phi] from old mice in the control group had significantly higher production of PGE2 compared with those from young mice in the control group, and M[var phi] from old mice in the vitamin E group produced PGE2 at levels comparable with those seen in young M[var phi], indicating that the age-related increase in PGE2 production was eliminated by dietary vitamin E supplementation. Furthermore, they showed that vitamin E exerts its effect by decreasing COX-2 activity. However, LPS-induced COX-2 protein expression was not altered by vitamin E supplementation and in accordance, nor was COX-2 mRNA expression affected. Thus, the vitamin E-induced decrease in COX activity of M[var phi] from old mice is not a result of its regulation of COX transcription or translation. Other investigators [148, 149], who reported no effect of vitamin E on COX expression, confirmed these results later.

If vitamin E does not alter COX-2 protein level then what alternative mechanisms would explain its effect in reducing PGE2 production? Several possibilities may exist as discussed below. COX activity requires the presence of oxidant hydroperoxides [150,151,152]. The lag-phase, in attaining maximal COX activity, was shortened or eliminated by endogenous or exogenous hydroperoxides, while being delayed by antioxidants [150]. Vitamin E is an effective biological antioxidant and a chain-breaking, free-radical scavenger; therefore, it can be speculated that vitamin E may attenuate COX activity by scavenging the oxidant hydroperoxide necessary for COX activation.

Free-radical NO has been shown to be involved in the regulation of COX activity and eicosanoid synthesis. It has been suggested that NO stimulates COX activity via direct stimulation of the enzyme [153]. LPS-stimulated peritoneal M[var phi] from old mice were shown to produce more NO than those from young mice [154, 155], and dietary supplementation with vitamin E was shown to reduce NO production in M[var phi] from old mice [154]. NO can be metabolized further to peroxynitrite (ONOO) in the presence of superoxide, and ONOO has been shown to increase the activity of COX without affecting its expression [156]. Therefore, we hypothesized that decreased NO and thus, ONOO formation may mediate the inhibition of COX activity by vitamin E. This hypothesis was tested in a study conducted by Beharka et al. [154], in which young (6-month) and old (24-month) mice were fed 30 (control) or 500 ppm (supplementation) vitamin E for 30 days. Results from this study confirmed previous findings that M[var phi] from old mice produced more NO than those from young mice. Furthermore, the age-associated increase of NO was reduced by vitamin E supplementation, which did not affect LPS-induced superoxide generation but reduced the further potentiated superoxide generation in the presence of superoxide-generating agents. The addition of NO donor to cell culture to increase NO levels did not change PGE2 production and COX activity in young or old mice. However, when the NO donor was added in the presence of superoxide to elevate ONOO levels in the culture, vitamin E-induced inhibition of COX activity in the M[var phi] from old mice was diminished. On the other hand, when NO and superoxide inhibitors were added to M[var phi] of old mice fed a control diet to block generation of ONOO, COX activity was reduced significantly. These results suggest that vitamin E reduces COX activity in old M[var phi] by decreasing NO production, which leads to a lower production of ONOO in M[var phi] from old mice. Some other antioxidants, such as α-lipoic acid [157], γ-tocopherol [148], resveratrol [158], and avenanthramide (a polyphenol from oats; authors’ unpublished data), might also impact PGE2 production through this mechanism, as they were shown to inhibit PGE2 production without affecting COX-2 enzyme levels. Suggested mechanisms for age-associated up-regulation in PGE2 production and its reversal by vitamin E in M[var phi] are summarized in Figure 3.

Fig. 3.
Mechanisms for age-associated up-regulation of PGE2 production and its interruption by vitamin E in M[var phi]. The binding of LPS to its receptor CD14 at the M[var phi] surface triggers its association with transmembrane protein TLR, mainly TLR2 and ...

An inflammatory state develops with aging in adipose tissue: implications for an age-associated increase in T2D as well as other diseases

Studies have shown low-grade inflammation in adipose tissue of the obese, which may be a key contributor to obesity-induced insulin resistance. Adipose tissue of the obese expresses an increased amount of proinflammatory molecules such as TNF-α, IL-6, IL-1β, inducible NO synthase (iNOS), and MCP-1, all of which decrease insulin sensitivity. Of these molecules, TNF-α and IL-6 have been studied most intensively for their involvement in inducing insulin resistance. Recently, increased M[var phi] infiltration into adipose tissue has been reported in obese animals [159, 160] and humans [159, 161], and these cells are thought to represent the main source of proinflammatory cytokines in adipose tissue. It is thus speculated that a low-grade inflammatory signal delivered by adipocytes in the obese may act on M[var phi] to propagate the initial inflammatory signal [162, 163].

An age-associated decrease in glucose tolerance has been noted since 1920 [164]. This early finding was confirmed by later observation that tissue responsiveness to insulin was diminished in elderly subjects [165, 166]. More recent epidemiological studies have shown that the prevalence of T2D in the United States increases with age (1.4, 10.2, and 18.5% in 2007 for 0–40, 45–64, and 65–74 years, respectively) [167], and this high prevalence continues in people over the age of 75 [168, 169]. The mechanism underlying this age-related phenomenon is not well elucidated. Information regarding the involvement of adipose tissue in insulin resistance and T2D is mainly obtained from the studies about obesity, an increasingly recognized key risk factor in etiology of T2D. However, the sharp increase in T2D prevalence with advancing age cannot be explained fully by the prevalence of obesity, as the obesity rate in the elderly with T2D or in the general population is not higher than in their younger counterparts [170]. Fat mass peaks at middle age or early old age and then declines substantially in advanced old age [171]. In contrast, a decline in insulin sensitivity begins in the middle age and progressively increases in the later years of life [172]. Moreover, even when young, middle-aged, and old subjects are selected to be close to an ideal body weight and have a similar lean mass and obesity index, the age-associated decline in insulin sensitivity persists [173]. Increased insulin resistance has been observed in elderly humans [174] and old rats [175] after taking into account the extent of adiposity. Although decreased lean body mass and physical activity contribute to an age-associated increase in insulin resistance, the magnitude of these changes does not match that observed in the age-associated increase in insulin resistance and T2D incidence [172].

An increased inflammation state with aging has been proposed, as mentioned above. As insulin resistance sharply increases with advancing age, and low-grade inflammation in adipose tissue plays a key role in development of insulin resistance, it may be hypothesized that aging is associated with increased adipose tissue inflammation.

We recently tested this hypothesis [176] and showed that visceral adipose tissue from old C57BL/6 mice had significantly higher mRNA expression of proinflammatory cytokines IL-1β, IL-6, TNF-α, and COX-2 (263, 208, 165, and 115% higher, respectively) and lower expression of anti-inflammatory peroxisome proliferator-activated receptor (PPAR)-γ (60% lower) than those from young mice. Adipose tissue is composed of adipocytes and nonadipocytes, collectively called stromal vascular fraction cells (SVC), which are a complex of different cells including fibroblasts, preadipocytes, Μ[var phi], endothelial cells, and epithelial cells among other cell types. Previous studies have shown that SVC contribute predominantly to obesity-induced expression of inflammatory molecules, in which increased infiltration of M[var phi] is a key factor. In the adipose tissue of diet-induced or genetic mouse models of obesity, these M[var phi] express higher levels of inflammatory genes, which are responsible for almost all TNF-α, a significant amount of iNOS, and some of the IL-6 expression in adipose tissue [159, 160]. It has been reported that aging impairs adipocyte maturation, resulting in the presence of more preadipocytes in the fat tissue of old rats compared with that of the young [171] and that the adipose tissue from old mice has a lower mRNA level of PPAR-γ, a nuclear receptor shown to promote adipocyte differentiation [176]. Thus, higher expression of the inflammatory molecules in adipose tissue may simply reflect a larger SVC population in the aged. To test this, Wu et al. [176] isolated adipocytes from SVC and found that adipocytes, and not SVC as a whole, are responsible for this higher inflammatory state of the aged adipose tissue (AT). FACS results showed that M[var phi] in SVC from old mice were about half (56%) of that of young mice, but old mice had almost twice (1.86-fold) as many SVC in the same amount of adipose tissue by weight compared with young mice, resulting in no difference in the number of Μ[var phi] per gram of adipose tissue between young and old mice. Consistent with this, immunohistochemistry of adipose tissues from young and old mice showed a comparable abundance of M[var phi] (F4/80+ cells), which is in accordance with the lack of difference in MCP-1 production between young and old. These results indicate that the age-associated increase in adipose tissue inflammation is distinguished from that seen in obesity, in which increased infiltration of M[var phi] into adipose tissue is the main contributor.

Although the authors found no difference in production of inflammatory products by total SVC, this does not rule out the possibility that individual cellular components of SVC might have altered capacity with age in producing these products, in particular, given the fact that the number of M[var phi] in old SVC is only half of that in young SVC. Indeed, the authors found higher intracellular levels of IL-6 and TNF-α in M[var phi] residing in old compared with those in young adipose tissue. As an age-related difference in IL-6 and TNF-α production is not generally observed in M[var phi] residing in other tissues such as peritoneal M[var phi], we hypothesized that the environment in adipose tissue of old mice may be responsible for promoting the inflammatory response of M[var phi]. To test this, Wu et al. [176] determined whether conditioned medium from adipocytes of young and old mice would differentially affect cytokine production by Μ[var phi]. Results showed that although there is no difference in IL-6 and TNF-α production by young and old M[var phi], adipocyte-conditioned medium from old mice induced significantly higher production of IL-6 and TNF-α by M[var phi] from young or old mice compared with that when young adipocyte-conditioned medium was used. Together, these results imply that adipocytes develop an inflammatory state in adipose tissue as a result of aging, which promotes the inflammatory response of M[var phi] and thus, further propagates inflammation.

All of the inflammatory mediators tested in that study showed an increased expression with aging, which suggests the existence of a common mechanism. NF-κB is a central transcription factor in regulating inflammatory responses, as it controls the activation of genes encoding the synthesis of the majority of inflammatory markers and mediators, including those tested in the study by Wu et al. [176]. There are many environmental and physiological factors known to affect NF-κB activation, and the sphingolipid ceramide is suggested to be one activating agent. Ceramide and NF-κB are implicated in insulin resistance, in insulin target cells, as well as in inflammatory signaling in other cells. In the following mechanistic study, Wu et al. [176] found that old AD had a larger content of ceramide compared with young AD. Reducing ceramide levels or inhibiting NF-κB activation decreased cytokine production, and adding exogenous ceramide or inducing release of endogenous ceramide increased cytokine production in young AD to a level comparable with that seen in old AD. These results suggest that ceramide-induced activation of NF-κB plays a key role in adipose tissue inflammation. This study demonstrated for the first time an age-related, inflammatory state in adipose tissue. The information obtained from this study will help us better understand the basis of age-related inflammation in general, and it may also shed light on the underlying mechanisms of the age-related increase in insulin resistance and T2D incidence in particular. Figure 4 depicts the proposed mechanism of age-related increase in adipose tissue inflammation. Further studies are needed to establish a direct link between an age-associated inflammation and insulin resistance and to find effective nutritional interventions to impede this age-associated change.

Fig. 4.
Working model: An age-associated up-regulation in adipocyte production of proinflammatory cytokines. We hypothesize that the age-related increase in adipocyte inflammation is a result of up-regulation of NF-κB, which is, in turn, a result of ceramide-induced ...

CONCLUDING REMARKS

There is convincing evidence that aging is associated with a decline in immune function. The central defect in this age-related change is in T cell compartment. Impaired T cell function is a key contributing factor to the higher rate of morbidity and mortality in the elderly. Mechanistic studies have revealed multiple intrinsic changes taking place in T cells, including those in immune synapse formation, signaling molecule recruitment, and phosphorylation, and downstream events leading to the activation of genes for key cytokines. On the other hand, increased synthesis of suppressive factor PGE2 by M[var phi] has been observed in the aged, which provides an additional mechanism for understanding the age-associated decline in T cell functions.

Another increasingly recognized, age-related immune disorder is increased inflammatory response, particularly, a low-grade and chronic inflammation state, which has been implicated in the pathogenesis of several age-related diseases. As M[var phi] are the predominant sources of T cell-suppressive PGE2, a lipid inflammatory mediator itself, and the majority of protein inflammatory mediators, it is important to understand the regulation of inflammatory signaling pathways in this cell type to develop targeted, therapeutic strategies. Nutritional intervention has proven to be a practical approach in modulating dysregulated immune and inflammatory responses. The efficacy of such intervention, as with vitamin E, for example, has been demonstrated in clinical trials using infections as an endpoint. At the same time, mechanistic studies have deciphered how vitamin E affects T cell functions at cellular and molecular levels and thus, lend further support to the efficacy of nutrient supplementation in modulating the age-related immune dysregulation. A better understanding of the mechanisms underlying age-associated changes as well as the mode of action for nutritional intervention will provide further opportunity for developing new, preventive and therapeutic strategies to combat age-related immune and inflammatory pathologies.

Acknowledgments

This work was supported by National Institute on Aging Grant RO1-AG09140-09, Office of Dietary Supplement, and by U.S. Department of Agriculture Contract #58-1950-7-707. We would like to thank Stephanie Marco for her assistance in preparation of the manuscript.

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