Age-associated Inflammatory Changes: Role of Nutritional Intervention

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1 December 2007(II): S213 S216 Age-associated Inflammatory Changes: Role of Nutritional Intervention Simin Nikbin Meydani, DVM, PhD, Dayong Wu, MD, PhD Accumulating evidence suggests that aging is associated with dysregulated immune and inflammatory responses. Investigation into the cellular and molecular mechanisms underlying this phenomenon suggests that an up-regulated cyclooxygenase (COX)-2 expression, and resulting increase in production of prostaglandin E 2 (PGE 2 ), is a critical factor. Macrophages from old mice have significantly higher levels of PGE 2 production compared with those from young mice, a result of increased COX-2 expression and protein levels leading to increased COX enzyme activity. Further, it is possible that the age-associated increase in macrophage PGE 2 production is due to ceramide-induced up-regulation of nuclear factor-kappa B activation. Such processes may also occur in cell types other than macrophages, lending further insight into potential mechanisms of age-related disease. More research is necessary to determine the efficacy of nutrient/dietary modifications, such as antioxidants and lipids, for reducing the age-related increase in COX activity and PGE 2 production that are associated with several disease states. Key words: aging, inflammatory response, macrophages, ceramide, sphingomyelinase, cyclooxygenase 2, prostaglandin E 2, nuclear factor-kappa B International Life Sciences Institute doi: /nr.2007.dec.S213 S216 INTRODUCTION Aging is associated with a number of chronic inflammatory conditions and a dysregulation of immune system function that increases risk of morbidity and mortality. 1 The upregulated production of prostaglandins, and particularly of the pro-inflammatory prostaglandin E 2 (PGE 2 ), is implicated in many of these agerelated conditions including cardiovascular disease, Alzheimer s disease, and type 2 diabetes as well as T-cell suppression associated with infectious disease and tumorigenesis. 2 5 Many of these deleterious effects are attributed to excess PGE 2 production in macrophages (M ), which are a major source of inflammatory mediators. 6 Nevertheless, the consequences of increased PGE 2 production depend largely on what target tissues are affected. For example, increased production of PGE 2 in M localized to arterial plaques may be associated with plaque rupture in humans, 7 while within the nervous system, it may contribute to neuropathic pain. 8 Excess PGE 2 production can also result in suppression of T cell function. Thus, an understanding of the regulation of PGE 2 synthesis in M may help elucidate the processes underlying several age-related diseases. Moreover, interventions to inhibit upregulation of PGE 2 may be explored as potential preventive and therapeutic strategies for such disease states. Dr. Meydani is Senior Scientist and Professor and Dr. Wu is Scientist II and Assistant Professor at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University and Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachussetts, USA. Please direct correspondence to: Simin Nikbin Meydani at the Nutritional Immunology Laboratory of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. Phone: , Fax: , simin.meydani@tufts.edu CYCLOOXYGENASE-INDUCED INCREASE IN PGE 2 PRODUCTION WITH AGING Age-associated increase in PGE 2 production has been demonstrated in a number of animal models 9,10 and in humans. 11,12 In one such study, peritoneal M from aged (24-mo) and young (6-mo) mice were stimulated with lipopolysaccharide (LPS) and M from aged mice produced significantly more PGE 2 compared with M from young mice. 13 The higher levels of PGE 2 production in the aged mice was attributed to increased cyclo- Nutrition Reviews, Vol. 65, No. 12 S213

2 oxygenase (COX) activity. COX is the rate-limiting enzyme in prostaglandin biosynthesis. 6 It is now apparent that its inducible isoform, COX-2, rather than its constitutively expressed isoform, COX-1, contributes to the increased PGE 2 production with age. While COX-2 mrna and protein expression were higher in M isolated from aged compared to young mice, no difference in COX-1 expression was observed between the two age groups. 13 This increase in COX-2 mrna expression is due to a higher rate of gene transcription in M isolated from aged mice, rather than an increased mrna stability. 13,14 CERAMIDE IS A KEY FACTOR UNDERLYING INCREASED COX-2 EXPRESSION WITH AGING Regulation of COX-2 expression involves complex interactions among a number of intracellular mediators (Figure 1), a key factor being the availability of ceramide, a sphingolipid second messenger formed by the action of the enzyme sphingomyelinase (SMase) on sphingomyelin, or by de novo synthesis Addition of ceramide to the cultured mouse M increased COX-2 activity and, consequently, PGE 2 production. 14 In M of aged mice, ceramide levels were found to increase after LPS stimulation by a larger magnitude compared with M from young mice, consistent with the timing of enhanced COX-2 activity and PGE 2 production. 14 Although the precise mechanism underlying the increased generation of ceramide with aging is unknown, it may involve a reduction in glutathione concentrations, which normally exerts an inhibitory control over SMase. 14,17,18 The age-related increase in COX-2 expression and activity induced by ceramide is now known to be mediated by nuclear factor-kappa B (NF- B), while other transcription factors including activator protein-1 (AP-1) and CRE-binding protein (CREB) do not appear to be involved. 6 Thus, exogenously administered ceramide in the absence or presence of LPS was found to significantly increase NF- B binding to the promoter region of the COX-2 gene, and binding of NF- B to the COX-2 promoter was shown to occur at a faster rate in M from aged compared with young animals following LPS stimulation, presumably due to the increase in ceramide concentrations with aging. 6 Although many of the intermediary processes involved in the regulation of NF- B binding remain to be resolved, these findings suggest an altered activity of the inhibitory protein I B, which normally anchors NF- B in the cytoplasm until an activating signal is received. 6 With aging, the cytoplasmic degradation of I B is increased, resulting in an enhanced rate of NF- B translocating into nucleus and binding to the COX-2 promoter in mouse M. 6 Such effects are blocked by the addition of Bay , which prevents Figure 1. Mechanisms for age-induced changes in macrophage (M ) PGE 2. Binding of LPS to its receptor CD14 at M surface triggers the activation of I B kinase (IKK) complex, including IKK, IKK, and IKK /NF- B essential modulator (NEMO), downstream of TRAF-6. IKK is a major kinase responsible for the phosphorylation of I B. Phosphorylated I B is further ubiquitinated and eventually degraded, leaving the NF- B dimer free to translocate to nucleus. In the nucleus, NF- B binds to the promoter region of COX-2 gene and initiates its transcription. The resulting mrna of COX-2 encodes synthesis of COX-2 enzyme. COX-2 catalyzes metabolism of AA to PGH 2, which is further isomerized to PGE 2. The age-associated increase in activation leads to higher expression of COX-2, COX-2 activity, and PGE 2 production. Ceramide upregulates COX-2 expression through NF- B activation in aging. The mechanism by which ceramide activates NF- B degradation can only be speculated at this time (shown as dotted lines) and remains to be determined. Vitamin E inhibits COX activity but has no effect on expression levels of protein and mrna of either COX-1 or COX-2. Reprinted from Meydani et al. 16 (Immunol Rev. 2005;205: ) with permission from Blackwell Publishing. the phosphorylation and consequent degradation of I B, or by administering an NF- B decoy that competes for transcription site binding. 6 Thus, applying these inhibitors is able to reduce the enhancement in COX-2 activity and PGE 2 production typically observed in LPS-stimulated M of aged mice. 6 A number of studies have suggested that a similar inflammatory process may take place in cell types other than M Adipocytes are cells of particular interest, owing to their association with the development of insulin resistance in type 2 diabetes. 22 The prevalence of type 2 diabetes increases with age, although it is not necessarily accompanied by an increase in weight One avenue of research is the possibility that insulin resistance in aging individuals may be a consequence of increased production of inflammatory products within adipose tissue, without an increase in the size of fat mass. S214 Nutrition Reviews, Vol. 65, No. 12

3 INTERVENTIONS TO DECREASE AGE- RELATED INCREASE IN COX-2 Understanding the processes underlying the increased production of PGE 2 is important for developing rational intervention strategies. Although anti-inflammatory drugs that inhibit COX-1 and/or COX-2 activity and thereby reduce PGE 2 synthesis have shown some clinical benefit in several age-related diseases, their utility may be limited by concerns of unwanted effects This has led to investigation of alternate therapies such as dietary/ nutritional interventions that may reduce COX-2 activity and/or PGE 2 production. 30,31 One nutritional compound that appears to have some efficacy is vitamin E supplementation, which diminishes the increased PGE 2 production in M of old mice by inhibiting COX activity, with negligible effects in young mice. 31 A low-fat diet with high fish consumption for n-3 polyunsaturated fatty acid enrichment has also been shown to effectively reduce inflammatory products, lowering baseline PGE 2 production in elderly individuals by 63% over a 6-month period, compared with a 30% reduction in those with a lower fish intake. 30 Several studies are currently underway to explore the possible COX-2- and PGE 2 -lowering benefits of various plant-derived phenolic compounds, or calorierestriction, in aging individuals. CONCLUSIONS Aging is associated with a number of chronic inflammatory conditions and a dysregulation of immune system function. M are a primary source of inflammatory mediators, and altered PGE 2 production with aging in these cells may contribute to the onset and progression of various age-related conditions. Mechanistic studies for the processes mediating increased PGE 2 production in M with aging suggest that ceramide may serve as a triggering factor that induces increased binding of NF- B to the nuclear transcription site of COX-2, resulting in a higher rate of COX-2 transcription and, eventually, excessive PGE 2 production. These same or similar mechanisms may occur in other cell types, and preliminary evidence suggests that higher levels of ceramide in adipocytes from old mice relative to those from young mice are a promising avenue for further study. Certain dietary/nutritional interventions appear to be effective in inhibiting the excessive production of PGE 2 seen in the aging, and may represent an important preventive and therapeutic strategy. ACKNOWLEDGMENT Supported by NIA grant RO1-AG and by US Department of Agriculture under agreement REFERENCES 1. Sebastian C, Espia M, Serra M, Celada A, Lloberas J. MacrophAging: a cellular and molecular review. Immunobiology. 2005;210: Oshima H, Taketo MM, Oshima M. Destruction of pancreatic beta-cells by transgenic induction of prostaglandin E2 in the islets. J Biol Chem. 2006; 281: Liang X, Wang Q, Hand T, et al. Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer s disease. J Neurosci. 2005;25: Paramo JA, Rodriguez JA, Beloqui O, Orbe J. Monocyte cyclooxygenase-2 activity: a new therapeutic target for atherosclerosis? Curr Drug Targets Cardiovasc Haematol Disord. 2005;5: Wu D, Meydani SN. Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. Brain Behav Immun. 2004;18: Wu D, Marko M, Claycombe K, Paulson KE, Meydani SN. Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through up-regulation of NF-kappa B activity. J Biol Chem. 2003;278: Cipollone F, Prontera C, Pini B, et al. Overexpression of functionally coupled cyclooxygenase-2 and prostaglandin E synthase in symptomatic atherosclerotic plaques as a basis of prostaglandin E(2)- dependent plaque instability. Circulation. 2001;104: Ma W, Quirion R. Targeting invading macrophagederived PGE2, IL-6 and calcitonin gene-related peptide in injured nerve to treat neuropathic pain. Expert Opin Ther Targets. 2006;10: Shimizu N, Yamaguchi M, Uesu K, Goseki T, Abiko Y. Stimulation of prostaglandin E2 and interleukin- 1beta production from old rat periodontal ligament cells subjected to mechanical stress. J Gerontol A Biol Sci Med Sci. 2000;55:B Millatt LJ, Siragy HM. Age-related changes in renal cyclic nucleotides and eicosanoids in response to sodium intake. Hypertension. 2000;35: Schwab R, Hausman PB, Rinnooy-Kan E, Weksler ME. Immunological studies of ageing. X. Impaired T lymphocytes and normal monocyte response from elderly humans to the mitogenic antibodies OKT3 and Leu 4. Immunology. 1985;55: Wu D, Meydani M, Leka LS, et al. Effect of dietary supplementation with black currant seed oil on the immune response of healthy elderly subjects. Am J Clin Nutr. 1999;70: Hayek MG, Mura C, Wu D, et al. Enhanced expression of inducible cyclooxygenase with age in murine macrophages. J Immunol. 1997;159: Claycombe KJ, Wu D, Nikolova-Karakashian M, et al. Ceramide mediates age-associated increase in macrophage cyclooxygenase-2 expression. J Biol Chem. 2002;277: Vesper H, Schmelz EM, Nikolova-Karakashian MN, Dillehay DL, Lynch DV, Merrill AH, Jr. Sphingolipids in food and the emerging importance of sphingolipids to nutrition. J Nutr. 1999;129: Meydani SN, Han SN, Wu D. Vitamin E and immune response in the aged: molecular mechanisms and Nutrition Reviews, Vol. 65, No. 12 S215

4 clinical implications. Immunol Rev. 2005;205: Sasaki T, Senda M, Kim S, Kojima S, Kubodera A. Age-related changes of glutathione content, glucose transport and metabolism, and mitochondrial electron transfer function in mouse brain. Nucl Med Biol. 2001;28: Furukawa T, Meydani SN, Blumberg JB. Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. Mech Ageing Dev. 1987;38: Mitchell JA, Belvisi MG, Akarasereenont P, et al. Induction of cyclo-oxygenase-2 by cytokines in human pulmonary epithelial cells: regulation by dexamethasone. Br J Pharmacol. 1994;113: Maloney CG, Kutchera WA, Albertine KH, McIntyre TM, Prescott SM, Zimmerman GA. Inflammatory agonists induce cyclooxygenase type 2 expression by human neutrophils. J Immunol. 1998;160: Huttner JJ, Gwebu ET, Panganamala RV, et al. Fatty acids and their prostaglandin derivatives: inhibitors of proliferation in aortic smooth muscle cells. Science. 1977;197: Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106: Center for Disease Control. Prevalence of diagnosed diabetes by age, United States, Available at: Accessed May 30, Center for Disease Control. Rates of obesity per 100 adults with diabetes, by age, United States, Available at: statistics/comp/table7_3a.htm. Accessed May 30, Defronzo RA. Glucose intolerance and aging: evidence for tissue insensitivity to insulin. Diabetes. 1979;28: DeFronzo RA. Glucose intolerance and aging. Diabetes Care. 1981;4: Grosser T. The pharmacology of selective inhibition of COX-2. Thromb Haemost. 2006;96: Sanghi S, MacLaughlin EJ, Jewell CW, et al. Cyclooxygenase-2 inhibitors: a painful lesson. Cardiovasc Hematol Disord Drug Targets. 2006;6: Kremer J. From prostaglandin replacement to specific COX-2 inhibition: a critical appraisal. J Rheumatol Suppl. 2000;60: Meydani SN, Lichtenstein AH, Cornwall S, et al. Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived N-3 fatty acid enrichment. J Clin Invest. 1993;92: Wu D, Mura C, Beharka AA, et al. Age-associated increase in PGE2 synthesis and COX activity in murine macrophages is reversed by vitamin E. Am J Physiol. 1998;275(3 Pt 1):C S216 Nutrition Reviews, Vol. 65, No. 12

Nutrition and Age-Associated Inflammation :Role of Nutritional Intervention Simin Nikbin Meydani, DVM, PhD.

Nutrition and Age-Associated Inflammation :Role of Nutritional Intervention Simin Nikbin Meydani, DVM, PhD simin.meydani@tufts.edu Outline 1) Role of immune and inflammatory responses in age-related diseases