- Email: [email protected]
The impact of aging on the brain – Risk, resilience and repair
Brain, Behavior, and Immunity 26 (2012) 714–716
Contents lists available at SciVerse ScienceDirect
Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi
Brief Commentary
The impact of aging on the brain – Risk, resilience and repair Marina A. Lynch a,⇑, Rodney W. Johnson b a
Trinity Institute for Neuroscience, Trinity College, Dublin, Ireland Laboratory of Integrative Immunology and Behavior, Department of Animal Sciences, Division of Nutritional Sciences, and Neuroscience Program, University of Illinois, Urbana, United States
b
The world is getting older; just less than 1 in every 8 citizens in the US is 65 years or older and it is estimated that, by 2030, 1 in every 5 citizens will be 65 years or older. These figures are replicated in most western countries. This inexorable increase in the aging population is accompanied by increased risk of age-related diseases including neurodegenerative diseases, but also cardiovascular disease and diabetes which increase the likelihood of developing conditions that impact on neuronal function. Aging also affects resilience and the consequences of any insult, including trauma, stress, infection or surgery can have profound effects in an aged individual. The underlying cause of this age-related decrease in resilience may be a consequence of immunosenescence, which is associated with constituitive, though low-grade, inflammation (inflamm-aging) compromising the health of the elderly (McElhaney and Effros, 2009). It is well documented that the effects of infection are more profound in aged, compared with young, animals (Barrientos et al., 2006; Frank et al., 2009) and that resolution of infection is protracted in aged individuals. Studies in aged animals have demonstrated that this results from diminished ability of the cells of the immune system to respond to insult. In older humans, influenza is associated with increased mortality, delayed recovery and sometimes sequelae which diminish quality of life. Studies in aged mice suggest that the slower recovery following influenza infection is associated with a delay in recruitment of granulocytes into the lung accompanied by more persistent macrophage infiltration (Toapanta and Ross, 2009). However immunosenescence is associated with changes in numbers and function of several immune cell subsets. Overall numbers of B cells and T cells decrease with age, although an increase in memory T cells, in particular CD8+ T cells, occurs. The relatively poorer antibody response to influenza vaccination in aged individuals has been linked with an increase in the proportion of CD8+ CD28 cells (Saurwein-Teissl et al., 2002). An increase in these cells also occurs in aged individuals with latent cytomegalovirus (CMV) infection (Almanzar et al., 2005). In turn, the age-related changes in the immune system can reactivate CMV and related viruses triggering further inflammatory changes (Bennett et al., 2012). Age-related changes in natural killer (NK) cell function have also been described; the numbers of NK cells and NKT cells increase and the evidence indicates that NKT cells ⇑ Corresponding author. E-mail address: [email protected] (M.A. Lynch). 0889-1591/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.bbi.2012.02.005
prepared from livers of aged mice secrete more IL-17 than cells prepared from young mice. The increase in mortality in aged mice infected with systemic herpes viruses has been attributed to these changes (Stout-Delgado et al., 2009). Systemic infection also alters the course of neurodegenerative diseases and evidence suggests that infection may precipitate relapse or even trigger the onset of multiple sclerosis (Stratton and Wheldon, 2006). Infection has been reported to accelerate cognitive decline in patients with Alzheimer0 s disease (Holmes et al., 2003) and it has been suggested that infiltration of Chlamydophila pneumoniae into the brain may precipitate the disease (Stallings, 2008). Penetration of the microorganism into the brain is not required, however, for induction of CNS complications. Communication pathways between the peripheral immune system and brain (e.g., vagal afferents) are also critical during infection, as they stimulate brain microglia to produce inflammatory mediators that drive disease pathogenesis and behavioral pathology (Dantzer et al., 2008). It seems likely that immunosenescence occurs in the CNS as well as in the periphery and the key change is microglial dysfunction; the result of this is an impaired ability of these cells to provide neuroprotection and, ultimately, the development of neurodegenerative changes (Streit and Kincaid-Colton, 1995). There is little doubt that the well-described age-related neuroinflammatory changes are accompanied by microglial activation. Thus microglia in the brain of aged individuals express cell surface markers that are indicative of activation; these markers include CD11b which plays a role in cell mobility and chemotaxis, CD68 which may reflect phagocytic function and MHCII which indicates antigen presentation function. It appears that age-related changes in expression of these and other markers of activation are regionspecific, with more pronounced changes in caudal areas of the brain and in white matter (Hart et al., in press). The phenotypic changes in microglia render them hypersensitive to infectious agents and to signals derived from the peripheral immune system. This is a significant event leading to behavioral pathology in aged rodents with an infection. This is also likely to be the case in humans because acute cognitive disorders are common in older adults with peripheral infections (Chiovenda et al., 2002; Wofford et al., 1996). It has been consistently reported that aged animals, or microglia from aged animals, respond more profoundly to activation of Toll-like receptor (TLR)4 by lipopolysaccharide (LPS) and TLR2 by PamCSK3 exhibiting an increase in inflammatory cytokine
M.A. Lynch, R.W. Johnson / Brain, Behavior, and Immunity 26 (2012) 714–716
production (Chen et al., 2008; Njie et al., 2012). Treatment of aged animals with LPS also exerts a greater effect on hippocampaldependent behavioral tasks (Chen et al., 2008), sickness behavior (Godbout et al., 2005), as well as depressive-like behavior (Godbout et al., 2008). It is now recognized that, like macrophages, microglia can adopt a number of activation states (Colton, 2009); whereas inflammatory changes occur when the innate immune response is triggered, for example by activation of TLRs and when interferon-c (IFNc) stimulates classical activation, changes which play a role in resolution of inflammation occur when the alternative activation state is stimulated by anti-inflammatory cytokines like IL-4 (Colton, 2009). Thus we must now consider the possibility that age-related microglial activation may be multifaceted with altered response profiles, not only to LPS, but also to other stimuli, for example IL-4 (Fenn et al., 2012). Under resting conditions, microglia are maintained in a deactivated state which relies on the presence of IL-10 and transforming growth factor-b (TGFb) in the microenvironment and, in addition, the interaction of microglia with other cells enabled by interaction between ligand-receptor pairs further insures that microglia remain quiescent. In this context, a role for CD200–CD200R interaction has been reported and the evidence indicates that the agerelated decrease in CD200 expression is associated with activation of microglia and inflammatory changes (Lyons et al., 2007) and loss of synaptic contacts (Ojo et al., 2012), which impact on cognitive function. There is now general acceptance that the immune system and the CNS are inextricably linked (Romo-Gonzalez et al., 2012) and this link is consolidated by the observation that interventions which benefit one system also benefits the other. For example, the anti-inflammatory effects of exercise, and consequent improvements in health are well described (Gleeson et al., 2011) as are its beneficial effects on cognitive function. Accordingly, voluntary exercise in aged mice has been reported to shift the microglial phenotype towards neuroprotection(Kohman et al., 2012) and, in older adults, cardiovascular fitness is associated with reduced brain atrophy and improved cognitive function (Weinstein et al., 2012). Likewise, polyunsaturated fatty acids like docosahexaenoic acid, which have powerful anti-inflammatory actions, are known to improve cognitive function in aged individuals (Karr et al., 2011). This issue of Brain, Behavior and Immunity includes an assemblage of 12 original research articles related to aging and psychoneuroimmunology. They run the gamut from transcriptional profiling in glial cells from aged mice (Kremsky et al., in press) to in vivo assessment of brain atrophy by magnetic resonance imaging, to understanding how cardiovascular fitness improves cognition in elderly humans (Weinstein et al., 2012). Suzanne Segerstrom studied a cohort of older adults who received annual influenza vaccinations and found that distress and vulnerability interact affecting a number of post-vaccine responses (Segerstrom et al., 2012), while Bennett and colleagues present evidence suggesting that reactivation of multiple herpesviruses in older adults leads to increased inflammation (Bennett et al., 2012). These findings carry added significance now that we know peripheral infection and inflammation impinge upon the brain causing microglia with an activated phenotype to over-react. A collection of studies presented herein focused on the mechanisms responsible for agerelated changes to microglia. They advance our understanding of age-related microglial dysfunction by showing impaired neuronmicroglial cross-talk (Cox et al., 2012; Ojo et al., 2012), revealing activated microglia from aged mice are less sensitive to the antiinflammatory and M2-promoting effects of IL-4 (Fenn et al., 2012), and showing, for the first time, that microglial phenotype and function vary significantly between CNS compartments in
715
aged mice (Hart et al., in press). Results of another study suggest that excessive production of IL-6 in the brain of aged mice is paralleled by increased IL-6 receptor trans-signaling, which leads to cognitive deficits (Burton and Johnson, 2012). The good news is that there appear to be several pragmatic lifestyle changes that reduce neuroinflammation and improve cognitive aging—exercise and improved cardiovascular fitness (Kohman et al., 2012; Weinstein et al., 2012) and consuming a diet rich in anti-inflammatory n-3 polyunsaturated fatty acids (Luciano et al., 2012; Moranis et al., 2012).
Conflict of interest None declared. Acknowledgments We thank all of the authors who have contributed to this issue. M.A.L receives support from Science Foundation Ireland; R.W.J. receives support from the National Institutes of Health (AG16710). References Almanzar, G., Schwaiger, S., Jenewein, B., Keller, M., Herndler-Brandstetter, D., Wurzner, R., Schonitzer, D., Grubeck-Loebenstein, B., 2005. Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J. Virol. 79, 3675–3683. Barrientos, R.M., Higgins, E.A., Biedenkapp, J.C., Sprunger, D.B., Wright-Hardesty, K.J., Watkins, L.R., Rudy, J.W., Maier, S.F., 2006. Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol. Aging 27, 723–732. Bennett, J.M., Glaser, R., Malarkey, W.B., Beversdorf, D.Q., Peng, J., Kiecolt-Glaser, J.K., 2012. Inflammation and reactivation of latent herpesviruses in older adults. Brain Behav. Immun. In Press. Burton, M.D., Johnson, R.W., 2012. Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning. Brain Behav. Immun. In Press. Chen, J., Buchanan, J.B., Sparkman, N.L., Godbout, J.P., Freund, G.G., Johnson, R.W., 2008. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav. Immun. 22, 301–311. Chiovenda, P., Vincentelli, G.M., Alegiani, F., 2002. Cognitive impairment in elderly ED patients: need for multidimensional assessment for better management after discharge. Am. J. Emerg. Med. 20, 332–335. Colton, C.A., 2009. Heterogeneity of microglial activation in the innate immune response in the brain. J. Neuroimmune. Pharmacol. 4, 399–418. Cox, F.F., Carney, D., Miller, A.M., Lynch, M.A., 2012. CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav. Immun. In Press. Dantzer, R., O’Connor, J.C., Freund, G.G., Johnson, R.W., Kelley, K.W., 2008. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56. Fenn, A.M., Henry, C.J., Huang, Y., Dugan, A., Godbout, J.P., 2012. Lipopolysaccharideinduced interleukin (IL)-4 receptor-alpha expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain Behav. Immun. In Press. Frank, M.G., Barrientos, R.M., Hein, A.M., Biedenkapp, J.C., Watkins, L.R., Maier, S.F., 2009. IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats. Brain Behav. Immun. In Press. Gleeson, M., Bishop, N.C., Stensel, D.J., Lindley, M.R., Mastana, S.S., Nimmo, M.A., 2011. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615. Godbout, J.P., Chen, J., Abraham, J., Richwine, A.F., Berg, B.M., Kelley, K.W., Johnson, R.W., 2005. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. Faseb J. 19, 1329– 1331. Godbout, J.P., Moreau, M., Lestage, J., Chen, J., Sparkman, N.L., Connor, J.O., Castanon, N., Kelley, K.W., Dantzer, R., Johnson, R.W., 2008. Aging exacerbates depressivelike behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33, 2341–2351. Hart, A.D., Wyttenbach, A., Hugh Perry, V., Teeling, J.L., in press. Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav. Immun. Holmes, C., El-Okl, M., Williams, A.L., Cunningham, C., Wilcockson, D., Perry, V.H., 2003. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer0 s disease. J. Neurol. Neurosurg. Psychiatry 74, 788–789.
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Karr, J.E., Alexander, J.E., Winningham, R.G., 2011. Omega-3 polyunsaturated fatty acids and cognition throughout the lifespan: a review. Nutr. Neurosci. 14, 216– 225. Kohman, R.A., Clark, P.J., Deyoung, E.K., Bhattacharya, T.K., Venghaus, C.E., Rhodes, J.S., 2012. Voluntary wheel running enhances contextual but not trace fear conditioning. Behav. Brain Res. 226, 1–7. Kremsky, I., Morgan, T.E., Hou, X., Li, L., Finch, C.E., in press. Age-changes in gene expression in primary mixed glia cultures from young vs. old rat cerebral cortex are modified by interactions with neurons. Brain Behav. Immun. Luciano, M., Mottus, R., Starr, J.M., McNeill, G., Jia, X., Craig, L.C., Deary, I.J., 2012. Depressive symptoms and diet: Their effects on prospective inflammation levels in the elderly. Brain Behav. Immun. In Press. Lyons, A., Downer, E.J., Crotty, S., Nolan, Y.M., Mills, K.H., Lynch, M.A., 2007. CD200 ligand receptor interaction modulates microglial activation in vivo and in vitro: a role for IL-4. J. Neurosci. 27, 8309–8313. McElhaney, J.E., Effros, R.B., 2009. Immunosenescence. what does it mean to health outcomes in older adults? Curr. Opin. Immunol. 21, 418–424. Moranis, A., Delpech, J.C., De Smedt-Peyrusse, V., Aubert, A., Guesnet, P., Lavialle, M., Joffre, C., Laye, S., 2012. Long term adequate n-3 polyunsaturated fatty acid diet protects from depressive-like behavior but not from working memory disruption and brain cytokine expression in aged mice. Brain Behav. Immun. In Press. Njie, E.G., Boelen, E., Stassen, F.R., Steinbusch, H.W., Borchelt, D.R., Streit, W.J., 2012. Ex vivo cultures of microglia from young and aged rodent brain reveal agerelated changes in microglial function. Neurobiol. Aging 33 (195), e191–112. Ojo, B., Rezaie, P., Gabbott, P.L., Davies, H., Colyer, F., Cowley, T.R., Lynch, M., Stewart, M.G., 2012. Age-related changes in the hippocampus (loss of synaptophysin and glial-synaptic interaction) are modified by systemic treatment with an NCAMderived peptide. Brain Behav. Immun. In Press, FGL.
Romo-Gonzalez, T., Chavarria, A., Perez, H.J., 2012. Central nervous system: a modified immune surveillance circuit? Brain Behav. Immun. In Press. Saurwein-Teissl, M., Lung, T.L., Marx, F., Gschosser, C., Asch, E., Blasko, I., Parson, W., Bock, G., Schonitzer, D., Trannoy, E., Grubeck-Loebenstein, B., 2002. Lack of antibody production following immunization in old age: association with CD8(+)CD28() T cell clonal expansions and an imbalance in the production of Th1 and Th2 cytokines. J. Immunol. 168, 5893–5899. Segerstrom, S.C., Hardy, J.K., Evans, D.R., Greenberg, R.N., 2012. Vulnerability, distress, and immune response to vaccination in older adults. Brain Behav. Immun. Stallings, T.L., 2008. Association of Alzheimer’s disease and Chlamydophila pneumoniae. J. Infect. 56, 423–431. Stout-Delgado, H.W., Du, W., Shirali, A.C., Booth, C.J., Goldstein, D.R., 2009. Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection. Cell Host Microbe 6, 446–456. Stratton, C.W., Wheldon, D.B., 2006. Multiple sclerosis: an infectious syndrome involving Chlamydophila pneumoniae. Trends Microbiol. 14, 474–479. Streit, W.J., Kincaid-Colton, C.A., 1995. The brain’s immune system. Sci. Am. 273 (54–55), 58–61. Toapanta, F.R., Ross, T.M., 2009. Impaired immune responses in the lungs of aged mice following influenza infection. Respir. Res. 10, 112. Weinstein, A.M., Voss, M.W., Prakash, R.S., Chaddock, L., Szabo, A., White, S.M., Wojcicki, T.R., Mailey, E., McAuley, E., Kramer, A.F., Erickson, K.I., 2012. The association between aerobic fitness and executive function is mediated by prefrontal cortex volume. Brain Behav. Immun. In Press. Wofford, J.L., Loehr, L.R., Schwartz, E., 1996. Acute cognitive impairment in elderly ED patients: etiologies and outcomes. Am. J. Emerg. Med. 14, 649–653.
Contents lists available at SciVerse ScienceDirect
Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi
Brief Commentary
The impact of aging on the brain – Risk, resilience and repair Marina A. Lynch a,⇑, Rodney W. Johnson b a
Trinity Institute for Neuroscience, Trinity College, Dublin, Ireland Laboratory of Integrative Immunology and Behavior, Department of Animal Sciences, Division of Nutritional Sciences, and Neuroscience Program, University of Illinois, Urbana, United States
b
The world is getting older; just less than 1 in every 8 citizens in the US is 65 years or older and it is estimated that, by 2030, 1 in every 5 citizens will be 65 years or older. These figures are replicated in most western countries. This inexorable increase in the aging population is accompanied by increased risk of age-related diseases including neurodegenerative diseases, but also cardiovascular disease and diabetes which increase the likelihood of developing conditions that impact on neuronal function. Aging also affects resilience and the consequences of any insult, including trauma, stress, infection or surgery can have profound effects in an aged individual. The underlying cause of this age-related decrease in resilience may be a consequence of immunosenescence, which is associated with constituitive, though low-grade, inflammation (inflamm-aging) compromising the health of the elderly (McElhaney and Effros, 2009). It is well documented that the effects of infection are more profound in aged, compared with young, animals (Barrientos et al., 2006; Frank et al., 2009) and that resolution of infection is protracted in aged individuals. Studies in aged animals have demonstrated that this results from diminished ability of the cells of the immune system to respond to insult. In older humans, influenza is associated with increased mortality, delayed recovery and sometimes sequelae which diminish quality of life. Studies in aged mice suggest that the slower recovery following influenza infection is associated with a delay in recruitment of granulocytes into the lung accompanied by more persistent macrophage infiltration (Toapanta and Ross, 2009). However immunosenescence is associated with changes in numbers and function of several immune cell subsets. Overall numbers of B cells and T cells decrease with age, although an increase in memory T cells, in particular CD8+ T cells, occurs. The relatively poorer antibody response to influenza vaccination in aged individuals has been linked with an increase in the proportion of CD8+ CD28 cells (Saurwein-Teissl et al., 2002). An increase in these cells also occurs in aged individuals with latent cytomegalovirus (CMV) infection (Almanzar et al., 2005). In turn, the age-related changes in the immune system can reactivate CMV and related viruses triggering further inflammatory changes (Bennett et al., 2012). Age-related changes in natural killer (NK) cell function have also been described; the numbers of NK cells and NKT cells increase and the evidence indicates that NKT cells ⇑ Corresponding author. E-mail address: [email protected] (M.A. Lynch). 0889-1591/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.bbi.2012.02.005
prepared from livers of aged mice secrete more IL-17 than cells prepared from young mice. The increase in mortality in aged mice infected with systemic herpes viruses has been attributed to these changes (Stout-Delgado et al., 2009). Systemic infection also alters the course of neurodegenerative diseases and evidence suggests that infection may precipitate relapse or even trigger the onset of multiple sclerosis (Stratton and Wheldon, 2006). Infection has been reported to accelerate cognitive decline in patients with Alzheimer0 s disease (Holmes et al., 2003) and it has been suggested that infiltration of Chlamydophila pneumoniae into the brain may precipitate the disease (Stallings, 2008). Penetration of the microorganism into the brain is not required, however, for induction of CNS complications. Communication pathways between the peripheral immune system and brain (e.g., vagal afferents) are also critical during infection, as they stimulate brain microglia to produce inflammatory mediators that drive disease pathogenesis and behavioral pathology (Dantzer et al., 2008). It seems likely that immunosenescence occurs in the CNS as well as in the periphery and the key change is microglial dysfunction; the result of this is an impaired ability of these cells to provide neuroprotection and, ultimately, the development of neurodegenerative changes (Streit and Kincaid-Colton, 1995). There is little doubt that the well-described age-related neuroinflammatory changes are accompanied by microglial activation. Thus microglia in the brain of aged individuals express cell surface markers that are indicative of activation; these markers include CD11b which plays a role in cell mobility and chemotaxis, CD68 which may reflect phagocytic function and MHCII which indicates antigen presentation function. It appears that age-related changes in expression of these and other markers of activation are regionspecific, with more pronounced changes in caudal areas of the brain and in white matter (Hart et al., in press). The phenotypic changes in microglia render them hypersensitive to infectious agents and to signals derived from the peripheral immune system. This is a significant event leading to behavioral pathology in aged rodents with an infection. This is also likely to be the case in humans because acute cognitive disorders are common in older adults with peripheral infections (Chiovenda et al., 2002; Wofford et al., 1996). It has been consistently reported that aged animals, or microglia from aged animals, respond more profoundly to activation of Toll-like receptor (TLR)4 by lipopolysaccharide (LPS) and TLR2 by PamCSK3 exhibiting an increase in inflammatory cytokine
M.A. Lynch, R.W. Johnson / Brain, Behavior, and Immunity 26 (2012) 714–716
production (Chen et al., 2008; Njie et al., 2012). Treatment of aged animals with LPS also exerts a greater effect on hippocampaldependent behavioral tasks (Chen et al., 2008), sickness behavior (Godbout et al., 2005), as well as depressive-like behavior (Godbout et al., 2008). It is now recognized that, like macrophages, microglia can adopt a number of activation states (Colton, 2009); whereas inflammatory changes occur when the innate immune response is triggered, for example by activation of TLRs and when interferon-c (IFNc) stimulates classical activation, changes which play a role in resolution of inflammation occur when the alternative activation state is stimulated by anti-inflammatory cytokines like IL-4 (Colton, 2009). Thus we must now consider the possibility that age-related microglial activation may be multifaceted with altered response profiles, not only to LPS, but also to other stimuli, for example IL-4 (Fenn et al., 2012). Under resting conditions, microglia are maintained in a deactivated state which relies on the presence of IL-10 and transforming growth factor-b (TGFb) in the microenvironment and, in addition, the interaction of microglia with other cells enabled by interaction between ligand-receptor pairs further insures that microglia remain quiescent. In this context, a role for CD200–CD200R interaction has been reported and the evidence indicates that the agerelated decrease in CD200 expression is associated with activation of microglia and inflammatory changes (Lyons et al., 2007) and loss of synaptic contacts (Ojo et al., 2012), which impact on cognitive function. There is now general acceptance that the immune system and the CNS are inextricably linked (Romo-Gonzalez et al., 2012) and this link is consolidated by the observation that interventions which benefit one system also benefits the other. For example, the anti-inflammatory effects of exercise, and consequent improvements in health are well described (Gleeson et al., 2011) as are its beneficial effects on cognitive function. Accordingly, voluntary exercise in aged mice has been reported to shift the microglial phenotype towards neuroprotection(Kohman et al., 2012) and, in older adults, cardiovascular fitness is associated with reduced brain atrophy and improved cognitive function (Weinstein et al., 2012). Likewise, polyunsaturated fatty acids like docosahexaenoic acid, which have powerful anti-inflammatory actions, are known to improve cognitive function in aged individuals (Karr et al., 2011). This issue of Brain, Behavior and Immunity includes an assemblage of 12 original research articles related to aging and psychoneuroimmunology. They run the gamut from transcriptional profiling in glial cells from aged mice (Kremsky et al., in press) to in vivo assessment of brain atrophy by magnetic resonance imaging, to understanding how cardiovascular fitness improves cognition in elderly humans (Weinstein et al., 2012). Suzanne Segerstrom studied a cohort of older adults who received annual influenza vaccinations and found that distress and vulnerability interact affecting a number of post-vaccine responses (Segerstrom et al., 2012), while Bennett and colleagues present evidence suggesting that reactivation of multiple herpesviruses in older adults leads to increased inflammation (Bennett et al., 2012). These findings carry added significance now that we know peripheral infection and inflammation impinge upon the brain causing microglia with an activated phenotype to over-react. A collection of studies presented herein focused on the mechanisms responsible for agerelated changes to microglia. They advance our understanding of age-related microglial dysfunction by showing impaired neuronmicroglial cross-talk (Cox et al., 2012; Ojo et al., 2012), revealing activated microglia from aged mice are less sensitive to the antiinflammatory and M2-promoting effects of IL-4 (Fenn et al., 2012), and showing, for the first time, that microglial phenotype and function vary significantly between CNS compartments in
715
aged mice (Hart et al., in press). Results of another study suggest that excessive production of IL-6 in the brain of aged mice is paralleled by increased IL-6 receptor trans-signaling, which leads to cognitive deficits (Burton and Johnson, 2012). The good news is that there appear to be several pragmatic lifestyle changes that reduce neuroinflammation and improve cognitive aging—exercise and improved cardiovascular fitness (Kohman et al., 2012; Weinstein et al., 2012) and consuming a diet rich in anti-inflammatory n-3 polyunsaturated fatty acids (Luciano et al., 2012; Moranis et al., 2012).
Conflict of interest None declared. Acknowledgments We thank all of the authors who have contributed to this issue. M.A.L receives support from Science Foundation Ireland; R.W.J. receives support from the National Institutes of Health (AG16710). References Almanzar, G., Schwaiger, S., Jenewein, B., Keller, M., Herndler-Brandstetter, D., Wurzner, R., Schonitzer, D., Grubeck-Loebenstein, B., 2005. Long-term cytomegalovirus infection leads to significant changes in the composition of the CD8+ T-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons. J. Virol. 79, 3675–3683. Barrientos, R.M., Higgins, E.A., Biedenkapp, J.C., Sprunger, D.B., Wright-Hardesty, K.J., Watkins, L.R., Rudy, J.W., Maier, S.F., 2006. Peripheral infection and aging interact to impair hippocampal memory consolidation. Neurobiol. Aging 27, 723–732. Bennett, J.M., Glaser, R., Malarkey, W.B., Beversdorf, D.Q., Peng, J., Kiecolt-Glaser, J.K., 2012. Inflammation and reactivation of latent herpesviruses in older adults. Brain Behav. Immun. In Press. Burton, M.D., Johnson, R.W., 2012. Interleukin-6 trans-signaling in the senescent mouse brain is involved in infection-related deficits in contextual fear conditioning. Brain Behav. Immun. In Press. Chen, J., Buchanan, J.B., Sparkman, N.L., Godbout, J.P., Freund, G.G., Johnson, R.W., 2008. Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav. Immun. 22, 301–311. Chiovenda, P., Vincentelli, G.M., Alegiani, F., 2002. Cognitive impairment in elderly ED patients: need for multidimensional assessment for better management after discharge. Am. J. Emerg. Med. 20, 332–335. Colton, C.A., 2009. Heterogeneity of microglial activation in the innate immune response in the brain. J. Neuroimmune. Pharmacol. 4, 399–418. Cox, F.F., Carney, D., Miller, A.M., Lynch, M.A., 2012. CD200 fusion protein decreases microglial activation in the hippocampus of aged rats. Brain Behav. Immun. In Press. Dantzer, R., O’Connor, J.C., Freund, G.G., Johnson, R.W., Kelley, K.W., 2008. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56. Fenn, A.M., Henry, C.J., Huang, Y., Dugan, A., Godbout, J.P., 2012. Lipopolysaccharideinduced interleukin (IL)-4 receptor-alpha expression and corresponding sensitivity to the M2 promoting effects of IL-4 are impaired in microglia of aged mice. Brain Behav. Immun. In Press. Frank, M.G., Barrientos, R.M., Hein, A.M., Biedenkapp, J.C., Watkins, L.R., Maier, S.F., 2009. IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats. Brain Behav. Immun. In Press. Gleeson, M., Bishop, N.C., Stensel, D.J., Lindley, M.R., Mastana, S.S., Nimmo, M.A., 2011. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615. Godbout, J.P., Chen, J., Abraham, J., Richwine, A.F., Berg, B.M., Kelley, K.W., Johnson, R.W., 2005. Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system. Faseb J. 19, 1329– 1331. Godbout, J.P., Moreau, M., Lestage, J., Chen, J., Sparkman, N.L., Connor, J.O., Castanon, N., Kelley, K.W., Dantzer, R., Johnson, R.W., 2008. Aging exacerbates depressivelike behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33, 2341–2351. Hart, A.D., Wyttenbach, A., Hugh Perry, V., Teeling, J.L., in press. Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav. Immun. Holmes, C., El-Okl, M., Williams, A.L., Cunningham, C., Wilcockson, D., Perry, V.H., 2003. Systemic infection, interleukin 1beta, and cognitive decline in Alzheimer0 s disease. J. Neurol. Neurosurg. Psychiatry 74, 788–789.
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