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Potential associations between systemic inflammation and social support received by a sample of 120 older adults were examined here. Inflammatory markers, cognitive function, social support and psychosocial wellbeing were evaluated. A structural equation modelling approach was used to analyse the data. The model was a good fit χ 108 2 = 256 . 13 , p < 0.001; comparative fit index = 0.973; Tucker-Lewis Index = 0.962; root mean square error of approximation = 0.021; standardised root mean-square residual = 0.074). Chemokine levels were associated with increased age ( β = 0.276), receipt of less social support from friends ( β = -0.256) and body mass index ( β = -0.256). Results are discussed in relation to social signal transduction theory.

The recognized role of neuroinflammation in the age-related deterioration of neuronal function highlights the importance of understanding the factors that control microglial activation. Microglia, as the immune cells of the brain, are the arbiters of the inflammatory profile in the brain. Normally they are maintained in a quiescent state by means of ligand-receptor interactions with neurons, within a prevailing anti-inflammatory microenvironment. The evidence indicates that, as the ageing process continues, microglia become activated, shift towards an inflammatory phenotype and alter the milieu in the brain. Although there has been progress in identifying factors that contribute to age-related microglial activation, our understanding remains incomplete. Here we report that there was an age-related increase in circulating inflammatory cytokines, accompanied by microglial activation. Neutrophils, and to a greater extent, macrophages, infiltrate the brain with age, perhaps as a result of increased chemokine expression in the brain, specifically CXCL1 and CCL2. We sought to determine whether macrophages might trigger microglial activation and the evidence shows that conditioned medium obtained from interferon-γ (IFNγ)-stimulated macrophages potently activated microglia. The data suggest that infiltrating macrophages may be one factor that contributes to age-related microglial activation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Altered synaptic morphology, progressive loss of synapses and glial (astrocyte and microglial) cell activation are considered as characteristic hallmarks of aging. Recent evidence suggests that there is a concomitant age-related decrease in expression of the presynaptic protein, synaptophysin, and the neuronal glycoprotein CD200, which, by interacting with its receptor, plays a role in maintaining microglia in a quiescent state. These age-related changes may be indicative of reduced neuroglial support of synapses. FG Loop (FGL) peptide synthesized from the second fibronectin type III module of neural cell adhesion molecule (NCAM), has previously been shown to attenuate age-related glial cell activation, and to 'restore' cognitive function in aged rats. The mechanisms by which FGL exerts these neuroprotective effects remain unclear, but could involve regulation of CD200, modifying glial-synaptic interactions (affecting neuroglial 'support' at synapses), or impacting directly on synaptic function. Light and electron microscopic (EM) analyses were undertaken to investigate whether systemic treatment with FGL (i) alters CD200, synaptophysin (presynaptic) and PSD-95 (postsynaptic) immunohistochemical expression levels, (ii) affects synaptic number, or (iii) exerts any effects on glial-synaptic interactions within young (4 month-old) and aged (22 month-old) rat hippocampus. Treatment with FGL attenuated the age-related loss of synaptophysin immunoreactivity (-ir) within CA3 and hilus (with no major effect on PSD-95-ir), and of CD200-ir specifically in the CA3 region. Ultrastructural morphometric analyses showed that FGL treatment (i) prevented age-related loss in astrocyte-synaptic contacts, (ii) reduced microglia-synaptic contacts in the CA3 stratum radiatum, but (iii) had no effect on the mean number of synapses in this region. These data suggest that FGL mediates its neuroprotective effects by regulating glial-synaptic interaction., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The FGL peptide is a neural cell adhesion molecule (NCAM) mimetic comprising a 15-amino-acid-long sequence of the FG loop region of the second fibronectin type III module of NCAM. It corresponds to the binding site of NCAM for the fibroblast growth factor receptor 1. FGL improves cognitive function through enhancement of synaptic function. We examined the effect of FGL on synaptic and dendritic structure in the brains of aged (22-month-old) rats that were injected subcutaneously (8 mg/kg) at 2-day intervals until 19 days after the start of the experiment. Animals were perfused with fixative, brains removed and coronal sections cut at 50 microm. The hippocampal volume was measured, tissue embedded and ultrathin sections viewed in a JEOL 1010 electron microscope. Analyses were made of synaptic and dendritic parameters following three-dimensional reconstruction via images from a series of approximately 100 serial ultrathin sections. FGL affected neither hippocampal volume nor spine or synaptic density in the middle molecular layer of the dentate gyrus. However, it increased the ratio of mushroom to thin spines, number of multivesicular bodies and also increased the frequency of appearance of coated pits. Three-dimensional analysis showed a significant decrease in both post-synaptic density and apposition zone curvature of mushroom spines following FGL treatment, whereas for thin spines the convexity of the apposition zone increased. These data indicate that FGL induces large changes in the fine structure of synapses and dendritic spines in hippocampus of aged rats, complementing data showing its effect on cognitive processes.

The age-related decline in cognitive function has been associated with biochemical changes that can be attenuated following n-3 polyunsaturated fatty acid treatment. Dietary supplementation with docosahexaenoic acid (DHA) has been shown to reverse age-related changes in synaptic function. Here, lipidomic analyses were undertaken to examine changes in lipid classes and phospholipid species in cortical tissue of young (2-4 months) and aged (20-22 months), control- and DHA-treated (10mg daily) rats following treatment for 8 weeks, aiming to explore the mechanism of DHA action. Dietary supplementation normalised the age-related decrease in unsaturation index, reduced the levels of arachidonic acid-containing phospholipids in both young and aged animals, and gave rise to production of new phosphatidylserine and phosphatidylinositol species. These findings suggest that DHA may mediate some of its effects through alterations in the membrane lipid composition that can consequently affect the production of pro-inflammatory mediators and signalling molecular species.

Ageing is accompanied by a myriad of changes, which lead to deficits in synaptic function and recent studies have identified an increase in concentration of the proinflammatory cytokine, interleukin-1beta (IL-1beta), as a factor which significantly contributes to deterioration of cell function. Here, we consider that increased IL-1beta concentration and upregulation of IL-1beta-induced cell signalling cascades may be accompanied by downregulation of survival signals, perhaps as a consequence of decreased neurotrophins-associated signalling. The data indicate that increased IL-1beta concentration was coupled with downregulation of ERK and phosphoinositide-3 kinase (PI-3 kinase) in cortical tissue prepared from aged rats. These changes could not be attributed to decreased concentration of NGF or BDNF but the evidence suggested that they may be a consequence of an age-related change in the anti-inflammatory cytokine, IL-4. Significantly, treatment of aged rats with eicosapentaenoic acid reversed the age-related increases in IL-1beta and IL-1beta-induced signalling and also the age-related changes in IL-4, ERK and PI-3 kinase.

Most mammalian continuously renewing tissues are maintained by stem cells located within stem cell niches. Each niche contains a number of stem cells that replicate asymmetrically to give differentiated cells and also undergo periodic deletion and compensatory replacement by symmetrical "self-renewal" divisions of stem cells remaining within the niche. It has been recognized that there is selective pressure for an increased rate of self-renewal divisions and that the increasingly likely consequence is neoplasia. However, to date it has not been appreciated that there is also an independent selective pressure for a decreased rate of asymmetrical divisions. In this article, the origin of this second type of selective pressure is explained and its consequences explored through the use of computer modeling. It is shown that age-related changes in a range of mammalian stem cell compartments can be understood in the context of a decreased rate of asymmetrical stem cell divisions with an increased propensity for self-renewal divisions. It is proposed that a decreased rate of asymmetrical divisions impairs the ability of old stem cell compartments to respond effectively to stress.

Synaptophysin expression was assessed in dentate gyrus prepared from aged (22 months) and young (4 months) rats by immunoblotting and post-embedding immunolabelling at electron microscope level. Immunoblotting showed qualitatively that there was a marked reduction in synaptophysin expression in synaptosomes of aged compared with young rats. Immunogold labelling studies in the medial molecular layer of the dentate gyrus demonstrated that gold particles were restricted to pre-synaptic boutons, and were present mainly on the membranes of the synaptic vesicles or occasionally inside vesicles. In aged rats, immunolabelling patterns and the density of immunogold particles per pre-synaptic bouton were almost 50% lower than in younger rats. However, because boutons were larger in older rats the actual labelling density per unit area of bouton (3.77) was even lower than in the young rats (7.74). The role of synaptophysin in neural plasticity and ageing should be further examined.

Several age-related changes have been identified in rat hippocampus; among these are deficits in glutamate release and long-term potentiation in dentate gyrus. These deficits correlate with a decrease in the concentration of arachidonic acid in hippocampus. In this study, the effects of dietary supplementation for 8 weeks with omega -6 or omega -3 fatty acids were assessed in groups of aged and young rats. The data presented indicate that dietary supplementation in aged rats restored the concentrations of arachidonic acid and docosahexanoic acid in hippocampal preparations to those observed in tissue prepared from young rats. In parallel, aged rats which received the experimental diets sustained long-term potentiation in a manner indistinguishable from young rats. The evidence presented supports the view that an age-related increase in reactive oxygen species production is linked with the decrease in polyunsaturated fatty acids and that a diet enriched in eicosapentanoic acid has antioxidant properties which may play a key role in reversal of the observed age-related deficits., (Copyright 2002 Elsevier Science Ltd.)

Previous findings have indicated that nerve growth factor may play a role in the expression of long-term potentiation in perforant path-granule cell synapses and that nerve growth factor treatment restores the ability of aged rats to sustain long-term potentiation. In this study, we have attempted to analyse the changes which occur in nerve growth factor release and tyrosine receptor kinase phosphorylation following tetanization in tissue prepared from dentate gyrus of young rats, as well as aged rats which did or did not sustain long-term potentiation. We report that KCl-stimulated nerve growth factor release was significantly increased in slices of the dentate gyrus or whole hippocampus, but not in synaptosomes prepared from the dentate gyrus. KCl-induced nerve growth factor release was also significantly enhanced in slices prepared from tetanized, compared with untetanized, tissue obtained from young rats and aged rats which sustained long-term potentiation; this response was absent in tissue prepared from aged rats which failed to sustain long-term potentiation, perhaps due to the enhanced basal nerve growth factor release observed in this tissue. Tetanization increased tyrosine receptor kinase phosphorylation in the dentate gyrus of young rats and aged rats which sustained long-term potentiation. In parallel with the changes in nerve growth factor release, tyrosine receptor kinase phosphorylation was markedly increased in untetanized tissue, which may contribute to the lack of effect in tetanized tissue prepared from aged rats which failed to sustain long-term potentiation. We observed that nerve growth factor concentration and tyrosine receptor kinase expression were decreased in aged, compared with young, rats. The data suggest that deficits in nerve growth factor release and subsequent signalling may contribute to age-related deficits in long-term potentiation.

The age-related impairment in long-term potentiation in the rat dentate gyrus is coupled with an increase in the proinflammatory cytokine, interleukin-1beta (IL-1beta). It is possible that this increase in IL-1beta might be a consequence of the age-related increase in reactive oxygen species production in hippocampal tissue. In this study we set out to identify the underlying cause of the age-related increase in reactive oxygen species production and to establish whether any consequences of such a change might impact on the ability of aged rats to sustain long-term potentiation (LTP). We report that there was an age-related increase in the activity of superoxide dismutase but no parallel increases in activities of glutathione peroxidase or catalase, while age-related decreases in the concentration of the scavengers, vitamins E and C and glutathione were also observed. We propose that these compromises in antioxidative strategies may result in an increase in reactive oxygen species production. The data described indicate that IL-1beta and H2O2 increase the activity of two stress-activated mitogen-activated protein kinases, c-Jun NH2-terminal kinase (JNK) and p38 in vitro, while age-related increases in both kinases were observed. We propose that the endogenous increase in these parameters which occurs with age induces the increase in activity of the stress-activated kinases, which in turn impacts on the ability of the aged rat to sustain LTP.

Among the age-related changes identified in rat hippocampus are impairments in LTP and glutamate release. These deficits have been coupled with decreased arachidonic acid concentration. In this study we compared LTP and glutamate release in groups of aged and young rats fed for 8 weeks on a control diet or on a diet enriched in alpha-lipoic acid. Dietary supplementation in aged rats restored hippocampal arachidonic acid concentration to levels observed in tissue prepared from young rats. We observed that aged rats that received the experimental diet sustained LTP in perforant path-granule cell synapses in a manner indistinguishable from young rats whereas the age-related impairment in glutamate release was reversed in synaptosomes prepared from dentate gyrus obtained from these rats. The evidence presented supports the hypothesis that the alpha-lipoic acid-enriched diet has antioxidant properties, because the age-related increase in superoxide dismutase activity and decrease in alpha-tocopherol concentration were reversed. The finding that the age-related increase in interleukin-1 (IL-1)beta concentration was also reversed suggests a possible role for this cytokine in ageing.

Background: The proinflammatory cytokine, interleukin-1, is traditionally associated with the immune response but recent evidence indicates that it plays a role in neuronal function. Its expression is increased in neurodegenerative conditions and preliminary evidence suggests that it is also increased with increasing age. Receptors for interleukin-1 are differentially distributed in the brain with a high density in the hippocampus, where interleukin-1beta exerts inhibitory effects on release and calcium channel function., Objective: The aim of this study was to investigate the possibility that interleukin-1 might lead to age-related changes in membrane composition., Methods: Lipid peroxidation was assessed in the presence or absence of interleukin-1beta in hippocampal tissue prepared from 4- and 22-month-old rats. These data were analysed in parallel with age-related changes in arachidonic acid and interleukin-1beta concentrations in the hippocampus., Results: We report that interleukin-1beta increased lipid peroxidation in hippocampal tissue prepared from 4- but not 22-month-old rats, and that this effect was inhibited by alpha-tocopherol. The attenuated response to interleukin-1beta in tissue prepared from aged rats correlated with increased expression of endogenous interleukin-1beta. Thus, using an ELISA, we have demonstrated an age-related increase in the concentration of interleukin-1beta, which is accompanied by an age-related decrease in membrane arachidonic acid., Conclusion: We propose that increased interleukin-1beta expression impacts on membrane composition and therefore contributes to age-related impairments in neuronal function.

Depolarization-induced transmitter release in synaptosomes prepared from the hippocampus of aged rats is decreased compared with release from young animals. Although the underlying cause of this deficit is not known, some evidence suggests that increased membrane rigidity may contribute to these age-related synaptic changes. One possible consequence of the decreased transmitter release in the hippocampus of aged rats is a reduced ability to sustain long-term potentiation in perforant path-granule cell synapses, a pathway in which maintenance of long-term potentiation and increased glutamate release have been coupled. The observation that there is an age-dependent impairment in long-term potentiation is consistent with this view. If the age-related deficits in release and long-term potentiation are a consequence of increased membrane rigidity, it must be predicted that any manoeuvre which reverses membrane rigidity should reverse these functional deficits. In the present study, we investigated the effect of dietary manipulation of aged rats with omega-3 fatty acids on synaptic function. The data obtained indicate that an eight-week modified feeding schedule reversed the age-related impairments in long-term potentiation and depolarization-induced glutamate transmitter release. We also report that the concentrations of both docosahexanoic acid and arachidonic acid, two main polyunsaturated fatty acids in neuronal membranes, were decreased in the hippocampus of aged rats, and were restored by dietary manipulation. The data are consistent with the hypothesis that these deficits results from a change in membrane composition.

Ageing is associated with impairments in a variety of biological functions, one of the most striking might be considered to be the impairment in cognitive function. This impairment probably relates to the vulnerability of the hippocampus to the ageing process, since several cognitive functions rely on the integrity of this brain area. Analysis of the mechanisms underlying the effect of ageing on hippocampal function has focused to a great extent on analysis of age-related changes in long-term potentiation (LTP) in hippocampus of experimental animals. LTP is a remarkable form of synaptic plasticity which is characterized by a persistent increase in synaptic efficacy following tetanic stimulation of an afferent pathway to one of the hippocampal subfields. On the basis of its properties, LTP has been proposed as a biological substrate for learning and/or memory. There is general agreement that aged rats exhibit an impaired ability to sustain LTP but there is no agreement on the underlying cause of this deficit. In this review, the evidence which suggests that age-related changes in membrane composition, triggered by oxidative changes, might significantly contribute to the impairment in LTP, is considered. These findings are supported by recent data which indicates that dietary supplementation with the antioxidant vitamins, E and C, reversed the age-related impairment in LTP, in parallel with reversing the age-related decrease in alpha-tocopherol concentration and the age-related increase in lipid peroxidation. The possibility that the proinflammatory cytokine, interleukin-1 beta, triggers several age-related changes in hippocampus is considered and, based on the evidence presented, the hypothesis that interleukin-1 beta plays a significant role in ageing in the hippocampus is proposed.

Evidence suggests that reactive oxygen species in brain may play a role in the development of age-related neuronal impairments, and that the increase in the concentration of the proinflammatory cytokine, interleukin-1beta (IL-1beta), in aged brain tissue, may also be a contributory factor. In this study, we have analyzed changes in enzymatic and nonenzymatic antioxidant levels, in parallel with interleukin-1beta concentration, in cortical tissue prepared from young and aged rats. We report that there was an age-related increase in the activity of superoxide dismutase without concomitant changes in the activity of catalase or glutathione peroxidase and an age-related decrease in the concentrations of alpha-tocopherol and ascorbate. These observations, coupled with age-related increases in lipid peroxidation and interleukin-1beta concentration, are consistent with a compromised antioxidant defense in cortex of aged rats, a proposal supported by the finding that these changes were not observed in cortical tissue prepared from rats fed on a diet supplemented with alpha-tocopherol and ascorbate for 12 weeks.

The process of ageing is common to all organisms but despite its universality, understanding of the cellular and molecular changes which accompany ageing is poor. With the increase in the ageing population, the need for systematic study of the process becomes a priority but the development of a systematic approach to the problem requires the development of a testable theory of ageing. While several theories of ageing have been proposed /336/, between which there is at least some overlap, no generally-accepted theory has been identified. In relation to the brain, four interrelated theories of ageing have received significant attention; these are (1) the membrane hypothesis, (2) the free radical hypothesis, (3) the calcium hypothesis and (4) the glucocorticoid theory. The overlap between these hypotheses is such that a causal relationship between them is very likely with age-related changes in membrane composition triggered by changes in free radical production, while changes in membrane composition are likely to account for changes in membrane function including age-related changes in calcium homeostasis. The glucocorticoid theory could equally well be termed the stress hypothesis of ageing, which in the hippocampus at least, might trigger age-related changes in free radical production. This review is not intended to be a balanced appraisal of each theory but emphasizes aspects of the membrane hypothesis of ageing and discusses some relevant aspects of the other hypotheses. Attention is focussed on analysis of the biochemical changes which might underlie age-related changes in hippocampal function, particularly maintenance of long-term potentiation (LTP), and these changes are discussed in the context of the four hypotheses of ageing.

Aging is associated with a change in membrane composition that includes a decrease in membrane polyunsaturated fatty acids, including arachidonic acid, and an increase in membrane cholesterol. Alterations in membrane structure are likely to impact on transmitter release, which relies on the fusion of synaptic plasma and synaptic vesicle membranes, and it may therefore be the underlying cause of the age-related decrease in glutamate release in hippocampal preparations. Recent evidence indicates that interleukin-1, by binding with its receptor, inhibits glutamate release in hippocampal synaptosomes prepared from young but not aged rats. The age-related attenuated effect may be due to impaired ligand-receptor interactions arising from the change in membrane composition, which should theoretically be reversed by increasing membrane polyunsaturated fatty acid concentration. To test this hypothesis, we have investigated the effect of a diet supplemented with arachidonic acid and its precursor, gamma-linolenic acid, on membrane arachidonic acid concentration, glutamate release and on the release response to interleukin-1 in hippocampal tissue prepared from aged and young rats. We report that dietary supplementation reversed the age-related changes in membrane arachidonic acid and expression of IL-1beta. We also present data that indicate that the age-related decrease in glutamate release from hippocampal synaptosomes was reversed in aged animals that had been fed on the experimental diet. The data support the view that changes in membrane composition contribute to certain age-related deficits, in particular the decrease in glutamate release observed in hippocampal synaptosomes.

Long term potentiation (LTP) in dentate gyrus is impaired in aged rats, and this has been associated with an age-related decrease in membrane arachidonic acid concentration. In this study, we considered whether the trigger for this age-related decrease in arachidonic acid might be increased lipid peroxidation stimulated by the proinflammatory cytokine, interleukin-1beta. Groups of aged and young rats were fed on a control diet or a diet supplemented with alpha-tocopherol and assessed for their ability to sustain LTP. Aged rats fed on the control diet exhibited an impaired ability to sustain LTP and analysis of tissue prepared from these rats exhibited increased interleukin-1beta, increased lipid peroxidation, and decreased membrane arachidonic acid concentration compared with young rats fed on either diet. Aged rats fed on the supplemented diet sustained LTP in a manner indistinguishable from young rats, and the age-related increases in interleukin-1beta and lipid peroxidation and the decrease in membrane arachidonic acid concentration were all reversed. We propose that interleukin-1beta may be the trigger that induces these age-related changes and may therefore be responsible for the deficit in long term potentiation in aged rats. The observation that alpha-tocopherol reverses these changes is consistent with the hypothesis that some age-related changes in hippocampus might derive from oxidative stress.

Several cytokines and their receptors are identified in brain; one of these is the proinflammatory cytokine interleukin-1beta that is synthesized and released from neurons and glia in response to stress or insult. Among the actions of interleukin-1beta is its ability to inhibit long-term potentiation in the hippocampus in vitro, an action that mimics one of the consequences of stress and age. It has been shown that the concentration of interleukin-1beta in brain tissue is increased in neurodegenerative conditions, and recent evidence from our laboratory has indicated an increase in the concentration of interleukin-1beta in the hippocampus of aged rats. These observations led us to consider that the underlying common cause of impaired long-term potentiation in aged and stressed rats might be increased endogenous interleukin-1beta concentration in hippocampus. The data presented here indicate that there was an inverse relationship between concentration of interleukin-1beta in the dentate gyrus and long-term potentiation in perforant path-->granule cell synapses in aged rats, stressed rats, and rats pretreated with interleukin-1beta. The evidence suggested that the cytokine induces formation of reactive oxygen species that triggers lipid peroxidation in vivo, as well as in vitro, and that these changes lead to depletion of membrane arachidonic acid that correlates with impaired long-term potentiation. We propose that three theories of aging, the glucocorticoid theory, the membrane theory, and the free radical theory, constitute three facets of age with one underlying trigger: an increase in the endogenous concentration of interleukin-1beta in hippocampus.

The ability of aged rats to sustain long-term potentiation in the dentate gyrus of the hippocampus is impaired and this impairment correlates with decreased release of glutamate and a decrease in membrane arachidonic acid concentration. Twenty-two-month-old rats receiving a diet supplemented with arachidonic acid and its precursor, gamma-linolenic acid, sustained long-term potentiation in a manner indistinguishable from four-month-old controls. Dietary supplementation also restored arachidonic acid concentrations in membranes prepared from hippocampus of these aged animals to levels observed in hippocampus of four-month-old rats. Glutamate release stimulated by depolarization was similar in dentate gyrus prepared from young rats and aged rats which received the experimental diet, but was markedly reduced in aged animals which received the control diet. In addition, the synergism between arachidonic acid and the metabotropic glutamate receptor agonist, trans-1-amino-cyclopentyl-1,3-dicarboxylate, on glutamate release, which was observed in hippocampal synaptosomes prepared from four-month-old rats, was also observed in hippocampal preparations obtained from aged rats which had been fed with the experimental diet, but was absent in hippocampal preparations obtained from aged animals which were fed with control diet. Thus, reversing the age-related decrease in membrane arachidonic acid concentration restored ability of aged animals to sustain long-term potentiation and reversed age-related changes in glutamate release.

We have examined protein synthesis in entorhinal cortex following induction of long-term potentiation (LTP) in perforant path-granule cell synapses. The data presented here indicate that there was an increase in [35S]methionine labelling of TCA-precipitated proteins and [35S]methionine labelling of synaptophysin in the ipsilateral entorhinal cortex 40 min after induction of LTP in dentate gyrus. Intraventricular injection of both the NMDA antagonist, D-amino-phosphonovalerate, and the protein synthesis inhibitor, anisomycin reduced protein synthesis though the decrease caused by anisomycin was much more profound. Both agents blocked induction of LTP and the increase in protein synthesis and synaptophysin synthesis which accompanied LTP. These data indicate a close coupling of increased protein synthesis in the entorhinal cortex and expression of LTP in the dentate gyrus. This coupling was further suggested by the absence of an LTP-associated increase in protein synthesis in aged animals, in which LTP was markedly attenuated. The possibility that these changes impact on morphological changes which accompany LTP is discussed.

The proinflammatory cytokine, interleukin-1, is synthesized in neuronal and glial cells and is released in response to stress/injury. IL-1 exerts profound effects on the central nervous system, which include an inhibitory effect on synaptic activity in hippocampus, a brain area expressing a high density of IL-1 receptors. We report that IL-1 beta has an inhibitory effect on KCl-stimulated release of glutamate and KC1-stimulated [45Ca] influx in synaptosomes prepared from hippocampus of 4-month-old rats. These effects were inhibited by the endogenous receptor antagonist, IL-1ra, and by the phospholipase A2 (PLA2) inhibitor, quinacrine, suggesting that IL-1 receptor activation is coupled to PLA2. An inhibitory effect of IL-1 beta on protein kinase C activity was also observed. KC1-induced calcium-dependent release and calcium influx, and protein kinase C activity were significantly decreased in hippocampal synaptosomes prepared from 22-month-old compared to 4-month-old animals. In contrast to the inhibitory effect of IL-1 beta in synaptosomes prepared from young adult animals, no effect was observed on release, calcium influx, or protein kinase C activity in synaptosomes prepared from aged animals. We report that there is an age-related increase in expression of IL-1 beta in hippocampus and propose that this change may underlie the attenuated responses to IL-1 beta in hippocampus of aged animals.

Activation of the metabotropic glutamate receptor by the specific agonist trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD) increases release of glutamate and activation of protein kinase C in the presence of a low concentration of arachidonic acid in hippocampal synaptosomes prepared from 4-month-old rats. The data presented indicate an age-related decrease in both [3H]glutamate release and protein kinase C activation and an age-related decrease in the release response to arachidonic acid and ACPD, with no corresponding change in protein kinase C activation. The finding that the interaction between arachidonic acid and ACPD on release was absent in synaptosomes prepared in the presence of heparin, an antagonist at inositol trisphosphate receptors, suggests that mobilization of intracellular calcium stores plays a role in the synergism between arachidonic acid and ACPD on [3H]glutamate release in hippocampal synaptosomes.

We have used synaptosomes prepared from rat hippocampus to investigate the role of protein tyrosine kinase and Ca2+/calmodulin-dependent protein kinase II in modulating glutamate release in young animals and to investigate possible parallel age-related changes in release and kinase activity. We report that depolarization of synaptosomes with 40 mM KCl, which stimulated glutamate release, also significantly increased activity of both kinases, while the protein tyrosine kinase inhibitor, genistein and the Ca2+/calmodulin-dependent protein kinase II inhibitor, KN62 (1-(N,O-bis[5-isoquinolinesulfonyl]-N-methyl-tyrosyl)-4-phenylpiperax ine) decreased K(+)-stimulated, Ca2(+)-dependent release of glutamate. K(+)-stimulated release of glutamate was significantly decreased in hippocampal synaptosomes prepared from aged, compared to young, animals. In parallel with these changes in release, we report an age-related decrease in activities of both protein tyrosine kinase and Ca2+/calmodulin-dependent protein kinase II. We conclude that these kinases play a role in modulating release of glutamate in hippocampus and that the age-related decrease in glutamate release may be partly due to an age-related decrease in kinase activities.

Aging decreases skeletal muscle mass and strength, making elderly subjects particularly vulnerable to catabolic effects of age-related diseases. Clenbuterol, a muscle anabolic beta 2-adrenergic agonist, has reduced or restored skeletal muscle losses in experimental catabolic states. However, the doses of clenbuterol used to prevent or reverse muscle wasting in most animal models have exceeded the estimated safe dose in man. Recently, another beta 2-adrenergic agonist, salbuamol (albuterol), has been shown to increase muscle weight and protein content in young rats at a dose similar to that used clinically. In contrast to clenbuterol, salbutamol is currently approved for human use as a bronchodilator in the United States. This study has compared the muscle and protein anabolic effects of salbutamol at a clinically relevant dose with those of clenbuterol at a dose typically used in animal models of muscle wasting. Salbutamol and clenbuterol were administered by implanted osmotic minipumps to Fisher-344 rats aged 3 and 24 months at doses of 1.03 mg and 600 micrograms per kilogram per 24 hours for 3 weeks. The weights of five hindlimb muscles, as well as carcass protein and fat content, were determined. Salbutamol and clenbuterol increased combined hindlimb muscle weight 19% and 28% in young rats, with 19% and 25% increases in old rats. Similarly, these drugs increased gastrocnemius weight and protein content 19% and 24% in young rats, with 19% and 23% increases in old rats. Salbutamol and clenbuterol increased carcass protein content 20% and 30% in young rats, with 12% and 21% increases in old rats.(ABSTRACT TRUNCATED AT 250 WORDS)

WE have investigated changes in inositol phospholipid turnover and membrane arachidonic acid concentration in the dentate gyrus and frontal cortex of animals aged 3-6 months, 14 months or 22 months which were trained in the Morris water maze. Ageing was associated with poorer performances in the behavioural test, characterized by increased variability in retention and acquisition amongst individuals, a decrease in membrane arachidonic acid concentration and increased unstimulated inositol phospholipid metabolism in synaptosomes prepared from frontal cortex and dentate gyrus. Arachidonic acid stimulated inositol phospholipid metabolism in synaptosomes, but in the older groups, stimulation was associated with good performance in the Morris water maze. In slices prepared from frontal cortex, responsiveness of inositol phospholipid metabolism to glutamate was also age- and performance-dependent. The findings highlight a correlation between age, inositol phospholipid metabolism and performance in the Morris water maze.

Musical processing involves long-term memory representations of invariant properties of auditory patterns and working memory representations of patterns heard in the present moment. Musical scales are formalized sets of pitches on which much of musical composition and improvisation is based, and frequency relations among scale notes are invariant within categorical boundaries. Studies of young adults have indicated that adjustments of frequency relations are better detected when melodies are based on culturally familiar scales than on culturally unfamiliar scales. A proposed account for this finding has been that knowledge about musical frequency relations is stored in long-term memory. In the present study, old and young adults performed equivalently well in detection of frequency relation adjustments in a culturally familiar scale context, but young adults performed better than old adults in culturally unfamiliar scale contexts. The performance of old adults in a culturally unfamiliar scale context was correlated with high-frequency (8 kHz) hearing sensitivity. These findings suggest that influences of aging on processing of auditory events involve relations of auditory cognition and hearing sensitivity.

There is a need for new therapeutic agents designed to prevent or restore skeletal muscle loss in frail, elderly subjects resulting from injury or disease and associated catabolic stresses such as malnutrition. Since the beta 2-adrenergic agonist clenbuterol increases skeletal muscle mass in rats, the effect of this agent on recovery of muscle mass and carcass protein content following protein malnutrition was studied in young and old rats. The 3-week period of severe dietary protein restriction reduced body weight 21%, hind-limb muscle weight 24 and 15%, and carcass protein content 31 and 19%, respectively, in 3- and 24-month-old rats. During the 3-week recovery period induced by feeding a complete diet, 10 mg clenbuterol per kg diet increased hind-limb muscle weight 34 and 30% and carcass protein content 27 and 25%, respectively, in 3- and 24-month-old rats. Restoration was complete in animals of both ages fed clenbuterol and incomplete in animals fed the control diet. These observations suggest that clenbuterol or similar beta 2-adrenergic agonists may be useful in hastening the recovery of muscle mass and body protein stores lost because of malnutrition in frail, elderly humans.

We examined the induction and maintenance of long-term potentiation (LTP) in vivo in the dentate gyrus of 4-month-old and 22-month-old urethane-anaesthetized rats. High-frequency stimulation of the perforant path induced an immediate increase in the slope of the population excitatory postsynaptic potential (EPSP), which was sustained in the 4-month-old animals for the duration of the experiment (45 min post-tetanus). In the 22-month-old group, the mean slope of the population EPSP decreased almost to baseline by the end of the experiment. Examination of the individual records indicated that LTP was sustained for the duration of the experiment in half of the 22-month-old animals, while in the others only post-tetanic potentiation was observed. Membrane arachidonic acid concentration was reduced in aged compared with young animals and was lowest in the subgroup of aged animals which failed to sustain LTP. Potassium-stimulated, calcium-dependent release of glutamate was also decreased in aged compared with young animals, but LTP was associated with an increase in glutamate release in the 4-month-old group and 22-month-old subgroup in which LTP was successfully sustained; no change was observed in the 22-month-old group in which LTP was not sustained. The results indicate a correlation between membrane arachidonic acid concentration, glutamate release and ability to sustain LTP in aged animals.

Neonatal and adult myocardium respond differently to ischemia. In addition, the neonatal heart possesses a limited preload reserve. The effect of uninterrupted hypothermic ischemia on recovery of left ventricular function and preload reserve was studied in two groups of isolated rabbit hearts: group 1 (neonates, n = 8), 7 to 10 days old; group 2 (adults, n = 15), 6 to 12 months old. Peak left ventricular systolic pressure, the first derivative of left ventricular systolic pressure, and heart rate were measured at left ventricular pressures of 0, 5, 10, and 15 mm Hg before and after 120 minutes of global ischemia at 27 degrees C. Before ischemia, left ventricular systolic pressure increased significantly at each increment of left ventricular end-diastolic pressure for both groups of hearts. After hypothermic ischemia, recovery of left ventricular systolic pressure was significantly reduced at each level of left ventricular end-diastolic pressure among neonatal hearts (range 75% to 79% of control values). The postischemic recovery of left ventricular systolic pressure in the adult hearts was markedly reduced from baseline values (range 43% to 53% of control values) and was significantly worse than that of neonatal hearts at each level of left ventricular end-diastolic pressure (p less than 0.001). Both groups were able to respond to increasing preload after ischemia. The slope of the curve describing the relationship between left ventricular end-diastolic pressure and percent recovery of left ventricular systolic pressure was not different from zero for neonatal hearts but was significantly greater than zero among the adults (0.22 +/- 0.21 versus 0.73 +/- 0.07, p = 0.0056). After ischemia, the first derivative of left ventricular systolic pressure fell significantly from control values among neonatal hearts (71% of control values). The reduction was considerably greater, however, among the adult hearts (54% of control values). These data indicate that the neonatal heart recovers systolic function better than the adult heart after global ischemia with moderate hypothermia.

It has long been suspected that cellular senescence is an anticancer mechanism; however, it has been difficult to understand the advantage for the organism of retaining mutant cells in a postmitotic state rather than simply deleting them by apoptosis. It is proposed that in certain circumstances apoptosis promotes neoplasia by causing cells adjacent to the deleted cell to divide and that the role of cellular senescence is to prevent this. This may be particularly important in mammalian stem cell niches. After loss of a stem cell from a niche, another stem cell within the same niche divides symmetrically to restore the original number. The most important human malignancies arise from tissues maintained by stem cells, and there is increasing evidence that stem cells are the targets for at least the initial genetic changes that occur during carcinogenesis. If a subset of stem cells within a niche arises containing an oncogenic mutation, then tumor suppressor mechanisms promote apoptosis of these cells, and the niche restores the original number of stem cells by replication of both normal and mutated stem cells. Thus, paradoxically apoptosis increases turnover of mutant cells with associated risk of further genetic changes. However, if in addition mutant cells can become senescent, then the niche is progressively filled by senescent cells until either the mutant cells are eliminated or the niche is completely occupied by postmitotic cells, thereby preventing further evolution of the neoplastic clone. The consequences of this hypothesis are explored by computer modeling. [ABSTRACT FROM AUTHOR]