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The Aging Mind: Opportunities in Cognitive Research B— Homeostatic Processes in Brain Aging: The Role of Apoptosis, Inflammation, and Oxidative Stress in Regulating Healthy Neural Circuitry in the Aging Brain Carl W. Cotman INTRODUCTION Research over the past several years has shown that the brain regions most vulnerable to mechanisms of inflammation, apoptosis, and free radical generation are those that serve primary functions in cognition. This must mean that mechanisms serving cognition and plasticity leave these circuits more vulnerable to injury and dysfunction. Curiously, many of the same molecules and molecular pathways can serve either beneficial or detrimental functions, depending on the exact cell, level of the factor, and acute versus chronic state. The mechanism can be local or can spread from the very local cellular microenvironment to cellular units and to entire systems. The progressive nature of the challenge faced can increasingly compromise cognitive functions. During brain aging, the brain accumulates a series of insults and injuries and therefore must compensate through the activation of homeostatic mechanisms. Some of these mechanisms, however, once activated, may become part of degenerative cascades. Thus, the aging brain must accomplish homeostatic maintenance without the engagement of unregulated degenerative mechanisms. Over time, the compromising of circuitry integrity and function will take an inevitable toll on cognitive function. This paper presents the hypothesis that brain aging at a mechanistic level is resolvable into a series of distinct phases. These phases are associated with discrete molecular events that evolve into cascades, and, importantly, each phase may require different intervention strategies and certainly must be resolved in order to understand
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The Aging Mind: Opportunities in Cognitive Research the overall aging process. The literature discussed in support of this hypothesis has been limited due to space constraints and thus some citations may have been unintentionally omitted. BRAIN AGING, A MULTIPHASE PROCESS: INITIATION AND PROPAGATION PHASES Several investigators have suggested that Alzheimer's disease may represent an accelerated decline of the normal processes of brain aging. Thus, for example, the normal aged brain appears to accumulate plaques and tangles. This hypothesis suggests that Alzheimer's disease then is simply a further progression in the accumulation of these hallmarks and that relative risk factors would determine the nature of when and how fast accumulation and cognitive decline occur. Hence, all individuals would be subject to the same basic mechanism, and only the rate constant would differ with aging. While this hypothesis is one possibility at a mechanistic level, it is imprecise and does not address the current body of data suggesting that Alzheimer's disease results from a series of mechanisms and cascades that, over time, drive progressive pathology. I suggest that the aging process can be resolved into a series of distinct states (Figure B-1). Let us assume that under the arbitrary age of 120 it is FIGURE B-1 Model for distinct phases in brain aging. It is becoming increasingly clear that at a mechanistic level, the primary driving mechanisms leading to progressive loss are multiphasic. The implication is that different therapeutic strategies will be needed at different phases of the processes.
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The Aging Mind: Opportunities in Cognitive Research possible to maintain normal brain function. This must be true, since some individuals maintain function for this period of time. Indeed, it appears that cognitive function can be preserved in some individuals even though some sensory functions may be compromised. Thus, as illustrated in Figure B-1, the successful aging line can be relatively flat. Let us further postulate that the mechanism of decline can be divided into two general phases: initiation and propagation (Johnson et al., 1998). The initiation phase is distinct in terms of relative risk factors (e.g., APOE genotype) and protective factors. According to this hypothesis, the phase is relatively reversible and very amenable to interventions; it is relatively stable even though decline does occur. This idea is consistent with epidemiology data (e.g., Breitner, 1996) and histochemical data on factors affecting the accumulation of β-amyloid (see Johnson et al., 1998). For example, APOE at low levels of amyloid accumulation can determine the average age of decline onset. Once amyloid accumulation (or a similar process) reaches a certain level, however, the propagation phase is set in motion. The propagation phase is distinct in that self-reinforcing molecular cascades are the net driving force; these cascades supersede contributing risk factors and accelerate pathogenesis. In terms of β-amyloid accumulation, this phase is largely independent of APOE-ε4, although it may have gender factors. Examples of possible autocatalytic cascades that could contribute to a propagation phase include the ability of amyloid to induce the amyloid precursor protein (APP) and chronic inflammation (see Cotman and Su, 1996). Such a propagation phase could be reversible up to a threshold point; however, once past this point, it may be irreversible. This hypothetical model must also be considered in the context of the microenvironment. Thus, in the initiation phase, one would postulate that pathology is focused on vulnerable regions, but within those regions is largely confined to local domains, perhaps even individual cells. Subsequent transition/entry into the propagation phase results in the spread of pathology throughout the network. This propagation mechanism is unknown but may represent a breakdown of the local microenvironment. This is an important issue and is not addressed in the context of most current molecular mechanisms. The progression of pathology is embodied in the Braak and Braak staging, in which the induction of tangles spreads through the limbic system network and is in essence the morphological equivalent of this set of events. Recently, my colleagues and I have established morphological evidence for transsynaptic propagation of neurofibrillary tangle pathology. We examined a series of neuropathologically staged cases and traced the temporal induction of AT8 and PHF staining in a well-established trisynaptic pathway: entorhinal stellate neurons, dentate gyrus granule cells, and CA4 pyramidal neurons. Cellular changes along this circuit appeared to initiate in the entorhinal cor-
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The Aging Mind: Opportunities in Cognitive Research tex in early Alzheimer's disease and progress through the circuit as the disease progressed, suggestive of a transsynaptic mechanism of propagation. The stimulus/agent is, of course, unknown. In summary, I suggest that a separation of mechanisms may occur in the evolution of Alzheimer's disease. These stages may parallel various clinical stages. The relatively flat progression has been referred to as successful aging, optimal aging, etc. The initiation phase may be similar to the phase called mild cognitive impairment. The propagation phase may be the entry into Alzheimer's disease and related dementias. Of course, the correlation between brain changes and functional state is challenging due in no small part to the reserves and functional plasticity of circuits, particularly in the successful aging and initiation phases. Thus, for example, it would be anticipated that changes that occur in the initiation phase are subclinical for many measures, even though from a mechanistic viewpoint these changes are signatures of progression. The implication of this concept is that it suggests that different therapeutics will be necessary to abort or slow the mechanism, depending on the stage of progression. Thus the initiation phase may be amenable to such interventions as nonsteroidal anti-inflammatory drugs, estrogen, education, antioxidants, etc. The later propagation phase may be much less sensitive or even insensitive to such interventions, although there is evidence to suggest that antioxidants such as Vitamin E can modulate progression at this point. THE INITIATION PHASE AND EARLY EVENTS IN A PATHOLOGICAL CASCADE To study the initiation phase in vitro or in vivo, it is necessary to develop a model in which subthreshold insults occur that do not cause overt cell death but rather impair cellular function. An appropriate stimulus to promote cell dysfunction is Aβ, since this neurotoxic protein accumulates in the form of senile plaques in the aged human and canine brain. Exposing cell cultures to sufficient levels of Aβ causes cell death in neurons and glia (see Cotman et al., 1999, for a review). Neurons die by initiating programmed cell death pathways, the up-regulation of pro-apoptotic proteins or the down-regulation of anti-apoptotic proteins (Paradis et al., 1996). To identify events associated with the initiation phase, we are now using subthreshold levels of Aβ that do not cause overt neuronal death to determine the sequence of events that occur early in response to an injury. These events may be subtle indicators of neuron dysfunction that develops prior to the classic forms of pathology found in the aged brain, such as senile plaques, neurofibrillary tangles, and cell death. Once neurons are exposed to a potentially toxic stimulus, signal transduction pathways are activated that initiate a cascade of events leading to neuronal dysfunction. This hypothesis led us to examine the role of signal
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The Aging Mind: Opportunities in Cognitive Research transduction pathways in neurons as early mediators of neuron dysfunction and subsequent death. Signal Transduction Pathways May Be Compromised Much Sooner Than Degeneration Develops One of the components that is critical in signal transduction is CREB (cyclic AMP response element binding protein), a molecule that mediates a plethora of responses involving gene transcription. Briefly, the pathway leading to the activation of CREB starts with an increase in Ca2+ or cAMP, which leads to the activation of calcium calmodulin-dependent (CAM) Kinase IV or cAMP-dependent protein kinase (protein kinase A). CAM Kinase IV or protein kinase A translocates into the nucleus and phosphorylates CREB, thereby activating this protein. Once CREB is phosphorylated, it can bind to cyclic AMP response element (CRE) in the promoter region of specific genes and increase transcription, leading to increased RNA and protein levels. One of these proteins is brain-derived neurotrophic factor (BDNF), which promotes neuron survival and plasticity (Cellerino et al., 1996; Galuske et al., 1996; Ma et al., 1998). As the actions of CREB become more elucidated, it is becoming apparent that CREB is functionally important for neuroplasticity (Ahn et al., 1999; Bailey et al., 1996; Glazewski et al., 1999; Schultz et al., 1999; Segal et al., 1998). Recent data suggest that transgenic mice that do not express CREB or mice treated with antisense mRNA to CREB show impaired long-term potentiation, a physiological mechanism thought to underlie short-term memory (Glazewski et al., 1999; Schultz et al., 1999). A recent study also indicates that brains of humans diagnosed with Alzheimer's disease have decreased levels of phosphorylated CREB (pCREB) (Yamamoto-Sasaki et al., 1999), and it is hypothesized that this decline may have a role in memory decrements. While a direct mechanism or causal effect of declines in pCREB has not been established in normal aging in humans or animals, it is hypothesized that short-term memory deficits that occur as mild cognitive impairment in humans or as memory impairments in individual old canines may be a consequence of neuronal dysfunction associated with decreased phosphorylation of CREB signal transduction mechanisms or other transcription factors. This leads to the question of whether a similar series of events occurs with sublethal exposures to Aβ, as would be expected in the early initiation phase. Depolarization of cells, as would occur in vivo with long-term potentiation, induces the phosphorylation of CREB. However, in the presence of sub-threshold levels of Aβ, there is a significant reduction in pCREB (Tong et al., in press). One interpretation of these results is that transcriptional activation by CREB could be compromised in dysfunctional neurons prior to overt cell death. If the neuron can reverse dysfunction, such as a diminished CREB
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The Aging Mind: Opportunities in Cognitive Research signaling pathway or an Aβ insult, then it can be returned to a functional state. Otherwise, apoptotic degenerative pathways may be initiated and the neuron removed from the system entirely. Does the loss of pCREB regulation affect the encoding of proteins that are involved in neuroplasticity? The answer appears to be yes. CREB is involved with the transcription of BDNF, which is involved with learning and memory mechanisms, encoding long-term potentiation, cell health and survival, and protection from injury. In our culture model system, Aβ decreases depolarization-mediated induction of BDNF transcription (Tong et al., in press). Thus, subthreshold Aβ exposure can lead to some remarkable changes in neuron function, including decreased transcription of BDNF, a protein important for promoting neuron survival in the absence of any overt pathological change. In fact, BDNF is decreased in brains with Alzheimer's disease. The proinflammatory cytokines are another illustration of the ability of the same molecule to support neuronal functions or contribute to dysfunction/degeneration. Experimentally, TNFα and IL-1β have been implicated in multiple examples of neurodegeneration (Feuerstein et al., 1998; Griffin et al., 1989; Martin et al., 1997). The engagement of these receptors can govern such diverse cellular responses as cellular proliferation, differentiation, and effector functions, or drive cells into apoptosis (Baker and Reddy, 1996, 1998). Therefore, the same signals that induce proliferation and differentiation can also induce cell death under different conditions, such as different activation states, developmental states, or cellular associations (Kang et al., 1992; Lenardo, 1991; Radvanyi et al., 1993). TNFα represents an excellent example of the pleiotrophic nature of these cytokines. TNFα can directly trigger apoptosis but has also been found to be neuroprotective in certain instances (Bruce et al., 1996). This difference in the response to TNFα may depend on the metabolic state of the cells and tissue being exposed to TNFα, because when TNFα is applied to a healthy brain, it typically does not induce neurodegeneration. However when TNFα is combined with an insult such as ischemia, TNF induces a robust increase in neuronal death (Rothwell and Hopkins, 1995). In addition to having a direct effect on cellular physiology, TNFα has been shown to disrupt the signal transduction pathways induced by other physiological ligands, such as insulin (Peraldi et al., 1996; Paz et al., 1997). More recently, a new mechanism resulting in neurodegeneration involving TNFα has been proposed by Venters et al. (1999). They noted that in addition to an increase in TNFα during an inflammation in the central nervous system, there is also an increased expression of the hormone insulin-like growth factor (IGF-I). Activation of the IGF-I receptor on neurons is neuroprotective, inhibiting apoptosis (Dudek et al., 1997; Russell et al., 1998). Previous reports have shown that simply changing the ratio of IGF-1 and TNFα can shift the balance between survival and neuronal death (Barone et
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The Aging Mind: Opportunities in Cognitive Research al., 1997; Loddick et al., 1998). Venters et al. found that TNRα significantly reduces the ability of IGF-I to promote survival in cerebellar granule neurons. These investigators proceeded to show that TNFα inhibits the ability of IGF-I to initiate tyrosine phosphorylation of the insulin receptor substrate 2 (IRS-2), thereby blocking the activation of downstream P13-kinase. Thus diseases of the central nervous system that have an inflammatory component involving TNFα, such as multiple sclerosis, AIDS-dementia complex, and Alzheimer's disease, may use intracellular cross-talk between TNFα and IGF-I receptors to inhibit survival signaling by IGF-I and perhaps other neurotrophic factors. Thus some molecules promote homeostasis by multiple mechanisms, and in diseases such as Alzheimer's disease, these mechanisms may be recruited into cascades that trigger disease progression. In summary, neurons that experience pro-apoptotic insults appear to shut down key signal transduction pathways. At the single cell level, this is probably a wise strategy, because it potentially removes dysfunctional cells from the network. This would then, in turn, allow the fully functional cells to maintain brain function and possibly activate auxiliary use-dependent plasticity mechanisms (Figure B-2). FIGURE B-2 Neurons subjected to sublethal pro-apoptotic insults may be deficient in their ability to regulate key signal transduction pathways serving functional plasticity. The presence of sublethal concentrations of B-amyloid results in an inability to phosphorylate CREB and thus control of essential transcriptional mechanisms. Thus these neurons are partially removed from the circuit (shaded cell).
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The Aging Mind: Opportunities in Cognitive Research Interventions during the Initiation Stage What types of interventions could be implemented in the initiation stage of brain aging to promote successful aging? Clearly, the issue is to discover interventions that will in turn establish the validity of mechanistic predictions. One possibility is to regulate the expression of BDNF, a downstream product of the CREB signal transduction pathway. In general, behavioral modifications and exercise may have merit. Several years ago, we began to examine the possibility that simple behavioral interventions, such as voluntary running, could promote neuron function via increased expression of BDNF. The experimental design of these studies included providing rats with access to a running wheel and recording the distance traveled while allowing each animal to run voluntarily. Voluntary exercise increased BDNF mRNA in hippocampal areas after several hours (Oliff et al., 1998) or days (Neeper et al., 1995, 1996). Recently, we also have examined the possible involvement of CREB-mediated signal transduction and found that pCREB increased in response to the voluntary running paradigm during a period of seven days, while total levels of CREB were unchanged (Shen et al., in press). Recent data also suggest that exercise improves memory in aged humans (Binder et al., 1999; Grealy et al., 1999; Williams et al., 1997), but the cause of this improvement in cognition has not yet been determined. However, together these data suggest that exercise can be a driving force on plasticity mechanisms by enhancing the activation of factors that promote transcription of genes involved with neuron function and ultimate survival. Other interventions may also increase the expression of BDNF and have functional consequences. Several studies have been examining this question; the work on environmental enrichment is particularly important (Kempermann et al., 1997, 1998). Three weeks of environmental enrichment significantly stimulated cell proliferation, BDNF expression and resistance to insults, and inhibited apoptotic cell death (Young et al., 1999). Proliferating cell nuclear antigen (PCNA) levels were increased and double-stranded DNA breaks (TUNEL) were decreased in the enrichment group relative to controls, suggesting that neurogenesis occurred in response to environmental enrichment. Furthermore, rats in the enriched environment were resistant to kainate-induced seizures, and neuron death in response to seizures was ameliorated (Young et al., 1999). Finally, the expression levels of BDNF were higher in the enrichment group relative to controls. Upstream of BDNF expression, the authors also showed that environmental enrichment increased the expression of CREB and pCREB, particularly in the proliferating zone of new neurons. To summarize, many studies indicate that environmental enrichment and exercise, relatively modest interventions, can promote successful aging by modifying brain health at the single neuron level. Studies on behavioral
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The Aging Mind: Opportunities in Cognitive Research interventions and brain aging are currently understudied in humans. Behavioral interventions in brain aging are popular at the community level, but clinical studies in patient populations are greatly lacking, as are mechanistic studies in animal models. PROPAGATION PHASE: MANY INDUCERS OF APOPTOSIS ACCUMULATE IN THE AGING BRAIN In the propagation phase, mechanisms including apoptosis, inflammation, and oxidation are activated either in combination or chronically beyond a certain level. Homeostatic balances are exceeded and dyshomeostasis prevails. This phase illustrates the importance of homeostasis in brain aging and the identification of mechanisms that can lead into dyshomeostasis. The discussion below illustrates the key principles. Apoptosis normally serves during development to remove excess cells, and in disease or injury it serves to destroy damaged cells. This is a well-accepted concept in all basic biological systems. With age, a variety of stimuli accumulate in the brain that may induce apoptotic pathways in neurons. In the aging and Alzheimer's-affected brain, β-amyloid, a 40–42 amino acid peptide, accumulates in the extracellular space as small deposits and senile plaques. Based on the observation that neurites surrounding β-amyloid deposits exhibit both sprouting and degenerative responses, we proposed that this peptide is not metabolically inert, but rather possesses biological activity. Our findings established two key principles: β-amyloid induces neurotoxicity in a conformation-specific manner, and apoptotic mechanisms underlie this toxicity (Cotman and Anderson, 1995; Anderson et al., 1995; Loo et al., 1995, 1993; Watt et al., 1994); these observations have since been confirmed by many others. Interestingly, prior to causing cell death, β-amyloid also induces the formation of dystrophic-like neurite morphology in cultured neurons (Pike et al., 1992; Fraser et al., 1994). Oxidative insults also readily initiate apoptosis (Whittemore et al., 1994), and oxidative damage is known to occur in the aging and Alzheimer's-affected brain (Benzi and Moretti, 1995). Similarly, reductions in glucose metabolism have been suggested to contribute to neurodegeneration in Alzheimer's disease (Beal et al., 1993; Goto et al., 1993; Haxby and Rapoport, 1986; Hoyer et al., 1988; McGeer et al., 1986), and β-amyloid has been shown to exacerbate neurodegeneration in cultured neurons when glucose levels are reduced (Copani et al., 1991). Furthermore, excitotoxic damage can, under some conditions, initiate apoptosis, and many investigators have suggested that excitotoxic damage contributes to neurodegenerative diseases, including Alzheimer's disease (Dodd et al., 1994). Recent studies have also shown that glutamate transport proteins may be greatly reduced in the Alzheimer's-affected brain (Masliah et al., 1996; Simpson et al., 1994), which could exacerbate excitotoxic mechanisms. The profile of initiating factors strongly sug-
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The Aging Mind: Opportunities in Cognitive Research gests that in the course of aging and age-related neurodegenerative disease, neurons are increasingly subjected to apoptosis inducers. In some cases, these factors may act synergistically. For example, neuronal apoptosis may be significantly potentiated by the addition of subthreshold doses of β-amyloid and either excitotoxic or oxidative insults (Dornan et al., 1993; Koh et al., 1990; Mattson et al., 1992; Pike et al., 1997). Finally, mitochondrial damage may contribute to apoptosis as an intracellular effector. Mitochondria are a major source of free radicals and the release of cytochrome c is a potent inducer of caspase activation. Indeed, this organelle may be a prime target of aging and thus a contributor to the apoptosis cascade. Some genetic risk factors also increase the probability that cells will engage apoptotic mechanisms. Overexpression of presenilin (PS) 1 or 2 results in an increased susceptibility of cells to apoptotic insults. PS mutations sensitize neurons to apoptosis by trophic factor withdrawal, metabolic insults and β-amyloid (Deng et al., 1996; Wolozin et al., 1996; Kim et al., 1997). It has been suggested that PS mutations cause perturbed calcium release from the endoplasmic reticulum and increased levels of oxidative stress (Mattson et al., 1998). Indeed, introduction of PS-1 into oocytes results in enhanced release of intracellular calcium and this is further increased by the presence of a PS-1 mutation. The effect appears to be downstream from the inositol trisphosphate receptor, because inositol trisphosphate injected directly into the cell elicits the increased release. Thus, because calcium homeostasis contributes to apoptosis, these gene products increase the probably that neurons may degenerate via apoptosis. Thus, in patients carrying PS mutations, apoptosis is likely to be one of the mechanisms of neuronal degeneration. The amyloid precursor protein itself appears capable of initiating apoptosis. There is growing evidence that the amyloid precursor protein is a receptor resembling a polypeptide hormone receptor (Nishimoto et al., 1997). The cytoplasmic portion of the protein contains a G-protein activator sequence (H657–K676) and will bind and activate G0. It has been suggested that the mutations result in a constitutively active G0 and that this causes apoptosis (Nishimoto et al., 1997; Yamatsuji et al., 1996). Clearly then, there is ample potential for the induction of apoptosis mechanisms in the aging and Alzheimer's-affected brain. In this context, it is essential to determine if such pathways are activated in the Alzheimer's-affected brain. Indeed, a growing body of evidence supports this hypothesis (see Cotman et al., 1999). In general, it appears as if brain aging acute phase responses often become chronic and escape the local microenvironment. The same mechanisms that are normally adaptive can become dysfunctional. This is ''dysfunctional plasticity," in which the same adaptive mechanisms turn against the system as overcompensation evolves, safety margins decline, and redundancy is lost. Multiple-level cascades can shift the balance between beneficial and
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The Aging Mind: Opportunities in Cognitive Research nonbeneficial functions: The significance of cellular change to cognitive function evolves in a hierarchy from the cell, to cellular units, to systems. Each participating brain region in an overall system is selectively vulnerable to select genetic and/or environmental/disease-related conditions. Dysfunction in one part of the system can compromise the entire connectionist network. Dyshomeostasis is encoded into the network and alters input/output profiles, which may be optimal for the residual system, but the system now operates at another state function. Systems homeostasis/plasticity is understudied in aging, and that which is represented is largely limited to rodents. Progressively more network plasticity and more good cells are required to maintain even normal baseline functions. This further weakens the linkages. One process affects the others. Inflammatory Mechanisms May Convert a Precarious State into Net Degeneration Acute injury initiates inflammatory mechanisms. Inflammatory mechanisms include the activation of complement pathways that lead to cell lysis and the up-regulation of death receptors and their respective ligands. These death receptors in the immune system serve to maintain homeostasis through selective cell death by way of apoptosis. In the brain, acute inflammatory responses are part of the natural repair process, but chronic inflammation probably drives degeneration, much like a chronic infection. Thus, inflammatory mechanisms are another example of the delicate balance. Clearly, inflammatory mechanisms suppress the initiation phase as anti-inflammatory medications delay the age of onset for Alzheimer's disease. It is, of course, unknown at the present time whether the same interventions will be effective during the propagation phase, but there are strong arguments to indicate they will probably be ineffective. Inflammation and beneficial actions have also been dramatically brought to the forefront by the discovery that antibodies developed against amyloid can activate the immune system to cause the remove of senile plaques (Schenk et al., 1999). Thus the balance of immune activity in the nervous system is highly critical. Some age-related risk factors such as Aβ, oxidative damage, and imbalances in glutamate may contribute to the emergence of inflammation and place cells at further risk for degeneration. Recent evidence suggests that reactive oxygen intermediates (ROIs) are potent inducers of FasL and that antioxidants suppress this transcriptional dependent process. Inhibition of FasL expression appears associated with decreased binding of nuclear factor NF-kB, an important redox-controlled transcription factor (Bauer et al., 1998). In response to oxidative stress, there is an increase in FasL expression
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The Aging Mind: Opportunities in Cognitive Research in young individuals. Coinciding with the changes in the TNFRs was an increase in TNFR-associated death domain protein (TRADD) and a decrease in TNFR-associated factor 2 (TRAF-2). These changes mirror those previously reported by Ware et al. (1991) following T-cell activation. However, in the case of lymphocytes from aged individuals, there was no increase in the expression of activation antigens, thus indicating that the T-cells were not in an activated state but rather reflect changes associated with an aging immune system. The potential importance of the change in the ratio of the two TNF receptors becomes obvious when one considers that the TNFRI contains a death domain and, when oligomerized by TNFα binding, recruits TRADD and FADD, resulting in the activation one of the initiator caspases, caspase-8. The TNFRII and TRAF-2 are involved in activation of NFkB and JNK, which are believed to mediate the anti-apoptotic effects of TNFα (Baker and Reddy, 1996, 1998). Based on these observations, Gupta and colleagues have proposed that the cellular and subcellular basis of this age-related immuno-senescence appears to at least partially involve increases in receptors linked with apoptosis and decreases in related compensatory receptors (Aggarwal and Gupta, 1998, 1999; Aggarwal et al., 1999). Age-related changes may extend to other organs and may be displayed in the ratio of gene expression patterns. The recent introduction of gene chip technology into the field may have particular application to the field of aging. Thus, for example, the gene expression profile of aging in muscle tissue and the influence of caloric restriction have been described (Lee et al., 1999). In essence, using high-density oligonucleotide arrays representing 6,347 genes, it was shown that aging resulted in a differential gene expression pattern that reflected increased cellular stress and lower expression of metabolic and bio-synthetic genes. Some of these, such as DNA repair enzymes, are the same as those induced in the nervous system with age and degeneration. An example of an up-regulated gene found in the muscle is GADD45, which as discussed above, we have found is also induced in Alzheimer's disease. Importantly, caloric restriction, which is the only really true intervention known to retard aging in mammals, almost completely prevented the gene expression pattern changes that occur with aging. This is a technology that should find particular use in the study of brain aging and cognition but will probably be difficult to get funded through peer review panels because it will be considered just a ''fishing expedition." These gene patterns summarize in one experiment the literature for the past 10 years of individual gene expression patterns. These expression patterns can be envisioned in essence as a fingerprint of homeostasis versus dyshomeostasis. In fact, this pattern of gene expression can be looked at as a view of the cells to engage homeostasis and plasticity mechanisms to compensate for age-related change.
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The Aging Mind: Opportunities in Cognitive Research CELLULAR PLASTICITY MECHANISMS AND THE MAINTENANCE OF HOMEOSTASIS As cells degenerate and their numbers are reduced in circuitry, other mechanisms become engaged at a cell and systems level beyond those of the molecular level. Examples include the sprouting of new synapses in response to nearby cell loss and the sprouting of dendrites in neighboring cells. In addition, whole networks respond in terms of altered processing using somewhat redundant, but maybe initially suboptimal strategies. These, oftentimes, can increase the time for cognitive processing, but will still accomplish the task. There is also a growing body of literature indicating that, in the course of brain aging, more of the brain has to be involved in a task that would normally require only minimal activation of circuits; thus, the circuits are working much harder to accomplish the same task. This would indicate that use-dependent change and practice effects, together with appropriate pharmaceuticals, might have a rational basis for cognitive rehabilitation. STRATEGIES AND SOLUTIONS FOR THE FUTURE In conclusion, there are several principles that appear to be evolving in the field that are in need of additional testing: Brain aging is not a linear process; the aging process passes through phases. The initiation phase can compromise neuronal function and is probably reversible as it represents functional homeostasis. Interventions include antioxidants, use-dependent plasticity (behavioral/physical/cognitive stimulation), regulation of inflammation, estrogen replacement therapy, etc., and are most effective in this phase. The propagation phase is initiated through a series of molecular cascades driven by accumulating failures and compensation mechanisms and is less readily reversible. Interventions may be phase-dependent, and effective interventions at one phase may be inappropriate/inadequate at others. Strategies must and can be developed to identify weak molecular linkages and to assist cells in correcting them prior to irreversible losses and the development of cascades. There is a clear significant and major gap in supported research in the essential hierarchical areas, and circuit-based analyses at a systems level are needed. Transgenic animals offer great promise, but there is a great need for
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The Aging Mind: Opportunities in Cognitive Research aged animals and standard behavioral protocols. Other animal models should be supported. The single-variable approach inherent in most molecular studies at present is too limited; there is a great need to explore complex interactions at a molecular level. Many behavioral theories, particularly in the practice of neuropsychology, lack solid mechanistic foundations and quantitative support, handicapping the growth of the field. There is, in general, a gap between cognitive research and molecular mechanistic studies in brain aging. The National Institute on Aging should be encouraged continually to stimulate innovative approaches. In summary, the key may very well be to create a shift in the intellectual environment in brain aging and cognition as well as pursue the leads already defined. REFERENCES Aggarwal, S., S. Gollapudi, and S. Gupta 1999 Increased TNF-alpha-induced apoptosis in lymphocytes from aged humans: Changes in TNF-alpha receptor expression and activation of caspases. Journal of Immunology 162(4):2154–2161. Aggarwal, S., and S. Gupta 1998 Increased apoptosis of T cell subsets in aging humans: Altered expression of fas (CD95), fas ligand, Bcl-2, and bax. Journal of Immunology 160(4):1627–1637. 1999 Increased activity of caspase 3 and caspase 8 in anti-fas-induced apoptosis in lymphocytes from ageing humans. Clinical and Experimental Immunology 117(2):285–290. Ahn, S., et al. 1999 A late phase of cerebellar long-term depression requires activation of CaMKIV and CREB. Neuron 23(3):559–568. Anderson, A.J., C.J. Pike, and C.W. Cotman 1995 Differential induction of immediate early gene proteins in cultured neurons by beta-amyloid (A beta): Association of c-jun with a beta-induced apoptosis. Journal of Neurochemistry 65(4):1487–1498. Anderson, A.J., C.J. Pike, and C.W. Cotman 1995 Differential induction of immediate early gene proteins in cultured neurons by beta-amyloid (A beta): Association of c-jun with a beta-induced apoptosis. Journal of Neurochemistry 65(4):1487–1498. Anderson, A.J., W.W. Ruehl, L.K. Fleischman, K. Stenstrom, T.L. Entriken, and B.J. Cummings In press DNA damage is correlated with a beta deposition and unrelated to cytoskeletal neuropathology in the canine model of Alzheimer's disease. Progress in Neuro-Pharmacology and Biological Psychiatry 24. Azizeh, B., F.L. Van Muiswinkel, D.H. Cribbs, A.J. Tenner, and C.W. Cotman 1999 Non-filbrillar β-amyloid: Priming the respiratory burst of rat microglial cells and human monocytes. Neurobiology of Aging (submitted). Bailey, C.H., et al. 1996 Toward a molecular definition of long-term memory storage. Proceedings of the National Academy of Sciences of the United States of America 93(24):13445–13452. Baker, S.J., and E.P. Reddy 1996 Transducers of life and death: TNF receptor superfamily and associated proteins. Oncogene 12(1):1–9.
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