Chapter 62: Cellular and Neurochemical Aspects of the Aging Brain

Many cellular and molecular aspects of brain aging are shared with other organ systems, including increased oxidative damage to proteins, nucleic acids and membrane lipids, impaired energy metabolism, and the accumulation of intracellular and extracellular protein aggregates. However, given the molecular and structural complexity of neural cells that express approximately 50 to 100 times more genes than cells in other tissues, there are age-related changes that are unique to the nervous system. For example, complex cellular signal transduction pathways involving neurotransmitters, trophic factors, and cytokines that are involved in regulating neuronal excitability and plasticity are subject to modification by aging. This chapter describes cellular and molecular changes that occur in the brain during aging and how such changes may predispose to neurodegenerative diseases.

A large segment of the world population will experience some degree of cognitive decline during aging (Figure 62-1). This decline most typically affects working memory as well as short-term and delayed memory recall; however, a smaller group of individuals will also experience reduced information processing speed and spatial memory. Most of the decline appears to occur after the age of 60 with minimal or nonexistent changes occurring between the age of 20 and 60. Functional magnetic resonance imaging and positron emission tomography studies suggest that the cognitive decline might be linked to the progressive reduction in the volume of specialized memory-forming and -processing brain areas (Figure 62-2). Similar age-associated changes have also been observed in nonhuman primates, dogs, rats, and mice, suggesting intrinsic age-associated events. Nonmedical interventions, such as physical exercise, cognitive stimulation, and diet together with treatment of common medical comorbidities, such as obesity, hypertension, hypercholesterolemia, diabetes, and metabolic/hormonal imbalances might help mitigate age-associated declines.

It is widely projected that an exponentially increasing number of individuals will suffer from dementia and other cognitive disorders that will affect their daily function and increase mortality (see Figure 62-1). In 2000, the number of patients with dementia worldwide was estimated to be over 20 million. This number is projected to exceed 100 million by 2040, with an average of 5 million new cases every year. Rates of increase are not uniform. Developed countries initially shared most of the “dementia burden”; however, as a result of significant improvement in economic and social conditions, developing countries are now experiencing a larger disease burden as well. Consequently, the rate of increase in the number of patients with dementia is projected to be almost 100% in developed countries and over 300% in developing countries. Major attention is now being given to the diagnosis of mild cognitive impairment (MCI), a transitional stage between normal aging and dementia. Patients with MCI display more severe cognitive deficits and more evident brain structural changes. In general, when diagnosed they still retain independence and are able to function normally within the society. However, they are at high risk to develop dementia, most typically Alzheimer disease (AD), with an annual rate of conversion between 10% and 15% (see Figure 62-1). Careful memory evaluation, lifestyle changes, and medical correction of existing risk factors might help delay conversion into clinical dementia.

The ability of the brain to reorganize, develop, and prune neural pathways is called synaptic plasticity. There are two components of synaptic plasticity that are thought to be important for learning and memory formation: long-term potentiation (LTP) and long-term depression (LTD). LTP involves a rapid influx of calcium into the neuronal cell, leading to the enhancement of cell excitability by the activation of intracellular signaling cascades that increase protein transcription, translation, and the insertion of new receptors into the cell membrane. LTD has the opposite effect, modulating transcription, translation, and the induction of receptors back into the cell that leads to decreased cell excitability. It is commonly believed that LTP and LTD are the cellular correlates of learning and memory and, therefore, great attention has been devoted into understanding how they are influenced by aging. In general, aged rodents show consistent deficits in induction and maintenance of LTP in the cornu ammonis area 1 (CA1) and in the dentate gyrus, two essential memory-forming areas of the brain. These deficits correlate with performance in hippocampal-dependent memory tasks. Furthermore, LTP is reduced in the hippocampus of aged rats that demonstrate cognitive impairments relative to aged unimpaired (resilient) rats. Studies have also demonstrated that aged impaired rats are more susceptible to LTD. Specifically, the stimulus threshold for the induction of LTD is lower in aged rats, perhaps making it easier to erase memories. Finally, mouse models of accelerated aging display early and evident deficits in both LTP and LTD that correlate with memory impairment on behavioral tests.

In conclusion, the normal aging process is accompanied by specific changes in neuronal activities that are related to the formation and consolidation of memory, thus leading to a decline in cognitive functions. Given the significant increase in average lifespan that we are experiencing, the cognitive decline is becoming more evident forcing us to devote significant efforts in understanding the genetic, molecular, and biochemical changes that characterize the aging brain.

Aging is characterized by significant molecular, structural, cytoskeletal, neurochemical and vascular changes (see Figure 62-2) in the brain. Structural changes (see Figure 62-3) are diffuse and affect the cerebellum as well. Gray matter volumes show a linear decline while white matter volumes show a nonlinear decline. At the cellular level, all major cell types in the brain undergo structural changes as a function of age. These changes include nerve cell death, dendritic retraction and expansion, synaptic loss and remodeling, and glial cell (specifically, astrocytes and microglia) reactivity. Such structural changes may result from alterations in cytoskeletal proteins and the deposition of insoluble proteins such as tau and α-synuclein inside neuronal cells and amyloid in the extracellular space. Finally, alterations in cellular signaling pathways that control cell growth and motility may contribute to both adaptive and pathologic structural changes in the aging brain. Table 62-1 provides a brief summary of the most prominent changes.

Cytoskeletal Changes

The cell cytoskeleton consists of polymers of different sizes and protein compositions. The three major types of polymers are actin microfilaments (6 nm in diameter), microtubules (25 nm in diameter) which are comprised of tubulin, and intermediate filaments (10–15 nm in diameter) which are made of specific intermediate filament proteins that differ in different cell types (eg, neurofilament proteins in neurons and glial fibrillary acidic protein in astrocytes). To regulate the processes of filament assembly and depolymerization, and to link the cytoskeleton to membranes and other cell structures, neurons and glial cells employ an array of cytoskeleton-associated proteins. For example, neurons express several microtubule-associated proteins (MAPs) that are differentially distributed within the complex architecture of the cells; MAP-2 is present in dendrites but not in the axon, whereas tau is present in axons but not in dendrites. While there are no major changes in the levels of the most abundant cytoskeletal proteins with aging, there are changes in the cytoskeletal organization and in posttranslational modifications of cytoskeletal proteins. For example, increased amounts of phosphorylated tau occur in some brain regions, particularly those involved in learning and memory (eg, hippocampus and basal forebrain). In addition, there is evidence that calcium-mediated proteolysis of MAP-2 and spectrin (a protein that links actin filaments to membranes) is increased in some neurons during aging. Oxidation of certain cytoskeletal proteins is suggested by studies demonstrating their modification by glycation and covalent binding of the lipid peroxidation product 4-hydroxynonenal (see “Free Radicals and the Aging Brain” later in this chapter). A consistent feature of brain aging in humans and laboratory animals is an increase in levels of glial fibrillary acidic protein, a marker of astrocyte activation, which may represent a reaction to subtle neurodegenerative changes.

Tau proteins are perhaps the most studied microtubule-associated proteins in neurobiology. They consist of a group of alternatively spliced proteins that ensure microtubule-dependent neuronal functions by binding and stabilizing the microtubules. In general, the degree of phosphorylation inversely correlates with binding. As a result, hyperphosphorylated tau proteins dissociate from microtubules and aggregate to form cytosolic filaments, which ultimately result in neurofibrillary tangles (NFT), pathogenic aggregates that characterize different forms of age-associated frontotemporal dementia (globally referred to as tauopathies) as well as Alzheimer disease. The number and distribution of NFT also increase as a function of age. In addition to the phosphorylation status, the proaggregating properties of tau depend on the differential splicing of the MAPT gene, which results in the different tau isoforms. The pattern of phosphorylation and splicing of tau differs in the fetal and adult brain and in the central and peripheral nervous system. It also differs among mammals, probably explaining why only humans and nonhuman primates develop classical NFT. Work in multiple mouse models has shown that abnormal tau metabolism can cause memory deficits. Additionally, mutations in the gene encoding tau proteins (MAPT) have been associated with hereditary forms of frontotemporal dementias, whereas polymorphisms in the same gene appear to act as genetic risk factors for sporadic progressive supranuclear palsy and corticobasal degeneration.

Intraneuronal pathogenic aggregates are also observed in other neurodegenerative diseases, underscoring common features. In Parkinson disease, degenerating neurons of the central nervous system accumulate Lewy bodies, which are comprised of α-synuclein, ubiquitin, and neurofilament protein, with associated MAPs (particularly MAP-1b) and actin-related proteins such as gelsolin. In amyotrophic lateral sclerosis, lower motor neurons are filled with aggregates made of superoxide dismutase 1 (SOD1), TDP-43, and neurofilaments, which concentrate in proximal regions of the axon. The specific molecular events involved in the formation of cytoskeletal alterations in different neurodegenerative disorders have not been clearly and definitively established. More information on specific pathogenic aggregates that characterize different neurodegenerative diseases can be found in Chapters 66, 67, and 68.

Synaptic Changes

Synapses are dynamic structural specializations where neurotransmission and other intercellular signaling events occur. There is considerable evidence for synaptic “remodeling” in the brain as we age. Most studies using nonbiased methods indicate that aging does not induce a substantial loss of total neurons in memory-forming and -processing areas of the brain. However, several studies in rodents and nonhuman primates indicate that neurogenesis decreases in the aging brain, with the greatest decline occurring in middle-age groups. In addition to decreased neurogenesis, evidence suggests that aging is accompanied by loss of synapses. As an example, the extent of synaptic loss in the hippocampus has been correlated to the severity of learning impairment observed in aged rodents, supporting the notion that the loss of hippocampal synapses directly contributes to the cognitive impairment. The synaptic loss observed in the hippocampus of aged rats may be due to the loss of both presynaptic and postsynaptic terminals. Ultrastructural studies using electron microscopy have also revealed age-related changes in the type of terminals formed. For example, aged female monkeys with memory impairment have fewer multiple-synapse boutons and twice as many nonsynaptic boutons in the dentate gyrus. Furthermore, aged rodents and monkeys display significant loss of postsynaptic spines in the hippocampus and cortex associated with reduced cognitive performance.

Synapse loss occurs in neurodegenerative disorders and is strongly correlated with clinical symptoms. Accumulating data suggest that synaptic degeneration, resulting from excitotoxic events localized to synapses, may initiate the neuronal death process in Alzheimer disease, Parkinson disease, Huntington disease, and stroke. Glutamate receptors are highly concentrated in postsynaptic dendritic spines, which represent sites of massive calcium influx during normal physiologic synaptic transmission. Age-related decreases in energy availability and increases in oxidative stress, and disease-specific alterations, such as amyloid β-peptide (Aβ) accumulation in AD and trinucleotide expansions of the huntingtin protein, may render synapses vulnerable to excitotoxic injury.

Vascular Changes

As in other organ systems, vessels that supply blood to the brain are vulnerable to age-related atherosclerosis and arteriosclerosis, which render the vessels susceptible to occlusion or rupture (stroke), a major cause of disability and death in the older population. Reduced brain perfusion in the absence of overt stroke may play a role in age-related cognitive dysfunction. Decreased cerebral blood flow occurs with advancing age and is accompanied by declines in cerebral metabolic rate for oxygen and glucose use. Age-related changes in cerebral vasculature are generally similar to those that occur in vessels elsewhere in the body and are therefore likely to result from common cellular and molecular changes, including accumulation of atherosclerotic plaques, oxidative damage to vascular endothelial cells, and an inflammatory response in which macrophages may penetrate the blood-brain barrier.

Age-dependent cerebral vascular changes are strongly linked to heart disease and hypertension. Interestingly, apolipoprotein E polymorphisms are linked to increased risk of both atherosclerosis and Alzheimer disease, with the apolipoprotein E4 increasing the risk. This association suggests that age-related vascular changes may make an important contribution to the neurodegenerative process in Alzheimer disease. Finally, important transport functions of cells (endothelial cells and astrocytes) that comprise the blood-brain barrier may also be impaired in the aging brain and more so in Alzheimer disease. Many of the same medical, behavioral, and dietary approaches now recognized to forestall cardiovascular disease may also forestall cerebrovascular disease; these approaches include correcting existing risk factors such as hypertension and hypercholesterolemia, engaging in physical and mental activities, preventing and/or correcting obesity, and taking a low-calorie and a high antioxidant diet.

Amyloid Accumulation

Aβ is a 38- to 49-amino acid peptide that arises from a much larger membrane-spanning precursor, the amyloid precursor protein (APP). During normal aging, and to a much greater extent in Alzheimer disease, Aβ forms insoluble aggregates in the brain parenchyma and vasculature. Of the above different Aβ species, the 40- and 42-aa long peptides are by far the most abundant; Aβ40 preferentially accumulates in the vasculature while Aβ42 preferentially accumulates in the parenchyma. Small Aβ aggregates (oligomers) can be neurotoxic, and can increase neuronal vulnerability to metabolic, excitotoxic, and oxidative insults. Aβ aggregates are organized as fibrils of approximately 7 to 10 nm in the amyloid plaques (also referred to as senile plaques), which accumulate in the brain parenchyma and are intermixed with nonfibrillary forms of the peptide and often surrounded by dystrophic neurites.

In addition to Alzheimer disease brains, amyloid/senile plaques are also present in the hippocampus and neocortex of cognitively normal aged individuals and tend to increase in an age-dependent fashion. Although still under debate, it is now becoming apparent that the number and/or distribution of amyloid plaques does not immediately correlate with cognitive decline. The synaptic loss and the number/distribution of neurofibrillary tangles appear to be better predictors of memory deficits. Indeed, the neuronal/synaptic loss of the hippocampal formation, entorhinal cortex, and entorhinal-hippocampal association system appears to be the only feature able to distinguish normal aging from MCI and the early stages of Alzheimer disease. Although amyloid plaques do not closely correlate with memory deficits, a high plaque load is rarely observed in the absence of cognitive impairment.

Detailed information on the mechanisms that lead to the generation and accumulation of Aβ in the brain as well as Alzheimer disease–relevant pathogenic features can be found elsewhere in this book (see Chapter 66).

A free radical is any molecule with an unpaired electron in its outer orbital; in biological systems, oxygen-based molecules are the predominant free radical species. A major oxyradical in cells is superoxide (O₂^–•) which is generated during the mitochondrial electron transport process; superoxide dismutases (MnSOD and Cu/ZnSOD) eliminate O₂^–• by converting it to hydrogen peroxide (H₂O₂). H₂O₂ can be converted to hydroxyl radical (OH^•) via the Fenton reaction which is catalyzed by Fe²⁺ and Cu⁺. Peroxynitrite (ONOO^–) arises from the interaction of nitric oxide (NO) with O₂^–; calcium influx is a major stimulus for NO production. While OH^• and ONOO^– can cause direct damage to proteins and deoxyribonucleic acid (DNA), their major means of damaging cells is by attacking fatty acids in membranes and initiating a process called lipid peroxidation. Studies of aging have provided compelling evidence that there is an increase in production and accumulation of oxidatively damaged molecules in essentially all tissues of the body during the aging process, including the brain.

Lipid Peroxidation

Levels of lipid peroxidation products such as lipid peroxides and 4-hydroxynonenal are significantly elevated in the brain parenchyma and cerebrospinal fluid in Alzheimer disease. Immunohistochemical analyses of brain tissue from Alzheimer disease and Parkinson disease patients and spinal cord tissue from amyotrophic lateral sclerosis patients, using antibodies directed against 4-hydroxynonenal adducts revealed increased levels of 4-hydroxynonenal in association with degenerating neurons and neuritic plaques suggesting a role for this aldehyde in the neurodegenerative process. Studies of cell culture and animal models of Alzheimer disease and amyotrophic lateral sclerosis show that lipid peroxidation can impair the function of the plasma membrane glucose and glutamate transporters and render neurons vulnerable to excitotoxicity and apoptosis. Administration of antioxidants such as vitamin E to cultured cells and transgenic mice expressing mutations that cause Alzheimer disease or amyotrophic lateral sclerosis can retard the neurodegenerative process, suggesting a causal role for lipid peroxidation in these diseases.

Protein Oxidation

Levels of protein oxidation, measured as protein carbonyls, are significantly elevated in the brains of aged rodents, and such age-associated protein oxidation can be prevented by administration of antioxidants. Studies of membrane structure have provided evidence for oxidation-related alterations in membrane protein conformation in old rodents. Studies of brain tissues of patients with Alzheimer disease and Parkinson disease have revealed increased levels of protein oxidation in vulnerable brain regions and, in particular, in degenerating neurons. Oxidation of proteins impairs their function and is therefore a likely contributor to age-related cellular dysfunction and neuronal degeneration. Progressive addition of sugar residues to many different proteins occurs during the aging process. This process, called glycation, may promote oxidative stress in cells. Two proteins that have been shown to be heavily glycated in Alzheimer disease are Aβ and tau, the major components of plaques and neurofibrillary tangles, respectively.

DNA Damage

Very little nuclear DNA damage occurs in the nervous system during aging, but DNA damage may contribute to the pathogenesis of neurodegenerative disorders. Damage to nuclear DNA in striatum of Huntington disease patients, and in hippocampus and vulnerable cortical regions of Alzheimer disease patients, has been documented. Specifically, levels of 8-hydroxyguanosine are increased. This DNA damage may be caused by oxyradicals, with hydroxyl radical and peroxynitrite being the major culprits. Progressive oxidative damage to mitochondrial DNA occurs during aging, and may be exacerbated in neurodegenerative disorders. Mitochondrial DNA is particularly prone to damage because this organelle is the site where the vast majority of free radicals are generated and because cells do not possess effective systems for repair of damaged mitochondrial DNA. Damage to mitochondrial DNA can lead to failure of electron transport and reduced adenosine triphosphate (ATP) production. Moreover, the important calcium sequestering function of mitochondria may be compromised as the result of age-related DNA damage which may increase neuronal vulnerability to excitotoxicity and apoptosis.

Mechanisms That Promote Oxidative Stress in Aging

Mitochondria-derived oxyradicals are likely to play a central role in the cumulative oxidative damage to various cellular constituents that accrue with aging. Age-related impairments in energy availability and metabolism may contribute to an acceleration of oxyradical production with aging. Levels of cellular oxidative stress (as indicated by oxidation of proteins, lipids, and DNA) are decreased in many different nonneural tissues of rats and mice maintained on a calorie-restricted diet (30%–40% reduction in calories). Recent studies suggest that levels of oxidative stress are also reduced in the brains of calorie-restricted rodents. The current dogma for the underlying mechanism is that reduced mitochondrial metabolism because of reduced energy availability results in a net decrease in mitochondrial reactive oxygen species (ROS) production over time, and hence less radical-mediated cellular damage.

In addition to the oxyradical damage that accrues with usual aging, there are specific initiators of oxidative stress that appear to play key roles in different age-related neurodegenerative disorders. For example, in Alzheimer disease the increased generation and accumulation of Aβ may be a pivotal event that enhances oxidative stress in neurons. There is evidence that increased levels of Fe²⁺ in the substantia nigra plays a role in the degeneration of dopaminergic neurons in Parkinson disease. The damage to neurons in the brain of stroke victims is the result of a combination of factors including excessive calcium influx and the presence of blood components such as Fe²⁺ and thrombin. In Huntington disease, the presence of trinucleotide repeats in the huntingtin protein may induce oxidative stress in striatal neurons by a yet-to-be-determined mechanism.

During the aging process, changes that occur in cerebral blood vessels, as well as in the neural cells themselves, appear to result in reduced energy availability to neurons. These age-related changes may be accelerated in several different neurodegenerative disorders including Alzheimer disease and Parkinson disease.

Cerebral Metabolism

Reduced glucose use, and changes in enzymes involved in energy metabolism, may occur during normal aging, but are not dramatic. Studies of aging rodents document decreases in glucose and ketone body oxidation, oxygen consumption, local cerebral glucose use, and glycolytic compounds (eg, fructose-1,6-diphosphate). Additional studies show that brain cells in older animals exhibit increased vulnerability to metabolic stresses. Incorporation of glucose into amino acids declines in the brain of aging mice, and older people are much more vulnerable to metabolic encephalopathy than young people. In contrast to normal aging, activities of several enzymes involved in energy metabolism are severely reduced in Alzheimer disease brain tissue. Three such enzymes, which are involved in mitochondrial oxidative metabolism, are the pyruvate dehydrogenase complex, the α-ketoglutarate dehydrogenase complex, and cytochrome c oxidase. These defects may result from age-associated oxidative damage to the DNA encoding these enzyme systems and/or reduced activity of the proteins in these systems.

Another factor that may contribute to reduced neuronal energy metabolism is impairment of the function of glucose transporter proteins in neuronal membranes. Studies of postmortem brain tissue of Alzheimer disease patients document reduced levels of glucose transporters, and experimental studies of cultured hippocampal neurons and synaptosomes show that insults relevant to the pathogenesis of Alzheimer disease (exposure to Aβ and oxyradical-generating agents) can impair glucose transport. Impairment of glucose transport and mitochondrial dysfunction would be expected to lead to ATP depletion and render neurons vulnerable to excitotoxicity.

Mitochondrial Function

Age-related structural changes in synaptic mitochondria have been reported and include a decrease in numbers and increase in size. During normal aging levels of mitochondrial protein synthesis are unchanged. However, decreases in synthesis of specific mitochondrial proteins that are components of the electron transport chain occur in aging rodents. Damage to mitochondrial DNA progressively increases in somatic cells during the aging process, with the most pronounced damage occurring in postmitotic cells such as neurons. Mitochondrial dysfunction has been linked to several neurodegenerative disorders. In Parkinson disease there are marked decreases in complex I and α-ketoglutarate dehydrogenase activities. Exposure of cultured dopaminergic neurons to insults relevant to the pathogenesis of Parkinson disease (eg, MPTP and Fe²⁺) cause mitochondrial dysfunction. In Alzheimer disease, cytochrome c oxidase and α-ketoglutarate dehydrogenase activity levels are markedly reduced in vulnerable brain regions. Interestingly, mitochondrial deficits are also observed in nonneuronal cells, including platelets and fibroblasts, of Alzheimer disease patients. When mitochondria from platelets of Alzheimer disease patients are introduced into cultured neuroblastoma cells, levels of oxidative stress are increased suggesting an important contribution of mitochondrial alterations to the increased oxidative stress present in neurons of Alzheimer disease brain. Mitochondrial alterations in neurons have been documented in studies of mouse models of Alzheimer disease (APP and presenilin mutant mice), Parkinson disease (α-synuclein mutant mice), Huntington disease (huntingtin mutant mice), and stroke (middle cerebral artery occlusion).

Among the properties of neurons that set them apart from many other cell types is their excitability, which is regulated by a complex array of neurotransmitters and ion channels. Neurons express voltage-dependent sodium channels, as well as multiple types of calcium and potassium channels that are differentially expressed among neuronal populations, and are segregated in different cellular compartments (eg, L-type calcium channels in the cell body, N-type calcium channels in the dendrites, and T-type calcium channels in presynaptic terminals). In addition, neurons possess ion-motive ATPases that play critical roles in reestablishing ion gradients following neuronal stimulation. A variety of age-related alterations in electrophysiologic parameters of neurons have been described in rodents (described earlier in this chapter) and, in some cases, in humans, including increased thresholds for induction of action potentials in cranial nerves, increased after hyperpolarizations in hippocampal neurons, and impaired LTP/LTD of synaptic transmission in the hippocampus. Moreover, a generalized decrease in neuronal inhibition appears to occur during the aging process.

The calcium ion plays fundamental roles in regulating neuronal survival and plasticity in both the developing and adult nervous system. Calcium mediates some of the effects induced by neurotransmitters and neurotrophic factors on neurite outgrowth, synaptogenesis, and cell survival in many different regions of the developing nervous system. Furthermore, in the adult nervous system, calcium regulates neurotransmitter release from presynaptic terminals and influences postsynaptic changes associated with learning and memory processes. Aging may result in decreases in the activity of the plasma membrane calcium ATPase and in levels of calcium-binding proteins, while increasing calcium influx through voltage-dependent channels and increasing the activation of calcium-dependent proteases.

Several studies have measured and determined changes in calcium transmission across the neuronal membrane in aged rodents. The final step in synaptic transmission that triggers LTP or LTD is dependent on the amount of calcium entering the cell. Therefore, changes in calcium conductance across the cell membrane could have significant effects on synaptic plasticity in aged animals. Studies have revealed that aged rats display an increased density of L-type Ca⁺⁺ channels in CA1 pyramidal cells, leading to increased L-type Ca⁺⁺ currents. In addition, CA1 pyramidal cells from aged rodents also show an increased duration of calcium-mediated action potentials. The inward flux of calcium in response to an action potential activates a calcium-mediated inward potassium current. These potassium channels are slower to open and close than calcium channels, which leads to a temporary afterhyperpolarization of the cell following an action potential. Studies have revealed that this phenomenon is increased in aged rodents and rabbits, leading to less frequent firing of action potentials in response to a prolonged depolarizing current. Taken together, these data demonstrate that age-related changes in calcium transmission underly detrimental changes in synaptic plasticity and may partially explain the deficits in plasticity seen over the course of aging.

A number of alterations in different neurotransmitter systems have been documented in studies of aging rodents, and in analyses of brain tissues from humans with age-related neurodegenerative disorders. While some of these alterations likely result from neuronal degeneration, others appear to occur in the absence of cell injury.

Cholinergic Systems

Acetylcholine is employed as a neurotransmitter in select populations of neurons in the brain, prominent among which are basal forebrain neurons that innervate widespread regions of the neocortex and hippocampus; these cholinergic neurons are known to play key roles in learning and memory processes in humans and rodents. Deficits in one or more aspects of cholinergic signal transduction may occur with aging including choline transport, acetylcholine synthesis, acetylcholine release, and coupling of muscarinic receptors to their GTP-binding effector proteins. Cholinergic deficits are much more severe in Alzheimer disease patients and also differ qualitatively from the changes observed during normal aging. Particularly striking is a reduced ability of muscarinic agonists to activate GTP-binding proteins in cortical neurons. Increased levels of membrane lipid peroxidation in neurons may contribute to impaired cholinergic signaling; for example, Aβ, Fe²⁺, and the lipid peroxidation product 4-hydroxynonenal can impair coupling of muscarinic receptors to the GTP-binding protein G_q11.

Dopaminergic Systems

Prominent reductions in both pre- and postsynaptic aspects of dopaminergic neurotransmission occur during brain aging. Decreases in dopamine levels and dopamine transporter levels in the striatum occur with advancing age, and there is an age-related decrease in levels of D₂ receptor-binding sites in striatum. As with cholinergic signal transduction, there also appears to be an age-related impairment of coupling of dopamine receptors to their GTP-binding effector proteins. The contribution of oxidative stress to changes in dopaminergic signaling has not been established, although the prominent role of oxyradicals in the pathogenesis of Parkinson disease argues that similar oxidative processes contribute to dopaminergic dysfunction during normal aging. These changes in dopaminergic signaling likely play a role in age-related deficits in motor control and may explain the fact that the older adults are susceptible to extrapyramidal effects of dopamine receptor antagonist drugs.

Monoaminergic Systems

Norepinephrine and serotonin are the major monoamine neurotransmitters in the brain. Noradrenergic neurons are located primarily in the locus caeruleus and serotonergic neurons in the raphe nucleus; both types of neurons project to widespread regions of cerebral cortex. There are several subtypes of receptors for norepinephrine, some of which couple to GTP-binding proteins. There are also several subtypes of serotonin receptors; some couple to GTP-binding proteins while others are ligand-gated ion channels. There appears to be increased levels of norepinephrine with aging in some brain regions, while levels of α₂-adrenergic receptors may decrease in cerebral cortex with advancing age. Levels of serotonin may decrease in the striatum, hippocampus, and cerebral cortex. Age-related decreases in levels of evoked serotonin release and of serotonin-binding sites have been reported, and may contribute to affective disorders such as depression.

Amino Acid Transmitter Systems

The amino acid glutamate is the major excitatory neurotransmitter in the human brain. Glutamate stimulates ionotropic receptors that flux calcium and sodium; excessive activation of ionotropic glutamate receptors may play a role in the degeneration of neurons in several age-related disorders including stroke, Alzheimer disease, Parkinson disease, and Huntington disease. Levels of ionotropic glutamate receptors were reported to decrease with aging, but these decreases may be the result of degeneration of the neurons expressing the receptors. The contribution of dysfunction of glutamatergic transmission, in the absence of neuronal death, to age- and disease-related deficits in brain function is unknown. The major inhibitory neurotransmitter in the human brain is γ-aminobutyric acid (GABA). Relatively little information is available concerning the impact of aging on GABAergic systems, although levels of glutamate decarboxylase and GABA-A binding sites may be decreased. Interestingly, GABAergic interneurons are typically spared in various neurodegenerative disorders including Alzheimer disease.

A variety of age-related alterations in neuroendocrine systems have been documented. Of particular importance for human brain aging and neurodegenerative disorders are changes in levels of steroid hormones, particularly glucocorticoids and estrogens. There is considerable evidence for age-related alterations in the diurnal regulation of circulating glucocorticoid levels, and an increase in the mean level. Moreover, regulation of the hypothalamic-pituitary-adrenal axis is altered in Alzheimer disease patients, such that plasma levels of glucocorticoids are increased. Increased levels of glucocorticoids, including those induced by physiologic or psychological stress, can increase the vulnerability of hippocampal neurons to injury and death caused by ischemic and excitotoxic insults, suggesting that glucocorticoids may have a negative impact on the outcome of both acute (eg, stroke) and chronic (eg, Alzheimer disease) age-related neurologic disorders. Estrogen (17β-estradiol) may have a beneficial effect on brain aging. Epidemiologic studies suggest a reduced risk of Alzheimer disease in postmenopausal women who take estrogen replacement therapy, and older women who take estrogens perform better on cognitive tasks. Surgical ovariectomy in rodents causes changes in neurotrophin receptor signaling, promotes the generation and accumulation of Aβ, and is associated with memory deficits. These effects are abrogated by exogenous estrogens. Finally, animal and cell culture studies have shown that 17β-estradiol can protect neurons from being damaged and killed by insults relevant to ischemia and Alzheimer disease, including glucose deprivation, exposure to Aβ, and expression of Alzheimer disease–linked presenilin mutations. Results of clinical findings, however, have not provided any convincing evidence that estrogen treatment either reduces risk for Alzheimer disease or related illnesses or enhances cognition. In contrast, findings from the Women’s Health Initiative indicated that extended therapy with both opposed and unopposed conjugated equine estrogen (CEE) increased risk for dementia, heart disease, stroke, and cognitive decline in older postmenopausal women.

While the blood-brain barrier limits access of circulating lymphocytes to neurons in the brain, it is becoming increasingly evident that the brain is by no means devoid of immune responses. The brain possesses resident immune effector cells called microglia that may respond to age- and disease-related neurodegenerative processes. Some data suggest that a decline in peripheral immune function during aging may lead to an autoimmune-like phenomenon in the brain wherein microglia is activated. Inflammatory processes are associated with, and contribute to, the neurodegenerative process in Alzheimer disease and other age-related neurodegenerative disorders; these include activation of microglia in the affected brain regions, increased local cytokine production in association with the neuropathologic changes, and activation of components of the complement cascade system. Collectively, the emerging data suggest a role for chronic inflammatory reactions in the pathogenesis of at least some neurodegenerative disorders. Recent studies have revealed that the choroid plexus, an epithelial monolayer that produces cerebrospinal fluid and maintains a dynamic interface between the cerebrospinal fluid and the blood, undergoes age-associated changes that are consistent with a type I interferon effect. Importantly, blocking type I interferon activity in aged mice is sufficient to reestablish a “young” choroid plexus activity and improve memory functions. Also intriguing is the fact that these changes appear to be driven by inflammatory changes that originate from both the brain parenchyma and the systemic circulation. Together, these results suggest that changes in inflammatory markers in the brain or in the periphery can influence (positively or negatively) memory functions; they also suggest that the choroid plexus plays an important role in the age-associated cognitive decline.

Cells in the nervous system produce a variety of proteins which serve the function of promoting neuronal survival and growth, and protecting the neurons against injury and death. Examples of such “neurotrophic factors” (also referred to as neurotrophins) include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3, neurotrophin-4, basic fibroblast growth factor (bFGF), and insulin-like growth factor (IGF). Neurotrophic factors are remarkable in that they can protect neurons against a variety of insults relevant to the pathogenesis of age-related neurodegenerative conditions. For example, bFGF can protect hippocampal and cortical neurons against metabolic, oxidative, and excitotoxic insults, and can greatly reduce brain damage in rodent models of stroke. One or more neurotrophic factors have also been shown to protect particular neuronal populations against neurodegenerative disorder-specific insults. Examples are the ability of BDNF to protect dopaminergic neurons against MPTP toxicity (Parkinson disease model) and hippocampal neurons against Aβ-mediated toxicity (Alzheimer disease model). The precise mechanism(s) whereby neurotrophic factors can rescue or prevent neuronal degeneration are unclear, and might be different in different neuronal populations. However, some of the protective effects may be linked to increased cellular resistance to oxidative stress and stabilization of cellular calcium homeostasis. In addition to preserving existing neurons, neurotrophic factors may stimulate the production of new neurons from neuronal stem cells. Such neural stem cells may be able to replace lost or damaged neurons, and are therefore receiving considerable attention for their potential use in the treatment of neurodegenerative disorders. An intriguing feature of neurotrophic factors is that their expression is increased by activity in neuronal circuits. Experimental studies in cell culture and in vivo show that such activity-dependent production of neurotrophic factors plays a major role in promoting neuronal survival and neurite outgrowth. Rearing of rodents in an “intellectually enriched” environment results in expansion of dendritic arbors and increased numbers of synapses in hippocampus and certain regions of cerebral cortex.

The activity and the specificity of neurotrophic factors depend on specific cell-surface receptors. Examples are the tyrosine-kinase family of receptors, TrkA, TrkB, and TrkC, and the p75 neurotrophin receptor (p75^NTR). These receptors can assemble as homo- and heterodimers, which display different affinity to specific neurotrophic factors and provide signaling specificity. For example, TrkA:p75^NTR heterodimers have higher affinity to NGF than TrkA:TrkA and p75^NTR:p75^NTR homodimers. Therefore, depending on how these receptors assemble on the neuronal surface, they can transduce slightly different or completely different signals. During aging the levels of TrkA decrease while those of p75^NTR increase, thus an expression pattern that favors the formation of TrkA:TrkA homodimers will switch toward an expression pattern that favors the formation of TrkA:p75^NTR heterodimers and p75^NTR:p75^NTR homodimers. While this switch occurs, the levels of NGF remain overall unchanged. However, since the affinity of the above receptor complexes for NGF is different, the signaling cascade will change as a result of aging. As an example, the above TrkA-to-p75^NTR switch has been linked to cognitive decline and increased risk of Alzheimer disease in rodents. A TrkA-to-p75^NTR switch has also been observed following surgical menopause in rodents, suggesting a possible impact in postmenopausal women.

The above competing activity of neurotrophin receptors is further complicated by the competing activity of neurotrophins. An example is BDNF competing with NGF for binding on TrkA:TrkA homodimers and pro-NGF competing with NGF for binding on p75^NTR:p75^NTR homodimers and TrkA:p75^NTR heterodimers. Importantly, levels of pro-NGF increase as a function of age while those of NGF remain unchanged. Mice with increased levels of pro-NGF develop a brain phenotype that resembles Alzheimer disease, and postmortem Alzheimer disease brain tissues express more pro-NGF than age-matched controls. In conclusion, complex scenarios can result as a function of aging leading to different neurotrophin-receptor interactions and, ultimately, to different biological effects. Since some of these changes are brain areas specific, we can expect different physiologic/pathologic outcomes.

Several microarray studies have now been performed in mice, rats, nonhuman primates, and humans to analyze the genetic profile of the aging brain. They all indicate that normal aging is not accompanied by a genome-wide dysregulation of transcription but rather by specific changes that affect only a small subset of genes, which accounts for about 3% to 5% of all the genes expressed in the brain. These changes (Table 62-2) will not be discussed here as their overall biological significance is still uncertain. Of note, a similar expression profile was also found in patients with Alzheimer disease supporting the view that a continuum might exist between normal aging and Alzheimer disease.

Longevity Genes

It is now evident that specific genetic, biochemical, and molecular pathways are intrinsically related to aging. Some of these pathways were initially identified in lower organisms and then later confirmed in higher organisms while others were immediately identified in higher organisms. These include the insulin-like growth factor 1 receptor (IGF-1R), Delta40p53, and Klotho.

Among them, IGF-1R has probably received more attention. The first evidence that IGF-1R signaling can regulate the progression of aging came from Caenorhabditis elegans where mutations that reduce IGF-1R activity were able to increase the lifespan of the animal. Similar results were then obtained in Drosophila melanogaster and, later on, in mammals. Importantly, mutations that act on IGF-1R downstream targets were also able to modify the lifespan of the animals providing robust and definitive connection between IGF-1R and aging. Overall, reduced IGF-1R activity extends lifespan and delays age-associated events while increased IGF-1R activity achieves the opposite effects. A partial block of IGF-1R signaling is also achieved by caloric restriction, which extends the maximum lifespan and delays many biological changes that are associated with aging. In humans, genetic variations that cause reduced IGF-1R signaling appear to be beneficial for old age survival and preservation of cognitive functions, suggesting that the mechanisms regulating lifespan and aging via this pathway are evolutionary conserved. Finally, reduced IGF-1R signaling can rescue Alzheimer disease in mouse models.

Delta40p53 is a short N-terminal truncated isoform of the tumor suppressor gene TP53. The common TP53 gene generates at least 12 different proteins through a combination of alternative promoter usage, alternative splicing, and alternative initiation of translation. Of them, p53 is the most “famous” and most studied due to its pathogenic role in many forms of cancer. Delta40p53 (also referred to as p44 or p47) lacks the first N-terminal 39 amino acids of full-length p53 but retains the DNA-binding domain as well as one of the two transactivation domains. Delta40p53 retains some of p53 functions but lacks others; it retains some of the regulatory elements but lacks others. Mice overexpressing full-length p53 (“Super p53” mice) are resistant to cancer development but have normal maximum lifespan. In contrast, mice overexpressing Delta40p53 (p44^+/+ mice) display a progeroid phenotype that mimics an accelerated form of aging. The phenotype includes early onset of diabetes, osteoporosis, memory impairment, and reduced lifespan. To date at least five additional mouse models with altered p53 activity have been shown to develop an accelerated aging phenotype providing robust and definitive connection between TP53 and aging. Recent studies have also shown that Delta40p53 regulates the generation of Aβ as well as the phosphorylation status of tau, suggesting a possible connection with the accumulation of amyloid plaques and neurofibrillary tangles that characterizes the aging as well the Alzheimer disease brain (discussed earlier in this chapter). Interestingly, mice engineered to overexpress p44 develop an accelerated form of Alzheimer disease neuropathology.

Klotho is a cell-surface membrane protein that can also be released in the circulation. Klotho has glycosidase-like activity. Its levels and enzymatic activity decline during aging. Genetic variants of KLOTHO are associated with human aging and klotho-deficient mice display a progeroid phenotype that resembles aging. The phenotype includes atherosclerosis, skin atrophy, osteoporosis, reduced fertility, emphysema, memory defects, and reduced lifespan. In contrast, mice overexpressing klotho display increased lifespan and increased resistance to several age-associated features. A possible connection between klotho and IGF-1R has also been delineated. Human variations that lead to increased circulating levels of klotho are associated with greater cortical volumes in the brain. Finally, overexpression of klotho in the mouse enhances cognition and rescues some of deficits that characterize Alzheimer disease.

In addition to the above, polymorphisms that are associated with longevity and preserved physiologic functions have also been identified in two cholesterol-related genes, apolipoprotein E (APOE) and cholesteryl ester transfer protein (CETP). APOE carries cholesterol in the circulation while CETP facilitates the transfer of cholesteryl esters and triglycerides between circulating lipoproteins. Individuals normally inherit two APOE alleles, of which there are three isoforms (E2, E3, and E4). The E2 allele has been linked to longevity and reduced incidence of Alzheimer disease. In contrast, the E4 allele has been linked to increased risk for Alzheimer disease. Certain CETP variants have been linked to increased levels of high-density lipoproteins (HDL), reduced progression of atherosclerosis, and longevity. The “longevity effect” of APOE and CETP might be explained, at least in part, by their ability to reduce the progression of atherosclerosis in the vasculature.

Another possible longevity gene is that encoding an isoform of angiotensin-converting enzyme, although its mechanistic links to aging are unclear. Finally, the multigene major histocompatibility system appears to influence lifespan, and may act by sustaining functions of the immune system. Additional information on longevity genes and their impact in age-associated events can be found in Chapter 1.

Disorder-Specific Genes

Considerable progress has been made in characterizing human genetic disorders that cause progeroid syndromes, which are characterized by a disease phenotype mimicking an “accelerated” form of aging. Although progeroid syndromes can be classified as unimodal (affecting one tissue/organ) and segmental (affecting multiple tissues/organs), the term progeroid syndrome is usually limited to the segmental forms of the disease (Table 62-3). Examples include Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford progeria syndrome, and Cokayne syndrome. Patients affected by these disorders have limited lifespan and develop a complex array of disease manifestations, including type 2 diabetes, osteoporosis, hair loss, skin atrophy, atherosclerosis, cardiomyopathy, heart failure, chronic obstructive pulmonary disease, renal insufficiency, and neurologic abnormalities. The neurologic defects are often subtle and difficult to diagnose; when evident, they include bulbar, extrapyramidal and cerebellar symptoms, deafness, retinopathy, cognitive deficits, corticospinal symptoms, and peripheral neuropathy. Brain imaging shows diffused white matter pathology as well as different degrees of gray matter pathology in memory-forming and -processing areas. The genetic defect has been mapped in most classical forms of progeroid syndromes. Specifically, Werner syndrome has been associated with mutations in WRN; Bloom syndrome has been associated with mutations in BLM; Rothmund-Thomson syndrome has been associated with mutations in RECQL4; Hutchinson-Gilford progeria syndrome has been associated with mutations on LMNA; and Cokayne syndrome has been associated with mutations in ERCC8 and ERCC6. All the above genes encode proteins that are involved in different aspects of DNA transcription, repair, or recombination underscoring common pathogenic elements.

Although progeroid syndromes manifest with symptoms and physical features that are—at least in part—reminiscent of an accelerated form of aging, they must be viewed as diseases rather than true forms of accelerated aging. It is plausible to assume that the dissection of the molecular phenotype of these diseases will inform us about aging. However, it is also plausible to expect that the underlying defects of human progerias are substantially different from those of normal aging. Additional discussion of human progerias can be found in Chapter 1.

Considerable progress has also been made in identifying genetic factors that play pathogenic roles in Alzheimer disease, the most common form of dementia associated with aging. Specifically, disease-causing mutations in APP, PSEN1, and PSEN2 have been identified in familial (early-onset) forms of Alzheimer disease. In addition, several “predisposition” genes have been identified in which polymorphisms increase the risk for developing sporadic (late-onset) Alzheimer disease. Description of the most important polymorphisms identified to date as well as pathogenic roles of APP, PSEN1, and PSEN2 can be found in Chapter 66.

The Brain as a Regulator of Lifespan

Among the very first mouse models of extended lifespan were the Ames and the Snell dwarf mice. Both models had a selective defect in the secretion of key hormones from the pituitary gland, specifically, growth hormone (GH), prolactin, and thyroid-stimulating hormone. The 40% to 60% extension of lifespan was also accompanied by evidence of delayed aging. The increased lifespan of the Ames and Snell mice was primarily linked to the deficiency of the GH-IGF1 axis. GH is released in the circulation by the pituitary gland; upon binding to its own receptor in the liver, it causes secretion of IGF1, which then binds to IGF-1R and stimulates IGF-1R signaling. Mice with isolated deficiency in growth hormone secretion (Little mice) or lacking the growth hormone receptor (GHR-KO mice) also displayed longevity. The lifespan extension in the Little and GHR-KO mice was in the 25% to 55% range. Finally, mice with reduced secretion of IGF1 or reduced levels of IGF-1R also displayed different levels of increased lifespan. In essence, the Ames and Snell mice represent the very first evidence that the brain itself (or specialized sets of neurons in the brain) could influence the lifespan of the animals. Following studies in lower organisms (C elegans and D melanogaster) clearly confirmed this conclusion. More recently, genetic disruption of IRS2, an adaptor protein that acts downstream of IGF-1R and the insulin receptor, in the mouse brain (bIrs^–/+ and bIrs^–/–) also caused a significant increase in the lifespan of the animals. Regardless of the specific mechanism(s) involved in the phenotype of the above genetic models, it is now well accepted that in addition to being affected by aging, the brain (or the nervous system) itself can affect aging.

It is now evident that the diet can affect one’s risk of age-related neurodegenerative disorders. In particular, emerging findings indicate that several dietary risk factors for prominent age-related diseases including cardiovascular disease, cancer, and diabetes are also risk factors for Alzheimer disease, Parkinson disease, and stroke. A summary of possible preventive measures to improve brain health can be found in Table 62-4.

Calorie Intake

Apart from genetic manipulation, the only known means of increasing the lifespan of rodents and nonhuman primates is by decreasing their calorie intake; both maximum and mean lifespan can be increased by up to 40%. The average lifespan of humans is certainly decreased by overeating, although it remains to be determined whether maximum lifespan can be increased through calorie restriction. Epidemiologic data suggest that individuals with a low-calorie intake are at a reduced risk for Alzheimer disease and Parkinson disease. Biochemical markers of aging, and deficits in learning and memory and motor function, are retarded in rodents maintained on dietary restriction. Neurons in the brains of rats and mice maintained on dietary restriction are more resistant to dysfunction and death in experimental models of Alzheimer disease, Parkinson disease, Huntington disease, and stroke. A 20-year longitudinal study in Rhesus macaques showed that a 30% reduction in daily calorie intake reduced the rate of age-related deaths as well as the incidence of typical age-associated diseases, such as diabetes, cancer, cardiovascular disease, and brain atrophy. The ability of calorie restriction to prevent brain atrophy was observed across several gray matter areas involved in both motor and executive functions. Magnetic resonance imaging also showed preserved volumes and insulin sensitivity in memory-forming and -processing areas while postmortem histology showed reduced astrogliosis. Therefore, a large body of evidence from lower organisms to nonhuman primates delineates a relationship between calorie intake and progression of aging and/or incidence of age-associated events. The mechanism whereby caloric restriction increases the resistance of neurons to the adverse effects of aging is not entirely known. Studies in yeast, worms, flies, rodents, and monkeys suggest that the reduced calorie intake causes a comprehensive metabolic reprogramming that involves key nutrient-responsive signaling pathways.

Folic Acid (Homocysteine)

It was recognized long ago that folic acid deficiency can cause abnormalities in the developing nervous system. Subsequently, it was shown that people with low levels of folic acid tend to have elevated levels of homocysteine and that this condition is associated with increased risk of cardiovascular disease and stroke. Homocysteine is produced during metabolism of methionine, and folic acid plays an important role in removing homocysteine via remethylation. Epidemiologic findings suggest that people with elevated homocysteine levels may be at increased risk of Alzheimer disease and Parkinson disease. Animal studies support a cause-effect relationship between elevated homocysteine levels and neuronal vulnerability to neurodegenerative disorders. For example, hippocampal neurons of APP mutant mice (Alzheimer disease model) and substantia nigra dopaminergic neurons in MPTP-treated mice (Parkinson disease model), exhibit increased vulnerability to degeneration when maintained on a folic acid–deficient diet. By increasing homocysteine levels, folic acid deficiency may promote accumulation of DNA damage by inhibiting DNA repair. In neurons, the increased DNA damage can trigger apoptosis, particularly under conditions of increased oxidative or metabolic stress. Of note, results of clinical studies to date have failed to provide any convincing evidence that folic acid supplementation either reduces risk for dementia or vascular diseases.

Antioxidants

Neurons are subjected to increased levels of oxidative stress during normal aging, and more so in neurodegenerative disorders. It is therefore reasonable to consider the possibility that dietary antioxidants might promote successful brain aging. Epidemiologic findings support a protective effect of antioxidants in fruits and vegetables against stroke, and possibly Alzheimer disease. Studies in animal models of Alzheimer disease, Parkinson disease, Huntington disease, stroke, and amyotrophic lateral sclerosis have documented beneficial effects of some antioxidants. Positive effects have been reported for several commonly used dietary supplements, including vitamin E, creatine, and ginkgo biloba. However, the effects of such antioxidants are relatively subtle compared to the quite striking neuroprotective effects of dietary restriction. Notably, results of a large randomized clinical trial using 2000 units of vitamin E in patients with mild-to-moderately severe Alzheimer disease showed a 6-month delay in progression of cognitive symptoms and a significant reduction in caregiver stress. In contrast, a large randomized clinical trial showed no beneficial effects of ginko biloba in patients with Alzheimer disease.

Stimulatory Phytochemicals

Epidemiologic findings suggest that individuals who regularly consume vegetables and fruits have a lower risk of developing age-related neurodegenerative disorders compared to those who eat few such plant products. Several phytochemicals have been reported to enhance neuronal plasticity and survival in studies of animal models of neurodegenerative disorders. Examples include sulforaphane, curcumin, allicin, resveratrol, and other grape-derived polyphenols. Instead of functioning as direct antioxidants, many of these beneficial phytochemicals may stimulate mild adaptive stress responses that result in increased production of antioxidant enzymes, neurotrophic factors, and other protective proteins in neurons. The possible therapeutic benefits of several such stimulatory phytochemicals are currently being tested in human subjects with age-related neurologic disorders.

Structural changes occur in the brain during aging and appear to be compensatory responses to adverse changes in cellular metabolism that accompany the aging process. There are several biochemical processes that may predispose neurons to dysfunction and death in aging and neurodegenerative disorders. The discovery that the lifespan of an organism can be regulated by specific genetic, molecular, and biochemical pathways has changed our view of aging itself and has spurred active interest in studying the basic biology of aging to understand diseases. At the same time disease-driven research has helped to discover pathways that are relevant for aging. Convergence between age- and disease-related research has yielded an unprecedented body of information that will help us understand how the brain evolves and adapts to aging and how we can modulate these changes to improve the quality of life of a growing segment of our population.