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BRAIN

Humans and other vertebrates possess a central nervous system (CNS)—the brain and spinal cord—containing specialized cells called neurons. The nervous system is essential for virtually every aspect of life and, along with the body's other systems (muscular-skeletal, endocrine, etc.), performs the following seven basic, interrelated tasks:

1. Maintenance of vital functions, including control of the cardiovascular system and homeostasis (regulation of temperature, weight, internal milieu in general).
2. Obtaining information via the sensory systems (auditory, visual, somatosensory, olfactory, etc.) and processing that information. Information about ourselves and the world is provided by the sensory portions of the nervous system.
3. Storage and retrieval of information by the processes of learning and memory. Changes occur in the brain every time something new is learned, and the changes often last in the form of memories. Moreover, the brain must be adept at retrieving that information from storage when needed.
4. Production of behavior, including movement, locomotion, autonomic responses, and communicative behavior such as language. The brain's motor systems operate skeletal muscles that move the limbs, facial muscles, mouth, vocal cords, and so on.
5. Integration of information and output: tying things together to make "decisions" ranging from simple reflexes to complex social and cognitive processes (intelligence, language, spatial orientation, etc.).
6. Modulation of the overall activity levels of the brain and body associated with emotion, arousal, and sleep.
7. Carrying out the genetic mandate to pass on one's genes to the next generation, especially with respect to sex, reproductive behavior, parenting, and aggression.

It is evident from our everyday observations that any or all of the seven functions may operate at sub-par levels as people get older. For example, maintaining body temperature may become more difficult under extreme conditions; the eyes, ears, and other senses may not pick up as much as they used to; it can become harder to remember names; athletic skills decline; "intelligence" for new technological concepts seems poorer compared to that of young people; a good night's sleep is often harder to get; and the frequency of sexual activity may change. Because all seven functions are beholden to the nervous system, it follows that age-related changes in the system's components are part and parcel of these problems.

Understanding how the nervous system and its components fare as individuals age, how agerelated neural changes are manifested behaviorally, and how this knowledge may be used to improve the quality of life is an immensely daunting task because, irrespective of aging, the nervous system is bafflingly complex.

The nervous system and its complexity

The number of neurons in the human brain is vast—many billions (although glial cells, which provide various support functions, are even more numerous). A thread-like axon (nerve fiber) extends from the neuron, often branching repeatedly, to provide functional connections to other neurons located at its endings (terminals), sometimes at remote locations within the nervous system. Electrical impulses (action potentials) are generated in or near a neuron's cell body and travel outward along the axons, much as telegraph impulses are sent from an operator, traversing wires to receiving destinations (other neurons). A unique feature of neurons that greatly increases the number of axon terminals that can contact them are dendrites—elaborate tree-like arrays emanating from the cell body. The evolution of extensive dendritic trees, coupled with branching axons, has led to the development of neural "wiring diagrams" of enormous complexity. The situation is further complicated by the properties of synapses, the sites where dendrites and axon terminals "communicate." For the most part, the communication between neurons uses chemical neurotransmitters that are typically stored in the axon terminals. Packets of neurotransmitter molecules are released by mechanisms associated with the arrival of nerve impulses generated by the axons' parent neuron. The neurotransmitter quickly diffuses across the narrow synaptic cleft to reach a dendrite or cell body of the target neuron. The neurotransmitter molecules find their way to synaptic receptors, specialized sites in or on the receiving neuron that react with the neurotransmitter. The reaction between neurotransmitter and synaptic receptors alters some physiological properties of the receiving neuron, changing its activity and output. This neuron is, of course, connected to other neurons via the synapses made by its own axon terminals, which are in turn affected. And so on.

A number of different types of neurotransmitters are used by the nervous system, such as acetylcholine, dopamine, serotonin, and many others. Moreover, for a particular neurotransmitter there can be a variety of receptor types on one receiving neuron or another, so that the same neurotransmitter can produce different effects. The large number of possible permutations of neurotransmitter and receptors confer yet another layer of complexity upon the brain.

All of these highly varied, interacting aspects of neural circuits somehow work together in a manner that miraculously allows the nervous system to accomplish its basic functions. By the same token, they provide many "targets" for deleterious age-related changes. Reviewing some basics of the nervous system structure and function and their neurogerontological implications will help impart a sense of the mischief that aging can visit upon the nervous system. Then, after addressing a few of the basic functions, some possible ways by which age-related changes in the nervous system might be modified for the better will be outlined.

Organization of neurons into a nervous system and basic neuroanatomy

For meaningful behavior to occur, information from the body and environment must get into the brain, and instructions from the brain must be delivered to the muscles and glands so that the body can perform. The portion of the nervous system that provides this interface is called the peripheral nervous system. It has two basic subsystems: the somatic system and the autonomic system. The somatic system brings information into the brain via axons originating in the sensory organs and sends messages outward through axons to skeletal muscles causing them to contract. The autonomic system is linked to our emotions and arousal states, and activates glands (e.g., sweat glands), smooth muscles (e.g., controlling the pupils of the eye, blood vessels, etc.), and heart. The autonomic system contains two subsystems: the sympathetic system readies us for action (increases heart rate, dilates pupils), whereas the parasympathetic system has the opposite effect, restoring us toward a resting level when warranted. Some age-related changes often occur in the peripheral systems, such as loss or thinning of nerve fibers or changes in the "target organs" (muscles and glands), and these may result in poorer performance.

In the central nervous system (CNS), the spinal cord extends below the brain, encased by the vertebral bones of the neck and back. The spinal cord relays incoming sensory messages from the periphery to the brain and outgoing instructions from the brain to spinal cord neurons whose axons leave the CNS to activate muscles. However, in addition to being a relay to and from the brain, the spinal cord itself contains impressive assemblies of neuronal circuitry that perform a number of sensory-motor behaviors, such as withdrawal from a painful stimulus or rhythmic movements associated with locomotion. Changes in the spinal cord can occur in older people that make it less efficient at relaying the information up and down.

Merging with the spinal cord is the brainstem, the lowest region of the brain. Its basic subdivisions (moving upwards) are the medulla, pons, and midbrain. At the top of the brainstem is the thalamus. The neural traffic between the brain and spinal cord travels along axons that traverse the brainstem. In addition, sensory information (coded in trains of action potentials) enters the brainstem from the head and the special sense organs (ears, eyes, etc.), while other messages leave the brainstem to control the face, mouth, eyes, and so on. The brainstem controls a number of activities without a necessary contribution from higher levels of the brain. For example, comparison of acoustic input from the two ears to compute the location of sounds in space is a function of brainstem circuits. Some regions of the brainstem are especially vulnerable to agerelated changes that can affect a variety of behaviors.

Behind the brainstem, near the base of the skull, is the cerebellum. It plays key roles in coordinating movements, balance, and even some types of learning. The cerebellum has numerous axons communicating with the brainstem that, in turn, communicate with the higher regions of the brain and the spinal cord below. The cerebellum is required for balance, posture, gait, and the adjustment and coordination of movements. Age-related changes observed in neurons of the cerebellum include loss of dendrites and spines and changes in neurotransmitter systems, and these are likely to affect movements.

The bulk of the brain lies above and around the thalamus. The basal ganglia are prominent parts of the interior brain adjacent to the thalamus, and deal with movement (they play important roles in cognition, as well). To the side, but folded over so as to sit deep in the middle of the brain, is the hippocampus, a structure that is essential for certain types of learning and memory as well as spatial behaviors. The amygdala, along with the hypothalamus and other parts of the limbic system, comprise the "emotional brain." At the base of the brain is the hypothalamus, a collection of small subdivisions that regulate a number of essential functions such as eating and drinking, body temperature, biological rhythms, and reproductive behavior. The hypothalamus produces hormones that influence the release of other hormones by the neighboring pituitary gland. At least some of these hormone systems become less responsive with age because of reduced production by hypothalamic neurons, changes in receptor sensitivity for the hormones, and/or changes in the endocrine glands. The fact that relatively small hypothalamic subdivisions control important biological functions has suggested that subtle changes might contribute to aging in a fundamental way.

If one looks at a human brain, it is dominated by two large, folded cerebral hemispheres. On the surface of the hemispheres (and folded into the creases or sulci) are several layers of neurons that comprise the cerebral cortex. The cerebral cortex, working in concert with the rest of the brain, is capable of incredible feats, most notably in humans, in which its size and complexity far exceeds that of other species. Language, complex thoughts, logic, and many other "higher" functions are beholden to a highly advanced cerebral cortex. The left and right hemispheres communicate with one another with millions of axons, most of which are contained in a huge band of axons called the corpus callosum. Studies have found evidence that the transfer of information between cerebral hemispheres across the corpus callosum can be slowed or diminished with age.

Neurobiology and aging

In order to understand how the "slings and arrows" of aging can affect the brain, some basics of neurobiology must be appreciated.

Neurons lack the capacity to regenerate. With a few exceptions, new neurons are not produced once the maximum number is established early in life, and the ability of CNS neurons to be repaired when damaged is quite limited. We can lose neurons as we age, but we cannot grow new ones. The exact number of neurons lost by the human brain during aging has been elusive, plagued by methodological issues that include technical difficulty in counting neurons, post-mortem changes that can occur in human brains from autopsy, differences in the pre-mortem condition of young and old people who are autopsied (for example, older people are more likely to have died from chronic illnesses that could have resulted in brain pathology), and the unwitting inclusion of patients with undetected dementia. Even when nonhuman animals are studied, inconsistencies arise, stemming from species differences, variability among genetic strains within the same species, and the fact that different parts of the brain often show different age changes. All of this suggests that no general pattern of neuron loss occurs in aging nervous systems. However, there is a growing consensus that some older studies probably overestimated the degree to which neurons die as people age. The current view is more optimistic: at least in the neocortex, many (perhaps most) healthy older people exhibit a minimal loss of neurons, although other brain regions may be more vulnerable.

Neurons require a disproportionate share of the blood supply. Neurons have a ravenous appetite for the blood's precious cargo of glucose and oxygen, and the percentage of the body's blood and oxygen consumption in the brain at any time is far out of proportion with the rest of the body. It has to be this way because reducing the supply of blood/oxygen to neurons results in impairment, damage, or destruction depending on the severity and duration. Thus, conditions that reduce the brain's blood supply, such as atherosclerosis, diabetes, and, of course, stroke are cause for concern. Each of these conditions becomes more prevalent with age, as do other changes in the vascular system serving the brain, even in the absence of diseases.

Neurons are at risk from various toxins. Over a lifetime, neurons, like other cells, are exposed to toxins. These can be environmental or endogenous—produced by the brain itself. For example, glutamate is the major neurotransmitter used by neurons to synaptically activate (excite) other neurons. Under certain conditions, such as hypoxia or tissue damage, the effects of glutamate can become exaggerated, resulting in excessive entry of calcium into the neurons, and such excitotoxic events prove to be damaging to neurons. If aging were associated with weakening of the defenses against excitotoxicity, negative age effects could accrue. Indeed, this process appears to be involved in certain types of dementia and neurodegenerative conditions that can accompany aging.

The neuron's nucleus regulates many functions. The synthesis of proteins is coded by DNA, the genetic material found in the nucleus of neurons and other cells. Many varieties of protein are produced for use as structural components of neurons (e.g., the microtubules and microfilaments in axons that transport molecules used for neurotransmitters and provide structural support), enzymes that control the numerous biochemical reactions necessary for cellular activities, synaptic receptors, and many other uses. Damage to DNA that can accrue in cells with age has the potential to alter many facets of neuronal physiology.

Dendritic branches and spines are at risk with aging. The size, shape, orientation, and complexity of the neuron's dendritic tree have a great deal to do with the number of functioning contacts that can be made with other neurons. Dendritic spines are small extensions that provide many additional sites for synapses. One of the best documented age-related changes in neurons is a reduction in the number of dendritic branches and spines. Even if neurons do not die off, a loss of synaptic contacts is likely to reduce the information-processing capacity of neural circuits, negatively affecting brain function.

Parts of the brain are differentially vulnerable to aging. Age effects vary greatly among different components of the nervous system. Various behavioral and cognitive functions are affected to different extents, depending on how each brain region fares. For example, the hippocampus is very important for storing memories. Research has shown that portions of the hippocampus are often damaged during aging, and this may be responsible for learning and memory deficits.

The speed of information processing slows with age. Behavior and cognition tend to become slower with age. Indeed, behavioral/cognitive slowing has been proposed as a marker of aging (i.e., a measure that can differentiate chronological age from functional age). There is a good deal of research indicating a general slowing of brain processes, with cognitive slowing likely to reflect the sluggishness of smaller components (sensory, motor, and interconnected central circuits). Possible causes of slowing might include slower conduction of action potentials because of changes in the axons; slower synaptic transmission because of structural and/or chemical changes; diminished intracellular metabolism (e.g., associated with damage to energy-producing mitochondria); reduced production of neurotransmitters or other critical products; impaired gene expression (e.g., associated with DNA damage); and many other potential changes that would interfere with optimal neural performance. Changes in the peripheral sensory and motor systems (e.g., loss or thinning of axons) probably make only small contributions to slowing. More salient are the central neural circuits that intervene between stimuli and responses.

Aging and the basic functions of the nervous system

Only a few examples of how aging affects the seven functions of the nervous system are presented, but they show the types of age effects that have been observed.

Obtaining information with the sensory systems. The neural means by which sensory stimuli are experienced involve multistage processes requiring high-quality representation of stimuli by the peripheral sensory apparatus, undistorted neural messages carried by action potentials into the brain, and accurate processing of the information by the central sensory systems. Disruption of any of these processes with age would have the potential to cause problems in the sensory domain. The sad truth is that our sensory abilities almost inevitably decline with age. The rate and severity of the decline may vary considerably among individuals and across sensory modalities within individuals, but few, if any, octogenarians possess the same sensory capacities they started out with. All the sensory modalities suffer with age, including hearing and the auditory system.

The term "presbycusis" or "presbyacusis" is typically used to describe the changes in hearing associated with aging. Whereas the most commonly mentioned manifestation of presbycusis is a loss of sensitivity for high frequency sounds, the types of hearing problems confronting older listeners extend to speech perception, hearing in noisy backgrounds, distorted loudness of sounds, and tinnitus ("ringing in the ears"). Presbycusis typically involves progressive damage to the inner ear: the cochlea (where acoustic events are ultimately translated to neural events) and the cochlear neurons (where sounds are coded as trains of action potentials and sent, via the auditory nerve, to the brain for processing). Damage to any part of the cochlea diminishes the amount and quality of auditory input to the brain, with deleterious effects on hearing.

It is in the CNS where the action potential–coded sensory information originating in the inner ear is somehow transformed into auditory perception and experience. The central components of the auditory system are threatened by two adverse correlates of aging. First, changes in the structure or function of the brain's neurons occur in the context of biological aging discussed above. Second, an otherwise "healthy" central auditory system may be secondarily affected by damage to the cochlea. It has been shown that, when certain central neurons are deprived of their normal synaptic input, physiological and anatomical changes are induced. The effects can produce additional hearing deficits. Because the altered neurons provide input to other neurons, the effects could spread. Because the central sensory systems of older individuals might be affected in two rather different ways, it is useful to differentiate two types of age-related central changes. The term central effects of biological aging (CEBA) refers to sensory changes stemming from age-related changes in neurons, metabolism, support systems, and so on. The term central effects of peripheral pathology (CEPP) also refers to sensory changes associated with modifications of neurons and neural circuits in the brain. However, these are secondary to the removal or alteration of peripheral sensory input. It would be expected that CEBA and CEPP often occur in combination, since many older people have some loss of receptor function as well as various CNS deficits.

Whether CEBA, CEPP, or both are at work, the changes that occur in the auditory CNS are multifaceted. Some neurons die off or come to perform less efficiently, becoming "sluggish" in their responses to sound. By contrast, other neurons come to respond more vigorously, probably because aging is accompanied by deficits in inhibitory neurotransmitters, which normally dampen the responses of neurons and prevent hyperactivity. A combination of these and other types of central changes are likely to contribute to difficulties that many older people have in understanding speech, even when it is loud enough for them to hear.

The storage of information (learning and memory).Research indicates that, to varying extents (according to individual differences, genotype, species, etc.), circuits and neurotransmitter systems relevant for learning and memory often exhibit deleterious changes with age; deficiencies in any of these can cause some sort of learning/memory deficit. Learning and memory involve modifications (plasticity) of synapses in neural circuits. For example, one type of synaptic change associated with learning is long-term potentiation (LTP): lasting changes in neural responses induced by situations similar to those involved with learning. Experiments have shown changes in LTP in hippocampus neurons of old rats that have learning deficits. Thus, in addition to the general types of changes that occur in aging nervous systems, processes specific to learning may be affected as well.

Production of behavior (movement, etc.). Whereas some of the age-related declines in motor skill are associated with a decrease in muscle mass and a loss of strength, the most important and interesting stories are found in the workings of the nervous system. A large portion of the nervous system is devoted to movement—deciding what to do, planning how to do it, and carrying it out. Each has been demonstrated to exhibit some degree of age-related change that might result in less effective movement. For example, the primary motor cortex is the major source of descending axons to the motor neurons of the spinal cord that control the muscles. Several studies have described abnormalities in the large neurons of the primary motor cortex of older brains, including a loss of dendrites and dendritic spines. In addition to the motor cortex, the basal ganglia (the next lower set of structures controlling movement) are involved in self-initiated, complex movements, the control of postural adjustments, and other aspects of motor behavior. The effects of damage to the basal ganglia are evident in the motor symptoms of Parkinson's and Huntington's diseases, disorders affecting these structures. Some of the mild motor disturbances that occur in healthy older people could be a consequence of less severe basal ganglia damage that has been observed during normal aging.

Modulation of behavior (emotion, arousal, stress).Our behavior varies constantly—up and down, this way and that way—in accordance with emotions, arousal, and biological clocks. One powerful modulator of behavior is stress: Various stimuli, events, or situations that are actually or potentially threatening (stressors) elicit activation of the sympathetic nervous system and a sequence of hormonal reactions, including the release of glucocorticoid hormones from the adrenal gland. Whereas the stress response is adaptive (e.g., it increases the probability of surviving dangerous situations), too much stress is generally considered to be a bad thing. Indeed, high blood pressure, suppression of the immune system, and exacerbation of diseases are known concomitants of stress. Thus, the relationship between stress and aging is potentially important. Moreover, there is evidence that, over time, glucocorticoids can actually damage the hippocampus, contributing to negative changes in the aging brain.

Modifying changes in the aging nervous system

Neural plasticity is a term that describes the ability of synapses, dendrites, axons, and other aspects of neurons to change—usually in an adaptive fashion. Plasticity is very potent in developing organisms, and it is now established that older brains retain much capacity for change as well. Research has shown that new synapses can form in older brains in response to injury or environmental manipulations, and that dendrites continue to be modifiable. However, the process generally takes longer and may not reach the magnitude typical of younger brains. The ability of the adult nervous system to engage mechanisms of synaptic plasticity has at least two important implications. First, degenerative tendencies may be counteracted by replacement of damaged synapses and repair of neural circuits. Second, the nervous system can continue to manifest the normal, adaptive types of synaptic plasticity exhibited by young individuals.

The dynamic properties of the older nervous system provide potential opportunities for the development of strategies aimed at modulating the direction or severity of negative age-related changes. A number of approaches are being investigated by researchers. In one way or another, most approaches attempt to enhance neural functioning by promoting the activity of various neurotransmitters or other physiologically important substances that protect neurons from age-related damage or improve neural functioning per se. For example, diets that promote the general health of cardiovascular and other systems are also good for the nervous system.

Neurotrophic factors such as nerve growth factor (NGF) are essential for the maintenance, growth, and survival of neurons both during development and in adults. Administration of neurotrophic factors has been shown to retard or prevent neural degeneration in experimental animals, and infusion of NGF may be able to prevent shrinkage of neurons typically observed with age. It appears that neurotrophic factors may have a variety of potentially beneficial effects on the aging nervous system. Some of these may be harnessed for clinical use.

Calorically restricted diets can extend longevity of rodents, slow certain age-related physiological declines, and decrease tumors and diseases. Although much of this research has focused on non-neural systems, there is ample evidence that dietary restriction modulates aging of the brain. Effects of dietary restriction on some of the general concomitants of neural aging, such as accumulation of lipofuscin ("age pigment") in neurons, the efficacy of glial cells, and loss of dendritic spines, have been reported.

Relatively simple environmental manipulations can have beneficial effects on the brain. Young and old rats living in an "enriched" environment (e.g., ten rats per cage, large space, toys) may exhibit a thicker cerebral cortex, compared to like-aged unenriched rats. Enhancement of dendritic growth and complexity have also been demonstrated in studies of environmental enrichment. Some evidence has linked neurotrophic factors to environmental enrichment and improved cognitive performance. The expression of NGF has been found to increase under these conditions. It could be that enriched environments or behaviors are associated with increased neural activity, which results in an upregulation of nerve growth factors, which in turn leads to enhanced neuronal survival, growth, and plasticity.

Unfortunately, age-related damage to neurons can be too severe to be managed by neurotrophins or environmental manipulations. This is especially true of neurodegenerative diseases. In such cases, transplantation or grafting of new neurons into the damaged site might prove to be feasible approach. The main problems are survival of the graft and, more importantly, appropriate rewiring of circuitry with the host brain. There is a tendency of the grafted tissue to make contacts appropriate for their neurotransmitters and circuits, although this depends on brain region and other variables. The possibility of replacing brain tissue lost to aging—thereby restoring function—is intriguing. Although controversial and inconsistent, improvements have been obtained by grafting tissue from the adrenal gland or fetal substantia nigra into Parkinson's patients. Encouraging results have been obtained from animal research in other brain regions as well, and several studies have shown that fetal brain tissue can be successfully transplanted into the brains of aged rodents. A big issue is whether complex behaviors and cognitive processes of humans might ever benefit from neural grafting. It is one thing to enhance dopamine activity in Parkinson's patients and another to replace intricate neural circuitry underlying cognitive processes. The latter may never be attainable. For now, the utility of neural grafts is likely to be found in their capacity to generate growth factors and other beneficial substances, or boost the activity of certain circuits by replenishing neurotransmitters.

JAMES WILLOTT

See also ALZHEIMER'S DISEASE; BALANCE AND MOBILITY; CELLULAR AGING; DEMENTIA; EMOTION; HEARING; INTELLIGENCE; LANGUAGE DISORDERS; MEMORY; NEUROBIOLOGY; NEUROTRANSMITTERS; PARKINSONISM; STRESS AND COPING.

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