As indicated in the preceding chapter, standards of growth, development, and maturation provide a frame of reference against which every pathologic process in early life must be viewed. It has been less appreciated, however, that at the other end of the life cycle, neurologic deficits must be judged in a similar way, against a background of normal aging changes (senescence). The earliest of these changes begins long before the acknowledged period of senescence and continues throughout the remainder of life. Most authors use the terms aging and senescence interchangeably, but some draw a fine semantic distinction between the purely passive and chronologic process of aging and the composite of bodily changes that characterize this process (senescence).
Biologists have measured many of these changes. Table 29-1 gives estimates of the structural and functional decline that accompanies aging between ages 30 and 80 years. It appears that all structures and functions share in the aging process. Some persons withstand the onslaught of aging far better than others, and this constitutional resistance to the effects of aging seems to be familial. It can also be said that such changes are unrelated to Alzheimer disease and other degenerative diseases but that in general, the changes of aging reduce the capacity to recover from virtually any illness or trauma. An entity of "frailty" has been conceived to encompass the sum of breakdown in multiple organ systems as a result of aging. The review by Clegg and colleagues is recommended on this subject. With respect to the nervous system, it entails loss of muscle mass, strength and endurance, decreased appetite, unintentional weight loss, and reduced mobility and balance. A working definition of frailty has been given by Fried and is summarized in Table 29-2. In the past, this was referred to as "failure to thrive," a term adopted from pediatrics.
Effects of Aging on the Nervous System
Of all the age-related changes, those in the nervous system are of paramount importance. Actors portray old people as being feeble, idle, obstinate, given to reminiscing and having tremulous hands, quavering voices, stooped posture, and slow, shuffling steps. In so doing, they have selected some of the most obvious effects of aging on the nervous system. The lay observer, as well as the medical one, often speaks glibly of the changes of advanced age as a kind of second childhood. "Old men are boys again," said Aristophanes.
Critchley, in 1931 and 1934, drew attention to a number of neurologic abnormalities that he had observed in octogenarians and for which no cause could be discerned other than the effects of aging itself. Several reviews of this subject have appeared subsequently (see especially those of Jenkyn, of Benassi, and of Kokmen  and their associates). The most consistent of the neurologic signs of aging are the following:
- Neuroophthalmic signs: progressive smallness of pupils, decreased reactions to light, and near farsightedness (hyperopia) as a result of impairment of accommodation (presbyopia), insufficiency of convergence, restricted range of upward conjugate gaze, frequent loss of the Bell phenomenon, diminished dark adaptation, and increased sensitivity to glare.
- Progressive hearing loss (presbycusis), especially for high tones, and commensurate decline in speech discrimination. Mainly these changes are a result of a diminution in the number of hair cells in the organ of Corti.
- Diminution in the sense of smell and, to a lesser extent, of taste (see Chap. 12).
- Motor signs: reduced speed and amount of motor activity, slowed reaction time, impairment of fine coordination and agility, reduced muscular power (legs more than arms and proximal muscles more than distal ones) and thinness of muscles (sarcopenia), particularly the dorsal interossei, thenar, and anterior tibial muscles. A progressive decrease in the number of anterior horn cells is partially responsible for these changes, as described further on.
- Changes in tendon and frontal reflexes: A depression of tendon reflexes at the ankles in comparison with those at the knees is observed frequently in persons older than 70 years of age, as is a loss of Achilles reflexes in those older than 80 years of age. The snout or palmomental reflexes, which can be detected in mild form in a small proportion of healthy adults, are frequent findings in the elderly (in as many as half of normal subjects older than 60 years of age, according to Olney). However, other so-called cortical release signs, such as suck and grasp reflexes, when prominent, are indicative of frontal lobe disease but sometimes are expected simply as a result of aging.
- Impairment or loss of vibratory sense in the toes and ankles. Proprioception, however, is impaired very little or not at all. Thresholds for the perception of cutaneous stimuli increase with age but require the use of refined methods of testing for their detection. These changes correlate with a loss of sensory fibers on sural nerve biopsy, reduced amplitude of sensory nerve action potentials, probably as a result of loss of dorsal root ganglion cells.
- The most obvious neurologic aging changes—those of stance, posture, and gait—are fully described in Chap. 7 and further on in this chapter.
Jenkyn and colleagues, based on their examinations of 2,029 individuals aged 50 to 93 years, have determined the incidence of certain common neurologic signs of aging. Notable again is the high frequency of snout and glabellar responses, but also limited downgaze and upgaze in approximately one-third of persons older than age 80 years. Table 29-3 summarizes these data.
Table 29-3 Frequency of Neurologic Signs in Uncomplicated Aging (in Percent) ||Download (.pdf)
Table 29-3 Frequency of Neurologic Signs in Uncomplicated Aging (in Percent)
Glabellar sign (inability to inhibit blink)
Abnormal visual tracking
Unable to recall 3 words
Unable to spell world backward
With regard to the interesting population of the "oldest old," those older than 85 years of age, Kaye and colleagues reported that deficits in balance, olfaction, and visual pursuit are distinctly worse than in younger elderly persons. Also of interest is the observation by van Exel and colleagues that women in this age group perform better than men on cognitive tests.
Effects of Aging on Memory and Other Cognitive Functions
Probably the most detailed information as to the effects of age on the nervous system comes from the measurement of cognitive functions. In the course of standardization of the original Wechsler-Bellevue Intelligence Scale (1955), cross-sectional studies of large samples of the population indicated that there was a steady decline in cognitive function starting at 30 years of age and progressing into old age. Apparently all forms of cognitive function partake of this decline—although in general certain elements of the verbal scale (vocabulary, fund of information, and comprehension) withstand the effects of aging better than those of the performance scale (block design, reversal of digits, picture arrangement, object assembly, and the digit symbol task).
However, the concept of a linear regression of cognitive function with aging has had to be modified in the light of subsequent longitudinal studies. If the same individual is examined over a period of many years, there is virtually no decline in his performance, as measured by tests of verbal function, until 60 years of age. Beyond this age, verbal intelligence does decline, but very slowly—by an average of less than 5 percent through the seventh decade and by less than 10 percent through the eighth decade (Schaie and Hertzog). Also, in a series of 460 community-dwelling individuals (55 to 95 years of age) studied by Smith and coworkers (1992), there was no significant decline with age in verbal memory and in registration–attention; similar results were found by Petersen and colleagues in 161 normal, community-dwelling individuals 62 to 100 years of age. The most definite effects of age were in learning and memory and in problem solving—cognitive impairments probably attributable to a progressive reduction in the speed of processing information. The latter may be reflected in the slowing of event-related evoked potentials and by a number of special psychologic tests (see Verhaeghen et al).
As regards these cognitive functions, the ability to memorize, acquire, and retain new information, recall of names, and avoidance of distraction once set on a course of action, diminishes with advancing age, particularly in those older than 70 years of age. Moreover, memory function may be disturbed in this way despite the relative retention of other intellectual abilities. Characteristically, there is difficulty with recall of a name or the specific date of an experience ("episodic" memory) despite a preservation of memory for the experience itself or for the many features of a person whose name is momentarily elusive ("tip-of-the-tongue syndrome"). Also characteristic is an inconsistent retrieval of the lost name or information at a later date. It has been found, however, that if older persons are allowed to learn new material very well, until no errors are made, they forget this information at a rate similar to that of younger individuals.
Kral, who first wrote informatively on this type of memory disturbance 50 years ago, referred to it as benign senescent forgetfulness. He pointed out that such a memory disturbance, in distinction to that of Alzheimer disease, worsens very little or not at all over a period of many years and does not interfere significantly with the person's work performance or activities of daily living. Crook and coworkers have refined the diagnostic criteria for senescent forgetfulness and have proposed a new term—age-associated memory impairment (AAMI). The diagnostic criteria for AAMI include age of 50 years or older, a subjective sense of decline in memory, impaired performance on standard tests of memory function (at least one SD below the mean), and absence of any other signs of dementia. The current terminology is minimal cognitive impairment, but there has been increasing recognition that Kral's original notion of a benign condition may have been incorrect and that cognitive decline in later years may be a symptom of Alzheimer disease.
In judging the degree of cognitive decline, several abbreviated tests of mental status have been developed and are of practical value (Kokmen et al, 1991; Folstein et al) in that they can be administered in the office or at the bedside in 5 to 10 min. Repetition of spoken items, such as a series of digits, orientation as to place and time, capacity to learn and to retain several items, tests of arithmetic and calculation (concentration), and specific tests for memory (particularly tests of delayed recall or forgetfulness) distinguish the performance of normal aging persons from that of patients with Alzheimer disease (Larrabee et al). With regard to performance on the Mini-Mental Status Examination (see Table 21-6; Folstein et al), a study by Crum and associates of a large urban population indicates a median score of 19 to 20 for individuals older than age 80 years who have a fourth grade education and 27 for those with a college education (out of maximum score of 30).
The foregoing effects of age on mental abilities are extremely variable. Some 70-year-olds perform better on psychologic testing than some "normal" 20-year-olds. And a few individuals retain exceptional mental power and perform creative work until late life. Verdi, for example, composed Otello at the age of 73 and Falstaff at 79. Humboldt wrote the five volumes of his Kosmos between the ages of 76 and 89 years; Goethe produced the second part of Faust when he was more than 70 years old; Galileo, Laplace, and Sherrington continued to make scientific contributions in their eighth decades; and Picasso continued to paint in his nineties. It must be pointed out, however, that these accomplishments were essentially continuations of lines of endeavor that had been initiated in early adult life. Indeed, little that is new and original is started after the fortieth year. High intelligence, well-organized work habits, and sound judgment compensate for many of the progressive shortcomings of old age.
Personality Changes in the Aged
These are less-easily measured than cognitive functions, but certain trends are nevertheless observable and may seriously disturb the lives of aged persons and those around them. Many old people become more opinionated, repetitive, self-centered, and rigid and conservative in their thinking; the opposite qualities—undue pliancy, vacillation, and the uncritical acceptance of ideas—are observed in others. Often these changes can be recognized as exaggerations of lifelong personality traits. Elderly persons tend to become increasingly cautious; many of them seem to lack self-confidence and require a strong probability of success before undertaking certain tasks. These changes may impair their performance on psychologic testing. Kallman's studies of senescent monozygotic twins suggest that genetic factors are more important than environmental ones in molding these traits.
One of the weaknesses of studies of the aged has been the bias in selection of patients. Many of the reported observations have been made in cohorts of individuals residing in nursing homes. Studies of functionally intact old people of comparable age and living independently, such as those of Kokmen (1977) and of Benassi and their colleagues, reveal fewer deficits, consisting mainly of forgetfulness of names, smallness of pupils, restriction of convergence and upward conjugate gaze, diminished Achilles reflexes and vibratory sense in the feet, stooped posture, and impairments of balance, agility, and gait (as mentioned earlier and below).
Effects of Aging on Stance and Gait and Related Motor Impairments (See also Chap. 7)
These are among the most conspicuous manifestations of the aging process. Motor agility actually begins to decline in early adult life, even by the thirtieth year; it seems related to a gradual decrease in neuromuscular control as well as to changes in joints and other structures. The reality of this motor decrement is best appreciated by professional athletes who retire at age 35 or thereabout because their legs give out and cannot be restored to their maximal condition by training. They cannot run as well as younger athletes, even though the strength and coordination of their arms, when tested independently of other functions, are relatively preserved. More subtle and imperceptibly evolving changes in stance and gait are ubiquitous features of aging (see Chap. 7). Gradually the steps shorten, walking becomes slower, and there is a tendency to stoop. The older person becomes less confident and more cautious in walking and habitually touches the handrail in descending stairs, to prevent a misstep.
To be distinguished from the ubiquitous and subtle changes in gait of the "normal" older population is a more rapidly evolving and inordinate deterioration of gait that afflicts a small proportion of the aging population while they remain relatively competent in other ways. In all likelihood, this latter disorder represents an age-linked degenerative disease of the brain, as most instances of it are sooner or later accompanied by mental changes. The basis of this gait disorder is probably a combined frontal lobe–basal ganglionic degeneration, the anatomy of which has never been fully clarified, as discussed in "Frontal Lobe Disorder of Gait" in Chap. 7. However, in many of such patients we have observed, there is no disproportionate atrophy or reduction of blood flow in the frontal lobes, making the cause of the gait disorder obscure. It has also been postulated that age-related changes in the substantia nigra are the cause of the parkinsonian appearance of the gait of the aged, but it does not respond to l-dopa or to any other therapeutic measure. The main differential diagnostic consideration is normal-pressure hydrocephalus, correctable by a ventriculoperitoneal shunt, which accounts for the gait disorder of a sizable group of these elderly patients, as discussed in Chaps. 7 and 30. Parkinson disease is yet another potentially treatable cause of walking difficulty. Progressive supranuclear palsy is a degenerative process in which gait and stability are affected early and profoundly.
Urinary incontinence, defined as a state in which "involuntary loss of urine is a social or hygienic problem and is objectively demonstrated," is a common occurrence in the elderly (Wells and Diokno). Doubtless this complex of motor impairments is based on the aforementioned neuronal losses in the spinal cord, cerebellum, and cerebrum.
Among elderly persons without apparent neurologic disease, falls constitute a major health problem. Approximately 30 percent suffer one or more falls each year; this figure rises to 40 percent among those older than age 80 years and to more than 50 percent among elderly persons living in nursing homes. According to Tinetti and colleagues, 10 to 15 percent of falls in the elderly result in fractures and other serious injuries; they are reportedly an underlying cause of about 9,500 deaths annually in the United States.
Several factors, some mentioned earlier in regard to deterioration of gait, are responsible for the inordinately high rate of falling among older persons. Impairment of visual function and particularly of vestibular function with normal aging are important contributors. In a group of 34 elderly patients who were free of neurologic disease, postural hypotension, and leg deformities, Weiner and colleagues found a moderate or severe degree of postural reflex impairment in two-thirds. The failure to make rapid postural adjustments, which is a product of aging alone, accounts for the occurrence of falls in the course of usual activities such as walking, changing position, or descending stairs. Orthostatic hypotension, often because of antihypertensive agents and the use of sedative drugs, is another important cause of falling in the elderly.
Of course, falling is an even more prominent feature of certain age-related neurologic diseases: stroke, Parkinson disease, normal-pressure hydrocephalus, and progressive supranuclear palsy, among others.
Other Restricted Motor Abnormalities in the Aged
These are too numerous to be more than catalogued. They reflect the many ways in which the motor system can deteriorate. Compulsive, repetitive movements are the most frequent: mouthing movements, stereotyped grimacing, protrusion of the tongue, side-to-side or to-and-fro tremor of the head, odd vocalizations such as sniffing, snorting, and bleating. In some respects these disorders resemble tics (quasivoluntary movements to relieve tension), but careful observation shows that they are not really voluntary. Haloperidol and other drugs of this class have an unpredictable therapeutic effect, seeming at times to benefit the patient only by the superimposition of a drug-induced rigidity and are not recommended.
Old age is thought always to carry a liability to tremulousness, and indeed, one sees this association with some frequency. The head, chin, or hands tremble and the voice quavers, yet there is not the usual slowness and poverty of movement, facial impassivity, or flexed posture that would stamp the condition as parkinsonian. Some instances of tremor are clearly familial, having appeared or worsened only late in life. However, the relation of tremulousness to aging is sometimes open to doubt. Charcot, in a review of over 2,000 elderly inhabitants of the Salpêtrière Hospital, could find only about 30 with tremor. Some cases probably represent the exaggeration or emergence of essential tremor, but many cases cannot be explained on this basis.
Spastic or spasmodic dysphonia, a disorder of middle and late life characterized by spasm of all the throat muscles on attempted speech, is discussed in Chap. 6.
Morphologic and Physiologic Changes in the Aging Nervous System
These have never been fully established. From the third decade of life to the beginning of the tenth decade, the average decline in weight of the male brain is from 1,394 to 1,161 g, a loss of 233 g. The pace of this change, very gradual at first, accelerates during the sixth or seventh decades. The loss of brain weight, which correlates roughly with enlargement of the lateral ventricles and widening of the sulci, is presumably the result of neuronal degeneration and replacement gliosis. The counting of cerebrocortical neurons is fraught with technical difficulties, even with the use of computer-assisted automated techniques (see the critical review of neuron-counting studies by Coleman and Flood). Most studies, point to a depletion of the neuronal population in the neocortex, especially evident in the seventh, eighth, and ninth decades.
Cell loss in the limbic system (hippocampus, parahippocampal, and cingulate gyri) is of special interest in regard to memory. Ball, who measured the neuronal loss in the hippocampus, recorded a linear decrease of 27 percent between 45 and 95 years of age. Dam reported a similar degree of cell loss and replacement gliosis. These changes seem to proceed without relationship to Alzheimer neurofibrillary changes and senile plaques (Kemper). However, more recent morphologic work, summarized by Morrison and Hof, suggests that cerebral cell loss with aging is less pronounced than previously thought. Furthermore, as pointed out by Morrison, the hippocampus may have only minimal cell loss. Moreover, this is partially a result of neurogenesis in this region. Brain shrinkage is accounted for in part by the reduction in size of large neurons, not their disappearance. There is a more substantial reduction in neuronal number in the substantia nigra, locus ceruleus, and basal forebrain nuclei. It may be possible to differentiate normal aging from disease in the medial temporal lobe by distinguishing between cell loss in specific regions (see Small et al), but novel techniques are required.
Mueller and colleagues employed quantitative volumetric MRI techniques to examine a cohort of 46 nondemented elderly individuals. They found small, constant rates of loss of brain volume with aging. Moreover, the rates of volume loss in the last decades of life were no greater than in the immediately preceding decades, suggesting that large changes in brain volume in the elderly are attributable to the dementing diseases common to this age period. Rusinek and colleagues found that serial MRIs of elderly persons predict which individuals will develop disproportionate atrophy and dementia. In particular, hippocampal atrophy increases at the rate of less than 2 percent per year in healthy elderly people, in comparison to 4 to 8 percent a year in early Alzheimer disease. This longitudinal method of study is more sensitive than cross-sectional population studies.
Among lumbosacral anterior horn cells, sensory ganglion cells, and putaminal and Purkinje cells, neuronal loss amounts to at most 25 percent between youth and old age. Not all neuronal groups are equally susceptible. For example, the locus ceruleus and substantia nigra, as already commented, lose approximately 35 percent of their neurons, whereas the vestibular nuclei and inferior olives maintain a fairly constant number of cells throughout life. A very subtle loss, decade by decade, of the major systems of nerve cells and myelinated fibers of the spinal cord was demonstrated by Morrison. This accelerates after the age of 60 (Tomlinson and Irving).
As described earlier in normal aging, there is a gradual decline in memory and in some cognitive functions. In light of the studies just summarized, it is no longer considered that these changes can be ascribed simply to neuronal loss. Rather, they are probably caused, at least in part, by alterations in synaptic connectivity within critical cortical structures.
Scheibel and coworkers have described a loss of neuronal dendrites in the aging brain, particularly the horizontal dendrites of the third and fifth layers of the neocortex. However, the Golgi method, which was used in these studies, is difficult to interpret because of artifacts. The morphometric studies of Buell and Coleman showed that the surviving neurons actually exhibit expanded dendritic trees, suggesting that even aging neurons have the capacity to react to cell loss by developing new synapses. With advancing age, there is an increasing tendency for neuritic (amyloid and neurofibrillary) plaques to appear in the brains of nondemented individuals. At first the plaques appear in the hippocampus and parahippocampus, but later they become more widespread. These are loose aggregates of amorphous argentophilic material containing amyloid. They occur in increasing numbers with advancing age; by the end of the ninth decade of life, few brains are without them. However, as shown by Tomlinson and colleagues, relatively fewer plaques are present in the brains of mentally intact old people, in contrast to the large numbers in those with Alzheimer disease. Even more impressive is the correlation of neurofibrillary tangles and Alzheimer disease. Very few such tangles are found in the brains of mentally sound individuals, and those that are found are essentially confined to the hippocampus and adjacent entorhinal cortex. By contrast, neurofibrillary tangles are far more abundant and diffusely distributed in patients with Alzheimer disease.
The view is often expressed that neuritic plaques and Alzheimer type of neurofibrillary changes simply represent an acceleration of the natural aging process in the brain. Most investigators are more inclined to the idea that the plaques and neurofibrillary changes represent an acquired age-linked disease, analogous in this respect to certain cerebrovascular diseases or osteoarthritis. In support of this latter view are several observations. First, Homo sapiens is the only animal species in which Alzheimer neurofibrillary changes and neuritic plaques are regularly found in the aging brain. A few plaque-like structures (but no neurofibrillary changes) have been seen occasionally in old dogs and monkeys but not in mice or rats. It seems unbiologic that human aging should differ from that of all other animal species. Second, some of the most severe forms of Alzheimer disease occur in middle adult life, long before old age. Third, these histopathologic changes in variable proportion occur in a number of other diseases unrelated to aging, such as dementia pugilistica ("punch-drunk" state), Down syndrome, postencephalitic Parkinson disease, and progressive supranuclear palsy. Fourth, neurofibrillary tangles can be reproduced in the experimental animal by such toxins as aluminum, vincristine, vinblastine, and colchicine. Finally, a small proportion of Alzheimer cases are definitely familial, as described in Chap. 39.
Virtually every molecular structure within the cell is subject to age-related biochemical modifications, such as the formation of carbonyl proteins, glycation of sugars, and oxidative changes in lipids. Some of these subcellular phenomena contribute to the aging process (see Mrak et al for details), as do the accumulation of mitochondrial DNA mutations and shortened lengths of the telomeres. Among the visible biochemical alterations is an increasing accumulation of lipofuscin granules in the cytoplasm of neurons, sometimes extreme in degree. Also, there is an age-related neuronal accumulation of iron and other pigment bodies. Granulovacuolar changes are a regular finding in aging hippocampi, regardless of the mental state of the individual. The accumulation of glycogen-containing concretions (corpora amylacea) around nerve roots and diffusely in the subpial space is yet another aging effect, which has no known clinical correlate.
Cerebral atherosclerosis is, of course, a frequent finding in the elderly, but it does not parallel aging with any degree of precision, being severe in some 30- to 40-year-old individuals and practically absent in some octogenarians. In the normotensive individual, it tends to occur in scattered, discrete plaques mostly in the aorta and cervical arteries (carotid bifurcation and higher segments), proximal middle cerebral arteries, and at the vertebrobasilar junction and basilar portions of the cerebral arterial system. In the hypertensive and diabetic, it is more diffuse and extends into finer branches of the cerebral and cerebellar arteries. One or more cerebral infarcts are found in approximately 25 percent of all individuals older than 70 years of age who were carefully examined postmortem. In addition to atherosclerotic disease, the basilar arteries become somewhat larger and more tortuous and opaque in the elderly.
Cerebral blood flow has been extensively investigated in the elderly population. Most studies show that flow declines with age and that the cerebral metabolic rate declines in parallel. There is also an age-related increase in cerebrovascular resistance. Declines in flow are somewhat greater in the cortex than in white matter and greater in prefrontal regions than in other parts of the hemispheres. Obrist demonstrated a 28 percent reduction in cerebral flow by age 80. It is noteworthy, however, that every cohort of elderly persons tested in this way contained a significant proportion in which cerebral blood flow was equivalent to that in young control subjects. In fact, in a group of 72-year-old men rigorously selected on the basis of freedom from disease, Sokoloff demonstrated that cerebral blood flow and oxygen consumption did not differ from those of normal men 22 years of age. Nevertheless, cerebral glucose metabolism was reduced in all the elderly subjects.
With advancing age there is a general tendency for the electroencephalogram (EEG) to show a slowing of the alpha rhythm, an increase in beta activity, a decline in the percentage of slow-wave sleep, and an increasing intrusion of theta rhythms, particularly over the temporal lobes, although there are large individual differences.
With respect to the neurotransmitters, it is generally agreed that the concentrations of acetylcholine, norepinephrine, and dopamine decline in the course of normal aging. Also, the concentration of gamma-aminobutyric acid (GABA) has been shown to decline with age, particularly in the frontal cortex (Spokes et al). Analyses of postmortem human and animal brains have failed to demonstrate a decline with age in the concentration of serotonin or its metabolites (McEntee and Crook). Accurate assessment of other neurotransmitters has been more difficult because of their marked lability in postmortem material. Data from experiments in rats suggest that the glutamate content of the brain and the number of N-methyl-D-aspartate (NMDA) receptors diminish with age, but the functional significance of this finding is unclear. Unlike the case in Alzheimer disease, normal aging is associated with only slight and inconsistent abnormalities of cholinergic innervation of the hippocampus and cortex. This is true also of the acetylcholine content and the activity of choline acetyltransferase (the synthesizing enzyme of acetylcholine) in these regions and the number of cholinergic neurons in the nucleus basalis of Meynert (substantia innominata) and other nuclei of the basal forebrain (Decker). Again, the significance of these changes is difficult to judge. They probably reflect the depletion of cells that occurs with aging. The topics of cholinergic and glutamatergic function in the aging brain have been critically reviewed by McEntee and Crook.
Aging Changes in Muscles and Nerves
With advancing age, skeletal muscles lose cells (fibers) and undergo a gradual reduction in their weight more or less parallel to that of the brain. Atrophy of muscles and diminution in peak power and endurance are clinical expressions of these changes. Many processes contribute to this age-dependent loss of lean muscle mass, described as sarcopenia. These include decreased physical activity; diminished appetite associated with loss of smell and elevated levels of cholecystokinin, a satiety hormone; other endocrine changes such as diminished levels of growth hormone and androgens; and (as in the brain) the accumulation of subcellular defects such as nuclear and mitochondrial DNA mutations alluded to earlier. Moreover, with aging, the slow loss of motor neurons contributes to a component of denervation atrophy. Our own observations, with Dr. R.D. Adams, of neuropathologic material indicate that the wasting involves several processes, some principally myopathic and others relating to disuse or denervation from loss of motor neurons. In this material, denervation atrophy of the gastrocnemius muscles was found in 80 percent of individuals older than 70 years of age. The lost muscle fibers are gradually replaced by endomysial connective tissue and fat cells. The surviving fibers are generally thinner than normal (possibly because of disuse atrophy), but some enlarge, resulting in a wider-than-normal range of fiber size. Groups of fibers all at the same stage of atrophy undoubtedly relate to loss of motor innervation. The reduction in conduction velocity and decrease in amplitude of motor nerve potentials and, to a greater extent, of sensory nerves in the aged may be taken as other indices of loss of motor and sensory axons. All these changes are more marked in the legs than elsewhere. However, when Roos and colleagues examined the contractile speed and firing rates of the quadriceps muscle in young men and compared them to those of men close to 80 years old, they found little difference despite a 50 percent reduction in the maximum voluntary contraction force developed by the muscle in the older men.
It has been repeatedly observed that age is an important prognostic factor in a large number of human diseases. This effect is very evident, for example, in the markedly slower and less-complete recovery from Guillain-Barré polyneuropathy in older age groups compared with younger ones. One presumes that the structural changes of aging in peripheral nerves limit the degree of myelin regeneration and lower the threshold for failure of electrical transmission.