Recent advances in basic aging research on the nervous system in Japan

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Archives of Gerontology and Geriatrics 19 (1994) 123-133

ARCHIVES OF GERONTOLOGY AND GERIATRICS

Recent advances in basic aging research on the nervous system in Japan Kenro Kanda Laboratory of Central Nervous System. Tokyo Metropolitan Institute of Gerontology. 35-2. Sakaecho. Itabashi-ku. Tokyo 173. Japan

Abstract Recent studies on aging of the nervous system are reviewed with special reference to neuronal cell death, compensatory reaction, trophic factors, brain cholinergic systems and the autonomic nervous system. Studies on spinal motoneurons labeled with a tracer substance transported retrogradely demonstrated differential age effect on different types. Compensatory reactions were also seen among surviving motoneurons. Motoneuronal survival appears to be correlated with the amount of activity. However, the causal relationship between them is not yet conclusive. The effects of nerve growth factor on sympathetic and dorsal-root ganglion cells seem to be well preserved in the aged, although there are some controversial findings on the ratio of NGF-dependent neurons versus NGF-independent neurons. It has been shown that acidic fibroblast growth factor or other substances may prevent degeneration of the basal forebrain cholinergic neurons and improve memory and learning performance in aged animals. The cholinergic system also regulates the regional cerebral blood flow, and this function seems to be well maintained in aged rats. Microneurography techniques have revealed increased activity of postganglionic sympathetic nerves innervating muscles in aged human subjects. The activity of preganglionic sympathetic nerves innervating the adrenal gland and the secretion rate of noradrenaline have been shown to increase in the aged rat. These changes might cause high blood pressure in the aged, although some species differences have been noted between humans and rats. Keywords: Neuronal loss; Plasticity; Trophic factor; Cholinergic syslem; Autonomic nervous system; Aging

1. Introduction Neuronal loss is a major manifestation o f nervous system aging, and has been investigated extensively (Flood and Coleman, 1988). A decrease in the number of neu0167-4943/94/$07.00 © 1994 Elsevier Science Ireland Ltd. All rights reserved SSD! 0167-4943(94)00582-R

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rons is considered to be a main cause of functional deficits of the nervous systems under both normal and pathological conditions. It is now generally accepted that the extent of cell loss in the central and peripheral nervous systems varies greatly among different types of neurons and among different regions of the brain. Differences among species have also been reported. Elucidating the underlying mechanisms that cause the differential effects of aging among different types of neurons may provide new insight into the general mechanisms of nervous-system aging. However, estimating the exact number of neurons is not an easy task for a number of reasons. Accordingly, new methods should be developed and data should be correlated with the physiological and biochemical nature of the neurons concerned. As is well known, the nervous system does not replace neurons, whether lost by injury, disease, or the normal aging process. Neurons, however, can undergo a change in their signal-transmission efficacy through alteration of their number of synapses, receptor density, etc. Some surviving neurons in the aged brain actually show longer and more numerous dendritic arborizations than those in the young brain; such changes appear to compensate for functions lost by neuronal dropout during aging (Buell and Coleman, 1979). Such capability persists up to at least a certain age in the course of senescence. Thus, the aging brain consists of a mixture of dying neurons and neurons with expanded functions. A group of protein molecules known as trophic factors play important roles in the processes of cell survival, differentiation, and regeneration (Barde, 1989). Alterations in the synthesis and activity of the trophic factors with age are obviously very important areas of study in research on aging. The cholinergic neurons located in the basal forebrain nuclei have wide projections to the cerebral cortex and the hippocampus (Lehmann et al., 1980; Mesulam et al., 1983; Saper, 1984). Many findings in human and animal experiments suggest that the cholinergic system plays an important role in memory and learning (Fibiger, 1991). A decline in the functions of the brain cholinergic system and a concomitant ~'!'~ali~c io memory and learning capacity have been reported in the aged (Fischer et al., 1992). Pronounced deficits have been found in patients with Alzheimer's disease (Fibiger, 1991). Moreover, it has been revealed recently that the cholinergic system regulates the regional cerebral blood flow (Sato and Sato, 1992). Age-related changes of these systems deserve further studies to clarify the normal and pathological alter,~tions in the aging brain. Homeostasis is essential for life, and depends greatly on the autonomic nervous system. One aspect of aging might be a loss of the capacity to maintain homeostasis. The decline in autonomic functions that occurs with advancing age is generally considered to be the cause of many age-related diseases. Therefore, an important area to investigate is changes in the function of the autonomic nervous system with age. Finally, in this review article, ! have not intended to cover all of the literature related to nervous-system aging, but rather to survey a limited number of studies summarized under four categories. Studies related to Aizheimer's disease and to Parkinson's disease, and most of the neurochemical and behavioral investigations, were omitted from this review.

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2. Neuronal cell loss The number of neurons in a specific region or nucleus of the central nervous system has usually been estimated from the density of neurons in the histological sections. However, some neurons are split and are present in two adjacent sections; hence, a correction method such as Arbercrombie's procedure must be used. The size, shape, and orientation of the cell should be taken into account to use this method properly, which is not an easy task. Differentiating between neurons and glia cells is also sometimes difficult. Furthermore, to compare the number of neurons in a young brain with that in an old brain, one needs to know the volume of the specified region or nucleus in the young brain and its exact counterpart in the old brain. The borders of such a region are not usually clear, and atrophy increases the difficulty further. Hashizume et ai. (1988) have studied age-related changes in the number and size of defined motoneurons in the rat, using retrograde transport of horseradish peroxidase (HRP) (see also Ishihara et al., 1987; lshihara and Taguchi, 1993). They injected a small amount of H R P solution into the peripheral nerve, and labeled motoneurons innervating a particular muscle or a group of muscles (i.e. motoneurons belonging to a particular motor nucleus or nuclei). Each individual neuron was identified under a microscope with the aid of photomontages obtained from each serial section. Although some caution is needed, this method has the clear advantage of allowing the absolute size of a specific group of neurons to be obtained directly without the use of any correction methods. With labeled medial gastrocnemius (MG) motoneurons, the number seemed to remain constant until a certain age (probably 20-22 months old), and decreased thereafter. The average soma diameter in each MG nucleus was distributed bimodally with a clear boundary. Motoneurons could be divided into two groups with respect to soma size: large cells, which presumably were alpha-motoneurons, and smaller cells, which presumably were gamma-motoneurons. The mean number of cells presumed to be alpha-motoneurons was significantly less in the old (27 months) and very old (31 months) groups as compared to the young (7 months) and middle-aged (12 months) rats. In contrast, the number of cells presumed to be 7-motoneurons was similar across all of the age groups. These researchers concluded that there is a significant decrease in the absolute number of motoneurons in rats aged 27 months and older, with most of the decrease occurring among the larger alpha-motoneurons. However, the effects of aging on alpha-motoneurons seems to be different in different motor nuclei. No significant difference was found between the mean number of ulnar motoneurons of the forelimb in young (9-month-old) and aged (27-month-old) rats, whereas the mean number of medial gastrocnemius motoneurons of the hindlimb was significantly lower in aged rats than in young rats (Hashizume and Kanda, 1990). These findings agree with the observations that an age-related decline in force output and changes in the histochemicai profile are greater for hindlimb muscles than for forelimb muscles (Grimby et al., 1982; Nygaard and Sanchez, 1982; McDonagh et al., 1984). A study on the mechanical properties of individual motor units in aged rats suggested

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that age-related degenerative changes were greater for fast-twitch motor units (type FF and FR units) than slow-twitch units (type S units), and thus neuronal death might occur preferentially among the motoneurons belonging to fast-twitch units (Kanda and Hashizume, 1989). All of these findings suggest that age-related changes vary in terms of the magnitude and/or rate and time of progression among different types of neuron, and even within the motoneurons themselves. As described above, gamma-motoneurons are smaller than a-motoneurons. Motoneurons belonging to type S motor units tend to be smaller than those belonging to type FF and FR motor units, although a large overlap in size exists. Thus, the findings are in good agreement with the general notion that larger neurons preferentially dropout with advancing age. It is also of interest that the amount of activity is probably highest for gamma-motoneurons, intermediate for motoneurons belonging to type S motor units, and lowest for motoneurons belonging to type FF motor units. Motoneurons innervating the arm and hand muscles are probably more active than those innervating the hindlimb muscles. Furthermore, Hashizume and Kanda (1993) showed that long-term swimming exercise retarded the loss of motoneurons innervating the rat hindlimb muscle (see also Ishihara and Taguchi, 1993). Thus, these findings are in agreement with the notion of 'use it, or lose it' (Swaab, 1991). However, a causal relationship between the amount of daily activity and neuron survival has not yet been defined clearly for motoneuronal dropout in the aged. Neuronal loss in the hippocampus may cause serious problems since this brain structure is known to play an important role in memory processes. In general, memory and learning ability decline with advancing age. It has been reported that the adrenocortical hormones are deeply involved in mechanisms of both cell death and cell survival in the hippocampus (Gould and McEwen, 1993). Sapolsky et al. (1985) proposed that increased levels of plasma corticosterone cause hippocampal neuron death in aged rats. Mizoguchi et al. (1992) demonstrated that an increased blood corticosterone level induced by stress causes neuronal loss in the hippocampal CA3 and CA4 region of castrated rats, and that this neuronal loss was prevented by the administration of testosterone. This suggests that in the aged, a hypogonadal condition may be a risk factor for neuronal loss. However, changes in the function of the hypothalamo-pituitary-adrenal axis seem to be a matter of controversy. Tsuchiya et ai. (1992) investigated the effects of somatic sensory stimulation on plasma corticosterone in anesthetized rats, and found that the basal level and response to nociceptive mechanical stimulation remained unchanged in aged subjects.

3. Compensatory reaction and trophlc factors Some motor units in aged rats have been shown to produce very large tetanic tension compared with those in middle-aged rats (Kanda et al., 1986; Kanda and Hashizume, 1989). Such motor units have been found preferentially among the type S units. Several items of physiological and morphological evidence have suggested that those large units acquired extra fibers that were once denervated. This acquisition seems to lessen the decrease in force output caused by motoneuronal death, and

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can be considered as a compensatory reaction. The compensation is not perlect, however, because the contractile properties of the newly acquired muscle fiber may be altered (e.g. transformation from fast-twitch to slow-twitch fibers), and because all of the denervated fibers are not necessarily recaptured. Expansions of motor units might also cause muscle force to be controlled less precisely. The average regeneration rate of axons after injury slows with advancing age (Seheff et al., 1978; Pestronk et al., 1980; Tanaka and Webster, 1991). To recover its function, the regenerating axon has to recognize exact target cells precisely, and to form functioning synapses with them. Little is known about the capacity of the nervous system to restore actual function in the aged (Anderson et al., 1986). The potential capacity of aged motoneurons to reconstruct motor-units after a crushednerve injury was studied in the medial gastrocnemius muscle of male Fischer rats (Kanda and Hashizume, 1991). After a 3-month recovery period, the three different types of normal motor-unit organization were restored in the muscles of middle-aged (! 1 months old) and aged (28 months old) reinnervated muscles as measured by their relative distributions, mean twitch contraction times and mean tetanic tension. Some reinnervated units in both aged and middle-aged rats produced a large tetanic tension that exceeded the range for the intact units. These findings indicate that aged motoneurons maintain their ability to perform axonal regeneration and muscle fiber innervation, allowing them to reestablish normal motor-unit functioning. Neuronal cell survival as well as the compensatory reaction by sprouting collateral branches or axon regeneration depends on the supply of trophic factors from adjacent tissues and/or the responsiveness of the neuron itself to these factors. Using serum-free culture techniques, Fukuda et al. (1985, 1991) demonstrated that sympathetic nerve cells and trigeminal ganglion cells isolated from aged subjects, ineluding humans and shrews, were dependent on NGF in terms of the outgrowth and regeneration of neurites (see also Fukuda and Yamaguchi, 1981, 1982). The dependence of these cells on the NGF seems to alter with age, since the nerve cells of embryonic and newborn animals are regarded as totally dependent on NGF, and some cells in senescent animals appear to be independent. The possibility that non-neural cells growing in explants may release NGF or NGF-like substances cannot be excluded even if a serum-fi-ee culture medium is used. ltoh et al. (1993) investigated the dependency of dorsal root ganglion sensory cells on NGF using a single-neuron culture method, and confirmed the dependency of neurite growth on NGF. NGF significantly enhanced the number of branching points, total neurite length, and soma size in aged neurons. These effects of NGF on neurite geometry tended to be reduced in aged neurons compared with young adult neurons, but were well preserved. NGF, however, did not increase the proportion of process-bearing neurons in aged rats, indicating that neuronal survival was not promoted by NGF. The NGFresponsive subpopulation of neurons, found across the entire range of neuronal size, were preserved in aged rats in contrast to the observations of Fukuda's experiments, in which higher levels of NGF-independent neurons were found in aged neurons. The cause of the difference between these two results is obscure. In vivo experiments using chronic injection of NGF into the rat basal forebrain region improved performance by aged rats in spatial memory tests and increased the

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soma size of cholinergic neurons in the basal forebrain nucleus (Fischer et al., 1987). The effect of NGF on neuronal survival after axotomy has been demonstrated in the medial septum of the adult rat (Hefti, 1986; Williams et al., 1986; Kromer, 1987). Hayashi (1993) investigated the brain-derived neurotrophic factor (BDNF) mRNA levels in the brain of the macaque monkey using northern blot analysis, and found BDNF mRNA to be widely expressed in the brain. Levels of BDNF mRNA were decreased by 40%-60% in the hippocampus, frontal cortex, temporal cortex, motor cortex, somatosensory cortex and visual cortex of old monkeys ( > 30 years old) compared with those of young monkeys (2 and 10 years old). However, the relationship between naturally occurring neuronal death with advancing age and deficiency of neurotrophic factor(s) remains to be clarified at present. The sensitivity of neurons to trophic factor(s) and the mode of action by which trophic factor(s) affect neurons may change with age. In this respect, it is important to study the alteration of the receptors for these trophic factors. Yamamoto et al. (1993) studied the gene expression of NGF receptors in sympathetic and dorsal root ganglia of adult and aged human subjects. While high-affinity NGF receptor mRNA was expressed only in the sympathetic and dorsal root ganglia, low-affinity NGF receptor mRNA was found not only through the peripheral nervous system, but also in non-neural tissues. This expression was well preserved in the aged. Findings by Kanda and Hashizume (1989) do not seem to support the notion that lack of the trophic factor which is released from muscle fiber and transported retrogradely causes motoneuronal death. Judging from the distribution of tetanic tension produced by individual motor units in aged rats, they found that the loss of innervating muscle fibers (i.e. a decrease in size of motor-units) seemed to be small, and the decline in tetanic tension could be explained mostly by atrophy of individual muscle fibers. These findings do not, of course, exclude the importance of the trophic factors for the survival of motoneurons in the aging spinal cord. The roles played by the trophic factors, which are transported anterogradely or produced by other neurons or glia cells located adjacent to soma, deserve further study.

4. Basal forebrain chofinergic systems There is an accumulation of evidence from rat and mouse (SAM-P/8) studies suggesting that impairment of memory and learning capacity in the aged is due to a decline in the function of the cholinergic system (Ohta et al., 1991; Ikegami et al., 1992). In aged rats, intraperitoneal administration of dihydroergotoxine increased choline acetyltransferase activity and also the number of muscarinic cholinergic binding sites. This treatment also markedly improved learning impairment, as assessed by an operant-type brightness discrimination learning test (Ogawa et al., 1993). It has been shown that a cholecystokinin analog, SUT-8701 (Takahashi et al., 1993), and some of the hematopoietic factors (Konishi et al., 1993) act on cholinergic neurons to prevent degeneration. Acidic fibroblast growth factor (aFGF) has been reported to improve learning and memory ability of mice. Studies by Sasaki et al. (1993) suggest that long-term (9-month) administration of aFGF prevents the deterioration of learning and memory capability in senescence-accelerated mice (SAM-

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P/8) in passive avoidance and Morris water-maze tasks. The number of choline acethyltransferase positive neurons in the medial septai regions and the density of muscarinic and N-methyl-D-aspartate receptors in the hippocampus were significantly higher in aFGF-treated mice than in control mice. Tanaka and Ando (1990) investigated changes in synaptic function with age using synaptosome obtained from the mouse cortex. The data suggest that synthesis of acetylcholine in the presynaptic terminals does not decrease with age. Release of acetylcholine from synaptosomes in response to high-potassium solution, however, decreased by 30% in 24-month-old rats, although spontaneous release did not alter. Membrane potential, which was measured by a chemical method, was lower for the synaptosome obtained from 27-month-old mice than that from younger mice. This seemed to be due to decreased Na+,K+-ATPase activity. Another role of the basal forebrain cholinergic systems in the brain has been disclosed recently (Sato and Sato, 1992). Electrical or chemical stimulation of the nucleus basalis of Meynert (NBM) or the medial septal and Broca's diagonal band regions increases regional cerebral blood flow. This effect is independent of that of local metabolites, and is diminished greatly by muscarinic and nicotinic antagonists, such as atropine and mecamylamine. Furthermore, it has been suggested that NO is involved in this effect. Although there are some conflicting reports (Linviile and Arneric, 1991), increases in ACh release and cerebral blood flow in the parietal cortex and hippocampus produced by focal stimulation of the NBM or the septal complex have been found to be well maintained in aged rats (Kurosawa and Sato, 1989). 5. Autonomic nervous system

The systemic blood pressure, especially systolic pressure, tends to elevate with advancing age; the main reasons are believed to be declining elasticity of the arterial wall and increasing basal activity of the sympathetic nervous system. The plasma level of norepinephrine, which is released from postganglionic sympathetic nerve terminals and the adrenal medulla, increases with advancing age. lwase et al. (1991) used microneurography techniques to investigate muscle sympathetic nerve activity, which plays an important role in the control of systemic blood pressure, in human subjects aged from 18 to 75 years, and demonstrated directly that the resting sympathetic tone in the supine position increased with age. Kurosawa et al. (1988) measured the secretion rate of norepinephrine from the adrenal gland in both young adult and aged, anesthetized rats. For this purpose, they inserted a thin polyethylene tube into an adrenal vein and collected a small amount of adrenal blood. The average secretion rate of noradrenaline increased after 300 days of age, although there was a great deal of variation arnor.g individual rats. These researchers also recorded the activity of the preganglionic sympathetic nerves innervating the adrenal gland, and found that ongoing activity in an anesthetized and resting state increased drastically between 300 and 400 days of age; thereafter, a high discharge rate was maintained up to 900 days of age. Thus, increased sympathetic activity induces augmentation of the secretion rate of noradrenaline and elevates its systemic plasma level, which in turn leads to vasoconstriction. In the rat, however, the systemic blood

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pressure remained unchanged up to a very old age, even though the plasma level of noradrenaline increased with age. This is probably due to a decline in the sensitivity of blood vessels to noradrenaline in aged rats. The muscle sympathetic nerve activity increases when the longitudinal axis of the body changes from a supine to an upright position. This change is produced by the baroreceptor reflex to maintain a constant blood pressure. The effects of aging on this response were investigated in humans by lwase et al. (1991). They found that a head-up tilt enhanced muscle sympathetic nerve activity linearly with the sine of the tilt angle, and that the increase by orthostasis was negatively correlated with age. Thus, the increase in muscle sympathetic nerve activity when the posture changes from a supine to an upright position was significantly less in aged than in young subjeers (lwase et al., 1991). This might explain the relatively greater decline in blood pressure in the aged when the posture is changed from a supine to an upright position. Reduced sensitivity of the baroreceptors in the aged has been suggested as one possible mechanism of the age-related changes in sympathetic nerve activity. Kurosawa et al. (1987) investigated the effect of elevated blood pressure, which was induced by intravenous administration of phenylephrine, on the ongoing activity of preganglionic sympathetic nerves innervating the adrenal medulla. Reflex depression of adrenal sympathetic nerve activity in response to baroreceptor stimulation was not significantly different between young adult and aged rats. it has been reported, however, that the sclerotic char~ges in rat arteries are minor compared with those of humans. Baroreceptor sensitivity may depend on the elasticity of the arterial walls where the sensory endings are located, implying that differences in age-related changes of blood vessels may cause a difference in the baroreflex between human and rats. 6. Concluding remarks A characteristic leature of the aging process is the diversity of its progress, which contrasts with that of early development. The literature on differences in aging among species, individuals, systems, organs, cells, receptors and membrane constituents is considerable, and aging of the nervous system has been equally well investigated. Some groups of neurons are more vulnerable than others. Accordingly, caution in interpreting the experimental data is required, especially when a general conclusion (or concept) is drawn. However, careful analysis of differential age effects might provide new insight into the mechanisms of nervous system aging. We should also keep in mind that the nervous system is a highly integrated system. The function of a subsystem is closely related not only to other subsystems within the nervous system, but also to the immune and the hormonal systems. The nervous system has extensive redundancy and plastic capacity. Not all neurons or systems suffer declining function; at least up to a certain age in senescence, some become more active to compensate for functions lost by the dropout of other neurons and to maintain the system's function. Plasticity, however, may have a Janus-faced effect on the aging nervous system: while dendritic growth and/or axonal arborization may have compensatory effects, aberrant sprouting of axons or dendrites may confuse

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signal processing by increasing the n u m b e r o f faulty connections. It m a y also lead to hyperactivity, which induces e x h a u s t i o n a n d eventual cell death. The m e c h a n i s m s regulating n e u r o n a l plasticity a n d their c h a n g e s with a d v a n c i n g age as well as causes o f cell d e a t h deserve f u r t h e r i n v e s t i g a t i o n in studies o n aging o f the n e r v o u s system.

Acknowledgment T h e a u t h o r t h a n k s P r o f e s s o r K. K i t a n i for his e n c o u r a g e m e n t in the writing o f this review article.

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