Sci. Aging Knowl. Environ., 23 March 2005
Vol. 2005, Issue 12, p. pe8
[DOI: 10.1126/sageke.2005.12.pe8]

PERSPECTIVES

Age-Related Neurodegenerative Changes and How They Affect the Gut

Paul R. Wade, and Pamela J. Hornby

The authors are in the Enterology Research Team at Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Spring House, PA 19477, USA. E-mail: pwade{at}prdus.jnj.com (P.R.W.); phornby{at}prdus.jnj.com (P.J.H.)

http://sageke.sciencemag.org/cgi/content/full/2005/12/pe8

Key Words: gastrointestinal tract • enteric nervous system • neurodegeneration • ganglia • caloric restriction

The Gut Has a Mind of Its Own

Even those who are unfamiliar with the physiology of the gastrointestinal (GI) tract would not be surprised to learn that the gut has a mind of its own. That general understanding is rooted in the common observations of altered GI function during various life events. What may be surprising to some is the size and complexity of the gut's own nervous system. When Langley described the autonomic nervous system (ANS), he set the part that controls the GI tract apart from the sympathetic and parasympathetic divisions and called it the "enteric nervous system" (ENS) (1). It has been estimated that the number of nerve cells in the ENS is equivalent to that in the spinal cord, so it is indeed a large nervous system.

The ganglia of the ENS are collections of nerve cells densely packed together with glial cells and devoid of connective tissue. Thus, the ENS more closely resembles central nervous system (CNS) tissue, which shares these characteristics, than other peripheral nervous structures [see, for example, (2)]. These ganglia that comprise the ENS have been called the "little brains" of the gut, because they are remotely positioned collections of sensory neurons, integrative interneurons (which connect only with other neurons, rather than with muscle or sensory cells), and motor neurons that communicate with effector tissues of the gut. These autonomic effectors include the smooth muscle of the gut wall, the epithelium lining the gut, and the vascular smooth muscle of blood vessels of the GI tract. Substantial progress has been made in our understanding of the neural circuitry and pathways by which the ENS exerts local control over GI smooth muscle contractility/relaxation and propulsion, as well as water and electrolyte absorption/secretion across the mucosal epithelium, the innermost layer of the GI tract (3). The ganglia of the ENS are located in two interconnected networks: a myenteric plexus that is situated between the two layers of intestinal smooth muscle and that primarily controls motor activity, and a submucosal plexus that is situated in connective tissue beneath the inner mucosal lining of the gut and coordinates absorption and secretomotor functions of the epithelium.

Work in the early years of the last century led Langley (4) to propose that the ENS performs its jobs in a largely autonomous manner, based primarily on the observation that parasympathetic preganglionic nerve fibers projecting from the CNS to the ENS were far outnumbered by the multitude of enteric neurons. Thus, the concept of a one-to-one connectivity between ANS preganglionic and postganglionic neurons is not the case for the gut, as it is for other visceral organs such as the heart. Therefore, Langley hypothesized that nerve-fiber terminal innervation by the vagus (a cranial nerve that is the primary parasympathetic pathway between the brain and the gut) is selective to only a few ENS neurons. These selectively innervated ganglia were then thought to coordinate activity through multiple connections to other ganglia in the ENS. This idea has been somewhat modified by the exquisite neuronal tracing studies by Powley and colleagues [reviewed in (5)] suggesting that the vagus has widespread interactions with ganglia of the ENS. However, numerous investigators have also demonstrated the autonomy of the ENS from the CNS in that motor activity and local reflexes are coordinated in GI tissue that is completely isolated from extrinsic influences. Research in neurogastroenterology over the past 20 years has helped reconcile our view of the governance of the gut by "extrinsic" (that is, CNS) and "intrinsic" (that is, ENS) pathways. In general, the CNS can override the ENS in certain situations, but for day-to-day and moment-by-moment functioning of the GI tract, the CNS provides very permissive oversight to the independent decision-making activity of the ENS.

Therefore, the focus of this Perspective will be on the neurodegenerative changes in the intrinsic innervation of the gut that are associated with aging. Less attention will be paid to the age-related changes in the extrinsic innervation of the GI tract, due primarily to the paucity of evidence to support the notion of aging-related alterations in the extrinsic innervation of the gut, although there are some exceptions with regard to the upper GI tract.

The Gut Loses Its Mind with Age

Research into the degenerative changes of the CNS have been at the forefront of neuroscience for many years; indeed, there has been great progress in the understanding of the basic neuropathology of progressive neurodegenerative disease such as Parkinsonism and Alzheimer's disease. In these devastating CNS disorders, nerve cells are lost that would be preserved in otherwise healthy individuals of an equivalent age (see Andersen Review, Trojanowski and Lee Perspective, and "Detangling Alzheimer's Disease"). This loss of neurons in the CNS is attended by life-altering, and eventually life-threatening, symptoms. Therefore, since the ENS largely has autonomy to govern the activity of the gut, age-related neurodegenerative changes within the ENS might be expected to affect the gut.

Just as certain populations of CNS neurons seem to be vulnerable to the neurodegeneration associated with aging in some people (see Thal Perspective), certain enteric neurons seem to be more susceptible to loss with age than others, and particular regions of the GI tract seem to be harder hit by neurodegeneration than others. Evidence that the number of enteric neurons declines as a matter of "normal" aging has been gathered from nearly all regions of the GI tract from esophagus to rectum and in most commonly studied purpose-bred laboratory rodents (for example, mice, rats, and guinea pigs), as well as in humans. These reports have been recently reviewed (6-8). Briefly, the overarching theme of these studies is that every region of the GI tract investigated shows an age-related loss of neurons in the myenteric and submucosal plexus in each of the species studied (including mouse, rat, guinea pig, and human). The losses range from ~20 to 25% of total myenteric neurons in the esophagus of humans and rats to as high as 40 to 60% in the small intestine and distal colon.

Whereas initial studies demonstrated the overall loss of large numbers of neurons, especially in the colon, the state of enteric neurobiology has now progressed to the point where an incredible heterogeneity of neuronal phenotypes is recognized. As noted previously, ganglia of the ENS are comprised of collections of sensory neurons, interneurons, and motor neurons. On the basis of research completed within the past two decades, it is now possible to know the functional class of an enteric neuron based on a combination of its electrophysiological and morphological properties and its particular neurochemical "coding." This holds true especially for the guinea pig small intestine [see, for example, (9)], but the knowledge is expanding to other regions of the gut in other species. It is now possible to apply this more recent, detailed knowledge to the neurodegeneration of aging in the ENS. Applying these criteria makes it clear that certain classes of enteric neurons live longer than others and that some regions of the gut are less prone to aging-related changes than others. Thus, inhibitory motor neurons that project to the smooth muscle of the gut wall may be the least labile to the aging process. These neurons use nitric oxide (NO) as a transmitter and can be visualized and quantified by immunostaining with antibodies to neuronal NO synthase (NOS) or by histochemical detection of NADPH diaphorase activity, which is displayed by nitrergic neurons. This generality holds for regions of the gut from esophagus to colon in several species [see (6, 7)], with one conflicting study specifically quantifying a decrease in NOS expression in the rat colon with increased age, indicating that these neurons may also undergo age-related degeneration in this region of the GI tract (10).

Another population that is associated with aging-related changes consists of intrinsic sensory neurons, with cell bodies in either the submucosal or myenteric ganglia, that respond to physicochemical changes. These sensory neurons have been referred to by some scientists as intrinsic primary afferent neurons (IPANs) and have a particular phenotype: (i) they have the largest cell bodies among ENS neurons; (ii) they posses multiple, large, and long processes; and (iii) most of them express one or more calcium binding proteins, such as calbindin, calretinin, and calcineurin, again depending on the species. Evidence recently reviewed (6-8) indicates that, at least in the rat and guinea pig colon, the submucosal IPANs of the gut may degenerate disproportionately compared with all other enteric neurons. Initial observations suggest that there may actually be a compensatory plasticity in the guinea pig distal colon, because while the subpopulation of IPANs in the submucosal ganglia decreases with age, IPANs in the myenteric plexus are not only preserved but also increase in relative proportion (11) (Fig. 1).



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Fig. 1. (A) A laser confocal micrograph showing a myenteric ganglion from an aging guinea pig immunostained for both calbindin (green) and neuronal NOS (red). (B) An epifluorescence micrograph showing a submucosal ganglion from a similar animal immunostained for calbindin alone. This image illustrates the accumulation of the autofluorescent "aging pigment" lipofuscin (arrows) in calbindin-immunoreactive submucosal neurons.

 
However, peculiar resistance or susceptibility to aging-associated neurodegeneration might not be unique to inhibitory motor or sensory enteric neurons (respectively). The very latest data from aged guinea pigs has revealed that the subpopulations of myenteric neurons that are immunoreactive for calretinin (CR-IR) are altered with age (12). Interestingly, although the title of the article suggests a loss of these neurons, the cells that express both CR-IR and neurofilament triplet protein (NFT) actually increased in relative proportion in the aged animals (by 40%), whereas the proportion of CR-IR/NFTneurons slightly decreased (by 6%). In guinea pigs, CR-IR/NFT+ cells are interneurons that communicate information "up" the gut (orally), whereas CR-IR/NFT cells are excitatory motor neurons that project to the longitudinal smooth muscle. Similar sparing of CR-IR neurons in human small bowel has also been observed during aging (13).

Despite these neurodegenerative changes, the gut is rather remarkable in that sufficient functional reserve capacity has been built into the ENS that it can withstand such huge losses and continue to do its job into old age. The examples of changes in subpopulations of enteric neurons that carry out particular functions cited above may be telling in terms of relating the functional changes that are more commonly observed in the aged. The fact that some neurons are spared while others are lost is not necessarily a "good news/bad news" situation, particularly if the neurons that are preserved in old age are inhibitory motor neurons and those that are lost are sensory. Loss of sensory input into local reflex pathways while preserving inhibition of smooth muscle contraction would be predicted to reduce propulsive motility, and indeed this is precisely what has been observed in the isolated colon of rats and guinea pigs (14, 15).

Does the Entire GI Tract Become Senile?

As described above, the number of enteric neurons appears to decline in nearly all regions of the GI tract during "normal" aging. There is a correlation between the loss of neurons and altered function: The greatest loss of neurons observed in senescent rodents and in aged humans occurs in the distal colon, and this is the region of the gut that clinically seems to cause the most difficulties.

Evidence from studies of the upper GI tract supports the idea that sensory, rather than motor, pathways are more susceptible to changes in aging. Dysphagia (difficulty in swallowing) occurs with higher frequency in the elderly as compared with younger people. A protective mechanism preventing aspiration is the contraction of the upper esophageal sphincter (UES). This contraction can be reproducibly stimulated in patients by a pulse of air to the larynx, a reflex termed the laryngo-UES contractile reflex. Kawamura and colleagues (16) have shown that the frequency with which this reflex can be elicited decreases with age, although the magnitude of the change in UES pressure remains unchanged. This is consistent with a reduced sensory function on the sensory limb of the reflex in aged patients, rather than a motor deficit (16). Further support for the idea that the motor functions of the esophagus are not generally compromised in the aged population recently has been reviewed (17).

Aging does not seem to compromise the ability of the lower esophageal sphincter to retain a pressure barrier to reflux of acid from the stomach (18). Specifically, clinical studies have shown that lower esophageal sphincter resting pressure and relaxation, as well as esophageal peristalsis (waves of contraction passing through the esophagus), are not different in elderly and younger patients (19). However, although the number of gastroesophageal reflux episodes does not differ in elderly or younger patients, the duration of gastroesophageal reflux episodes was found to be longer in the older volunteers (20). The clearance of gastric contents from the esophagus following reflux is accomplished primarily by swallowing. This reflex may be triggered in response to the (subliminal) sensation of acid or mechanical stimulation in the esophagus. Healthy older persons have impaired clearance of refluxed materials associated with a high incidence of defective esophageal peristalsis (20). Hence, impaired sensory information from the esophagus may result in a longer duration of acid exposure and may contribute to the higher severity of reflux esophagitis (heart burn) in the elderly patient.

In addition to the "little" brain in the gut, the "big" brain governs reflex coordinated activity of the upper gut, especially the stomach. As mentioned above, the major pathway between the brain and the gut is the tenth cranial nerve, the vagus. This nerve comprises approximately four times as many sensory as motor fibers (21). In aged rats, an intriguing observation made was that cell loss in the myenteric plexus associated with aging in the stomach was correlated with the density of vagal innervation in the same region (22). It seems that the greater the density of vagal extrinsic innervation, the greater the myenteric neuron survival. However, the factors associated with vagal innervation and their potential protective effect on myenteric neurons from age-related attrition is unknown (22).

In one of the most recent reports from clinical investigation, gastric emptying, frequency of antral contractions (the pyloric antrum is the portion of the stomach closest to the duodenum), small-bowel transit, and colonic propulsive motility were assessed in aged (mean age 81 years) and in much younger adults (mean age 24 years) (23). Using state-of-the-art repetitive gamma-camera imaging after the oral administration of radiolabeled liquid and solid meals, only colonic function was significantly altered in the aged as compared with younger adults. The difference was not subtle: Mean colonic transit time was 66 hours in the elderly versus 39 hours in their younger counterparts. This elegant study underscores a problem that seems to be one of the most prevalent age-related changes in GI function, namely the development of chronic constipation. Indeed, 80% of the elderly who are in extended-care facilities and nursing homes complain of constipation (24). Chronic constipation is a quality-of-life issue for many of the aged population but is typically not a life-threatening disorder. Despite this, individuals can sometimes progress to fecal impaction, incontinence of liquid stool that passes around the impaction, and tremendous morbidity. Although the results are increased health-care costs and morbidity, there are as yet few effective medical therapies for these individuals.

Maintaining Good Enteric Mental Health in Old Age: Future Directions

In summary, two remarkable, if incongruous, observations are the following: (i) it is not unusual in most mammalian species studied, including humans, for the ENS to undergo significant age-related neurodegeneration (for example, up to 60% loss of neurons; see above); and (ii) GI function does not seem to be so radically altered in advanced age that it becomes a fatal condition. However, these overarching observations need to be viewed more closely in light of the fact that, until recently, the "neurogastroenterology of aging" was a niche of science sporadically visited and typified by descriptions of the neuroanatomical differences in the ENS that were observed between young adult and aged or senescent adult animals. Recently there seems to be increased interest in the field, undoubtedly reflective of the coming "epidemic" of old age--occurring because the fastest growing segment of the worldwide population is that of the "oldest old," those aged 85 years and older.

To date, caloric restriction (CR) is the only experimental manipulation that has been demonstrated to keep the aging gut from losing its mind (25). The difference between allowing rats unrestricted intake of food or limiting them to 15 g of food per day starting at 6 months of age is remarkable: At age 30 months, roughly half of the myenteric neurons of the ileum (the region of the small intestine adjacent to the colon) have been lost in rats fed ad libitum, whereas there was no detectable loss of neurons in the rats raised on CR diets (26). It could be that the logical approach to keeping the mind of one's GI tract intact over the years may be as simple as giving it less to do. CR as a means of achieving long-term enteric neuronal health and maintenance of GI function seems like a brilliant idea at a time when obesity is of epidemic proportions. Mechanisms by which CR produces its beneficial effect seem to involve enhanced antioxidant handling of reactive oxygen species that are produced at relatively high concentrations in aged enteric neurons [see, for example, (8)]. In fact, recent evidence suggests that antioxidants can have beneficial effects in an animal model of diabetic neuropathy (another common cause of GI dysfunction that increases with age) (27). As noted above, the presence of neural connections to the CNS may play a role in the survival of enteric neurons (22); therefore, discovering what neurotrophic factors might be involved in maintenance of ENS may lead to therapies that could help the GI tract keep its mind into old age. If loss of sensation is a basis for swallowing disorders, reduced colonic motility, and impaired rectal sensation in the elderly, then enhancement of the afferent signaling pathways that may remain would be a logical therapeutic approach.

Finally, it should be recognized that the ENS is only a part of the "neuromuscular apparatus" of the bowel that is responsible for moving contents in an orderly fashion from one end to the other. Two components are critical to this function: pacemaker cells called interstitial cells of Cajal (ICCs) and the smooth muscle itself. Age-related changes that result in reduced contractile properties of the latter recently have been reviewed elsewhere (28), but thus far it seems that age-related changes in properties of ICCs have not been reported. GI motility does not occur independently of GI absorption and secretion, and modulation of this mucosal function due to age-related changes in secretomotor function has only begun to be studied (29). The neurogastroenterology of aging is a fascinating field of study for many reasons; we think that chief among them is that the state of the art is just now at the transition period between descriptions of the phenomena related to structural changes that occur with age in the ENS and the discovery of functional correlates to those morphological alterations that may be amenable to therapeutic intervention.


March 23, 2005
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Citation: P. R. Wade, P. J. Hornby, Age-Related Neurodegenerative Changes and How They Affect the Gut. Sci. Aging Knowl. Environ. 2005 (12), pe8 (2005).








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