Functional changes in GI motility associated with advanced age include slowing of gastric emptying, decreased peristalsis, and slowing of colonic transit. These changes appear to be associated with region-specific loss of neurons and impaired function. The mechanism(s) underlying physiological aging are likely to be multifactorial. Alterations in specific signal transduction pathways have been reported at the level of the receptor and postreceptor events including kinase expression and function, mitochondrial function, and activation of the apoptosis cascade. Advanced age is associated with increased oxidative stress and its concomitant effects on cellular function. Whereas no specific genes have been causally linked to life span in mammals, studies involving nonmammalian species suggest that specific genes are involved in determining life span and age-related changes in cellular function. Caloric restriction is the only intervention shown to slow aging in a variety of species. Recent studies implicate a possible role for an insulin/IGF-I cascade in the region- and tissue-specific changes associated with physiological aging.
- oxidative stress
demographics of the aging baby boomer population have been well publicized. It is currently estimated that ∼20% of people in developed countries are >60 yr of age and that this number will double by 2050. There are >30 million people >65 yr of age in the United States. Approximately one-third of the current medical expenditures in the United States are utilized in the diagnosis and treatment of individuals >65 yr old.
The gastrointestinal (GI) tract demonstrates a number of changes that accompany advanced age. This brief review focuses primarily on animal studies that shed light on the mechanisms underlying changes in neuronal structure and function that accompany advanced age. I will not specifically address the contributions of pathological conditions on the aging process except where it may help provide insights into underlying mechanisms. Most mechanistic studies examining the aging process focus on extraintestinal sites, such as the brain, or they employ nonmammalian animal models, such as Caenorhabditis elegans.
Deciphering the mechanisms of physiological aging versus the consequences of disease is an ongoing challenge for gerontologists. In general, gastrointestinal function is well preserved in otherwise healthy individuals through the seventh decade. However, there are some notable changes in gut neuromuscular function that accompany advanced age. Functional impairments in GI motility associated with advanced age include slowing of gastric emptying, decreased peristalsis, and slowing of colonic transit. These changes have been reported in human and animal models. Investigators typically attribute these changes in GI motor function to age-associated deterioration in autonomic nerve function. This raises the question of whether age-dependent autonomic dysfunction involves loss of neurons and/or altered function. Furthermore, do age-associated changes involve extrinsic innervation of the gut, intrinsic innervation, or both? If advanced age is associated with either loss of neurons or altered neuronal function, how might these changes be explained?
AGE-ASSOCIATED CHANGES IN GI INNERVATION
Little is known about age-related changes in the extrinsic vagal projections to the gut. Sotanpour and Santor (21) did not observe any age-dependent effects on cell sizes or the microvasculature in the nodose ganglia or the sensory profiles of fibers that project peripherally from the nodose. In addition, the maximum conduction velocity of unmyelinated vagal fibers did not change with age. Neurons in the nucleus of the solitary tract did not demonstrate significant changes in their cellular properties with advanced age. Other investigators have noted accumulation of the age-associated pigment lipofuscin in the rat nodose ganglion and mitochondrial swelling that may indicate altered vagal sensory nerve function.
Sturrock (22) observed that the number of neurons of the dorsal motor nucleus of the vagus (DMNV) decreased by ∼40% with advanced age (31 mo) in the rat. In contrast, neuron counts in the DMNV did not appear to decrease in a 63-yr-old human. However, this is likely to be a relatively young age to detect significant change in the number of neurons in an otherwise healthy individual. Other investigators observed increased Lewy bodies and decreased substance P-containing neurons in the DMNV in humans with Parkinson's disease. Functional studies suggest that vagally mediated preganglionic control of the heart undergoes decreases with age in the rat.
Most quantitative studies examining age-associated changes in the number of neurons present in the myenteric plexus report significant decreases with advanced age. This observation is consistent across species and appears to be region specific in the GI tract (4). Additional studies are needed to address the following questions: 1) At what age does the loss of neurons begin? 2) Are there region-specific differences in rate of age-dependent neuronal loss and/or the magnitude of neuronal loss? and3) What are the mechanisms of physiological aging and how do pathological conditions affect the normal aging process?
Phillips and Powley (16) addressed the first two questions using the Fisher 344 rat model, and they observed that the loss of neurons in the GI tract was organ specific and demonstrated a gradient of increasing severity from proximal to distal. Investigators noted a positive relationship between the density of vagal extrinsic innervation and myenteric neuron survival.
Other investigators studied age-dependent changes in the enteric nervous system of the mouse. Nerve cell counts were quantified by using the panneuronal marker protein gene product 9.5 in the myenteric and submucosal plexi of the stomach, small intestine, and colon. Nerve cell loss was observed in both plexi in all regions of the GI tract in 12- and 24-mo-old animals compared with 3-mo-old mice. It is of interest that the loss of neurons was not associated with a change in the number of ganglia or in the ganglion area except in the myenteric ganglia of the colon. The relative density of nerve fibers did not change with age in the myenteric or submucosal plexi in any region except the antrum, where it increased. Mechanisms underlying these observations remain to be elucidated but may be related to the level of extrinsic innervation.
Does advanced age differentially effect neuronal subpopulations in the GI tract?
Changes in GI motility that occur with advanced age may reflect selective loss or selective impairment of function involving subpopulations of neurons. For example, do the longer transit times reported in aged humans and animals reflect differential effects on stimulatory (cholinergic and substance P) and/or inhibitory (vasoactive intestinal polypeptide and nitrergic) neural pathways? The number of substance P-, vasoactive intestinal polypeptide-, and somatostatin-immunoreactive neural elements were significantly decreased in the small intestine of aged rats compared with their youthful counterparts. Acetylcholine release and smooth muscle response were diminished in colon preparations from aged rats. These functional observations may reflect the loss of cholinergic (choline acetyltransferase-positive) neurons. Cowen et al. (1) reported a 50% reduction in ileal myenteric neurons from 24-mo-old Sprague-Dawley rats fed ad libitum (50–60 g per day standard rat chow) that was prevented by caloric restriction (15 g per day). Neurons that stained positive for nitric oxide synthase (NOS) did not demonstrate age or diet-related changes in the ileum. In contrast, NOS message, protein, and release of nitric oxide did decrease in the colon myenteric plexus in aged rats. Taken together, the current literature suggests that the effects of advanced age on the enteric nervous system are region specific.
Postulated Mechanisms to Explain Age-Associated Changes in Neuronal Structure and Function
It is generally well accepted that advanced age (senescence) is associated with increased vulnerability to disease and functional impairment in a variety of organ systems. Is this increased vulnerability related to relatively simple changes in the action of a limited number of genes, or does it reflect alterations in numerous alleles involving potentially thousands of loci?
Lessons from the senescent brain.
Anatomic and functional studies indicate that there is decrease in the human brain volume and weight in individuals >60 yr old. The brain regions most affected are the hippocampus and frontal lobes. It remains controversial whether the loss of brain volume represents neuronal loss, shrinkage, or both. Neuron loss does appear to occur in specific regions of the brain including the hippocampus, cerebral cortex, and amygdala.
Loss of synapses has been reported in some cortical regions. Controversy exists regarding the physiological loss of synapses with advanced age. Terry and Katzman (23) suggest that even in the absence of concomitant Alzheimer's disease, by the age of ∼130 yr a critical 60% reduction in synapses would be reached, resulting in clinical dementia. Other investigators did not observe age-associated changes in synapses in lamina III and V of the human frontal cortex.
Cognitive function reportedly declines with age, but it remains unclear whether this is a concomitant feature of physiological aging or the result of a pathological neurodegenerative disorder, such as Alzheimer's disease. Mayeux et al. (13) examined whether the possession of apolipoprotein E4 (apoE-4) is a risk factor for cognitive dysfunction, because it is a known genetic risk factor for Alzheimer's disease. Memory declined over time in a large sample of healthy elderly, but there was no significant loss of visuospatial/cognitive function or language, both of which are affected in Alzheimer's disease. Possession of an apoE-4 allele, however, resulted in a more rapid decline in cognitive function. apoE is probably important in maintenance of normal brain function. It is not known whether apoE plays a role in maintenance of GI neuromuscular function.
Neurofibrillary tangles and senile plaques are regarded as the histopathological hallmarks of Alzheimer's disease. Both markers are present in the brains of healthy individuals, as are Hirano bodies and granulovacuolar degenerative changes. In Alzheimer's disease, the number and distribution of these pathological markers are greater and more widespread.
MECHANISMS OF NEURODEGENERATION AND NEURONAL DEATH
Two fundamental questions have shaped much of the discussion regarding aging in the nervous system. Does loss of neurons occur naturally with senescence? If so, is physiological neuronal senescence a process that begins with neurodegeneration and culminates with neuronal death? Neurons appear to have at least two self-destruct programs. Similar to other cell types, neurons are capable of undergoing programmed death or apoptosis when this cascade is activated by appropriate conditions, such as infection or injury, or developmentally when the neurons are not needed. It also appears that neurons have a second, distinct self-destruct program involving their axons. The conceptual foundation for this second self-destruct program originates with the observation that degeneration of the long processes of neurons, the axons, frequently precedes the death of the soma and actually can be more relevant to a patient's clinical course. Four forms of axonal degeneration have been proposed by Raff et al. (18). First, Wallerian degeneration in response to cutting of the axon distally can occur in the central nervous system (CNS) and peripheral nervous system (PNS) in the presence of trauma, a vascular accident, infection, or immune-mediated injury to the axons. Second, dying-back axonal degeneration typically occurs when the axonal tree of an unhealthy neuron slowly degenerates in a distal-to-proximal progression. This is the most common pathology observed in the PNS in response to toxic, metabolic disturbances and infectious diseases. Examples include the polyneuropathies associated with alcoholism, diabetes, and acquired immunodeficiency syndromes. It is also observed in Parkinson's disease, Alzheimer's disease, and motor neuron disease. Third, axonal degeneration is associated with inadequate neurotrophin support when the distal axon of a sympathetic neuron is deprived of NGF in culture. That part of the axon degenerates, whereas the remaining part of the axon and cell body exposed to NGF do not undergo degeneration. Finally, normal development appears to be associated with degeneration of unnecessary axonal branches.
Wallerian degeneration is associated with breakdown of neurofilaments, a process that depends on the influx of calcium and activation of Ca2+-dependent protease calpain. Studies in the Wallerian degeneration slow mouse (Wlds) suggest that the degenerative process may be active. These mice exhibit a spontaneous mutation associated with slow progression of Wallerian degeneration, perhaps linked to the presence of an abnormal protective fusion protein that interferes with the degenerative process. Several lines of evidence suggest that both Wallerian degeneration and the axonal degeneration induced by local NGF withdrawal involve molecular mechanisms that are distinct from apoptosis. First, expression of a human (anti-apoptosis) bcl-2 transgene in mouse neurons blocks the axotomy-induced apoptosis of developing retinal ganglion cells but not the Wallerian degeneration of their axons. Second, apoptosis involves activation of cysteine proteases (caspases). Wallerian degeneration and axonal degeneration induced by NGF withdrawal do not require activation of caspases. Finally, Wallerian degeneration is slowed in the Wlds mouse but apoptosis is not affected.
Mechanisms underlying axonal degeneration and the question of whether axonal degeneration contributes to physiological aging have not been resolved. Is there evidence that any of the mechanisms proposed to explain axonal degeneration are involved in physiological aging? If axonal degeneration, rather than cell death, is responsible for many of the symptoms and signs of various neurodegenerative diseases, then crossing the Wlds mouse with mouse models that have these diseases may slow the course of the disease and prolong life. Thepmn/pmn mutant mouse develops a progressive motor neuronopathy, in which the axons of motor neurons degenerate in a dying-back pattern and the cell bodies undergo apoptosis. Introduction of bcl-2 transgene into the pmn/pmn mice prevented apoptosis involving the cell body but had no effect on axonal degeneration, disease progression, or time of death (24). Preliminary studies suggest that (Wlds × pmn/pmn)F1 mice live significantly longer than pmn/pmn mice.
One manifestation of axonal degeneration is the potential impact on neural synapses. Terry and Katzman (23) argue that synaptic loss is a normal feature of physiological aging in the absence of significant amyloid and/or neurofibrillary tangles, particularly in the neocortex. This hypothesis has been challenged (17). Stereological studies suggest that in otherwise healthy individuals, there is modest or no loss of neurons with age in most cortical regions. Some observers propose that significant cognitive decline has been difficult to document in nondemented individuals, other than decreased physical and cognitive reaction speed. This is only partially true, because decline in abstract neocortical function has been documented with advanced age (8). Taken together, these observations indicate that it is essential to carefully screen for signs of neuropathological disorders, such as Alzheimer's disease, when studying the neuroanatomic changes of physiological aging.
GENETICS AND AGING
There is little doubt that physiological aging is a multifactorial process. An evolving body of evidence supports a role for a genetic component in aging. The nature of the genetic component likely involves several mechanisms. The most obvious is a change in gene expression during aging, which results in the production of altered levels and/or forms of relevant regulatory proteins. Age-associated changes in the integrity of DNA itself have been implicated by studies of mitochondria and telomeres. Changes in DNA are likely the culmination of a complex process involving oxidative damage causing mutations in genes, shortening telomeres, and injury to mitochondrial DNA.
Accumulation of random mutations in genomic DNA could contribute to the gradual decline in cellular function observed in a variety of tissues (5) and help explain the age-related differences demonstrated by different individuals. Telomeres are the physical ends of chromosomes. In mammals, telomeres are composed of tandem repeats of (TTAGGG)n and appear to stabilize the structure of chromosomes. DNA replication machinery is unable to completely replicate the ends of linear chromosomes that result in shortening of the telomere with each round of DNA synthesis. Terminal repeats can be polymerized onto the ends of the chromosomes by the ribonucleoprotein telomerase. This enzyme, therefore, plays an important role in replicating cells to maintain telomere length and chromosome integrity. Telomere shortening, caused by oxidative damage or a problem with end replication, might result in the accumulation of postmitotic cells during aging. This process could impact a number of physiologically important events, such as tissue repair after injury. If telomere length plays an important role in the aging process, telomere knockout mice should demonstrate accelerated aging. There is, however, a lack of correlation between telomere length in cells and the maximum life span of the species from which they were derived. In addition, telomerase knockout mice do not demonstrate accelerated aging in the first two generations of animals despite having shortened telomeres.
Age-dependent accumulation of mutations in mitochondrial DNA may also contribute to the loss of cells in postmitotic tissues, such as muscle or neurons (2). Accumulation of damage in DNA suggests that there is an imbalance between two opposing processes: the generation of mutations and the removal of these mutations by DNA repair mechanisms. Werner's syndrome (WS) is an example of accelerated aging that appears to be caused by the presence of a variant allele of gene (WRN) coding for a DNA repair protein. This protein has both helicase and exonuclease functions. It is noteworthy that WS fibroblasts exhibit both cellular senescence and accumulation of mutations, resulting in demonstrable pathology, whereas WS T-lymphocytes only appear to exhibit accumulation of mutations and no evidence of pathology. This suggests that accumulation of mutations alone may not be causally linked to aging. The frequency of mitochondrial DNA damage is very low, calling into question the significance of its role in aging. Nevertheless, the accumulation of abnormal mitochondrial DNA could result in impaired cell function and activation of apoptosis. Presumably, this would be of particular significance in postmitotic tissues, such and muscle and neurons.
Genetic analysis of C. elegans reveals two pathways that may regulate aging, an insulin/IGF-I receptor-like cascade consisting of daf-2, age-1, pdk-1, daf-18, akt-1, and daf-16, and a clk pathway consisting of clk-1, clk-2, clk-3, and gro-1 (7). Both pathways require cytosolic catalase encoded by ctl-1 to exert aging regulatory activity. The mammalian counterparts of the daf-2 cascade include insulin/IGF-I-like receptor, PI3-kinase, PKD-1, Pten, Akt/PKB, and Forkhead transcriptional factor FKRHL1, FKRHL, AFX (9). The insulin/IGF-I receptor pathway is involved in the regulation of proliferation, apoptosis, and cancer. IGF-I can activate PI3-kinase that can trigger activation of Akt. Akt can inhibit apoptosis by preventing injury mediated by the proapoptosis member of the BCL-2 family, BAD.
In yeast, caloric restriction-mediated extension of life span requires two genes, the NPT1 gene that encodes an enzyme involved in the synthesis of nicotinamide adenine dinucleotide (NAD) and the SIR2 gene that encodes a NAD-dependent histone deacetylase (12). It appears that in yeast, histone deacetylation is associated with Sir2 protein-mediated silencing of gene transcription in specific regions of chromosomes and suppresses deleterious homologus recombination at highly repetitive ribosomal DNA. NAD may act as a link between energy metabolism and chromatin silencing.
There is increasing evidence that altered gene activity occurs during the normal aging of mammalian cells. Changes in transcription factor activity during aging could provide a mechanism by which patterns of gene activity could be altered in a consistent manner. The AP-1 transcription factor may serve as a useful example. AP-1 is composed of two protein subunits, a member of the c-fos family of proteins and a member of the c-jun family of proteins. The c-fos/c-jun ratio declines during aging in individual rat cerebellar cells based on in situ hybridization studies and in fibroblasts based on Western blot analysis (20). A causal link to aging has not been established.
A characteristic feature of aging in the brain is the fibrous appearance of astrocytes. The fibrous appearance may be caused by increased production of glial fibrillary acidic protein (GFAP), a component of the intermediate filaments (6). The gene encoding GFAP contains AP-1 consensus sequences in its promoter region that demonstrate age-associated changes in their expression. Age-dependent changes have also been reported in the composition and activity of NF-κB. Changes in the activities of AP-1 and NF-κB are potentially quite interesting and relevant to our understanding of senescence because these transcription factors are affected by the energy (redox) state of the cell (3). The redox state is dependent on the calorie utilization by the cell and, therefore, suggests a potential mechanism that links caloric restriction to delayed changes in gene expression. Thus advanced age is likely to be associated with altered activity (reflecting either altered synthesis or degradation) of numerous transcription factors. Studies that focus on age-associated changes in a single transcription factor will likely be incomplete, unless knockout models of a specific transcription factor can be causally and directly linked to senescence.
APOPTOSIS AND AGING
Does programmed cell death or apoptosis play a role in physiological aging? Despite keen interest in this question, what role apoptosis contributes remains unclear. It is well accepted that apoptosis plays an essential role in normal development. The apoptosis cascade is typically presented as having extrinsic and intrinsic pathways. The extrinsic pathway is activated by Fas ligand and signals through Fas receptor, Fas-associated protein with death domain, the initiator caspase-8, and executioner caspases-3 and -7. The intrinsic pathway involves mitochondria and signals through the apoptosome (a protein complex composed of cytochrome c, Apaf-1, and procaspase-9) and the executioner caspases-3, -6, and -7. Defects in the Fas-dependent (extrinsic) pathway are associated with autoimmune disease, whereas defects in the caspase-9 pathway are associated with abnormal brain development (10).
A number of studies suggest that there is an association between apoptosis and aging. It remains unclear whether age-associated apoptosis is physiological, pathophysiological, or perhaps both, depending on the circumstances. If the apoptosis cascade functions normally throughout an individual's life, then age-associated increases in apoptosis may reflect an appropriate response to the presence of increased numbers of damaged cells that need to be removed from the body. Thus apoptosis may have a beneficial effect to remove senescent cells, but this process could contribute to the decline of function by removal of nonregenerating postmitotic cells. However, in organs with regenerating cell populations, the increased presence of apoptosis could have a deleterious effect, if the ratio of apoptosis to cell replacement shifts significantly in the direction of apoptosis. For example, hepatocytes isolated from aged rats are more sensitive to oxidant (H2O2) inducers of apoptosis. The increased sensitivity to oxidant-induced apoptosis in hepatocytes from aged rats may be related to reduced activities in ERK and Akt kinase. These enzymes are activated by oxidative stress and protect cells from apoptosis. It will be interesting to examine this pathway as a function of age in other organs with regenerating cell populations, such as the gut mucosa. Advanced age may have a differential affect on apop tosis depending on the tissue and apoptosis pathway that is activated.
OXIDATIVE STRESS AND AGING
Aging is associated with an increase in oxidative stress (19). Reactive oxygen species (ROS) and H2O2 are the principle oxidants that mediate cell damage. These species are important products of normal cell metabolism. They are typically scavenged quickly, but aging may affect this removal process, resulting in the accumulation of toxic effects on macromolecules and organelles. Mitochondria are especially vulnerable to oxidative stress, presumably because of the lack of histone protection and the proximity of mitochondrial DNA (mDNA) to the source of ROS production. Oxidative damage to mDNA is threefold greater than that of nuclear DNA.
Several pathways have been implicated in regulation of cellular responses to potential genotoxic stress (25). MAPKs play an essential role in the regulation of cell proliferation, differentiation, and apoptosis. MAPKs are a ubiquitously expressed family of tyrosine/threonine kinases and include extracellular ERKs, JNKs, and p38 MAPKs. The JNKs and p38 MAPKs are referred to as the stress-activated protein kinases (SAPKs) because they are activated by stress-related stimuli. Many mediators of DNA damage activate MAPKs in mammalian cell lines. ERK activation has been implicated in cell proliferation and survival. SAPKs are activated in growth arrest and apoptosis. Overall, susceptibility to cell death appears to reflect a balance between survival (ERK) and death (SAPK) signaling pathways, particularly in response to stressful stimuli. Recent studies suggest that the p53 allele may also be involved in susceptibility to aging. Mice with a mutant p53 allele that was highly activated demonstrated symptoms and signs of accelerated aging, including increased apoptosis, but decreased risk of cancer. This observation demonstrates one of the potential ironies in the aging process, namely, that the intracellular pathways that promote survival and proliferation may also increase risk for development of cancer. Removal of dysfunctional senescent cells by apoptosis may protect against cancer but be associated with decreased functional capacity.
What happens to the life span of animals if the rate of oxidative stress-induced apoptosis is reduced? Migliaccio et al. (14) examined life span in p66shc knockout mice. This protein appears to play a role in regulation of oxidative stress-induced apoptosis. Under normal conditions, the life span of p66shc mice was 30% longer than the wild-type mice. When the mice were exposed to a generator of oxidative stress, the p66shc mice demonstrated a 40% increase in mean survival time compared with wild-type mice. It is of interest that the rate of hydrogen peroxide-induced apoptosis in p66shc knockout mouse embryo fibroblasts was significantly decreased compared with wild-type fibroblasts. It appears that aging is associated with an increase in oxidative stress and apoptosis, but a direct link between apoptosis and aging remains to be established.
INTERVENTIONS THAT MAY PREVENT AGE-ASSOCIATED CHANGES IN NEURONAL STRUCTURE AND FUNCTION
Caloric restriction is the only intervention shown to slow aging in a variety of species from yeasts to primates. Caloric restriction reduces oxidative stress. Caloric restriction-mediated effects on aging appear to involve the daf-2 and clk-1 pathways discussed previously. In addition to the potential preventive effects of caloric restriction, other approaches are being considered. The potential for neurotrophin-mediated regeneration, neuronal transplant, and stem cells are discussed elsewhere in this themes series. An emerging body of evidence suggests that an insulin/IGF-I-mediated pathway may attenuate specific age-dependent changes in CNS function. IGF-I influences neurogenesis during development, and aging is associated with decreased levels of IGF-I. The dentate gyrus of the hippocampus is one of the regions in the adult mammalian brain that demonstrates ongoing neurogenesis that declines with age. Advanced age is associated with a decrease in the number of newly generated cells in the adult dentate subgranular proliferative zone. Both intracerebroventricular and systemic infusion of IGF-I ameliorated age-associated diminution in hippocampal neurogenesis in the rat (11). In contrast, infusion of IGF-I into the lateral ventricle did not affect the numerical density of neurons or synapses in area CA3 of the hippocampus of aged rats. It is relevant that the density of neurons and synapses in area CA3 remained constant across the life span. The regenerative effects of IGF-I appear not to extend to CNS glial cells. This may represent an example of tissue- and region-specific actions of neurotrophic factors. The potential role of an insulin/IGF-mediated pathway on neurogenesis in the gastrointestinal tract or as a potential protective pathway to attenuate age-related neuronal loss in the gut has not been studied. It is noteworthy that both insulin and IGF-I promoted neurite outgrowth in cultured guinea pig myenteric ganglia (15). The neurite outgrowth was abolished by cytosine arabinofuranoside, an agent that is toxic to nonneuronal cells. This suggests that insulin and IGF-I were acting indirectly via glial support cells to stimulate neurite outgrowth.
In conclusion, much of the literature exploring the mechanisms underlying neuronal aging focuses on the CNS and nonmammalian animal models. Mechanistically focused studies examining neuronal aging in the gut is a fertile field for research. In this brief review, I have summarized the views of a number of investigative teams regarding how aging affects neuronal structure and function. At the present time, there is no unified hypothesis that fully explains the mechanisms underlying neuronal aging. One popular hypothesis emphasizes the role of age-associated changes in cell response to activators and modulators of stress and its manifestations on cellular function. This is an attractive hypothesis, because it helps to integrate the role of environmental factors on specific membrane receptors, downstream changes in mitochondria function, and activation of the apoptosis cascade. Whereas this provides a possible explanation for the mechanics of age-associated loss of neurons and, thereby, functional capacity, it does not address the fundamental question of which genes are causally linked to physiological aging. This is a challenging issue because of the general problem that correlation does not equal causation. Ongoing research utilizing the rapidly evolving technologies in genomics/proteomics, transfected cell lines, and transgenic knockout animal models will likely elucidate specific genes and, perhaps more importantly, altered gene products that are linked to physiological aging. The fundamental issue of how many genes or altered gene products are causally linked to physiological aging remains unresolved. In the meantime, there are some general conclusions that we can extrapolate from the available literature. First, the aging process does not affect all tissues equally. Experimental designs should take into consideration the tissue- and region-specific effects of advanced age on structure and function. Second, there is likely a role for oxidative stress as a contributing factor to the aging process. Three, increased oxidative stress correlates with activation of programmed cell death via activation of the apoptosis cascade. Age-related increase in programmed neurodegeneration may involve nonapoptosis mechanisms, for example, axonal degeneration. A potential role for oxidative stress in promoting axonal degeneration remains to be elucidated. Finally, the role of programmed cell death in physiological aging requires additional study. Does programmed cell death have a beneficial effect on an organism's life span by removal of senescent cells, a deleterious effect on functional capacity, or quite possibly both, depending on the circumstances?
Address for reprint requests and other correspondence: J. W. Wiley, University of Michigan General Clinical Research Center, A7119 UH, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0108 (E-mail:).
June 20, 2002;10.1152/ajpgi.00224.2002
- Copyright © 2002 the American Physiological Society