Sci. Aging Knowl. Environ., 12 May 2004
Vol. 2004, Issue 19, p. pe20
[DOI: 10.1126/sageke.2004.19.pe20]

PERSPECTIVES

The Ageless Question--What Accounts for Age-Related Cognitive Decline?

Alan Nagahara, and Mark H. Tuszynski

Alan Nagahara and Mark H. Tuszynski are in the Department of Neurosciences at the University of California-San Diego, La Jolla, CA 92093, USA, and Mark H. Tuszynski is affiliated with the Veterans Administration Medical Center, San Diego, CA 92165, USA. E-mail: mtuszynski{at}ucsd.edu (M.H.T.)

http://sageke.sciencemag.org/cgi/content/full/2004/19/pe20

Key Words: cognitive function • hippocampus • dentate gyrus • Arc

Introduction

Normal aging is associated with a decline in cognitive function in humans and across several species (1) (see Gazzaley Perspective and "All in Your Mind"). The mechanisms that underlie this age-related decline in brain function remain incompletely understood, but at first glance appear to be multifactorial in origin. Declines in (i) the concentrations of functional neuronal markers; (ii) the expression of early-immediate genes (a class of genes whose expression is regulated by neuronal activity, some members of which play an important role in memory consolidation); (iii) synaptic plasticity; and (iv) the volume of white matter (myelin-coated nerves that transmit information between regions of the nervous system) have all been reported to occur as a function of age (2, 3).

In the specific context of understanding mechanisms of age-related memory loss, most studies have focused on the hippocampal formation, which plays an important role in memory creation. The hippocampal formation encompasses the hippocampus proper (the dentate gyrus, CA subfields, and subicular complex) and the entorhinal cortex, where information flow into the hippocampus primarily originates. Surprisingly, careful and rigorous studies have shown little or no loss of cell number across most of the hippocampal formation in aged cognitively impaired rodents and primates relative to their younger counterparts (4-6). Because cell death does not appear to account for declining hippocampal function with aging, many researchers have turned to examining whether synaptic function or other cellular mechanisms are altered.

Decline in Dentate Gyrus Function During Aging

In the 4 May 2004 issue of Proceedings of the National Acadamy of Sciences U.S.A., Small and colleagues (7) contribute to our knowledge of age-related mechanisms that underlie cognitive decline by reporting specific decrements in the function of the dentate gyrus in aged rodents and nonhuman primates. The authors report significant reductions in cerebral blood volume (a reflection of cerebral metabolism) in aged versus young rhesus monkeys, as measured by magnetic resonance imaging (MRI). Notably, this reduction occurs only in the dentate gyrus, and the reduction correlates significantly with cognitive function in the monkeys.

There are some caveats to this finding, however. First, the paper does not actually present data that show that the cognitive performance of the aged monkeys was weaker than that of the young monkeys, although the author performing the primate studies confirmed that the aged monkeys were cognitively impaired (8). Second, the hippocampal vasculature was not histologically examined. Thus, cerebrovascular abnormalities in the dentate gyrus are not excluded as a potential mechanism of the altered cerebral blood flow as detected by MRI (9). Third, inspection of the data in the paper seems to indicate that of seven aged monkeys studied, only two exhibited the levels of cerebral blood flow that fell well outside the range displayed by young monkeys.

Changes in Arc Expression in the Dentate Gyrus During Aging

In the same study, the authors went on to examine expression of the immediate-early gene Arc in young, middle-aged, and aged rats after exposure to a novel environment, which stimulates neuronal activity. They discovered a reduction in the expression of Arc as aging progressed, and, in agreement with the results of the MRI study, this reduction was restricted to the dentate gyrus. Significant age-related loss of Arc expression did not occur in other regions of the hippocampal formation. Previous studies have demonstrated that stimulation of Arc expression occurs in the hippocampus coincidentally with induction of long-term potentiation (LTP; a phenomenon in which repetitive neuronal stimulation results in a prolonged level of neuronal depolarization) and spike activity (coordinated firing of neurons) (10), thereby relating Arc directly to putative mechanisms underlying learning and memory. The conclusions regarding rodent Arc expression must be accepted with the caveat that only approximately 1.7% of cells in the young dentate gyrus express Arc mRNA, whereas 60% of cells in the CA1 subfield and 35% of cells in the CA3 subfield express this marker (7). Thus, the overall impact of the change in Arc expression in the dentate gyrus is open to some interpretation. In fact, an earlier study showed that the behavioral paradigm used in this study--exposure to a novel environment--increased Arc expression in the CA1 and CA3 hippocampal subfields but not in the dentate gyrus in young rats (10).

Nonetheless, the findings by Small and colleagues (7) of a pattern of diminished Arc expression with aging in rodents, together with age-related reductions in blood flow (metabolism) in primates, identify a key potential locus of age-related cognitive decline: the dentate gyrus. Is this conclusion, which was based on the assessment of "functional" measures of blood flow and immediate-early gene expression, corroborated by other studies of aging?

Results from Previous Studies

In humans, a previous MRI study identified reductions in cerebral blood flow in both the dentate gyrus and the subiculum in aged versus young individuals (11). A previous stereological study also reported cell loss in the dentate gyrus and the subiculum of aged humans (12). ("Stereological" methods reduce the risk of artifactual errors in cell counts by eliminating several forms of measuring bias.) However, studies of aging in humans are subject to the caveat that sampled individuals might have as-yet-undiagnosed Alzheimer's disease (AD).

For this reason, the aged nonhuman primate, which does not develop AD, has also been used to gain insight into mechanisms that underlie "normal" age-related cognitive decline. Essentially all modern studies of nonhuman primates have indicated that the hippocampal formation, including the dentate gyrus, is spared actual cell loss as a function of aging (4, 13). Turning to analyses of other possible mechanisms for cognitive decline, studies of aged synapses (the functional units that subserve hippocampal function) have yielded conflicting data in primates. The current preponderance of evidence suggests that whereas changes in dendrites, spines (short extensions from dendrites), and synapses might occur with aging, they are relatively modest in degree (14, 15). On the other hand, concentrations of neurotransmitters and receptors diminish with aging in several subregions of the aged hippocampus, including the dentate gyrus (13). However, the patterns of change in receptor abundance suggest that age-related degeneration of inputs from the entorhinal cortex to the dentate gyrus may be a key locus of age-related memory loss. For example, N-methyl-D-aspartate (NMDA) receptors are ion channels controlled by the neurotransmitter glutamate that play a role in learning and memory. Age-related reductions in the density of some NMDA receptor types [(15), but see also (16)] are observed in the distal dendrites of dentate gyrus granule cells, a region that receives direct inputs from the entorhinal cortex. Changes in other transmitter systems are also observed in several aged primate hippocampus subfields, such as reductions in the concentrations of muscarinic, nicotinic, dopaminergic, and serotoninergic receptors (17-19): neurotransmitter systems that modulate activation of neuronal groups in the hippocampus. Finally, studies in primates also demonstrate age-related reductions in second messenger concentrations (17) and in general hippocampal glucose uptake, as determined by positron emission tomography scanning (20). Hence, a single locus of age-related cognitive decline in primates has yet to clearly emerge from these studies.

Extensive investigations have also been performed in rodent models to identify mechanisms of age-related memory decline. As observed in human and nonhuman primate studies, no actual cell death occurs throughout the hippocampal formation in aged cognitively impaired rats (5, 6). Diminished neurogenesis occurs in the aged rodent hippocampus, but the magnitude of this change does not correlate with cognitive impairment (21). Despite the absence of cell loss in the rodent hippocampus during aging, numerous other structural, biochemical, and electrophysiological changes have been reported in various subfields of the hippocampus. For example, age-related reductions occur in synaptic electrophysiological function as reflected by diminished LTP at the CA3-CA1 synapse and the perforant path-dentate gyrus synapse (3). The perforant path refers to nerve fibers that originate in the entorhinal cortex and end in the hippocampus, "perforating" the subiculum. Altered place-field plasticity (that is, the firing of ensembles of cells in the hippocampus when the animal is in a specific physical location) is also observed in the aged CA1 region (22). Decreases in the abundance of synaptic markers have been found in CA3 and the dentate gyrus during aging (23, 24). In addition, age-related alterations have been reported in a variety of neuronal markers in each of the subregions of the hippocampus, including changes in the concentrations of ion channels, neurotransmitters, and components of signaling pathways (3, 25, 26). Further, age-related changes in astrocytes have been reported in the CA1 subfield and the dentate gyrus in female mice (27). Thus, as in the primate studies, investigations in the rodent model suggest that cognitive decline during aging involves several mechanisms related to cell function, in several hippocampal regions.

Age-Related Changes in Extrahippocampal Regions That Influence Memory

In addition to the hippocampal formation, memory acquisition and retrieval are influenced by other cortical regions, including the frontal cortex. Recently, using stereological methods, we found a 32% reduction in neuronal number in aged cognitively-impaired monkeys as compared to young monkeys in area 8A of the dorsolateral prefrontal cortex, a region involved in working memory (Fig. 1) (28). Other subcortical neurons (that lie more deeply within the brain than those in area 8A) projecting to this cortical region also degenerated, a phenomenon known as "transneuronal degeneration" (loss of a neuron after it is deprived of a target). Yet another cortical region adjacent to area 8A that also contributes to working memory, area 46, showed no reduction in cell number. Hence, highly focal neuronal degeneration can occur in discrete brain regions related to cognition, but is detected only by detailed analysis of anatomical subregions. Other studies of nonhippocampal cortical regions that contribute to behavioral functions known to decline with aging have revealed changes similar to those described in the hippocampus: Subtle alterations in spine or synapse density are detected, together with more distinct changes in transmitter systems (2, 18, 19, 29, 30).



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Fig. 1. Age-related reductions in neuron number determined using stereological methods in the aged primate dorsolateral prefrontal cortex. [Reproduced with slight modifications with permission from (28)]

 
Finally, a variety of recent genetic screens have identified several molecular events that might be related to neural degeneration with aging, including (i) activity-related synaptogenesis (formation of new cell-cell interactions based on neuronal activity); (ii) oxidative stress; (iii) myelin turnover (replacement of myelin in the brain over time, which may be needed to support healthy cell function); and (iv) mitochondrial changes (which could affect efficient energy use by aged cells) (31). Telomere shortening and other cellular alterations have also been implicated in system-wide changes that occur as a consequence of aging, resulting in perturbation of cellular function.

Conclusion

As the field of aging ages, new findings emerge that enhance our understanding of mechanisms that lead to "normal" age-related cognitive decline. It appears that several such mechanisms exist, including declines in blood flow, white matter volume, and the function of glia (cells that support and interact with neurons), as well as changes specific to neurons themselves. The most consistent neuronal changes include (i) reductions in the concentrations of neurotransmitters or the enzymes that synthesize them, (ii) reductions in the abundance of excitatory transmitter receptors, and (iii) reductions in synaptic efficacy. Isolated brain regions also sustain neuronal loss, although this is not a broad mechanism of age-related neurodegeneration. Thus, age-related cognitive decline most likely arises from a constellation of atrophic events in neurons and their local surroundings, leading to processes that ultimately impair cognitive function and, in humans, quality of life, even in the absence of frank disease. A key remaining challenge to the field of aging is the identification of targets for preventing or ameliorating these functional declines to preserve quality of life.


May 12, 2004
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Citation: A. Nagahara, M. H. Tuszynski, The Ageless Question--What Accounts for Age-Related Cognitive Decline? Sci. Aging Knowl. Environ. 2004 (19), pe20 (2004).




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