Age-related changes in the morphology of neurons are selective and it seems that there is no universal pattern across the entire brain.
However, one finding that does seem to be consistent is that in most brain areas neuronal loss does not have a significant role in age-related cognitive decline.
Rather, small, region-specific changes in dendritic branching and spine density are more characteristic of the effects of ageing on neuronal morphology.
This is contrary to early investigations of aged nervous tissue in which profound neuron loss was reported to occur in advanced age.
In 1955, Brody was the first to suggest that age-related reductions in brain weight were due, in part, to a decline in neuron number in all cortical layers1.
Subsequent investigations corroborated this work, reporting a 10-60% decline in cortical neuron density between late childhood and old age.
In addition, profound cell loss was found in the hippocampus of ageing humans and the hippocampus and prefrontal cortex (PFC) of non-human primates.
The data obtained from these early reports, however, were confounded by various technical and methodological issues, such as tissue processing and sampling design, that later called into question their accuracy.
In the 1980s, when new stereological principles were developed, it became possible to identify and eliminate many of the confounding factors of the previous studies that had indicated a profound decline in neuron number occurring in advanced age.
The resulting conclusion was that in humans, non-human primates and rodents, significant cell death in the hippocampus and neocortex is not characteristic of normal ageing.
A notable exception to this idea, however, has recently been reported.
In aged non-human primates, there is a ~30% reduction in neuron number in all layers in area 8A of the dorsolateral PFC, which significantly correlates with impaired performance on a working memory task.
By contrast, area 46 of the PFC shows conservation of neuron number.
Similar to early reports of a decline in neuronal density with ageing, early investigations of dendritic branching suggested massive deterioration in the human entorhinal cortex and hippocampus.
These experiments, however, included both healthy individuals and people with dementia.
Subsequent investigations, which were more precisely controlled for the participants' mental status and applied stereological controls, found that normal aged individuals had extensive dendritic branching in layer II of the parahippocampal gyrus, the origin of the perforant pathway to the dentate gyrus.
Moreover, dendritic branching and length appeared to be greater in aged individuals than in younger adults or patients with senile dementia.
Other investigations have reported increased dendritic extent in the dentate gyrus of old compared with middle-aged humans.
In other subregions of the human hippocampus, however, including areas CA1 and CA3, and the subiculum, there is no change in dendritic branching with age.
Studies of dendritic extent in other animals have, in general, confirmed that there is no regression of dendrites with age.
In rats, there is no significant change in dendritic length of hippocampal granule cells between young (3 months), middle-aged (12-20 months) and aged (27-30 months) rats, with a trend towards an increase between middle-age (20 months) and old age (27 months).
There is also no decrease in dendritic extent between young (3 months) and old rats (26 months) in area CA1, although there is some evidence that a small subset of CA1 neurons from 24-month-old rats have increased basilar dendritic length and branching compared with 2-month-old rats.
The morphology of PFC neurons seems to be more vulnerable to the effects of ageing than that of hippocampal neurons.
In rats, dendritic branching of pyramidal neurons decreases with age for both apical and basal dendrites in superficial cortical layers.
A reduction in dendritic branching with age has also been observed in anterior cingulate layer V of the rat and the human medial PFC.
Similar to the investigations on dendritic branching during ageing, the data on spine density suggest that age associated alterations are also region-specific.
Even in the hippocampus, changes in spine density are not consistent across subregions.
In the dentate gyrus, there is no significant reduction in spine density in aged humans or rats.
There is also no reduction in spine density in area CA1 in aged compared with young rats.
In the subiculum of non-human primates, however, significant reductions in spine density with age have been observed in monkeys between the ages of 7 and 28 years.
In all subregions of the hippocampus, most electrical properties remain constant over the lifespan.
These include resting membrane potential; membrane time constant; input resistance; threshold to reach an action potential; and the width and amplitude of Na+ action potentials.
Numerous studies, however, have shown an increase in Ca2+ conductance in aged neurons.
CA1 pyramidal cells in the aged hippocampus have an increased density of L-type Ca2+ channels that might lead to disruptions in Ca2+ homeostasis, contributing to the plasticity deficits that occur during ageing.
Moreover, Ca2+ activates outward K+ currents that are responsible for the after hyperpolarizing potential (AHP) that follows a burst of action potentials.
Aged neurons in areas CA1 and CA3 have an increase in the amplitude of the AHP that results, at least in part, from age-related increases in Ca2+ conductance.
Other factors that might contribute to the larger AHP in aged animals include reduced basal cyclic AMP (cAMP) levels.
The larger AHP observed in aged hippocampal neurons suggests that aged CA1 pyramidal cells are less excitable, as they are further from action potential threshold than are young neurons during the AHP.
The only evidence that supports this idea is the finding that, in an in vitro hippocampal slice preparation, aged CA1 neurons fire fewer action potentials than do young neurons in response to a prolonged depolarization.
This is not the case, however, when pyramidal neurons are recorded in vivo under normal physiological conditions.
In awake, behaving rats, there is no difference in the firing rates of CA1 pyramidal neurons according to age, and, in fact, the firing rates of CA3 pyramidal neurons are actually slightly higher in aged than young rats.
Similar to neurons in the hippocampus, many electrophysiological properties of neurons in the PFC remain the same during normal ageing, including resting membrane potential; membrane time constant; threshold to elicit an action potential; and rise time and duration of an action potential.
There is some evidence of a small increase in the input resistance in PFC neurons of aged monkeys as well as a decrease in the amplitude and fall time of action potentials.
However, cognitive performance is not related to action potential amplitude, action potential fall time or input resistance.
Neurons in the PFC of aged monkeys also have a significantly larger AHP compared with young neurons, which suggests that Ca2+ homeostasis might also be disrupted in PFC neurons in advanced age.
In summary, during the normal ageing process, animals experience age-related cognitive decline.
Historically, it was thought that primary contributions to the aetiology of this decline were massive cell loss1 and deterioration of dendritic branching.
However, we now know that the changes occurring during normal ageing are more subtle and selective than was once believed.
In fact, the general pattern seems to be that most age-associated behavioral impairments result from region-specific changes in dendritic morphology, cellular connectivity, Ca2+ dysregulation, gene expression or other factors that affect plasticity and ultimately alter the network dynamics of neural ensembles that support cognition.
Of the brain regions affected by ageing, the hippocampus and the PFC seem to be particularly vulnerable, but even within and between these regions the impact of ageing on neuronal function can differ.
The morpho logy of neurons in the PFC is more susceptible to age-related change, as these cells show a decrease in dendritic branching in rats and humans.
There is also evidence of a small but significant decline in cell number in area 8A of monkeys that is correlated with working memory impairments.
Although there is evidence of Ca2+ dysregulation in aged PFC neurons, the functional consequences of this are not yet known.
Moreover, so far, there are no reports of multiple single unit recordings in the PFC of awake behaving animals.
More is known about the impact of ageing on hippo campal function.
Ca2+ dysregulation and changes in synaptic connectivity might affect plasticity and gene expression, resulting in altered dynamics of hippo campal neuronal ensembles.
Because more is known about the neurobiology of ageing in this brain region, there are therapeutic approaches on the horizon that might modify hippo campal neurobiology and slow age-related cognitive decline or partially restore mechanisms of plasticity.
For example, agents that reduce intracellular Ca2+ concentration following neural activity could modulate the ratio of long-term potentiation (LTP) and long-term depression (LTD) induction, thereby partially restoring normal network dynamics.
Considering that the average lifespan is increasing worldwide, understanding the brain mechanisms that are responsible for age-related cognitive impairment, and finding therapeutic agents that might curb this decline, becomes increasingly important.