Elsevier

Neurobiology of Aging

Volume 23, Issue 5, September–October 2002, Pages 707-717
Neurobiology of Aging

The glucocorticoid paradox of caloric restriction in slowing brain aging

https://doi.org/10.1016/S0197-4580(02)00017-9Get rights and content

Abstract

Glucocorticoids have a bimodal effect on cognition, hippocampal pyramidal neurons and long-term potentiation (LTP). Transient increases in glucocorticoids improve performance at spatial memory tasks and facilitate synaptic efficacy, depending on the context. On the other hand, long-term elevations of glucocorticoids are associated with decreased cognitive performance, attenuated synaptic efficacy and neuronal atrophy. Elevation of glucocorticoids during aging is also associated with mild cognitive impairment and hippocampal atrophy.

Caloric restriction (CR), a dietary manipulation which extends life-span in rodents, also increases free plasma corticosterone. Recent data suggests that CR attenuates many brain aging changes and increases resistance of neurons to toxins and injury. Thus, a paradox may be considered: if CR causes chronic elevation of glucocorticoids, and if glucocorticoids can increase the risk of neurodegeneration, how can CR be neuroprotective. We suggest that the neuroprotective effects of CR outweigh the deleterious effects of glucocorticoids. The neuroprotective effects of CR that are discussed here include decreased plasma glucose, attenuated free radical generation, alterations of the vasculature, increased expression of heat shock proteins and neurotrophic factors, and attenuation of age-related glial activation.

Introduction

Chronic caloric restriction (CR) is well established to increase the life-span and protect hippocampal functions during aging in rodents. CR, however, also elevates blood corticosterone. Elevations of blood glucocorticoids (CORT; cortisol in humans and corticosterone in rodents) during chronic stressful conditions are associated with cognitive impairment and hippocampal atrophy in both humans and rodents. Thus, a paradox may be considered: if CR causes chronic elevation of CORT, and if CORT can increase the risk of neurodegeneration, how can CR be neuroprotective.

This review focuses on how CR may protect hippocampal function despite the elevated CORT. In parallel, we briefly summarize the evidence suggesting that elevation in CORT during aging and stress contributes to cognitive impairment and hippocampal damage.

Section snippets

Brief review of CR

CR slows many aging processes and extends the life-span of laboratory rodents. More than 100 studies show that a reduction of ad libitum (AL) caloric intake by 10–40% in adult rodents, without deficiencies of micronutrients, proportionately extends their life-span [18], [59], [101], [110]. The increased life-span is due to a slower onset of many pathological conditions throughout the body that are associated with morbidity. The particular chronic and degenerative diseases that are attenuated by

Chronic CORT elevation is associated with cognitive impairment and hippocampal atrophy in humans

During aging, humans show an increasing risk of slow and progressive elevations of blood CORT, which is associated with a higher risk of cognitive impairments that range from severe changes in Alzheimer’s disease to mild changes in the speed of information processing. Why individuals differ so widely during aging remains a mystery. Valuable information has come from several longitudinal studies. The MacArthur Foundation Study on Successful Aging examined three different groups of healthy

Rodent studies: effects of CORT, aging and CR

Chronic CORT elevation in rodents is also associated with hippocampal damage. Muhlen and Ockenfels were the first to report that chronic treatment with cortisone preferentially causes pyknosis (shrinkage) of cell bodies and nuclei of pyramidal neurons in guinea pigs [72]. Many subsequent experiments have established that elevation of CORT by either stress or pharmacological administration can endanger hippocampal neurons [90]. An age-related increase in CORT also decreases post-maturational

How does CR attenuate age-related hippocampal impairment?

The brain has a very high demand for glucose and is particularly vulnerable to alterations in energy supply. Regional glucose utilization in the hippocampus, prefrontal cortex, and medial septum was correlated with escape latency in the Morris water maze [24]. Aging decreases regional cerebral blood flow in rat [25], [100], which may contribute to the age-related cognitive impairment. The reduction in cerebral blood flow in the aged AL rats is attributable to the combination of blood vessel

Role of astrocytes

The age-related increase in hippocampal hypertrophic astrocytes was positively correlated with CORT levels in middle-aged rats [40]. GFAP expression, which is a correlate of astrocytic activation, shows strong generalized increases with age in mice, rats, and humans [26], [43], [73]. This increase in GFAP expression and astrocytic fibrosis was associated with the rate of transcription [37] in sub-population of astrocytes [116]. In vitro, astrocytes expressing GFAP are inhibitory to neurites,

Role of microglia

Several lines of evidence suggest that neuro-inflammatory processes promote neurodegeneration (e.g. [1]). With age, there was an increase in microglial activation in several brain regions including the hippocampus [71]. Possible mechanisms could include microglial reaction to glyco-oxidized proteins. Non-enzymatic reactions of glucose and other reducing sugars with proteins slowly proceeds through Amadori rearrangement to form Maillard products that are also referred to as advanced glycation

Conclusion

Elevation of CORT during acute stress may be essential for immediate survival, but chronic elevation of CORT has multiple, slowly evolving deleterious effects. The age-related increase in CORT is associated with hippocampal atrophy, cognitive impairment, decreased LTP, and reduced neurogenesis. However, these effects are not observed in CR rodents despite the diurnal CORT elevation. CR improves the performance of aged rats at spatial memory tasks, protects the neurons from excitotoxins,

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