The glucocorticoid paradox of caloric restriction in slowing brain aging
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,
References (118)
- et al.
Inflammation and Alzheimer’s disease
Neurobiol. Aging
(2000) - et al.
Age-related ability of rats kept on a life-long hypocaloric diet in a spatial memory test. Longitudinal observations
Neurobiol. Aging
(1991) - et al.
Temporal and substrate-dependent patterns of stress protein expression in the hypothalamus of caloric restricted rats
Mech. Aging Dev.
(1994) - et al.
Chronic caloric restriction induces stress proteins in the hypothalamus of rats
Mech. Aging Dev.
(1994) - et al.
Caloric restriction and spatial learning in old mice
Physiol. Behav.
(1996) - et al.
Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice
Neurobiol. Aging
(1998) - et al.
Stress and cognition: are corticosteroids good or bad guys?
Trends Neurosci.
(1999) - et al.
Effect of age and caloric intake on protein oxidation in different brain regions and on behavioral functions of the mouse
Arch. Biochem. Biophys.
(1996) - et al.
Caloric restriction prevents age-related deficits in LTP and in NMDA receptor expression
Brain Res. Mol. Brain Res.
(2000) - et al.
Aging, metabolism, and Alzheimer disease: review and hypotheses
Exp. Neurol.
(1997)
Aging and caloric restriction affect mitochondrial respiration and lipid membrane status: an electron paramagnetic resonance investigation
Free Radic. Biol. Med.
Correlation of behavioral and cerebrovascular functions in the aging rat
Neurobiol. Aging
Stress: metaplastic effects in the hippocampus
Trends Neurosci.
Aging is associated with divergent effects on Nf-L and GFAP transcription in rat brain
Neurobiol. Aging
Increased affinity of type II corticosteroid binding in aged rat hippocampus
Exp. Neurol.
Dietary restriction selectively decreases glucocorticoid receptor expression in the hippocampus and cerebral cortex of rats
Exp. Neurol.
Effects of moderate caloric restriction on cortical microvascular density and local cerebral blood flow in aged rats
Neurobiol. Aging
Cellular bases of functional brain imaging: insights from neuron–glia metabolic coupling
Brain Res.
Influence of dietary restriction on ionotropic glutamate receptors during aging in C57B1 mice
Mech. Aging Dev.
Aging of glutamate receptors: correlations between binding and spatial memory performance in mice
Mech. Aging Dev.
Influence of diet restriction on NMDA receptor subunits and learning during aging
Neurobiol. Aging
NT-3, BDNF, and NGF in the developing rat nervous system: parallel as well as reciprocal patterns of expression
Neuron
Life-long diet restriction failed to retard cognitive aging in Fischer 344 rats
Neurobiol. Aging
Neuroprotective signaling and the aging brain: take away my food and let me run
Brain Res.
Signal transduction through NF-kappa B
Immunol. Today
Stress and cognitive function
Curr. Opin. Neurobiol.
Mid-life onset of dietary restriction extends life and prolongs cognitive functioning
Physiol. Behav.
The mosaic of brain glial hyperactivity during normal aging and its attenuation by food restriction
Neuroscience
GFAP mRNA increases with age in rat and human brain
Neurobiol. Aging
Messenger RNA for glial fibrillary acidic protein is decreased in rat brain following acute and chronic corticosterone treatment
Brain Res. Mol. Brain Res.
Redox-dependent regulation of nuclear import of the glucocorticoid receptor
J. Biol. Chem.
Role of calcium in neuronal cell injury: which subcellular compartment is involved?
Brain Res. Bull.
Role of adrenal steroid mineralocorticoid and glucocorticoid receptors in long-term potentiation in the CA1 field of hippocampal slices
Brain Res.
Deterioration of spatial and non-spatial reference and working memory in aged rats: protective effect of life-long calorie restriction
Neurobiol. Aging
Effect of life-long hypocaloric diet on age-related changes in motor and cognitive behavior in a rat population
Neurobiol. Aging
Molecular mechanisms of brain aging and neurodegenerative disorders: lessons from dietary restriction
Trends Neurosci.
Memory impaired aged rats: no loss of principal hippocampal and subicular neurons
Neurobiol. Aging
Do glucocorticoid concentrations rise with age in the rat?
Neurobiol. Aging
Glucocorticoids, stress, and their adverse neurological effects: relevance to aging
Exp. Gerontol.
Heat shock protein protection
Trends Neurosci.
Food restriction reduces brain damage and improves behavioral outcome following excitotoxic and metabolic insults
Ann. Neurol.
Macrophage migration inhibitory factor (MIF): a glucocorticoid counter-regulator within the immune system
Crit. Rev. Immunol.
Restoring production of hippocampal neurons in old age
Nat. Neurosci.
Inverted-U relationship between the level of peripheral corticosterone and the magnitude of hippocampal primed-burst potentiation
Hippocampus
Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function
Behav. Neurosci.
Altered alveolar macrophage function in calorie-restricted rats
Am. J. Respir. Cell. Mol. Biol.
Brain-derived neurotrophic factor mediates an excitoprotective effect of dietary restriction in mice
J. Neurochem.
Hematologic and serum electrolyte values of the C57BL-6J male mouse in maturity and senescence
Lab. Anim. Sci.
Cited by (100)
Micronutrients and the evolution of the human brain
2023, NFS JournalEffects of dietary restriction on gut microbiota and CNS autoimmunity
2022, Clinical ImmunologyCalorie restriction improves aging-induced impairment of cognitive function in relation to deregulation of corticosterone status and brain regional GABA system
2020, Mechanisms of Ageing and DevelopmentCitation Excerpt :In relation to the aforesaid discussion regarding the effect of CRH and ACTH release on aging-induced hypothalamic GABAergic neuronal deregulation, it may be mentioned that the CR diet supplementation under short-term condition to the aged (18 and 24 months) rats might attenuate the aging-induced HPA axis feedback mechanism and seems to down-regulate the corticosterone level in adrenal glands as well as in plasma (Table 5) towards its level of control rats and helps to minimize the aging-induced deteriorating effect of corticosterone on inhibitory neurotransmitter (GABA) system. In this context, it may be mentioned that although Patel and Finch (2002) and others (Wan et al., 2003; Marinković et al., 2007; Stamp et al., 2008) have shown that dietary restriction increases the corticosterone level in plasma which is not unlikely as they have restricted the calorie by depriving the food of the animals and this deprivation causes additional stress during their study. To avoid such appetite-induced stress, the present study has been designed with ad libitum supplementation of calorie restricted diet (Algeri et al., 1990; Pitsikas et al., 1990; Maliković et al., 2018).
Cognitive ability across the life course and cortisol levels in older age
2017, Neurobiology of AgingISX-9 can potentiate cell proliferation and neuronal commitment in the rat dentate gyrus
2016, NeuroscienceCitation Excerpt :On the other hand, we found a significant increase in circulating CORT levels in animals that received Isx-9 for 14 days. This finding is in accordance with previous studies that have also shown an increase in CORT with well-known pro-neurogenic factors such as environmental enrichment (Benaroya-Milshtein et al., 2004; Moncek et al., 2004), voluntary physical exercise (Adlard and Cotman, 2004), caloric restriction (Patel and Finch, 2002; Martin et al., 2006), and treatment with antidepressants such as fluoxetine [as previously demonstrated by us (Machado et al., 2012) and other groups (Duncan et al., 1998; Weber et al., 2006)]. One possible explanation for our findings is that similarly to these pro-neurogenic factors (i.e., environmental enrichment, voluntary physical exercise, caloric restriction, and fluoxetine), the repeated administration of Isx-9 may cause moderate stress in the animals, leading to an adaptive response and consequent activation of molecular mechanisms of neuroplasticity that outweigh the effects of increased CORT levels on hippocampal progenitor cells.
Metabolic Stress, Heat Shock Proteins, and Innate Immune Response
2016, The Innate Immune Response to Non-infectious Stressors: Human and Animal Models