ReviewOmega-3 fatty acids and brain resistance to ageing and stress: Body of evidence and possible mechanisms
Highlights
► ω-3 Dietary intakes in western countries are too low to meet brain DHA requirements. ► Human studies suggest that dietary ω-3 help the brain cope with ageing. ► ω-3 Modify stress responses, glutamatergic neurotransmission and glial reaction. ► The cerebral impairments due to ageing could thus be relieved by dietary ω-3.
Introduction
A disturbing feature of western diets is the growing imbalance between ω-6 and ω-3 PUFA that may restrict the availability of ω-3 long-chain polyunsaturated fatty acids (LC-PUFA) (mainly docosahexaenoic acid, DHA) to the tissues and lead to a mild ω-3 PUFA deficiency. Because DHA is more abundant in the brain than in most other tissues, there have been many studies on the effect of an inadequate ω-3 PUFA nutritional intake on brain function (cognition, behaviour) and disorders (psychiatric and neurodegenerative).
Several lines of evidence suggest that an adequate dietary intake of ω-3 PUFA throughout life can preserve cognitive function in the elderly. An increased dietary intake of ω-3 PUFA would therefore be a valuable nutritional strategy for coping with the health concerns in the ageing populations of the developed world. Many of the epidemiological studies questioning the link between the intake of ω-3 PUFA and brain ageing have shown that high ω-3 PUFA intakes are associated with a slower age-related cognitive decline and a lower risk of neurodegenerative dementia, including Alzheimer's disease. However, the many pitfalls associated with human nutritional studies make it almost impossible to clearly demonstrate the benefits of ω-3 PUFA for brain ageing. It is difficult to isolate the ω-3 PUFA intake of subjects from other environmental/cultural factors, and attempts to reduce cognitive decline or dementia with dietary supplements of ω-3 PUFA have so far given differing or inconsistent results.
We need to understand the part played by ω-3 PUFAs in the mechanisms contributing to brain ageing and cognitive decline in order to develop the nutritional guidelines and health claims suggested by epidemiological studies. The experimental data accumulated over the past two decades provide a number of clues to the role of ω-3 PUFAs (especially DHA, the main ω-3 PUFA in brain cell membranes) in regulating the glutamatergic synapses that are responsible for memory formation and maintaining their efficacy during ageing. Glutamate is the major excitatory neurotransmitter in the brain. Glutamatergic synapses are particularly abundant in the hippocampus, the brain area mainly involved in memory processes. The plasticity of the glutamatergic synapse is characterised by persistent increase (long-term potentiation, LTP) or decrease (long-term depression, LTD) in synaptic efficacy, which are generally considered to be the major cellular mechanisms that underlie learning and memory. The plasticity of glutamatergic synapses is supported by the concerted action of three cellular partners. These are the pre-synaptic and post-synaptic neuronal compartments and the surrounding astrocyte (the tripartite synapse: for review see Halassa et al., 2007). The homeostasis of the synaptic environment ensures the fine tuning of glutamatergic neurotransmission. Its disruption is an initiating and/or propagating step in age-related brain damage leading to cognitive decline.
This review assesses the numerous and disparate data on the topic to determine how ω-3 PUFA influence the maintenance of the efficient synaptic transmission needed to support memory formation throughout life. We focus on the emerging role of DHA in the neuron–astrocyte cross-talk at the glutamatergic synapse and in the process of hippocampal neurogenesis, both of which are crucial for maintaining proper synaptic function and the associated memory processes during ageing.
Another interesting effect of ω-3 PUFA is their possible ability to regulate the physiological responses to stress and putatively to reduce the deleterious impact of stress on the brain. The long-term consequences of repeated or prolonged stress on brain physiology, and especially on the glutamatergic synapse, may indeed greatly contribute to exacerbate age-related damage to the brain. We therefore also examined data exploring the positive impact of ω-3 PUFA on the resistance to stress, inasmuch as it can explain part of the neuroprotective action of ω-3 PUFA on brain ageing.
Section snippets
Imbalance between ω-6 and ω-3 PUFA in western diets
The ω-6 PUFA content of western diets has increased considerably over the past four decades, while the ω-3 PUFA content has remained unchanged. This is due to the increased consumption of vegetable oils rich in linoleic acid (LA, 18:2ω-6) and poor in α-linolenic acid (LNA, 18:3ω-3), such as peanut or sunflower oil, and to the increased ω-6/ω-3 LC-PUFA ratio in meat and dairy products resulting from changes in animal feeding. Therefore, the dietary intakes of ω-3 LC-PUFA (docosahexaenoic acid
Human studies linking ω-3 PUFA to brain ageing
Several lines of evidence suggest that an adequate dietary intake of ω-3 PUFA can prevent cognitive decline and attenuate the physiological disturbances of the brain that are associated with ageing.
There is evidence from several epidemiological studies for an inverse correlation between the ω-3 PUFA intake or fish consumption and the risk of Alzheimer's disease (Kalmijn, 2000, Morris et al., 2003, Morris et al., 2005, Barberger-Gateau et al., 2002, Barberger-Gateau et al., 2005, Schaefer et
Possible influence on stress-induced brain alteration
Stress response, which physiologically promotes the adaptation of the body to acute environmental changes, can also induce deleterious processes in the brain in case of chronic exposure. Chronic stress associated alterations are thought to be an aggravating factor in brain ageing. Because ω-3 PUFA seems to temper some features of stress response, one of their major neuroprotective actions may be through their involvement in the stress axis regulation.
Mechanistic leads
The hypothesis that a high brain content of DHA optimises the resistance of the brain to stress and ageing is supported by studies showing that DHA is involved in the mechanisms governing synaptic function and its regulation/protection. We will therefore examine the aspects of neuronal and astroglial activities that are influenced by the brain DHA status and may help maintain cognitive performance during ageing. We will focus on the tripartite synapse supporting glutamatergic transmission (the
Conclusion
Considering the nutritional imbalance between ω-6 and ω-3 PUFA in western diets, the risk of sub-optimal amounts of DHA in the brains of these populations is far from negligible. Analysis of the data from human and animal studies indicates that such a decrease in brain DHA may lead to the erosion of physiological regulation involved in stress responses and of that occurring in the brain during ageing. The aggravation of the impact of stress and ageing on brain, induced by a low status in ω-3
Acknowledgement
The authors thank Dr. Owen Parkes for revising the English manuscript.
References (259)
- et al.
Reduced numbers of dopamine neurons in the substantia nigra pars compacta and ventral tegmental area of rats fed an ω-3 polyunsaturated fatty acid-deficient diet: a stereological study
Neuroscience Letters
(2008) - et al.
Effect of a diet-induced (ω-3) polyunsaturated fatty acid depletion on cholinergic parameters in the rat hippocampus
Journal of Lipid Research
(2003) - et al.
Dietary docosahexaenoic acid (22: 6ω-3) as phospholipids or triglycerides both enhance the KCl-evoked release of acetylcholine in the rat hippocampus
Journal of Nutrition
(2005) - et al.
Temporal changes in dietary fats: role of ω-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity
Progress in Lipid Research
(2006) - et al.
Incorporation of docosahexaenoic acid into nerve membrane phospholipids: bridging the gap between animals and cultured cells
American Journal of Clinical Nutrition
(2003) - et al.
A diet high in omega-3 fatty acids does not improve or protect cognitive performance in Alzheimer's transgenic mice
Neuroscience
(2007) - et al.
Aged monkeys exhibit behavioral deficits indicative of widespread cerebral dysfunction
Neurobiology of Aging
(1991) Aging and the physiology of spatial memory
Neurobiology of Aging
(1988)- et al.
NMDA receptor activation in the aged rat: electrophysiological investigations in the CA1 area of the hippocampal slice ex vivo
Neurobiology of Aging
(1997) - et al.
Experimental models and mechanisms underlying the protective effects of n-3 polyunsaturated fatty acids in Alzheimer's disease
The Journal of Nutritional Biochemistry
(2009)
Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model
Neuron
Modification upon aging of the density of presynaptic modulation systems in the hippocampus
Neurobiology of Aging
Chronic administration of docosahexaenoic acid or eicosapentaenoic acid, but not arachidonic acid, alone or in combination with uridine, increases brain phosphatide and synaptic protein levels in gerbils
Neuroscience
Regulation of brain polyunsaturated fatty acid uptake and turnover
Prostaglandins, Leukotrienes and Essential Fatty Acids
Neurogenesis inhibition in the dorsal vagal complex by chronic immobilization stress in the adult rat
Neuroscience
Deficits in the expression of the NR2B subunit in the hippocampus of aged Fisher 344 rats
Neurobiology of Aging
Aging and surface expression of hippocampal NMDA receptors
Journal of Biological Chemistry
Exercise contributes to the effects of DHA dietary supplementation by acting on membrane-related synaptic systems
Brain Research
Chain reactions: early-life stress alters the metabolic profile of plasma polyunsaturated fatty acids in adulthood
Behavioural Brain Research
Calcium/calmodulin-dependent protein kinase II and synaptic plasticity
Current Opinion in Neurobiology
Maternal dietary (ω-3) fatty acid deficiency alters neurogenesis in the embryonic brain
Journal of Nutrition
Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP
Neurobiology of Aging
Fish, docosahexaenoic acid and Alzheimer's disease
Progress in Lipid Research
Glutamate uptake
Progress in Neurobiology
Fish consumption and cognitive function among older people in the UK: baseline data from the OPAL study
The Journal of Nutrition, Health & Aging
Fish oil prevents the adrenal activation elicited by mental stress in healthy men
Diabetes and Metabolism
Chronic dietary alpha-linolenic acid deficiency alters dopaminergic and serotoninergic neurotransmission in rats
Journal of Nutrition
Age-related changes in phospholipid fatty acid composition and monoaminergic neurotransmission in the hippocampus of rats fed a balanced or an ω-3 polyunsaturated fatty acid deficient diet
Journal of Lipid Research
Age-dependent alterations in hippocampal synaptic plasticity: relation to memory disorders
Neurobiology of Aging
Dietary intake of fish and omega-3 fatty acids in relation to long-term dementia risk
American Journal of Clinical Nutrition
ω-3 Fatty acid proportions in plasma and cognitive performance in older adults
American Journal of Clinical Nutrition
Dietary enrichment with omega-3 polyunsaturated fatty acids reverses age-related decreases in the GluR2 and NR2B glutamate receptor subunits in rat forebrain
Neurobiology of Aging
Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus
Cell Stem Cell
DHA-enriched phospholipid diets modulate age-related alterations in rat hippocampus
Neurobiology of Aging
Omega-3 fatty acids and rodent behavior
Prostaglandins, Leukotrienes and Essential Fatty Acids
Effects of restraint stress on the expression of proteins involved in synaptic vesicle exocytosis in the hippocampus
Neuroscience
Hippocampal markers of age-related memory dysfunction: behavioral, electrophysiological and morphological perspectives
Progress in Neurobiology
Region-selective stress-induced increase of glutamate uptake and release in rat forbrain
Brain Research
Strain, stress, neurodegeneration and longevity
Mechanisms of Ageing and Development
Inhibition of astroglial glutamate transport by polyunsaturated fatty acids: evidence for a signalling role of dopcosahexaenoic acid
Neurochemistry International
The tripartite synapse: roles for gliotransmission in health and disease
Trends in Molecular Medicine
Effect of omega-3 fatty acid-containing phospholipids on blood catecholamine concentrations in healthy volunteers: a randomized, placebo-controlled, double-blind trial
Nutrition
Fish oils and aggression or hostility
Progress in Lipid Research
Chronic administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid beta-infused rats
Journal of Nutrition
Inflammation in Alzheimer's disease
Clinical Neuroscience Research
Cognitive decline and fatty acid composition of erythrocyte membranes—the EVA study
American Journal of Clinical Nutrition
The ageing brain: normal and abnormal memory
Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences
Polyunsaturated fatty acids in the nervous system: evolution of concepts and nutritional implications throughout life
Reproduction, Nutrition, Development
Dietary intakes and food sources of ω-6 and ω-3 PUFA in French adult men and women
Lipids
Glucocorticoid regulation of GLT-1 glutamate transporter isoform expression in the rat hippocampus
Neuroendocrinology
Cited by (111)
Origins of nervous tissue susceptibility to ferroptosis
2023, Cell InsightForaging on anthropogenic food predicts problem-solving skills in a seabird
2022, Science of the Total EnvironmentDesign and methods for the Ranger Resilience and Improved Performance on Phospholipid bound Omega-3's (RRIPP-3 study)
2019, Contemporary Clinical Trials Communications