Review
Omega-3 fatty acids and brain resistance to ageing and stress: Body of evidence and possible mechanisms

https://doi.org/10.1016/j.arr.2013.01.007Get rights and content

Abstract

The increasing life expectancy in the populations of rich countries raises the pressing question of how the elderly can maintain their cognitive function. Cognitive decline is characterised by the loss of short-term memory due to a progressive impairment of the underlying brain cell processes. Age-related brain damage has many causes, some of which may be influenced by diet. An optimal diet may therefore be a practical way of delaying the onset of age-related cognitive decline. Nutritional investigations indicate that the ω-3 poyunsaturated fatty acid (PUFA) content of western diets is too low to provide the brain with an optimal supply of docosahexaenoic acid (DHA), the main ω-3 PUFA in cell membranes. Insufficient brain DHA has been associated with memory impairment, emotional disturbances and altered brain processes in rodents. Human studies suggest that an adequate dietary intake of ω-3 PUFA can slow the age-related cognitive decline and may also protect against the risk of senile dementia. However, despite the many studies in this domain, the beneficial impact of ω-3 PUFA on brain function has only recently been linked to specific mechanisms.

This review examines the hypothesis that an optimal brain DHA status, conferred by an adequate ω-3 PUFA intake, limits age-related brain damage by optimizing endogenous brain repair mechanisms. Our analysis of the abundant literature indicates that an adequate amount of DHA in the brain may limit the impact of stress, an important age-aggravating factor, and influences the neuronal and astroglial functions that govern and protect synaptic transmission. This transmission, particularly glutamatergic neurotransmission in the hippocampus, underlies memory formation. The brain DHA status also influences neurogenesis, nested in the hippocampus, which helps maintain cognitive function throughout life.

Although there are still gaps in our knowledge of the way ω-3 PUFA act, the mechanistic studies reviewed here indicate that ω-3 PUFA may be a promising tool for preventing age-related brain deterioration.

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)

  • F. Calon et al.

    Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model

    Neuron

    (2004)
  • P.M. Canas et al.

    Modification upon aging of the density of presynaptic modulation systems in the hippocampus

    Neurobiology of Aging

    (2009)
  • M. Cansev et al.

    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

    (2007)
  • C.T. Chen et al.

    Regulation of brain polyunsaturated fatty acid uptake and turnover

    Prostaglandins, Leukotrienes and Essential Fatty Acids

    (2008)
  • F. Chigr et al.

    Neurogenesis inhibition in the dorsal vagal complex by chronic immobilization stress in the adult rat

    Neuroscience

    (2009)
  • D.A. Clayton et al.

    Deficits in the expression of the NR2B subunit in the hippocampus of aged Fisher 344 rats

    Neurobiology of Aging

    (2001)
  • D.A. Clayton et al.

    Aging and surface expression of hippocampal NMDA receptors

    Journal of Biological Chemistry

    (2002)
  • G. Chytrova et al.

    Exercise contributes to the effects of DHA dietary supplementation by acting on membrane-related synaptic systems

    Brain Research

    (2010)
  • G. Clarke et al.

    Chain reactions: early-life stress alters the metabolic profile of plasma polyunsaturated fatty acids in adulthood

    Behavioural Brain Research

    (2009)
  • R.J. Colbran et al.

    Calcium/calmodulin-dependent protein kinase II and synaptic plasticity

    Current Opinion in Neurobiology

    (2004)
  • P. Coti Bertrand et al.

    Maternal dietary (ω-3) fatty acid deficiency alters neurogenesis in the embryonic brain

    Journal of Nutrition

    (2006)
  • T.R. Cowley et al.

    Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP

    Neurobiology of Aging

    (2012)
  • S.C. Cunnane et al.

    Fish, docosahexaenoic acid and Alzheimer's disease

    Progress in Lipid Research

    (2009)
  • N.C. Danbolt

    Glutamate uptake

    Progress in Neurobiology

    (2001)
  • A.D. Dangour et al.

    Fish consumption and cognitive function among older people in the UK: baseline data from the OPAL study

    The Journal of Nutrition, Health & Aging

    (2009)
  • J. Delarue et al.

    Fish oil prevents the adrenal activation elicited by mental stress in healthy men

    Diabetes and Metabolism

    (2003)
  • S. Delion et al.

    Chronic dietary alpha-linolenic acid deficiency alters dopaminergic and serotoninergic neurotransmission in rats

    Journal of Nutrition

    (1994)
  • S. Delion et al.

    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

    (1997)
  • L. De Toledo-Morrell et al.

    Age-dependent alterations in hippocampal synaptic plasticity: relation to memory disorders

    Neurobiology of Aging

    (1988)
  • E.E. Devore et al.

    Dietary intake of fish and omega-3 fatty acids in relation to long-term dementia risk

    American Journal of Clinical Nutrition

    (2009)
  • C. Dullemeijer et al.

    ω-3 Fatty acid proportions in plasma and cognitive performance in older adults

    American Journal of Clinical Nutrition

    (2007)
  • S.C. Dyall et al.

    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

    (2007)
  • J.M. Encinas et al.

    Division-coupled astrocytic differentiation and age-related depletion of neural stem cells in the adult hippocampus

    Cell Stem Cell

    (2011)
  • S. Favrelière et al.

    DHA-enriched phospholipid diets modulate age-related alterations in rat hippocampus

    Neurobiology of Aging

    (2003)
  • I. Fedorova et al.

    Omega-3 fatty acids and rodent behavior

    Prostaglandins, Leukotrienes and Essential Fatty Acids

    (2006)
  • Y. Gao et al.

    Effects of restraint stress on the expression of proteins involved in synaptic vesicle exocytosis in the hippocampus

    Neuroscience

    (2006)
  • Y. Geinisman et al.

    Hippocampal markers of age-related memory dysfunction: behavioral, electrophysiological and morphological perspectives

    Progress in Neurobiology

    (1995)
  • G.M. Gilad et al.

    Region-selective stress-induced increase of glutamate uptake and release in rat forbrain

    Brain Research

    (1990)
  • G.M. Gilad et al.

    Strain, stress, neurodegeneration and longevity

    Mechanisms of Ageing and Development

    (1995)
  • B. Grintal et al.

    Inhibition of astroglial glutamate transport by polyunsaturated fatty acids: evidence for a signalling role of dopcosahexaenoic acid

    Neurochemistry International

    (2009)
  • M.M. Halassa et al.

    The tripartite synapse: roles for gliotransmission in health and disease

    Trends in Molecular Medicine

    (2007)
  • K. Hamazaki et al.

    Effect of omega-3 fatty acid-containing phospholipids on blood catecholamine concentrations in healthy volunteers: a randomized, placebo-controlled, double-blind trial

    Nutrition

    (2005)
  • T. Hamazaki et al.

    Fish oils and aggression or hostility

    Progress in Lipid Research

    (2008)
  • M. Hashimoto et al.

    Chronic administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid beta-infused rats

    Journal of Nutrition

    (2005)
  • M.T. Heneka

    Inflammation in Alzheimer's disease

    Clinical Neuroscience Research

    (2006)
  • B. Heude et al.

    Cognitive decline and fatty acid composition of erythrocyte membranes—the EVA study

    American Journal of Clinical Nutrition

    (2003)
  • M.S. Albert

    The ageing brain: normal and abnormal memory

    Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences

    (1997)
  • J.M. Alessandri et al.

    Polyunsaturated fatty acids in the nervous system: evolution of concepts and nutritional implications throughout life

    Reproduction, Nutrition, Development

    (2004)
  • P. Astorg et al.

    Dietary intakes and food sources of ω-6 and ω-3 PUFA in French adult men and women

    Lipids

    (2004)
  • A.E. Autry et al.

    Glucocorticoid regulation of GLT-1 glutamate transporter isoform expression in the rat hippocampus

    Neuroendocrinology

    (2006)
  • Cited by (111)

    View all citing articles on Scopus
    View full text