Shlomo Yehuda, Bar Ilan University, Department of Psychology, Psychopharmacology Laboratory, Ramat Gan, Israel
“The aging process in the brain is associated with many biochemical, physiological and behavioral changes. While major structural changes occurring during this period have been studied – e.g., the gradual loss of neurons in various brain regions – the course of the progression of these alterations has not yet been established. It is not understood, for example, why the ability of the brain to create new synapses is diminished during ageing. Research has shown that major biochemical changes in the aging brain affect the neuronal membrane that is the site of action for many essential functions, such as the conduction of neuronal information along the nerve fiber (axon), regulation of membrane-bound enzymes, control of the ionic channels structure and activity, and maintenance of various types of receptors. The normal physiological functioning of the neuronal membrane is highly dependent on its structure, and while many factors can influence the membrane fluidity, one of the major factors is the lipid composition of the membrane. During aging, the level of cholesterol in the neuronal membranes, as well as the level of the toxic metabolite of cholesterol (24-OH- cholesterol) increases greatly, which reduces the membrane fluidity (1). On the other hand, the concentration of polyunsaturated fatty acids (PUFAs) in aged neuronal membranes decreases, which may be attributed to a reduced passage rate via the blood-brain barrier, or a decreased rate of incorporation into the membrane. Previous studies have shown that dietary supplementation with a particular ratio of a mixture of omega-3/omega-6 fatty acids can increase membrane fluidity and, thus, may prevent and/or restore many of the undesirable age-related effects in the brain.
At least six categories of PUFA-effects on brain functions have been noted and discussed (2): (a) modifica-tions of membrane fluidity; (b) modifications of the activity of membrane bound enzymes; (c) modifications of the number and affinity of receptors; (d) modifications of the function of ion channels; (e) modifications of the production and activity of neurotransmitters ; (f) signal transduction, which controls the activity of neuro-transmitters and neuronal growth factors. Included among the symptoms of essential fatty acid deficiency are fatigue, dermatological problems, immune problems, weakness, gastrointestinal disorders, heart and circulatory problems, growth retardation, and sterility. In addition to these symptomatic conditions, a lack of dietary essential fatty acids has been implicated in the development or aggravation of breast cancer, pros-tate cancer, rheumatoid arthritis, asthma, preeclampsia, depression, schizophrenia and attention deficit and hyperactivity disorders (ADHD).
Cholesterol is a complex lipid that is involved with many functions of the membrane. It is well established that cholesterol decreases the membrane fluidity index – with consequences on the activity of ion channels and receptor functions – and that the level of cholesterol is increased during aging. Various fatty acids have differential effects on cholesterol metabolism: the administration of omega-6 fatty acids reduces the level of cholesterol in the blood serum by redistributing cholesterol while the omega-3 fatty acids actually reduce the levels of cholesterol in the neuronal membrane (3). This may explain why a slight increase in cholesterol level in the blood is found in humans who consume omega-3 fatty acids supplements. It has been demonstra-ted that omega-3 essential fatty acids are more effective in reducing cholesterol levels in macrophages than omega-6 essential fatty acids. The mechanism by which omega-3 fatty acids are able to reduce the choleste-rol level in the membrane is still unclear.
PUFAs are major molecules responsible for regulating cellular differentiation and apoptosis. Studies on aging report a significant decrease in the level and turnover of PUFA, especially in the hippocampus, cortex, striatum and hypothalamus. Animal studies have shown that the level of docasahexanoic acid (DHA) and arachidonic acid (AA) is very low in the neuronal membrane of the aged hippocampus. Treatment with omega-3 fatty acids improved the membrane status (fluidity). Basically, there are two ways to explain the low level of PUFA in the aging brain: a reduced rate of penetration of PUFA from the blood into the brain and impaired pathways of fatty acid metabolism, responsible for fatty acid incorporation into the membrane.
Recent research has suggested that the treatment of older organisms with omega-3 fatty acids or with omega-3/omega-6 PUFA in the ratio of 1:4 can improve both brain biochemistry and behavior (4, 5). We found that a mixture of alpha-linolenic and linoleic acids with a ratio of 1:4 was the most effective in improving learning performance and the membrane fluidity index. In addition, this mixture was able to reduce some age-related markers such as homocysteine. Those findings indicate that treatment with a mixture of omega-3 and omega-6 fatty acids has much higher beneficial effects than treatment with omega-3 alone.”