Neurobiology of Aging 23 (2002) 843–853 The role of polyunsaturated fatty acids in restoring the aging neuronal membrane Shlomo Yehuda a,∗ , Sharon Rabinovitz a , Ralph L. Carasso b , David I. Mostofsky c a Psychopharmacology Laboratory, Department of Psychology, Bar Ilan University, Ramat Gan 52900, Israel b Department of Neurology, Hillel Yaffe Hospital, Hedera, Israel c Department of Psychology, Boston University, Boston, MA, USA Received 29 August 2001; received in revised form 30 January 2002; accepted 11 April 2002 Abstract In addition to a gradual loss of neurons in various brain regions, major biochemical changes in the brain affect the neuronal membrane that is the “site of action” for many essential functions including long-term potentiation (LTP), learning and memory, sleep, pain threshold, and thermoregulation. Normal physiological functioning includes the transmission of axonal information, regulation of membrane-bound enzymes, control of ionic channels and various receptors. All are highly dependent on membrane fluidity, where rigidity is increased during aging. The significantly higher level of cholesterol in aging neuronal membrane, the slow rate of cholesterol turnover, and the decreased level of total polyunsaturated fatty acids (PUFA) may result from poor passage rate via the blood–brain barrier, or from a decreased rate of incorporation into the membrane, or a decrease in the activities of delta-6 and delta-9 desaturase enzymes. The added oxidative stress, which leads to an increase of free radicals leading to a decrease in membrane fluidity, may respond to a restricted diet, and thereby overcome the damaging effects of the free radicals. A central focus of this review is that a specific ratio of n-3/n-6 PUFA can restore many of these age-related effects. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Essential fatty acids; PUFA; Neuronal membrane; Aging 1. Introduction Brain aging is a complex process involving many factors. Some are independent and others are inter-related. The ag- ing brain is associated with many biochemical, physiolog- ical and behavioral deficiencies including, but not limited to, reduction of long-term potentiation (LTP), learning and memory loss, sleep disturbance, pain threshold alteration, and disturbed thermoregulation. To better understand the aging process, the structural approach has been proposed, in which major structural changes occurring during this period are studied, e.g. the gradual loss of neurons in various brain regions. However, the course of the progression of these changes has not yet been established. While we know that it is a long and slow process, we do not know the appropriate statistic model to best predict the rate or form of the decline in either structure or function. The ability of the brain to create new synapses (synaptic genesis) is diminished during this period for rea- ∗ Corresponding author. Tel.: +972-3-531-8583; fax: +972-3-535-3327. E-mail address: yehudas@mail.biu.ac.il (S. Yehuda). sons that are not understood. Concurrently, there are major biochemical changes in the brain that affect the neuronal membrane, that is the “site of action” for many essential functions. Such functions include the conduction of neu- ronal information along the axon, regulation of membrane bound enzymes, control of the ionic channels structure and activity, and maintenance of various types of receptors. During aging, the level of cholesterol in the neuronal membranes as well as the level of the toxic metabolite of cholesterol (24-OH-cholesterol) is greatly increased, and the corresponding rigidity of the neuronal membrane is significantly increased ([3]; see also Section 14 of this pa- per). The normal physiological functioning of the neuronal membrane is highly dependent on its structure, and while many factors can influence the membrane fluidity index, one of the major factors is the lipid composition of the membrane, where cholesterol reduces the membrane flu- idity, and polyunsaturated fatty acids (PUFA) increase it. The brain can obtain long chain PUFA (LC-PUFA) directly from the diet, or it can use supplemented essential fatty acids (linoleic and alpha-linolenic) and convert them to longer chain fatty acids. 0197-4580/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII:S0197-4580(02)00074-X