Neurobiology of Aging 26S (2005) S98–S102

Essential fatty acids and the brain: From infancy to aging

S. Yehuda a,∗ , S. Rabinovitz a , D.I. Mostofsky b
a Psychopharmacology Laboratory, Department of Psychology and Brain Research, Institute, Bar Ilan University,
Ramat Gan 52900, Israel
b Department of Psychology, Boston University, Boston, MA, USA

Received 3 September 2005; accepted 11 September 2005

Abstract

The major effects of essential fatty acids (EFA) on brain structure and functions are reviewed. EFA determine the fluidity of neuronal
membrane and control the physiological functions of the brain. EFA is also involved in synthesis and functions of brain neurotransmitters,
and in the molecules of the immune system. Since they must be supplied from the diet, a decreased bioavailability is bound to induce major
disturbances. While the brain needs a continuous supply during the life span, there are two particularly sensitive periods—infancy and aging.
EFA deficiency during infancy delays brain development, and in aging will accelerate deterioration of brain functions. In discussing the role
of EFA two issues must be considered—the blood–brain barrier, which determines the bioavailability, and the myelination process, which
determines the efficiency of brain and retinal functions.
© 2005 Elsevier Inc. All rights reserved.

Keywords: Essential fatty acids; Brain; Infancy; Aging; Membrane fluidity; BBB

1. Introduction Clearly, the blood–brain barrier is a key to the bioavailability

Dietary essential fatty acids (EFA) mediate brain functions
and structures from infancy to aging, and are involved in many
brain related disorders. They are considered essential because
the body cannot synthesize them and they must be supplied
via diet. As one of the most fatty tissues in the body, the
brain needs fats (together with glucose) for energy and for
the maintenance of normal brain functions.
Fatty acids are commonly classified as saturated, monoun-
saturated, and polyunsaturated (PUFA) fatty acids, depending
on the chemical structure and the length of the chain that can
vary from 12 to 26 carbon bonds. Two types of PUFA are
EFA: linoleic acid and alpha-linolenic acid. EFA have the
shorter carbon chain (18 bonds), while other PUFA are deriva-
tives of these EFA, and have longer chains. The brain cannot
distinguish among longer chain fatty acids that have been
synthesized in the brain, and those same fatty acids that have
been obtained from diet and crossed the blood–brain barrier.
∗ Corresponding author. Tel.: +972 3 531 8583; fax: +972 3 535 3327.
E-mail address: yehudas@mail.biu.ac.il (S. Yehuda).
of brain EFA and PUFA.
Linoleic acid is a member of the omega-6 (n-6) fatty acids
family, while alpha-linolenic acid is an omega-3 (n-3) fatty
acid. These terms refer to characteristics in the chemical
structure of the fatty acids. Other omega-6 fatty acids, such
as gamma-linolenic acid (GLA), dihomo-gamma-linolenic
acid (DHGLA), and arachidonic acid (AA), can be manu-
factured in the body using linoleic acid as a starting point.
Similarly, other omega-3 fatty acids that are manufactured
in the body, using alpha-linolenic acid as a starting point,
include eicosapentaenoic acid (EPA) and docosahexaenoic
acid (DHA). The relationship between the omega-3 and
omega-6 families, and the role of various PUFA as precursors
to bioactive molecules (such as prostaglandin) is described
in Fig. 1.
Among the significant components of cell membranes are
the phospholipids that contain fatty acids. The types of fatty
acids in the diet determine the types of fatty acids that are
available to the composition of the cell membranes. A phos-
pholipid made from a saturated fat has a different structure
and is less fluid than one that incorporates an essential fatty

0197-4580/$ – see front matter © 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.neurobiolaging.2005.09.013
 S. Yehuda et al. / Neurobiology of Aging 26S (2005) S98–S102
Fig. 1. Some of the major essential fatty acids and their metabolites.
acid. In addition, linoleic and alpha-linolenic acids per se have
an effect on the neuronal membrane fluidity index. They are
able to decrease the cholesterol level in the neuronal mem-
brane, which would otherwise decrease membrane fluidity,
which in turn would make it difficult for the cell to carry out
its normal functions and increase the cell’s susceptibility to
injury and death. These consequences for cell function are not
restricted to absolute levels of EFAs alone, rather it appears
that the relative amounts of omega-3 fatty acids and omega-6
fatty acids in the cell membranes are responsible for affecting
cellular function.
At least six categories of PUFA effects on brain functions
have been discussed elsewhere [40], namely: (a) modifica-
tions of membrane fluidity; (b) modifications of the activity
of membrane bound enzymes; (c) modifications of the num-
ber and affinity of receptors; (d) modifications of the function
of ion channels; (e) modifications of the production and
activity of neurotransmitters; (f) signal transduction, that con-
trols the activity of neurotransmitters and neuronal growth
factors.
Symptoms of essential fatty acid deficiency include
fatigue, dermatological problems, immune problems, weak-
ness, gastrointestinal disorders, heart and circulatory prob-
lems, growth retardation, and sterility. In addition to these
symptoms, lack of dietary essential fatty acids has been impli-
cated in the development or aggravation of breast cancer,
prostate cancer, rheumatoid arthritis, asthma, preeclampsia,
depression, schizophrenia, and attention deficit and hyperac-
tivity disorders (ADHD) [39]. This list is neither exhaustive
nor conclusive.
S99
2. Membrane fluidity and myelin
Fatty acids are major components in brain structure. Very
high levels of fatty acids and lipids can be found in two struc-
tural components; the neuronal membrane and the myelin
sheath. About 50% of the neuronal membrane is composed
of FA, while in the myelin sheath lipids constitute about 70%.
The lipid component has a relatively high turnover rate, in
contrast to the protein component that is especially stable.
The membrane fluidity index is a common denominator
for the various effects of the various PUFAs and ratios of
omega-6 to omega-3 [34,37]. Some molecules are able to
change the physical state (e.g. the fluidity index) of the mem-
brane; e.g. alcohol fluidizes the membrane, while cholesterol
hardens it. The ability of PUFA to modify the neuronal
membrane fluidity index is correlated with different ratios
of various fatty acids that can change the neuronal functions,
and with supplementation of various fatty acids that can affect
the composition and the function of the neuronal membrane
[36,42].
The integrity of the myelin is of utmost importance for the
proper functions of axons in the nervous system. Breakage
or lesions in the myelin can lead to disintegration of many of
the nervous system functions. Recent studies emphasize the
major role of dietary EFA to the normal functions of myelin.
Moreover, the EFA are important in the active phase of the
myelin synthesis. If EFA are not available in this phase or
are metabolically blocked, amyelination, dysmyelination, or
demyelanation may occur [3,26]. If EFA deficiency occurs
during the postnatal period, a major delay in the myelination
S100 S. Yehuda et al. / Neurobiology of Aging 26S (2005) S98–S102
process will occur, accompanied by impaired learning, motor,
vision, and auditory abnormalities [30]. Similar impairments
in the myelination process and in the cognitive function are
found in postnatal iron deficient rodents and humans [43].
Disorders associated with myelin malfunction or with dys-
myelination, can also occur during the adult period, e.g.
multiple sclerosis. The rate of myelin lipids turnover is age-
dependent, and with a very slow turnover rate during aging,
and the rate of repairing damaged sections of myelin is cor-
respondingly slower [1].
3. Essential fatty acids, the blood–brain barrier, and
the brain
Since EFA must be supplied via the diet, it must be
possible for EFA and PUFA to cross the blood–brain barrier
(BBB). The involvement of the BBB is crucial in two devel-
opment periods: infancy and aging. The human infant is born
with an immature BBB with the structure and functions of
the BBB not at their optimal levels. There have been reports
of structural changes in the blood–brain barrier complex,
in aging and in Alzheimer’s patients, but our knowledge of
functional changes is quite limited. The important, but as
yet unanswered question is whether omega-6 and omega-3
fatty acids have different rates of transport into the brain.
[34].
A second issue concerns the immature infant brain’s abil-
ity to convert the linoleic and alpha-linolenic fatty acids
that are ingested from diet into longer chain fatty acids, e.g.
arachidonic acid (AA) and docosahexaenoic acid (DHA), The
majority of studies agree that even the infant brain has such
a capacity [34]. EFA and PUFA improve the functions of the
BBB while infusion of saturated fatty acids into the carotid
artery caused vasogenic edema and disruption of functions
[20]. This finding can explain the alteration in glucose trans-
port in the brain in omega-3 deficiency [31].
4. Brain neurotransmitters and PUFA
The relationships between PUFA ratios and the various
neurotransmitters are of special interest [36]. It is impor-
tant to note that omega-3 deficiency reduces the dopamine
vesicle density in the cortex and causes malfunction of
the dopaminergic mesocorticolimbic pathway. The ability to
recover from the dopaminergic effects of omega-3 deficiency
is age-dependent, while the contribution of alpha-linolenic
acids to recovery from omega-3 deficiency is dependent on
the specific member of the n-3 group.
5. PUFA and the immune system
Repeated demonstrations that PUFA can modify the
production and activity of various components of the
immune system leave unexplained the mode of action of
its effects. The PUFA mediation of immunological func-
tions and cytokines level is evident in several disorders
such as Alzheimer and schizophrenia [33]. Several mech-
anisms have been proposed, including membrane fluidity
(changes that might effect the capability of cytokines to
bind to their respective receptors on the cell membrane);
lipid peroxidation (decrease in free radical-induced tissue
damage); prostaglandin production (an indirect mechanism
whereby prostaglandins, which are derivatives of PUFA,
modify cytokine activity); and regulation of gene expression
(PUFA influences on the signal transudation pathways and
modified mRNA activity). The role of PUFA in immune func-
tion is complicated since n-3 and n-6 have different effects on
various immune components. A recent review [28] indicated
that n-3 fatty acids induce a decrease in lymphocyte prolifer-
ation in humans and rats, a decrease in IL-1 production, and
a decrease in IL-2 production in both humans and animals. In
addition, n-3 FA decreases TNFalpha production in humans
but increases it in mice macrophages, and also decreases nat-
ural killer cell (NK) activity. On the other hand, n-6 increases
the production of IL-2 in mice and decreases production of
TNFalpha production and NK cell activity. Still, other studies
have shown that linoleic acid (n-6) decreases the activity of
IL-2 [39] and increases IL-1 production and tissue response
to cytokines, while n-3 generally decreases IL-1 production
and activity [16]. Despite some disagreement among studies,
it seems that n-3 fatty acids (alpha-linolenic acid, DHA, EPA)
decrease the production and activity of the pro inflammatory
cytokines (IL-1, IL-6, TNFalpha ) [4,9,17,32] and that n-6 fam-
ily has the opposite effect [8,19,16]. The ability of n-3 PUFA
to reduce pro inflammatory cytokines and prostaglandin [9]
argues for the use of fish oil to relieve pain. Fish oil, rich in
n-3 PUFA, has been shown to decrease IL-6, IL-10, IL-12,
TNFalpha , and PGE2 [13].
Increasingly, the salutary effects of PUFA are being exam-
ined not only with respect to their absolute level in diet,
supplementation, or serum and tissue content, but also with
respect to their proportional relationship to other FAs. One
example of the critical nature and importance of a proper ratio
can be seen in the level of anti-inflammatory IL-2 production
that is increased following treatment by a mixture of n-3 to
n-6 FA in a ratio of 1:4 [41], and with an increase in n-3 in
the tissue [19].
6. Early development
In general, EFA improves learning and memory [37]. Most
studies on omega-3 deficiency cite the early development
period as an important if not ‘critical’ period for brain devel-
opment. A discussion of the merits of adding long chain
PUFA to baby formula is beyond the scope of this review, yet
it is interesting to note the discussion between Clandinin and
Fewtrel [10]. Both agree that LCPUFA supplements will at
least improve the short-term developmental outcome. PUFA
 S. Yehuda et al. / Neurobiology of Aging 26S (2005) S98–S102
deficiency may delay the process of myelination that may
explain several sensory deficits (vision, hearing, taste, and
smell) observed in EFA deficit babies [5] and in the develop-
ment of many neurological reflexes that was observed among
those babies [14]. Recently, EFA deficiency was induced a
delay in neurite growth in hippocampal neurons [7]. Malnu-
trition, including protein–energy malnutrition, induces PUFA
deficiency, which might contribute to the poor cognitive sta-
tus [21].
With few studies of the long-term effects of early PUFA
deficiency, speculative reports suggest that this deficiency
contributes to later presentations of Huntington’s disease
[11], schizophrenia [12], high blood pressure [2], and
increased appetite signaling [23].
7. Childhood development
Several studies illustrate the similarity between ADHD
children and the symptoms observed in EFA deficiency in
animals and humans [6]. Many ADHD children suffer from
EFA deficiency and mainly the n-3 subgroup of fatty acids
[25], with a high correlation between the severity of the
EFA deficiency and the severity of ADHD symptom (r = .80).
One explanation is a decrease in ERA intake from food, and
another is the impaired capacity of the ADHD’s neurological
system to convert EFA to longer chain FAs. Supportive stud-
ies showed the relationships between EFA deficiency and
ADHD [15,16,29]. Richardson [24] summarized two stud-
ies in which fatty acids supplements were given to ADHD
children, with an effective outcome in one study, and no
effect in the other. Our laboratory found that ADHD children
given essential fatty supplementation improved their mood
and sleep disturbances (submitted for publication).
8. Aging and Alzheimer disease
Several reviews were recently published on the possible
role of EFA in cognitive decline among aged people [5,38].
In short, most of the studies indicated a marked decrease in
the brain level of EFA. The decrease in not uniform across
the brain, and it affected mainly the cortex and hippocampus,
areas which mediate learning and memory. There are at least
two main possible reasons for this decline: a decrease in the
ability of dietary fatty acids to cross the BBB. It is well known
that the BBB is less effective during aging. The other factor
is a decrease in the level and activity of the enzyme delta
6-desaturase. This modified the turnover of cerebral mem-
brane [5]. Among Alzheimer patients the decrease in EFA is
more severe [38]. On the other hand, a high fat diet and dia-
betes are also important issues in aging. It has been found that
high fat diet is a risk factor for Alzheimer disease [22]. The
frequency of diabetes among elderly is constantly increas-
ing. Regardless of the mechanisms, several large prospective
studies have associated diabetes with cognitive decline and
S101
dementia. Some studies [38] showed that EFA supplementa-
tion can correct the EFA deficiency.
9. Retina
Retinal tissue is an integral part of the brain. The hall-
mark of EFA deficiency in infancy is visual disturbance [18].
Dopamine, which is the major neurotransmitter in the retina,
is under control of EFA [35]. Following several studies, San-
Giovanni and Chew [27] hypothesized that DHA deficiency
is involved in age related macular degeneration (AMD) and
other age related retinal disorders.
10. Conclusion
Infancy and aging are two sensitive and critical periods,
where adequate EFA and PUFA bioavailability is crucial for
proper functioning of the brain. PUFA deficiency in both peri-
ods has an effect on learning and memory, sensory function,
and mood. In addition, PUFA deficiency in infancy might
have tardive effects. The pivotal role of PUFA in the neu-
ronal membrane function renders it as an essential dietary
component that requires supplementation in cases of defi-
ciency.
Acknowledgements
We thank the Rose K. Ginsburg Chair for Research in
Alzheimer’s Disease and The William Farber Center for
Alzheimer Research for their support.
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