<html>
<head><title></title></head>
<body>
<h1></h1>
<p></p>
<blockquote>
<h2>
<span style="color: #222222"><span style="font-family: Helvetica"><span><strong>Fats, functions &
malfunctions</strong></span></span></span>
</h2>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span><strong>Saturated fatty acids
terminate the stress reactions, polyunsaturated fatty acids amplify them.</strong></span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span><strong>The most highly unsaturated
fats, including DHA, accumulate with aging, and their toxic fragments are increased in
Alzheimer's disease. </strong></span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span><strong>The most highly unsaturated
fats found in fish oil break down into chemicals that block the use of glucose and
oxygen.</strong></span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span><strong>The ratio of saturated fatty
acids to polyunsaturated fatty acids is decreased in cancer. Omega-3 fats promote
metastasis.</strong></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Around the beginning of the 20th
century, it was commonly believed that aging resulted from the accumulation of insoluble
metabolic by-products, sort of like the clinker ash in a coal furnace. Later, age pigment or
lipofuscin, was proposed to be such a material. It is a brown pigment that generally increases
with age, and its formation is increased by consumption of unsaturated fats, by vitamin E
deficiency, by stress, and by exposure to excess estrogen. Although the pigment can contribute
to the degenerative processes, aging involves much more than the accumulation of insoluble
debris; aging increases the tendency to form the debris, as well as vice versa.</span></span
></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>There is a growing recognition that
a persistent increase of free fatty acids in the serum, which is seen in shock, heart failure,
and aging, indicates a bad prognosis, but there is no generally recognized explanation for the
fact that free fatty acids are harmful. I want to mention some evidence showing that it is the
accumulation of polyunsaturated fats in the body that makes them harmful.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The physical and functional
properties of saturated fatty acids and polyunsaturated fatty acids (PUFA) are as different from
each other as day is from night. The different fatty acids are directly involved, very often
with opposite effects, in cell division and growth, cell stability and dissolution, the
organization of cells, tissues, and organs, the regulation of pituitary hormones, adrenalin and
sympathetic nervous activation, histamine and serotonin synthesis, adrenal cortex hormones,
thyroid hormones, testosterone, estrogen, activators of the immune system and inflammation
(cytokines), autoimmune diseases, detoxification, obesity, diabetes, puberty,
epilepsy, </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Parkinson's disease, other
degenerative nerve diseases and Alzheimer's disease, cancer, heart failure, atherosclerosis, and
strokes. In each of these situations, the PUFA have harmful effects.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Most people are surprised to hear
about the systematically harmful effects of the common dietary polyunsaturated fats and the
protective effects of saturated fats. That's because there is a pervasive mythology of fats in
our culture. Officials are proposing to tax saturated fats. Laws are being passed prescribing
the fats that can be served in restaurants, and people write letters to editors about them, and
great amounts of money are spent publicizing the importance of eating the right fats. Their
focus is on obesity, atherosclerosis, and heart disease. The details of the myth change a
little, as new fat products and industries appear. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>As I understand the basic myth, the
difference between the "essential" polyunsaturated fats and the saturated fats has to do with
their shape---the unsaturated fatty acids bend or fold in a way that makes them more mobile than
saturated fats of the same length, and this causes the all-important "membranes" of cells to be
more fluid, and thus to have "better functions," though the myth isn't very clear on the issue
of fluidity and functionality. At that point, it passes responsibility to the more fundamental
biological myth, of the metabolically active cell membrane. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Practically everyone learns, in
grade school and from television, about the good and the bad oils, and cell membranes, but it
might seem likely that people who spend their lives investigating the role of fats in organisms
would have acquired a different, more complicated, view. But one of the most famous food fat
researchers, J.M. Bourre, has succinctly (and thoughtlessly) expressed his understanding of the
function of fatty substances in the body: "In fact the brain, after adipose tissue, is the organ
richest in lipids, whose only role is to participate in membrane structure." (J.M. Bourre,
2004.) The fact that his editor let him publish the statement shows how the myth functions,
causing people to accept things because they are "common knowledge." The influence of the
medical and pharmaceutical industries is so pervasive that it becomes the context for most
biological research.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Luckily, many people are working
outside the myth, in specialized problems of physiology and cell biology, and their observations
are showing a reality much more complex and interesting than the mythology. </span></span
></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>When we eat more protein or
carbohydrate than we need, the excess can be converted to fats, to be stored (as triglycerides),
but even on a maintenance diet we synthesize some fats that are essential parts of all of our
cells, including a great variety of phospholipids. People seldom talk about the importance of
fats in the nucleus of the cell, but every nucleus contains a variety of lipids--phospholipids,
sphingolipids, cholesterol, even triglycerides--similar to those that are found elsewhere in the
cell and in every part of the body, including the brain (Balint and Holczinger, 1978; Irvine,
2002). Phospholipids are often considered to be "membrane lipids," but they have been
demonstrated in association with elements of the cell's skeleton, involved in cell division,
rather than in membranes (Shogomori, et al., 1993).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The cytoskeleton, a fibrous
framework of the cell that's responsible for maintaining the organized structure of the cell,
internal movement of organelles, coordination, locomotion, and cell division, is made up of
three main kinds of protein, and all of these are affected differently by different kinds of
fat. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Actions of lipids on the cell
skeleton can change cells' movements, migrations, and invasiveness. Unsaturated fats cause
clumping of some types of cell filament, condensation and polymerization of other types, in ways
that are associated with brain degenerative diseases and cancer. For example, DHA alters the
structure of the protein alpha-synuclein, causing it to take the form seen in Parkinson's
disease and other brain conditions. The synucleins regulate various structural proteins, and are
affected by stress, aging, and estrogen exposure, as well as by the polyunsaturated fats. One
type of synuclein is involved in the promotion of breast cancer. Saturated fatty acids have
exactly the opposite effects of PUFA on the synucleins, reversing the polymerization caused by
the PUFA (Sharon, et al., 2003). </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>When cancers are metastasizing,
their phospholipids contain less stearic acid than the less malignant tumors (Bougnoux, et al.,
1992), patients with advanced cancer had less stearic acid in their red blood cells (Persad, et
al., 1990), and adding stearic acid to their food delayed the development of cancer in mice
(Bennett, 1984). The degree of saturation of the body's fatty acids corresponds to resistance to
several types of cancer that have been studied (Hawley and Gordon, 1976; Singh, et al.,
1995).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The phospholipids are being
discussed in relation to drugs that can modify "signaling" by acting on phospholipid receptors,
using language that was developed in relation to hormones. A surface barrier membrane, with
receptors that send signals to the nucleus, is invoked by many of the recent discussions of
phospholipids. There's no question that the fats do affect regulatory processes, but the theory
and the language should correspond to the physiological and ecological realities. Vernadski's
metaphor, that an organism is a "whirlwind of atoms," is probably more appropriate than
"targeted signals and receptors" for understanding the physiology of fatty acids and
phospholipids. The rate of change and renewal of these structural fats is very high. In rats,
one study found a 30% decrease in the total phospholipid pool in the brain in the first 30
minutes after death (Adineh, et al., 2004). Another study in the brains of living rats
found that a particular class of brain lipids, ethanolamine plasmalogens, had a turnover time of
about 5 hours (Masuzawa, et al., 1984). (This type of lipid is an important component of the
lipoproteins secreted by the liver into the serum [Vance, 1990], and is also a major lipid in
the heart and brain.) Stresses such as the loss of sleep cause great distortions in
phospholipid metabolism throughout the body, especially in the brain and liver.</span></span
></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Actions of lipids on the cell
skeleton can change cells' movements, migrations, and invasiveness, even in short term
experiments. The effects of the "essential fatty acid" linoleic acid have been compared to the
drug colchicine, which is known to interfere with the cell skeleton and cell division. According
to Hoover, et al., (1981), it disturbed the structure of the cytoskeleton more than colchicine
does; it caused the cell filaments to clump together, while saturated fatty acids didn't have
such an effect.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The fatty molecules that participate
in the normal cell functions are made by cells even when they are grown in a fat-free solution
in a culture dish. They include saturated fatty acids such as palmitate and stearate, and
omega-9 unsaturated fats, such as oleic acid and omega-9 polyunsaturated fatty acids. The
saturated fatty acids found in the nucleus associated with the chromosomes are resistant to
change when the composition of the animal's diet changes (Awad and Spector, 1976), while the
unsaturated fats change according to the diet. These intracellular fats are essential for cell
division and the regulation of the genes, and for cell survival (Irvine, 2002). Although cells
make the saturated fats that participate in those basic functions, the high rate of metabolism
means that some of the lipids will quickly reflect in their structure the free fatty acids that
circulate in the blood. The fats in the blood reflect the individual's diet history, but
recently eaten fats can appear in the serum as free fatty acids, if the liver isn't able to
convert them into triglycerides.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The polyunsaturated fatty acids
differ from the saturated fats in many ways, besides their shape and their melting temperature,
and each type of fatty acid is unique in its combination of properties. The polyunsaturated
fatty acids, made by plants (in the case of fish oils, they are made by algae), are less stable
than the saturated fats, and the omega-3 and omega-6 fats derived from them, are very
susceptible to breaking down into toxins, especially in warm-blooded animals. Other differences
between saturated and polyunsaturated fats are in their effects on surfaces (as surfactant),
charges (dielectric effects), acidity, and their solubility in water relative to their
solubility in oil. The polyunsaturated fatty acids are many times more water soluble than
saturated fatty acids of the same length. This property probably explains why only palmitic acid
functions as a surfactant in the lungs, allowing the air sacs to stay open, while unsaturated
fats cause lung edema and respiratory failure.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The great difference in water/oil
solubility affects the strength of binding between a fatty acid and the lipophilic, oil-like,
parts of proteins. When a protein has a region with a high affinity for lipids that contain
double bonds, polyunsaturated fatty acids will displace saturated fats, and they can sometimes
displace hormones containing multiple double bonds, such as thyroxine and estrogen, from the
proteins that have a high specificity for those hormones. Transthyretin (also called prealbumin)
is important as a carrier of the thyroid hormone and vitamin A. The unsaturation of vitamin A
and of thyroxin allow them to bind firmly with transthyretin and certain other proteins, but the
unsaturated fatty acids are able to displace them, with an efficiency that increases with the
number of double bonds, from linoleic (with two double bonds) through DHA (with six double
bonds). </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The large amount of albumin in the
blood is important in normal fatty acid binding and transport, but it is also an important part
of our detoxifying system, since it can carry absorbed toxins from the intestine, lungs, or skin
to the liver, for detoxification. Albumin facilitates the uptake of saturated fatty acids by
cells of various types (Paris, et al., 1978), and its ability to bind fatty acids can protect
cells to some extent from the unsaturated fatty acids (e.g., Rhoads, et al., 1983). The liver's
detoxification system processes some polyunsaturated fats for excretion, along with hormones and
environmental toxins.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The movement of proteins from the
plasma into cells has often been denied, but there is clear evidence that a variety of proteins,
including IgG, transferrin haptoglobin, and albumin can be found in a variety of cells, even in
the brain (Liu, et al., 1989). Cells are lipophilic, and absorb molecules in proportion to their
fattiness; this long ago led people to theorize that cells are coated with a fat
membrane. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The idea of a semipermeable
membrane, similar in function to the membrane inside an egg shell, was proposed about 150 years
ago, to explain the ability of living cells to concentrate certain chemicals, such as potassium
ions, while excluding others, such as sodium ions. This idea of a molecular sieve was shown to
be invalid when radioactive isotopes made it possible to observe that sodium ions diffuse freely
into cells, and it was replaced by the idea of a metabolically active membrane, containing
"pumps" that made up for the inability to exclude various things, and that allowed cells to
retain high concentrations of some dissolved substances that are free to diffuse out of the
cell. The general idea of the membrane as a barrier persisted as a sort of "common sense" idea,
that has made people ignore experiments that show that some large molecules, including some
proteins, can quickly and massively enter cells. Albumin and transthyretin are two proteins that
are sometimes found in large quantities inside cells, and their primary importance is that they
bind and transport biologically active oily molecules. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>While the competition by PUFA for
protein binding sites blocks the effects of thyroid hormone and vitamin A, the action of PUFA on
the sex steroid binding protein (SBP, or SSBG, for sex steroid binding globulin) increases the
activity of estrogen. That's because the SSBG neutralizes estrogen by binding it, keeping it out
of cells; free PUFA keep it from binding estrogen (Reed, et al., 1986). People with low
SSBG/estrogen ratio have an increased risk of cancer. When the SSBG protein is free of estrogen,
it is able to enter cells, and in that estrogen-free state it probably serves a similar
protective function, capturing estrogen molecules that enter cells before they can act on other
proteins or chromosomes. Transthyretin, the main transporter of thyroid and vitamin A, and
albumin (which can also transport thyroid hormone) are both able to enter cells, while loaded
with thyroid hormone and vitamin A. Albumin becomes more lipophilic as it binds more lipid
molecules, so its tendency to enter cells increases in proportion to its fat burden. Albumin in
the urine is a problem associated with diabetes and kidney disease; albumin loaded with fatty
acids passes from the blood into the urine more easily than unloaded albumin, and it is the
fatty acids, not the albumin, which causes the kidney damage (Kamijo, et al., 2002). It's
possible that SSBG's opposite behavior, entering cells only when it carries no hormones, is the
result of becoming less lipophilic when it's loaded with estrogen.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Since most people believe that cells
are enclosed within a barrier membrane, a new industry has appeared to sell special products to
"target" or "deliver" proteins into cells across the barrier. Combining anything with fat makes
it more likely to enter cells. Stress (which increases free fatty acids and lowers cell energy)
makes cells more permeable, admitting a broader range of substances, including those that are
less lipophilic. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Linoleic acid and arachidonic acid,
which are said to "make the lipid membrane more permeable," in fact make the whole cell more
permeable, by binding to the structural proteins throughout the cell, increasing their affinity
for water, causing generalized swelling, as well as mitochondrial swelling (leading to reduced
oxidative function or disintegration), allowing more calcium to enter the cell, activating
excitatory processes, stimulating a redox shift away from oxidation and toward inflammation,
leading to either (inappropriate) growth or death of the cell. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>When we don't eat for many hours,
our glycogen stores decrease, and adrenaline secretion is increased, liberating more glucose as
long as glycogen is available, but also liberating fatty acids from the fatty tissues. When the
diet has chronically contained more polyunsaturated fats than can be oxidized immediately or
detoxified by the liver, the fat stores will contain a disproportionate amount of them, since
fat cells preferentially oxidize saturated fats for their own energy, and the greater water
solubility of the PUFA causes them to be preferentially released into the bloodstream during
stress.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>In good health, especially in
children, the stress hormones are produced only in the amount needed, because of negative
feedback from the free saturated fatty acids, which inhibit the production of adrenalin and
adrenal steroids, and eating protein and carbohydrate will quickly end the stress. But when the
fat stores contain mainly PUFA, the free fatty acids in the serum will be mostly linoleic acid
and arachidonic acid, and smaller amounts of other unsaturated fatty acids. These PUFA stimulate
the stress hormones, ACTH, cortisol, adrenaline, glucagon, and prolactin, which increase
lipolysis, producing more fatty acids in a vicious circle. In the relative absence of PUFA, the
stress reaction is self limiting, but under the influence of PUFA, the stress response becomes
self-amplifying. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>When stress is very intense, as in
trauma or sepsis, the reaction of liberating fatty acids can become dangerously
counter-productive, producing the state of shock. In shock, the liberation of free fatty acids
interferes with the use of glucose for energy and causes cells to take up water and calcium
(depleting blood volume and reducing circulation) and to leak ATP, enzymes, and other cell
contents (Boudreault and Grygorczyk, 2008; Wolfe, et al., 1983; Selzner, et al, 2004; van der
Wijk, 2003), in something like a systemic inflammatory state (Fabiano, et al., 2008) often
leading to death. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The remarkable resistance of
"essential fatty acid deficient" animals to shock (Cook, et al., 1981; Li et al., 1990; Autore,
et al., 1994) shows that the polyunsaturated fats are centrally involved in the maladaptive
reactions of shock. The cellular changes that occur in shock--calcium retention, leakiness,
reduced energy production--are seen in aging and the degenerative diseases; the stress hormones
and free fatty acids tend to be chronically higher in old age, and an outstanding feature of old
age is the reduced ability to tolerate stress and to recover from injuries.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Despite the instability of
polyunsaturated fatty acids, which tend to break down into toxic fragments, and despite their
tendency to be preferentially liberated from fat cells during stress, the proportion of them in
many tissues increases with age (Laganiere and Yu, 1993, 1987; Lee, et al., 1999; Smidova, et
al., 1990;Tamburini, et al., 2004; Nourooz-Zadeh J and Pereira, 1999 ). This progressive
increase with age can be seen already in early childhood (Guerra, et al., 2007). The reason for
this increase seems to be that the saturated fatty acids are preferentially oxidized by many
types of cell, (fat cells can slowly oxidize fat for their own energy maintenance). Albumin
preferentially delivers saturated fatty acids into actively metabolizing cells such at the heart
(Paris, 1978) for use as fuel. This preferential oxidation would explain Hans Selye's results,
in which canola oil in the diet caused the death of heart cells, but when the animals received
stearic acid in addition to the canola oil, their hearts showed no sign of damage.</span></span
></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Since healthy cells are very
lipophilic, saturated fatty acids would have a greater tendency to enter them than the more
water soluble polyunsaturated fats, especially those with 4, 5, or 6 double bonds, but as cells
become chronically stressed they more easily admit the unsaturated fats, which slow oxidative
metabolism and create free radical damage. The free radicals are an effect of stress and aging,
as well as a factor in its progression.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>When stress signals activate enzymes
in fat cells to release free fatty acids from the stored triglycerides, the enzymes in the
cytoplasm act on the surface of the droplet of fat. This means that the fatty acids with the
greatest water solubility will be liberated from the fat to move into the blood stream, while
the more oil soluble fatty acids will remain in the droplet. The long chain of saturated carbon
atoms (8 in the case of oleic acid, 15 in palmitic acid, and 17 in stearic acid) in the "tail"
of oleic, palmitic, and stearic acid will be buried in the fat droplet, while the tail of the
n-3 fatty acids, with only 2 saturated carbons, will be the most exposed to the lipolytic
enzymes. This means that the n-3 fatty acids are the first to be liberated during stress, the
n-6 fatty acids next. Saturated and monounsaturated fatty acids are selectively retained by fat
cells (Speake, et al., 1997).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Women are known to have a greater
susceptibility than men to lipolysis, with higher levels of free fatty acids in the serum and
liver, because of the effects of estrogen and related hormones. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Women on average have more DHA
circulating in the serum than men (Giltay, et al., 2004; McNamara, et al., 2008; Childs, et al.,
2008). This highly unsaturated fatty acid is the first to be liberated from the fat stores under
stress, and, biologically, the meaning of estrogen is to mimic stress. Estrogen and
polyunsaturated fatty acids have similar actions on cells, increasing their water content and
calcium uptake. Long before the Women's Health Initiative reported in 2002 that the use of
estrogen increased the risk of dementia, it was known that the incidence of Alzhemer's disease
was 2 or 3 times higher in women than in men. Men with Alzheimer's disease have higher levels of
estrogen than normal men (Geerlings, et al., 2006). The amount of DHA in the brain (and other
tissues) increases with aging, and its breakdown products, including neuroprostanes, are
associated with dementia. Higher levels of DHA and total PUFA are found in the plasma of
demented patients (Laurin, et al., 2003).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Another interesting association of
the highly unsaturated fats and estrogen in relation to brain function is that DHA increases the
entry of estrogen into the pregnant uterus, but inhibits the entry of progesterone (Benassayag,
et al., 1999), which is crucial for brain cell growth. When Dirix, et al., (2009) supplemented
pregnant women with PUFA, they found that fetal memory was impaired. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The crucial mitochondrial
respiratory enzyme, cytochrome c oxidase, declines with aging (Paradies, et al., 1997), as the
lipid cardiolipin declines, and the enzyme's activity can be restored to the level of young
animals by adding cardiolipin. The composition of cardiolipin changes with aging, "specifically
an increase in highly unsaturated fatty acids" (Lee, et al., 2006). Other lipids, such as a
phosphatidylcholine containing two myristic acid groups, can support the enzyme's activity
(Hoch, 1992). Even supplementing old animals with hydrogenated peanut oil restores mitochondrial
respiration to about 80% of normal (Bronnikov, et al., 2010). </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Supplementing thyroid hormone
increases mitochondrial cardiolipin (Paradies and Ruggiero, 1988). Eliminating the
polyunsaturated fats from the diet increases mitochondrial respiration (Rafael, et al.,
1984).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Excitotoxicity is the process in
which activation of a nerve cell beyond its capacity to produce energy injures or kills the
cell, by increasing intracellular calcium. Glutamic acid and aspartic acid are the normal
neurotransmitter excitatory amino acids. Estrogen increases the activity of the excitatory
transmitter glutamate (Weiland, 1992), and glutamate increases the release of free fatty acids
(Kolko, et al., 1996). DHA (more strongly even than arachidonic acid) inhibits the uptake of the
excitotoxic amino acid aspartate, and in some situations glutamate, prolonging their actions.
Thymocytes are much more easily killed by stress than nerve cells, and they are easy to study.
The PUFA kill them by increasing their intracellular calcium. The toxicity of DHA is greater
than that of EPA, whose toxicity is greater than alpha-linolenic acid, and linoleic acid was the
most potent (Prasad, et al., 2010). Excitotoxicity is probably an important factor in
Alzheimer's disease (Danysz and Parsons, 2003).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>When the brain is injured, DHA and
arachidonic acid contribute to brain edema, weakening the blood-brain-barrier, increasing
protein breakdown, inflammation, and peroxidation, while a similar amount of stearic acid in the
same situation caused no harm (Yang, et al., 2007). In other situations, such as the important
intestinal barrier, EPA and DHA also greatly increased the permeability (Dombrowsky, et al.,
2011).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The process by which excitotoxicity
kills a cell is probably a foreshortened version of the aging process. </span></span></span
>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Excitotoxins (including endotoxin)
increase the formation of neuroprostanes and isoprostanes (from n-3 and n-6 PUFA) (Milatovic, et
al., 2005), and acrolein and other fragments, which inhibit the use of glucose and oxygen.
DHA and EPA produce acrolein and HHE, which react with lysine groups in proteins, and modify
nucleic acids, changing the bases in DNA. </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Increased intracellular calcium
activates lipolysis (by phospholipases), producing more free fatty acids, as well as excitation
and protein breakdown, and in the brain neurodegenerative diseases, calcium excess contributes
to the clumping of synuclein (Wojda, et al., 2008), an important regulator of the cytoskeletal
proteins. The reduced function of normal synuclein makes cells more susceptible to
excitotoxicity (Leng and Chuang, 2006).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>If the cells adapt to the increased
calcium, rather than dying, their sensitivity is reduced. This is probably involved in the
"defensive inhibition" seen in many types of cell. In the brain, DHA and arachidonic acid
"brought the cells to a new steady state of a moderately elevated [intracellular calcium] level,
where the cells became virtually insensitive to external stimuli. This new steady state can be
considered as a mechanism of self-protection" (Sergeeva, et al., 2005). In the heart, the PUFAs
decreased the sensitivity to stimulation (Coronel et al., 2007) and conduction velocity
(Tselentakis, et al., 2006; Dhein, et al., 2005). Both DHA and EPA inhibit calcium-ATPase (which
keeps intracellular calcium low to allow normal neurotransmission) in the cerebral cortex; this
suggests "a mechanism that explains the dampening effect of omega-3 fatty acids on neuronal
activity" (Kearns and Haag, 2002).</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>In normal aging, most processes are
slowed, including nerve conduction velocity, and conduction velocity in the heart (Dhein and
Hammerath, 2001). A similar "dampening" or desensitization is seen in sensory, endocrine, and
immune systems, as well as in energy metabolism. Calorie restriction, by decreasing the
age-related accumulation of PUFA (20:4, 22:4, and 22:5), can prevent the decrease of
sensitivity, for example in lymphoid cells (Laganier and Fernandes, 1991). The known effects of
the unsaturated fats on the organizational framework of the cell are consistent with the changes
that occur in aging.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>One of the essential protective
functions that decline with aging is the liver's ability to detoxify chemicals, by combining
them with glucuronic acid, making them water soluble so that they can be excreted in the urine.
The liver (and also the intestine and stomach) efficiently process DHA by glucuronidation
(Little, et al., 2002). Oleic acid, one of the fats that we synthesize ourselves, increases
(about 8-fold) the activity of the glucuronidation process (Krcmery and Zakim, 1993; Okamura, et
al., 2006). However, this system is inhibited by the PUFA, arachidonic acid (Yamashita, et al.,
1997), and also by linoleic acid (Tsoutsikos, et al., 2004), in one of the processes that
contribute to the accumulation of PUFA with aging.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Animals that naturally have a
relatively low level of the highly unsaturated fats in their tissues have the greatest
longevity. For example, the naked mole rate has a life expectancy of more than 28 years, about 9
times as long as other rodents of a similar size. Only about 2% to 6% of its phospholipids
contain DHA, while about 27% to 57% of the phospholipids of mice contain DHA Mitchell, et al.,
2007). </span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The famously long-lived people of
Azerbaijan eat a diet containing a low ratio of unsaturated to saturated fats, emphasizing
fruits, vegetables, and dairy products (Grigorov, et al., 1991).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Some of the clearest evidence of the
protective effects of saturated fats has been published by A.A. Nanji's group, showing that they
can reverse the inflammation, necrosis, and fibrosis of alcoholic liver disease, even with
continued alcohol consumption, while fish oil and other unsaturated fats exacerbate the problem
(Nanji, et al., 2001). Glycine protects against fat accumulation in alcohol-induced liver injury
(Senthilkumar, et al., 2003), suggesting that dietary gelatin would complement the protective
effects of saturated fats.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>The least stable n-3 fats which
accumulate with age and gradually reduce energy production also have their short term effects on
endurance. Endurance was much lower in rats fed a high n-3 fat diet, and the effect persisted
even after 6 weeks on a standard diet (Ayre and Hulbert, 1997). Analogous, but less extreme
effects are seen even in salmon, which showed increased oxidative stress on a high n-3 diet (DHA
or EPA), and lower mitochondrial cytochrome oxidase activity (Kjaer, et al., 2008). </span
></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Maintaining a high rate of oxidative
metabolism, without calorie restriction, retards the accumulation of PUFA, and a high metabolic
rate is associated with longevity. An adequate amount of sugar maintains both a high rate of
metabolism, and a high respiratory quotient, i.e., high production of carbon dioxide. Mole rats,
bats, and queen bees, with an unusually great longevity, are chronically exposed to high levels
of carbon dioxide. Carbon dioxide forms carbamino bonds with the amino groups of proteins,
inhibiting their reaction with the reactive "glycating" fragments of PUFA.</span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>To minimize the accumulation of the
highly unsaturated fatty acids with aging, it's probably reasonable to reduce the amount of them
directly consumed in foods, such as fish, but since they are made in our own tissues from the
"essential fatty acids," linoleic and linolenic acids, it's more important to minimize the
consumption of those (from plants, pork, and poultry, for example).</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>In the resting state, muscles
consume mainly fats, so maintaining relatively large muscles is important for preventing the
accumulation of fats. </span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"
> </span>
</blockquote>
<blockquote>
<span style="color: #222222"> <span style="font-family: Helvetica"><span><strong><h3>
REFERENCES
</h3></strong></span></span></span>
</blockquote>
<blockquote></blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Program No. 680.23. 2004 Washington,
DC: Society for Neuroscience, 2004. Online. <strong>Postmortem rat brain analysis of
phospholipid composition using P31 NMR spectroscopy, </strong>Adineh M, Kent M, Shah S,
Polelstra R, White P, Simkins R.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Eur J Pharmacol. 2003 Apr
11;466(1-2):199-205. <strong>Vascular permeabilization by intravenous arachidonate in the
rat peritoneal cavity: antagonism by antioxidants.</strong> Alvarez-Guerra M, Hannaert
P, Hider H, Chiavaroli C, Garay RP.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Aging Cell. 2006
Dec;5(6):525-32. <strong>Disparate patterns of age-related changes in lipid peroxidation in
long-lived naked mole-rats and shorter-lived mice. </strong>Andziak B, Buffenstein
R.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Lipid Mediat Cell Signal. 1994
Mar;9(2):145-53. <strong>Essential fatty acid-deficient diet modifies PAF levels in stomach
and duodenum of endotoxin-treated rats.</strong> Autore G, Cicala C, Cirino G, Maiello
FM, Mascolo N, Capasso F.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochim Biophys Acta. 1976 Nov
19;450(2):239-51. <strong>Modification of the Ehrlich ascites tumor cell nuclear
lipids.</strong> Awad AB, Spector AA.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Lipids. 1997
Dec;32(12):1265-70. <strong>Dietary fatty acid profile affects endurance in rats.</strong
> Ayre KJ, Hulbert AJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Neoplasma.
1978;25(1):25-9. <strong>Neutral lipids in nuclei and chromatin fraction of young and old
Ehrlich ascites tumor cells. </strong>Balint Z, Holczinger L.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Trends Neurosci. 2004
Oct;27(10):595-600. <strong>Free radicals and aging.</strong> Barja G. "The degree of
unsaturation of tissue fatty acids also correlates inversely with maximum longevity."</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Br J Nutr. 2003
Apr;89(4):523-31. <strong>Influence of very low dietary intake of marine oil on some
functional aspects of immune cells in healthy elderly people. </strong>Bechoua S,
Dubois M, Vericel E, Chapuy P, Lagarde M, Prigent AF.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Prostaglandins Leukot Essent Fatty
Acids. 1999 May-Jun;60(5-6):393-9. <strong>Does high polyunsaturated free fatty acid level
at the feto-maternal interface alter steroid hormone message during pregnancy?</strong
> Benassayag C, Rigourd V, Mignot TM, Hassid J, Leroy MJ, Robert B, Civel C, Grange' G,
Dallot E, Tanguy J, Nunez EA, Ferre' F.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Int J Cancer. 1984 Oct
15;34(4):529-33. <strong>Effect of dietary stearic acid on the genesis of spontaneous
mammary adenocarcinomas in strain A/ST mice.</strong> Bennett AS.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Nutr Neurosci. 2010
Jun;13(3):144-50. <strong>Essential fatty acid deficiency reduces cortical spreading
depression propagation in rats: a two-generation study.</strong> Borba JM, et al.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Physiol. 2004 Dec 1;561(Pt
2):499-513. <strong>Cell swelling-induced ATP release is tightly dependent on intracellular
calcium elevations.</strong>Boudreault F, Grygorczyk R.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Breast Cancer Res Treat. 1992
Mar;20(3):185-94. <strong>Prognostic significance of tumor phosphatidylcholine stearic acid
level in breast carcinoma.</strong> Bougnoux P, <span>Chajes V, Lanson M, Hacene
K, Body G, Couet C, Le Floch O.</span></span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Nutr Health Aging.
2004;8(3):163-74. <strong>Roles of unsaturated fatty acids (especially omega-3 fatty acids)
in the brain at various ages and during ageing.</strong> Bourre JM.</span></span></span
>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochemistry (Mosc). 2010
Dec;75(12):1491-7. <strong>Dietary supplementation of old rats with hydrogenated peanut oil
restores activities of mitochondrial respiratory complexes in skeletal
muscles. </strong>Bronnikov GE, Kulagina TP, Aripovsky AV.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Proc Nutr Soc. 2008
Feb;67(1):19-27. <strong>Gender differences in the n-3 fatty acid content of
tissues. </strong>Childs CE, Romeu-Nadal M, Burdge GC, Calder PC.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Circ Shock.
1979;6(4):333-42. <strong>Resistance of essential fatty acid-deficient rats to endotoxic
shock. </strong>Cook JA, Wise WC, Callihan CS.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Cardiovasc Res. 2007 Jan
15;73(2):386-94. <strong>Dietary n-3 fatty acids promote arrhythmias during acute regional
myocardial ischemia in isolated pig hearts. </strong>Coronel R, Wilms-Schopman FJ, Den
Ruijter HM, Belterman CN, Schumacher CA, Opthof T, Hovenier R, Lemmens AG, Terpstra AH, Katan
MB, Zock P.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Int J Geriatr Psychiatry. 2003
Sep;18(Suppl 1):S23-32. <strong>The NMDA receptor antagonist memantine as a
symptomatological and neuroprotective treatment for Alzheimer's disease: preclinical
evidence.</strong> Danysz W, Parsons CG.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Naunyn Schmiedebergs Arch Pharmacol.
2001 Nov;364(5):397-408. <strong>Aspects of the intercellular communication in aged hearts:
effects of the gap junction uncoupler palmitoleic acid.</strong> Dhein S, Hammerath
SB.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Naunyn Schmiedebergs Arch Pharmacol.
2005 Mar;371(3):202-11. <strong>Antiarrhythmic and electrophysiologicl effects of
long-chain omega-3 polyunsaturated fattty acids.</strong> Dhein S, Michaelis B, Mohr
FW.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Prostaglandins Leukot Essent Fatty
Acids. 2009 Apr;80(4):207-12. <strong>Fetal learning and memory: weak associations with the
early essential polyunsaturated fatty acid status. </strong>Dirix CE, Hornstra G,
Nijhuis JG.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Nutr. 2011
Sep;141(9):1635-42. <strong>Ingestion of (n-3) fatty acids augments basal and platelet
activating factor-induced permeability to dextran in the rat mesenteric vascular
bed. </strong>Dombrowsky H, Lautenschläger I, Zehethofer N, Lindner B, Schultz H, Uhlig
S, Frerichs I, Weiler N.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Ann Nutr Aliment.
1980;34(2):317-32. <strong>[Polyunsaturated fatty acids and aging. Lipofuscins : structure,
origin and development] </strong>[Article in French] Durand G, Desnoyers F.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Physiol. 1998 Mar 1;507 ( Pt
2):541-7. <strong>Arachidonic acid increases cerebral microvascular permeability by free
radicals in single pial microvessels of the anaesthetized rat.</strong> Easton AS,
Fraser PA.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochem Mol Biol Int. 1998
Dec;46(6):1117-26. <strong>Age-related changes in plasma and tissue fatty acid composition
in Fischer 344 rats. </strong>Engler MM, Engler MB, Nguyen H.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>G Chir. 2008
Jan-Feb;29(1-2):51-7. <strong>[Traumatic shock--physiopathologic aspects]. </strong
>[Article in Italian] Fabiano G, Pezzolla A, Filograna MA, Ferrarese F.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Ann Neurol. 2006
Sep;60(3):346-55. <strong>Endogenous sex hormones, cognitive decline, and future dementia
in old men. </strong>Geerlings MI, Strozyk D, Masaki K, Remaley AT, Petrovitch H, Ross
GW, White LR, Launer LJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Am J Clin Nutr. 2004
Nov;80(5):1167-74. <strong>Docosahexaenoic acid concentrations are higher in women than in
men because of estrogenic effects.</strong> Giltay EJ, Gooren LJ, Toorians AW, Katan
MB, Zock PL.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Vopr Pitan. 1991
Mar-Apr;(2):36-40. <strong>[Characteristics of actual nutrition of the long-lived
population of Azerbaijan]</strong> [Article in Russian] Grigorov IuG, Kozlovskaia SG,
Semes'ko TM, Asadov ShA.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Ann Nutr Metab.
2007;51(5):433-8. <strong>Three-year tracking of fatty acid composition of plasma
phospholipids in healthy children.</strong> Guerra A, Demmelmair H, Toschke AM,
Koletzko B.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Lab Invest. 1976
Feb;34(2):216-22. <strong>The effects of long chain free fatty acids on human neutrophil
function and structure.</strong> Hawley HP, Gordon GB.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Am J Clin Nutr. 1989
Feb;49(2):301-5. <strong>Linoleic acid and linolenic acid: effect on permeability
properties of cultured endothelial cell monolayers. </strong>Hennig B, Watkins
BA.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Mol Cell Biol. 1981
Oct;1(10):939-48. <strong>Effects of free fatty acids on the organization of cytoskeletal
elements in lymphocytes.</strong> Hoover RL, Fujiwara K, Klausner RD, Bhalla DK, Tucker
R, Karnovsky MJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochim Biophys Acta. 1992 Mar
26;1113(1):71-133. <strong>Cardiolipins and biomembrane function.</strong> Hoch
FL.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Sci STKE. 2002 Sep
17;2002(150):re13. <strong>Nuclear lipid signaling. </strong>Irvine RF.</span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Kidney Int. 2002
Nov;62(5):1628-37. <strong>Urinary free fatty acids bound to albumin aggravate
tubulointerstitial damage. </strong>Kamijo A, Kimura K, Sugaya T, Yamanouchi M, Hase H,
Kaneko T, Hirata Y, Goto A, Fujita T, Omata M.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Prostaglandins Leukot Essent Fatty
Acids. 2002 Nov;67(5):303-8. <strong>The effect of omega-3 fatty acids on Ca-ATPase in rat
cerebral cortex.</strong>Kearns SD, Haag M.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Lipids. 2008
Sep;43(9):813-27. <strong>Dietary n-3 HUFA affects mitochondrial fatty acid beta-oxidation
capacity and susceptibility to oxidative stress in Atlantic salmon.</strong> Kjaer MA,
Todorcević M, Torstensen BE, Vegusdal A, Ruyter B.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Biol Chem. 1996 Dec
20;271(51):32722-8. <strong>Synergy by secretory phospholipase A2 and glutamate on inducing
cell death and sustained arachidonic acid metabolic changes in primary cortical neuronal
cultures. </strong>Kolko M, DeCoster MA, de Turco EB, Bazan NG.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochem Pharmacol. 1993 Sep
1;46(5):897-904. <strong>Effects of oleoyl-CoA on the activity and functional state of
UDP-glucuronosyltransferase.</strong>Krcmery M, Zakim D.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Lipids. 1991
Jun;26(6):472-8. <strong>Study on the lipid composition of aging Fischer-344 rat lymphoid
cells: effect of long-term calorie restriction.</strong>Laganiere S, Fernandes G.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Gerontology.
1993;39(1):7-18. <strong>Modulation of membrane phospholipid fatty acid composition by age
and food restriction.</strong> Laganiere S, Yu BP.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Alzheimers Dis. 2003
Aug;5(4):315-22. <strong>Omega-3 fatty acids and risk of cognitive impairment and
dementia.</strong> Laurin D, Verreault R, Lindsay J, Dewailly E, Holub BJ.</span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Free Radic Biol Med. 1999
Feb;26(3-4):260-5. <strong>Modulation of cardiac mitochondrial membrane fluidity by age and
calorie intake.</strong> Lee J, Yu BP, Herlihy JT.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Lipids Health Dis. 2006 Jan
23;5:2. <strong>Selective remodeling of cardiolipin fatty acids in the aged rat
heart.</strong> Lee HJ, Mayette J, Rapoport SI, Bazinet RP.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Lipids Health Dis. 2006 Jan
23;5:2. <strong>Selective remodeling of cardiolipin fatty acids in the aged rat
heart. </strong>Lee HJ, Mayette J, Rapoport SI, Bazinet RP.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Neurosci. 2006 Jul
12;26(28):7502-12. <strong>Endogenous alpha-synuclein is induced by valproic acid through
histone deacetylase inhibition and participates in neuroprotection against glutamate-induced
excitotoxicity.</strong> Leng Y, Chuang DM.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Circ Shock. 1990
Jun;31(2):159-70. <strong>Resistance of essential fatty acid-deficient rats to
endotoxin-induced increases in vascular permeability.</strong> Li EJ, Cook JA, Spicer
KM, Wise WC, Rokach J, Halushka PV.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Drug Metab Dispos. 2002
May;30(5):531-3. <strong>Glucuronidation of the dietary fatty acids, phytanic acid and
docosahexaenoic acid, by human UDP-glucuronosyltransferases. </strong>Little JM,
Williams L, Xu J, Radominska-Pandya A.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Acta Neuropathol.
1989;78(1):16-21. <strong>Immunohistochemical localization of intracellular plasma proteins
in the human central nervous system.</strong> Liu HM, Atack JR, Rapoport SI.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Neurochem. 1984
Apr;42(4):961-8. <strong>Turnover rates of the molecular species of ethanolamine
plasmalogen of rat brain.</strong> Masuzawa Y, Sugiura T, Ishima Y, Waku K.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Psychoneuroendocrinology. 2008 Nov
27. <strong>Gender differences in rat erythrocyte and brain docosahexaenoic acid
composition: Role of ovarian hormones and dietary omega-3 fatty acid composition.</strong
> McNamara RK, Able J, Jandacek R, Rider T, Tso P.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Chromatogr B Analyt Technol Biomed
Life Sci. 2005 Nov 15;827(1):88-93. <strong>Suppression of murine cerebral F2-isoprostanes
and F4-neuroprostanes from excitotoxicity and innate immune response in vivo by alpha- or
gamma-tocopherol.</strong> Milatovic D, VanRollins M, Li K, Montine KS, Montine
TJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Exp Gerontol. 2007
Nov;42(11):1053-62. <strong>Membrane phospholipid composition may contribute to exceptional
longevity of the naked mole-rat (Heterocephalus glaber): a comparative study using shotgun
lipidomics.</strong> Mitchell TW, Buffenstein R, Hulbert AJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Pharmacol Exp Ther. 2001
Nov;299(2):638-44. <strong>Dietary saturated fatty acids reverse inflammatory and fibrotic
changes in rat liver despite continued ethanol administration.</strong> Nanji AA,
Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Ophthalmic Res.
1999;31(4):273-9. <strong>Age-related accumulation of free polyunsaturated fatty acids in
human retina.</strong> Nourooz-Zadeh J, Pereira P.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochim Biophys Acta. 2000 Aug
24;1487(1):1-14. <strong>Fish oil diet affects on oxidative senescence of red blood cells
linked to degeneration of spleen cells in mice.</strong> Oarada M, Furukawa H, Majima
T, Miyazawa T.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochem Biophys Res Commun. 2006 Jul
14;345(4):1649-56. <strong>Fatty acyl-CoA as an endogenous activator of
UDP-glucuronosyltransferases.</strong>Okamura K, Ishii Y, Ikushiro S, Mackenzie PI, Yamada
H.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Mech Ageing Dev. 2000 Jan
10;112(3):169-83. <strong>Double bond content of phospholipids and lipid peroxidation
negatively correlate with maximum longevity in the heart of mammals.</strong> Pamplona
R, Portero-Otin M, Ruiz C, Gredilla R, Herrero A, Barja G.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochim Biophys Acta 1988 Aug
17;935(1):79-86. <strong>Effect of hyperthyroidism on the transport of pyruvate in
rat-heart mitochondria.</strong> Paradies G, Ruggiero FM</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Arch Biochem Biophys 1989
Mar;269(2):595-602. <strong>Decreased activity of the pyruvate translocator and changes in
the lipid composition in heart mitochondria from hypothyroid rats.</strong> Paradies G,
Ruggiero FM</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>FEBS Lett. 1997 Apr
7;406(1-2):136-8. <strong>Age-dependent decline in the cytochrome c oxidase activity in rat
heart mitochondria: role of cardiolipin. </strong>Paradies G, Ruggiero FM, Petrosillo
G, Quagliariello E.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Eur J Biochem. 1978 Feb
1;83(1):235-43. <strong>The role of serum albumin in the uptake of fatty acids by cultured
cardiac cells from chick embryo. </strong>Paris S, Samuel D, Jacques Y, Gache C,
Franchi A, Ailhaud G.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Br J Urol. 1990
Mar;65(3):268-70. <strong>Erythrocyte stearic to oleic acid ratio in prostatic
carcinoma.</strong> Persad RA, Gillatt DA, Heinemann D, Habib NA, Smith PJ.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Atherosclerosis. 1983
Jan;46(1):21-8. <strong>Increased ratio of plasma free fatty acids to albumin during normal
aging and in patients with coronary heart disease.</strong> Pickart L.</span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Cell Physiol. 2010
Nov;225(3):829-36. <strong>Role of calcium and ROS in cell death induced by polyunsaturated
fatty acids in murine thymocytes.</strong> Prasad A, Bloom MS, Carpenter DO.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Nutr. 1984
Feb;114(2):255-62. <strong>The effect of essential fatty acid deficiency on basal
respiration and function of liver mitochondria in rats.</strong>Rafael J, Patzelt J,
Schäfer H, Elmadfa I.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Prostaglandins Leukot Essent Fatty
Acids. 1993 Jan;48(1):111-6. <strong>The role of free fatty acids in regulating the tissue
availability and synthesis of sex steroids.</strong> Reed MJ, Dunkley SA, Singh A,
Thomas BS, Haines AP, Cruickshank JK.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Biol Chem. 2011 Jul
29;286(30):26931-42. <strong>Unsaturated fatty acids drive disintegrin and
metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating
membrane fluidity.</strong> Reiss K, Cornelsen I, Husmann M, Gimpl G, Bhakdi S.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Neurochem. 1982
May;38(5):1255-60. <strong>Effects of free fatty acids on synaptosomal amino acid uptake
systems. </strong>Rhoads DE, Kaplan MA, Peterson NA, Raghupathy E.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochem J. 1967
Sep;104(3):1040-7. <strong>Characterization and metabolism of ovine foetal lipids.</strong
> Scott TW, Setchell BP, Bassett JM.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Cell Death Differ. 2004 Dec;11 Suppl
2:S172-80. <strong>Water induces autocrine stimulation of tumor cell killing through ATP
release and P2 receptor binding. </strong>Selzner N, Selzner M, Graf R, Ungethuem U,
Fitz JG, Clavien PA.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Pol J Pharmacol. 2003
Jul-Aug;55(4):603-11. <strong>Glycine modulates hepatic lipid accumulation in
alcohol-induced liver injury.</strong> Senthilkumar R, Viswanathan P, Nalini N.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Reprod Nutr Dev. 2005
Sep-Oct;45(5):633-46. <strong>Regulation of intracellular calcium levels by polyunsaturated
fatty acids, arachidonic acid and docosahexaenoic acid, in astrocytes: possible involvement
of phospholipase A2. </strong>Sergeeva M, Strokin M, Reiser G.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Neuron. 2003 Feb
20;37(4):583-95. <strong>The formation of highly soluble oligomers of alpha-synuclein is
regulated by fatty acids and enhanced in Parkinson's disease.</strong> Sharon R,
Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Zygote. 1993
Aug;1(3):215-23. <strong>Non-plasmalemmal localisation of the major ganglioside in sea
urchin eggs.</strong> Shogomori H, Chiba K, Kubo H, Hoshi M.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Invasion Metastasis.
1995;15(3-4):144-55. <strong>Stearate inhibits human tumor cell invasion. </strong
>Singh RK, Hardy RW, Wang MH, Williford J, Gladson CL, McDonald JM, Siegal GP.</span></span
></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Physiol Bohemoslov.
1990;39(2):125-34. <strong>Proportion of individual fatty acids in the non-esterified
(free) fatty acid(FFA) fraction in the serum of laboratory rats of different
ages. </strong>Smidova L, Base J, Mourek J, Cechova I.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Exp Gerontol. 2005
Apr;40(4):335-43. <strong>Unsaturated fatty acids intake and all-causes mortality: a
8.5-year follow-up of the Italian Longitudinal Study on Aging. </strong>Solfrizzi V,
D'Introno A, Colacicco AM, Capurso C, Palasciano R, Capurso S,Torres F, Capurso A, Panza
F.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Pharm Biomed Anal. 2001
Mar;24(5-6):1157-62. <strong>Bioanalysis of age-related changes of lipid metabolism in
nonagenarians.</strong> Solichova D, Juraskova B, Blaha V, Bratova M, Kusalova M,
Zdansky P, Zadak Z.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochim Biophys Acta. 1997 Apr
21;1345(3):317-26. <strong>The preferential mobilisation of C20 and C22 polyunsaturated
fatty acids from the adipose tissue of the chick embryo: potential implications regarding
the provision of essential fatty acids for neural development.</strong> Speake BK,
Cerolini S, Maldjian A, Noble RC.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Nutr. 2003
Nov;133(11):3664-9. <strong>Fish intake is positively associated with breast cancer
incidence rate. </strong>Stripp C, Overvad K, Christensen J, Thomsen BL, Olsen A,
Moller S, Tjonneland A.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Br J Pharmacol. 2003
Jul;139(5):1014-22. <strong>Docosahexaenoic acid and arachidonic acid release in rat brain
astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently
regulated by cyclic AMP and Ca2+.</strong> Strokin M, Sergeeva M, Reiser G.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Aging Clin Exp Res. 2004
Dec;16(6):425-31. <strong>Effects of dietary restriction on age-related changes in the
phospholipid fatty acid composition of various rat tissues</strong>. Tamburini I, Quartacci
MF, Izzo R, Bergamini E. "The most abundant PUFAs, 20:4(n-6) and 22:6(n-3), either remained the
same or increased with age."</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Am J Physiol. 1989 Jan;256(1 Pt
1):G178-87. <strong>Saturated fatty acid diet prevents radiation-associated decline in
intestinal uptake.</strong> Thomson AB, Keelan M, Lam T, Cheeseman CI, Walker K,
Clandinin MT.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Surg Res. 2006
Sep;135(1):68-75. <strong>Inflammation effects on the electrical properties of atrial
tissue and inducibility of postoperative atrial fibrillation.</strong> Tselentakis EV,
Woodford E, Chandy J, Gaudette GR, Saltman AE.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochem Pharmacol. 2004 Jan
1;67(1):191-9. <strong>Evidence that unsaturated fatty acids are potent inhibitors of renal
UDP-glucuronosyltransferases (UGT): kinetic studies using human kidney cortical microsomes
and recombinant UGT1A9 and UGT2B7.</strong>Tsoutsikos P, Miners JO, Stapleton A, Thomas A,
Sallustio BC, Knights KM.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Aging Cell. 2007
Feb;6(1):15-25. <strong>N-3 polyunsaturated fatty acids impair lifespan but have no role
for metabolism.</strong> Valencak TG, Ruf T.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochim Biophys Acta. 1990 Jul
16;1045(2):128-34. <strong>Lipoproteins secreted by cultured rat hepatocytes contain the
antioxidant 1-alk-1-enyl-2-acylglycerophosphoethanolamine. </strong>Vance JE.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biol Chem. 2003 Oct
10;278(41):40020-5. <strong>Increased vesicle recycling in response to osmotic cell
swelling. Cause and consequence of hypotonicity-provoked ATP release.</strong> van der
Wijk T, Tomassen SF, Houtsmuller AB, de Jonge HR, Tilly BC.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Endocrinology. 1992
Dec;131(6):2697-702. <strong>Glutamic acid decarboxylase messenger ribonucleic acid is
regulated by estradiol and progesterone in the hippocampus. </strong>Weiland NG.</span
></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>IUBMB Life. 2008
Sep;60(9):575-90. <strong>Calcium ions in neuronal degeneration.</strong> Wojda U,
Salinska E, Kuznicki J.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Prog Clin Biol Res
1983;111:89-109. <strong>Energy metabolism in trauma and sepsis: the role of
fat. </strong>Wolfe RR, Shaw JH, Durkot MJ</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Biochem Pharmacol. 1997 Feb
21;53(4):561-70. <strong>Inhibition of UDP-glucuronosyltransferase activity by fatty
acyl-CoA. Kinetic studies and structure-activity relationship. </strong>Yamashita A,
Nagatsuka T, Watanabe M, Kondo H, Sugiura T, Waku K.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>Neurotoxicology. 2007
Nov;28(6):1220-9. <strong>Detrimental effects of post-treatment with fatty acids on brain
injury in ischemic rats.</strong> Yang DY, Pan HC, Yen YJ, Wang CC, Chuang YH, Chen SY,
Lin SY, Liao SL, Raung SL, Wu CW, Chou MC, Chiang AN, Chen CJ.</span></span></span>
</blockquote>
<blockquote>
<span style="color: #222222"><span style="font-family: Helvetica"><span>J Org Chem. 2007 Dec
7;72(25):9698-703. <strong>Asymmetric synthesis of 14-A4t-neuroprostane: hunting for a
suitable biomarker for neurodegenerative diseases.</strong> Zanoni G, Brunoldi EM,
Porta A, Vidari G. "Since isoprostanes are considered as golden standards for oxidative stress,
and due to the specificity of neuroprostanes for this condition in neurons and their relation
with Alzheimer's and Parkinson's diseases, they are envisioned to be suitable biomarkers for
these pathologies."</span></span></span>
</blockquote>
<p> </p>
© Ray Peat Ph.D. 2013. All Rights Reserved. www.RayPeat.com
</body>
</html>