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  1. <html>

  2.     <head><title></title></head>

  3.     <body>

  4.         <h1></h1>

  5. 

  6.         <p></p>

  7.         <blockquote>

  8.             <h2>

  9.                 <span style="color: #222222"><span style="font-family: Helvetica"><span><strong>Fats, functions &amp;

  10.                                 malfunctions</strong></span></span></span>

  11.             </h2>

  12.         </blockquote>

  13.         <blockquote></blockquote>

  14.         <blockquote>

  15.             <span style="color: #222222"><span style="font-family: Helvetica"><span><strong>Saturated fatty acids

  16.                             terminate the stress reactions, polyunsaturated fatty acids amplify them.</strong></span

  17.                     ></span></span>

  18.         </blockquote>

  19.         <blockquote>

  20.             <span style="color: #222222"><span style="font-family: Helvetica"><span><strong>The most highly unsaturated

  21.                             fats, including DHA, accumulate with aging, and their toxic fragments are increased in

  22.                             Alzheimer's disease.&nbsp;</strong></span></span></span>

  23.         </blockquote>

  24.         <blockquote>

  25.             <span style="color: #222222"><span style="font-family: Helvetica"><span><strong>The most highly unsaturated

  26.                             fats found in fish oil break down into chemicals that block the use of glucose and

  27.                             oxygen.</strong></span></span></span>

  28.         </blockquote>

  29.         <blockquote>

  30.             <span style="color: #222222"><span style="font-family: Helvetica"><span><strong>The ratio of saturated fatty

  31.                             acids to polyunsaturated fatty acids is decreased in cancer. Omega-3 fats promote

  32.                             metastasis.</strong></span></span></span>

  33.         </blockquote>

  34.         <blockquote></blockquote>

  35.         <blockquote>

  36.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Around the beginning of the 20th

  37.                         century, it was commonly believed that aging resulted from the accumulation of insoluble

  38.                         metabolic by-products, sort of like the clinker ash in a coal furnace. Later, age pigment or

  39.                         lipofuscin, was proposed to be such a material. It is a brown pigment that generally increases

  40.                         with age, and its formation is increased by consumption of unsaturated fats, by vitamin E

  41.                         deficiency, by stress, and by exposure to excess estrogen. Although the pigment can contribute

  42.                         to the degenerative processes, aging involves much more than the accumulation of insoluble

  43.                         debris; aging increases the tendency to form the debris, as well as vice versa.</span></span

  44.                 ></span>

  45.         </blockquote>

  46.         <blockquote></blockquote>

  47.         <blockquote>

  48.             <span style="color: #222222"><span style="font-family: Helvetica"><span>There is a growing recognition that

  49.                         a persistent increase of free fatty acids in the serum, which is seen in shock, heart failure,

  50.                         and aging, indicates a bad prognosis, but there is no generally recognized explanation for the

  51.                         fact that free fatty acids are harmful. I want to mention some evidence showing that it is the

  52.                         accumulation of polyunsaturated fats in the body that makes them harmful.</span></span></span>

  53.         </blockquote>

  54.         <blockquote></blockquote>

  55.         <blockquote>

  56.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The physical and functional

  57.                         properties of saturated fatty acids and polyunsaturated fatty acids (PUFA) are as different from

  58.                         each other as day is from night. The different fatty acids are directly involved, very often

  59.                         with opposite effects, in cell division and growth, cell stability and dissolution, the

  60.                         organization of cells, tissues, and organs, the regulation of pituitary hormones, adrenalin and

  61.                         sympathetic nervous activation, histamine and serotonin synthesis, adrenal cortex hormones,

  62.                         thyroid hormones, testosterone, estrogen, activators of the immune system and inflammation

  63.                         (cytokines), autoimmune diseases, detoxification, obesity, diabetes, puberty,

  64.                         epilepsy,&nbsp;</span></span></span>

  65.         </blockquote>

  66.         <blockquote></blockquote>

  67.         <blockquote>

  68.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Parkinson's disease, other

  69.                         degenerative nerve diseases and Alzheimer's disease, cancer, heart failure, atherosclerosis, and

  70.                         strokes. In each of these situations, the PUFA have harmful effects.</span></span></span>

  71.         </blockquote>

  72.         <blockquote></blockquote>

  73.         <blockquote>

  74.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Most people are surprised to hear

  75.                         about the systematically harmful effects of the common dietary polyunsaturated fats and the

  76.                         protective effects of saturated fats. That's because there is a pervasive mythology of fats in

  77.                         our culture. Officials are proposing to tax saturated fats. Laws are being passed prescribing

  78.                         the fats that can be served in restaurants, and people write letters to editors about them, and

  79.                         great amounts of money are spent publicizing the importance of eating the right fats. Their

  80.                         focus is on obesity, atherosclerosis, and heart disease. The details of the myth change a

  81.                         little, as new fat products and industries appear.&nbsp;</span></span></span>

  82.         </blockquote>

  83.         <blockquote></blockquote>

  84.         <blockquote>

  85.             <span style="color: #222222"><span style="font-family: Helvetica"><span>As I understand the basic myth, the

  86.                         difference between the "essential" polyunsaturated fats and the saturated fats has to do with

  87.                         their shape---the unsaturated fatty acids bend or fold in a way that makes them more mobile than

  88.                         saturated fats of the same length, and this causes the all-important "membranes" of cells to be

  89.                         more fluid, and thus to have "better functions," though the myth isn't very clear on the issue

  90.                         of fluidity and functionality. At that point, it passes responsibility to the more fundamental

  91.                         biological myth, of the metabolically active cell membrane.&nbsp;</span></span></span>

  92.         </blockquote>

  93.         <blockquote></blockquote>

  94.         <blockquote>

  95.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Practically everyone learns, in

  96.                         grade school and from television, about the good and the bad oils, and cell membranes, but it

  97.                         might seem likely that people who spend their lives investigating the role of fats in organisms

  98.                         would have acquired a different, more complicated, view. But one of the most famous food fat

  99.                         researchers, J.M. Bourre, has succinctly (and thoughtlessly) expressed his understanding of the

  100.                         function of fatty substances in the body: "In fact the brain, after adipose tissue, is the organ

  101.                         richest in lipids, whose only role is to participate in membrane structure." (J.M. Bourre,

  102.                         2004.) The fact that his editor let him publish the statement shows how the myth functions,

  103.                         causing people to accept things because they are "common knowledge." The influence of the

  104.                         medical and pharmaceutical industries is so pervasive that it becomes the context for most

  105.                         biological research.</span></span></span>

  106.         </blockquote>

  107.         <blockquote></blockquote>

  108.         <blockquote>

  109.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Luckily, many people are working

  110.                         outside the myth, in specialized problems of physiology and cell biology, and their observations

  111.                         are showing a reality much more complex and interesting than the mythology.&nbsp;</span></span

  112.                 ></span>

  113.         </blockquote>

  114.         <blockquote></blockquote>

  115.         <blockquote>

  116.             <span style="color: #222222"><span style="font-family: Helvetica"><span>When we eat more protein or

  117.                         carbohydrate than we need, the excess can be converted to fats, to be stored (as triglycerides),

  118.                         but even on a maintenance diet we synthesize some fats that are essential parts of all of our

  119.                         cells, including a great variety of phospholipids. People seldom talk about the importance of

  120.                         fats in the nucleus of the cell, but every nucleus contains a variety of lipids--phospholipids,

  121.                         sphingolipids, cholesterol, even triglycerides--similar to those that are found elsewhere in the

  122.                         cell and in every part of the body, including the brain (Balint and Holczinger, 1978; Irvine,

  123.                         2002). Phospholipids are often considered to be "membrane lipids," but they have been

  124.                         demonstrated in association with elements of the cell's skeleton, involved in cell division,

  125.                         rather than in membranes (Shogomori, et al., 1993).</span></span></span>

  126.         </blockquote>

  127.         <blockquote></blockquote>

  128.         <blockquote>

  129.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The cytoskeleton, a fibrous

  130.                         framework of the cell that's responsible for maintaining the organized structure of the cell,

  131.                         internal movement of organelles, coordination, locomotion, and cell division, is made up of

  132.                         three main kinds of protein, and all of these are affected differently by different kinds of

  133.                         fat.&nbsp;</span></span></span>

  134.         </blockquote>

  135.         <blockquote></blockquote>

  136.         <blockquote>

  137.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Actions of lipids on the cell

  138.                         skeleton can change cells' movements, migrations, and invasiveness. Unsaturated fats cause

  139.                         clumping of some types of cell filament, condensation and polymerization of other types, in ways

  140.                         that are associated with brain degenerative diseases and cancer. For example, DHA alters the

  141.                         structure of the protein alpha-synuclein, causing it to take the form seen in Parkinson's

  142.                         disease and other brain conditions. The synucleins regulate various structural proteins, and are

  143.                         affected by stress, aging, and estrogen exposure, as well as by the polyunsaturated fats. One

  144.                         type of synuclein is involved in the promotion of breast cancer. Saturated fatty acids have

  145.                         exactly the opposite effects of PUFA on the synucleins, reversing the polymerization caused by

  146.                         the PUFA (Sharon, et al., 2003).&nbsp;</span></span></span>

  147.         </blockquote>

  148.         <blockquote></blockquote>

  149.         <blockquote>

  150.             <span style="color: #222222"><span style="font-family: Helvetica"><span>When cancers are metastasizing,

  151.                         their phospholipids contain less stearic acid than the less malignant tumors (Bougnoux, et al.,

  152.                         1992), patients with advanced cancer had less stearic acid in their red blood cells (Persad, et

  153.                         al., 1990), and adding stearic acid to their food delayed the development of cancer in mice

  154.                         (Bennett, 1984). The degree of saturation of the body's fatty acids corresponds to resistance to

  155.                         several types of cancer that have been studied (Hawley and Gordon, 1976; Singh, et al.,

  156.                         1995).</span></span></span>

  157.         </blockquote>

  158.         <blockquote></blockquote>

  159.         <blockquote>

  160.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The phospholipids are being

  161.                         discussed in relation to drugs that can modify "signaling" by acting on phospholipid receptors,

  162.                         using language that was developed in relation to hormones. A surface barrier membrane, with

  163.                         receptors that send signals to the nucleus, is invoked by many of the recent discussions of

  164.                         phospholipids. There's no question that the fats do affect regulatory processes, but the theory

  165.                         and the language should correspond to the physiological and ecological realities. Vernadski's

  166.                         metaphor, that an organism is a "whirlwind of atoms," is probably more appropriate than

  167.                         "targeted signals and receptors" for understanding the physiology of fatty acids and

  168.                         phospholipids. The rate of change and renewal of these structural fats is very high. In rats,

  169.                         one study found a 30% decrease in the total phospholipid pool in the brain in the first 30

  170.                         minutes after death (Adineh, et al., 2004).&nbsp; Another study in the brains of living rats

  171.                         found that a particular class of brain lipids, ethanolamine plasmalogens, had a turnover time of

  172.                         about 5 hours (Masuzawa, et al., 1984). (This type of lipid is an important component of the

  173.                         lipoproteins secreted by the liver into the serum [Vance, 1990], and is also a major lipid in

  174.                         the heart and brain.)&nbsp; Stresses such as the loss of sleep cause great distortions in

  175.                         phospholipid metabolism throughout the body, especially in the brain and liver.</span></span

  176.                 ></span>

  177.         </blockquote>

  178.         <blockquote></blockquote>

  179.         <blockquote>

  180.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Actions of lipids on the cell

  181.                         skeleton can change cells' movements, migrations, and invasiveness, even in short term

  182.                         experiments. The effects of the "essential fatty acid" linoleic acid have been compared to the

  183.                         drug colchicine, which is known to interfere with the cell skeleton and cell division. According

  184.                         to Hoover, et al., (1981), it disturbed the structure of the cytoskeleton more than colchicine

  185.                         does; it caused the cell filaments to clump together, while saturated fatty acids didn't have

  186.                         such an effect.</span></span></span>

  187.         </blockquote>

  188.         <blockquote></blockquote>

  189.         <blockquote>

  190.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The fatty molecules that participate

  191.                         in the normal cell functions are made by cells even when they are grown in a fat-free solution

  192.                         in a culture dish. They include saturated fatty acids such as palmitate and stearate, and

  193.                         omega-9 unsaturated fats, such as oleic acid and omega-9 polyunsaturated fatty acids. The

  194.                         saturated fatty acids found in the nucleus associated with the chromosomes are resistant to

  195.                         change when the composition of the animal's diet changes (Awad and Spector, 1976), while the

  196.                         unsaturated fats change according to the diet. These intracellular fats are essential for cell

  197.                         division and the regulation of the genes, and for cell survival (Irvine, 2002). Although cells

  198.                         make the saturated fats that participate in those basic functions, the high rate of metabolism

  199.                         means that some of the lipids will quickly reflect in their structure the free fatty acids that

  200.                         circulate in the blood. The fats in the blood reflect the individual's diet history, but

  201.                         recently eaten fats can appear in the serum as free fatty acids, if the liver isn't able to

  202.                         convert them into triglycerides.</span></span></span>

  203.         </blockquote>

  204.         <blockquote></blockquote>

  205.         <blockquote>

  206.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The polyunsaturated fatty acids

  207.                         differ from the saturated fats in many ways, besides their shape and their melting temperature,

  208.                         and each type of fatty acid is unique in its combination of properties. The polyunsaturated

  209.                         fatty acids, made by plants (in the case of fish oils, they are made by algae), are less stable

  210.                         than the saturated fats, and the omega-3 and omega-6 fats derived from them, are very

  211.                         susceptible to breaking down into toxins, especially in warm-blooded animals. Other differences

  212.                         between saturated and polyunsaturated fats are in their effects on surfaces (as surfactant),

  213.                         charges (dielectric effects), acidity, and their solubility in water relative to their

  214.                         solubility in oil. The polyunsaturated fatty acids are many times more water soluble than

  215.                         saturated fatty acids of the same length. This property probably explains why only palmitic acid

  216.                         functions as a surfactant in the lungs, allowing the air sacs to stay open, while unsaturated

  217.                         fats cause lung edema and respiratory failure.</span></span></span>

  218.         </blockquote>

  219.         <blockquote></blockquote>

  220.         <blockquote>

  221.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The great difference in water/oil

  222.                         solubility affects the strength of binding between a fatty acid and the lipophilic, oil-like,

  223.                         parts of proteins. When a protein has a region with a high affinity for lipids that contain

  224.                         double bonds, polyunsaturated fatty acids will displace saturated fats, and they can sometimes

  225.                         displace hormones containing multiple double bonds, such as thyroxine and estrogen, from the

  226.                         proteins that have a high specificity for those hormones. Transthyretin (also called prealbumin)

  227.                         is important as a carrier of the thyroid hormone and vitamin A. The unsaturation of vitamin A

  228.                         and of thyroxin allow them to bind firmly with transthyretin and certain other proteins, but the

  229.                         unsaturated fatty acids are able to displace them, with an efficiency that increases with the

  230.                         number of double bonds, from linoleic (with two double bonds) through DHA (with six double

  231.                         bonds).&nbsp;</span></span></span>

  232.         </blockquote>

  233.         <blockquote></blockquote>

  234.         <blockquote>

  235.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The large amount of albumin in the

  236.                         blood is important in normal fatty acid binding and transport, but it is also an important part

  237.                         of our detoxifying system, since it can carry absorbed toxins from the intestine, lungs, or skin

  238.                         to the liver, for detoxification. Albumin facilitates the uptake of saturated fatty acids by

  239.                         cells of various types (Paris, et al., 1978), and its ability to bind fatty acids can protect

  240.                         cells to some extent from the unsaturated fatty acids (e.g., Rhoads, et al., 1983). The liver's

  241.                         detoxification system processes some polyunsaturated fats for excretion, along with hormones and

  242.                         environmental toxins.</span></span></span>

  243.         </blockquote>

  244.         <blockquote></blockquote>

  245.         <blockquote>

  246.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The movement of proteins from the

  247.                         plasma into cells has often been denied, but there is clear evidence that a variety of proteins,

  248.                         including IgG, transferrin haptoglobin, and albumin can be found in a variety of cells, even in

  249.                         the brain (Liu, et al., 1989). Cells are lipophilic, and absorb molecules in proportion to their

  250.                         fattiness; this long ago led people to theorize that cells are coated with a fat

  251.                         membrane.&nbsp;</span></span></span>

  252.         </blockquote>

  253.         <blockquote></blockquote>

  254.         <blockquote>

  255.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The idea of a semipermeable

  256.                         membrane, similar in function to the membrane inside an egg shell, was proposed about 150 years

  257.                         ago, to explain the ability of living cells to concentrate certain chemicals, such as potassium

  258.                         ions, while excluding others, such as sodium ions. This idea of a molecular sieve was shown to

  259.                         be invalid when radioactive isotopes made it possible to observe that sodium ions diffuse freely

  260.                         into cells, and it was replaced by the idea of a metabolically active membrane, containing

  261.                         "pumps" that made up for the inability to exclude various things, and that allowed cells to

  262.                         retain high concentrations of some dissolved substances that are free to diffuse out of the

  263.                         cell. The general idea of the membrane as a barrier persisted as a sort of "common sense" idea,

  264.                         that has made people ignore experiments that show that some large molecules, including some

  265.                         proteins, can quickly and massively enter cells. Albumin and transthyretin are two proteins that

  266.                         are sometimes found in large quantities inside cells, and their primary importance is that they

  267.                         bind and transport biologically active oily molecules.&nbsp;</span></span></span>

  268.         </blockquote>

  269.         <blockquote></blockquote>

  270.         <blockquote>

  271.             <span style="color: #222222"><span style="font-family: Helvetica"><span>While the competition by PUFA for

  272.                         protein binding sites blocks the effects of thyroid hormone and vitamin A, the action of PUFA on

  273.                         the sex steroid binding protein (SBP, or SSBG, for sex steroid binding globulin) increases the

  274.                         activity of estrogen. That's because the SSBG neutralizes estrogen by binding it, keeping it out

  275.                         of cells; free PUFA keep it from binding estrogen (Reed, et al., 1986). People with low

  276.                         SSBG/estrogen ratio have an increased risk of cancer. When the SSBG protein is free of estrogen,

  277.                         it is able to enter cells, and in that estrogen-free state it probably serves a similar

  278.                         protective function, capturing estrogen molecules that enter cells before they can act on other

  279.                         proteins or chromosomes. Transthyretin, the main transporter of thyroid and vitamin A, and

  280.                         albumin (which can also transport thyroid hormone) are both able to enter cells, while loaded

  281.                         with thyroid hormone and vitamin A. Albumin becomes more lipophilic as it binds more lipid

  282.                         molecules, so its tendency to enter cells increases in proportion to its fat burden. Albumin in

  283.                         the urine is a problem associated with diabetes and kidney disease; albumin loaded with fatty

  284.                         acids passes from the blood into the urine more easily than unloaded albumin, and it is the

  285.                         fatty acids, not the albumin, which causes the kidney damage (Kamijo, et al., 2002). It's

  286.                         possible that SSBG's opposite behavior, entering cells only when it carries no hormones, is the

  287.                         result of becoming less lipophilic when it's loaded with estrogen.</span></span></span>

  288.         </blockquote>

  289.         <blockquote></blockquote>

  290.         <blockquote>

  291.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Since most people believe that cells

  292.                         are enclosed within a barrier membrane, a new industry has appeared to sell special products to

  293.                         "target" or "deliver" proteins into cells across the barrier. Combining anything with fat makes

  294.                         it more likely to enter cells. Stress (which increases free fatty acids and lowers cell energy)

  295.                         makes cells more permeable, admitting a broader range of substances, including those that are

  296.                         less lipophilic.&nbsp;</span></span></span>

  297.         </blockquote>

  298.         <blockquote></blockquote>

  299.         <blockquote>

  300.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Linoleic acid and arachidonic acid,

  301.                         which are said to "make the lipid membrane more permeable," in fact make the whole cell more

  302.                         permeable, by binding to the structural proteins throughout the cell, increasing their affinity

  303.                         for water, causing generalized swelling, as well as mitochondrial swelling (leading to reduced

  304.                         oxidative function or disintegration), allowing more calcium to enter the cell, activating

  305.                         excitatory processes, stimulating a redox shift away from oxidation and toward inflammation,

  306.                         leading to either (inappropriate) growth or death of the cell.&nbsp;&nbsp;</span></span></span>

  307.         </blockquote>

  308.         <blockquote>

  309.             <span style="color: #222222"><span style="font-family: Helvetica"><span>When we don't eat for many hours,

  310.                         our glycogen stores decrease, and adrenaline secretion is increased, liberating more glucose as

  311.                         long as glycogen is available, but also liberating fatty acids from the fatty tissues. When the

  312.                         diet has chronically contained more polyunsaturated fats than can be oxidized immediately or

  313.                         detoxified by the liver, the fat stores will contain a disproportionate amount of them, since

  314.                         fat cells preferentially oxidize saturated fats for their own energy, and the greater water

  315.                         solubility of the PUFA causes them to be preferentially released into the bloodstream during

  316.                         stress.</span></span></span>

  317.         </blockquote>

  318.         <blockquote></blockquote>

  319.         <blockquote>

  320.             <span style="color: #222222"><span style="font-family: Helvetica"><span>In good health, especially in

  321.                         children, the stress hormones are produced only in the amount needed, because of negative

  322.                         feedback from the free saturated fatty acids, which inhibit the production of adrenalin and

  323.                         adrenal steroids, and eating protein and carbohydrate will quickly end the stress. But when the

  324.                         fat stores contain mainly PUFA, the free fatty acids in the serum will be mostly linoleic acid

  325.                         and arachidonic acid, and smaller amounts of other unsaturated fatty acids. These PUFA stimulate

  326.                         the stress hormones, ACTH, cortisol, adrenaline, glucagon, and prolactin, which increase

  327.                         lipolysis, producing more fatty acids in a vicious circle. In the relative absence of PUFA, the

  328.                         stress reaction is self limiting, but under the influence of PUFA, the stress response becomes

  329.                         self-amplifying.&nbsp;</span></span></span>

  330.         </blockquote>

  331.         <blockquote></blockquote>

  332.         <blockquote>

  333.             <span style="color: #222222"><span style="font-family: Helvetica"><span>When stress is very intense, as in

  334.                         trauma or sepsis, the reaction of liberating fatty acids can become dangerously

  335.                         counter-productive, producing the state of shock. In shock, the liberation of free fatty acids

  336.                         interferes with the use of glucose for energy and causes cells to take up water and calcium

  337.                         (depleting blood volume and reducing circulation) and to leak ATP, enzymes, and other cell

  338.                         contents (Boudreault and Grygorczyk, 2008; Wolfe, et al., 1983; Selzner, et al, 2004; van der

  339.                         Wijk, 2003), in something like a systemic inflammatory state (Fabiano, et al., 2008) often

  340.                         leading to death.&nbsp;</span></span></span>

  341.         </blockquote>

  342.         <blockquote></blockquote>

  343.         <blockquote>

  344.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The remarkable resistance of

  345.                         "essential fatty acid deficient" animals to shock (Cook, et al., 1981; Li et al., 1990; Autore,

  346.                         et al., 1994) shows that the polyunsaturated fats are centrally involved in the maladaptive

  347.                         reactions of shock. The cellular changes that occur in shock--calcium retention, leakiness,

  348.                         reduced energy production--are seen in aging and the degenerative diseases; the stress hormones

  349.                         and free fatty acids tend to be chronically higher in old age, and an outstanding feature of old

  350.                         age is the reduced ability to tolerate stress and to recover from injuries.</span></span></span>

  351.         </blockquote>

  352.         <blockquote></blockquote>

  353.         <blockquote>

  354.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Despite the instability of

  355.                         polyunsaturated fatty acids, which tend to break down into toxic fragments, and despite their

  356.                         tendency to be preferentially liberated from fat cells during stress, the proportion of them in

  357.                         many tissues increases with age (Laganiere and Yu, 1993, 1987; Lee, et al., 1999; Smidova, et

  358.                         al., 1990;Tamburini, et al., 2004; Nourooz-Zadeh J and Pereira, 1999 ). This progressive

  359.                         increase with age can be seen already in early childhood (Guerra, et al., 2007). The reason for

  360.                         this increase seems to be that the saturated fatty acids are preferentially oxidized by many

  361.                         types of cell, (fat cells can slowly oxidize fat for their own energy maintenance). Albumin

  362.                         preferentially delivers saturated fatty acids into actively metabolizing cells such at the heart

  363.                         (Paris, 1978) for use as fuel. This preferential oxidation would explain Hans Selye's results,

  364.                         in which canola oil in the diet caused the death of heart cells, but when the animals received

  365.                         stearic acid in addition to the canola oil, their hearts showed no sign of damage.</span></span

  366.                 ></span>

  367.         </blockquote>

  368.         <blockquote></blockquote>

  369.         <blockquote>

  370.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Since healthy cells are very

  371.                         lipophilic, saturated fatty acids would have a greater tendency to enter them than the more

  372.                         water soluble polyunsaturated fats, especially those with 4, 5, or 6 double bonds, but as cells

  373.                         become chronically stressed they more easily admit the unsaturated fats, which slow oxidative

  374.                         metabolism and create free radical damage. The free radicals are an effect of stress and aging,

  375.                         as well as a factor in its progression.</span></span></span>

  376.         </blockquote>

  377.         <blockquote></blockquote>

  378.         <blockquote>

  379.             <span style="color: #222222"><span style="font-family: Helvetica"><span>When stress signals activate enzymes

  380.                         in fat cells to release free fatty acids from the stored triglycerides, the enzymes in the

  381.                         cytoplasm act on the surface of the droplet of fat. This means that the fatty acids with the

  382.                         greatest water solubility will be liberated from the fat to move into the blood stream, while

  383.                         the more oil soluble fatty acids will remain in the droplet. The long chain of saturated carbon

  384.                         atoms (8 in the case of oleic acid, 15 in palmitic acid, and 17 in stearic acid) in the "tail"

  385.                         of oleic, palmitic, and stearic acid will be buried in the fat droplet, while the tail of the

  386.                         n-3 fatty acids, with only 2 saturated carbons, will be the most exposed to the lipolytic

  387.                         enzymes. This means that the n-3 fatty acids are the first to be liberated during stress, the

  388.                         n-6 fatty acids next. Saturated and monounsaturated fatty acids are selectively retained by fat

  389.                         cells (Speake, et al., 1997).</span></span></span>

  390.         </blockquote>

  391.         <blockquote></blockquote>

  392.         <blockquote>

  393.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Women are known to have a greater

  394.                         susceptibility than men to lipolysis, with higher levels of free fatty acids in the serum and

  395.                         liver, because of the effects of estrogen and related hormones.&nbsp;</span></span></span>

  396.         </blockquote>

  397.         <blockquote></blockquote>

  398.         <blockquote>

  399.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Women on average have more DHA

  400.                         circulating in the serum than men (Giltay, et al., 2004; McNamara, et al., 2008; Childs, et al.,

  401.                         2008). This highly unsaturated fatty acid is the first to be liberated from the fat stores under

  402.                         stress, and, biologically, the meaning of estrogen is to mimic stress. Estrogen and

  403.                         polyunsaturated fatty acids have similar actions on cells, increasing their water content and

  404.                         calcium uptake. Long before the Women's Health Initiative reported in 2002 that the use of

  405.                         estrogen increased the risk of dementia, it was known that the incidence of Alzhemer's disease

  406.                         was 2 or 3 times higher in women than in men. Men with Alzheimer's disease have higher levels of

  407.                         estrogen than normal men (Geerlings, et al., 2006). The amount of DHA in the brain (and other

  408.                         tissues) increases with aging, and its breakdown products, including neuroprostanes, are

  409.                         associated with dementia. Higher levels of DHA and total PUFA are found in the plasma of

  410.                         demented patients (Laurin, et al., 2003).</span></span></span>

  411.         </blockquote>

  412.         <blockquote></blockquote>

  413.         <blockquote>

  414.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Another interesting association of

  415.                         the highly unsaturated fats and estrogen in relation to brain function is that DHA increases the

  416.                         entry of estrogen into the pregnant uterus, but inhibits the entry of progesterone (Benassayag,

  417.                         et al., 1999), which is crucial for brain cell growth. When Dirix, et al., (2009) supplemented

  418.                         pregnant women with PUFA, they found that fetal memory was impaired.&nbsp;</span></span></span>

  419.         </blockquote>

  420.         <blockquote></blockquote>

  421.         <blockquote>

  422.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The crucial mitochondrial

  423.                         respiratory enzyme, cytochrome c oxidase, declines with aging (Paradies, et al., 1997), as the

  424.                         lipid cardiolipin declines, and the enzyme's activity can be restored to the level of young

  425.                         animals by adding cardiolipin. The composition of cardiolipin changes with aging, "specifically

  426.                         an increase in highly unsaturated fatty acids" (Lee, et al., 2006). Other lipids, such as a

  427.                         phosphatidylcholine containing two myristic acid groups, can support the enzyme's activity

  428.                         (Hoch, 1992). Even supplementing old animals with hydrogenated peanut oil restores mitochondrial

  429.                         respiration to about 80% of normal (Bronnikov, et al., 2010).&nbsp;</span></span></span>

  430.         </blockquote>

  431.         <blockquote>

  432.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Supplementing thyroid hormone

  433.                         increases mitochondrial cardiolipin (Paradies and Ruggiero, 1988). Eliminating the

  434.                         polyunsaturated fats from the diet increases mitochondrial respiration (Rafael, et al.,

  435.                         1984).</span></span></span>

  436.         </blockquote>

  437.         <blockquote></blockquote>

  438.         <blockquote>

  439.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Excitotoxicity is the process in

  440.                         which activation of a nerve cell beyond its capacity to produce energy injures or kills the

  441.                         cell, by increasing intracellular calcium. Glutamic acid and aspartic acid are the normal

  442.                         neurotransmitter excitatory amino acids. Estrogen increases the activity of the excitatory

  443.                         transmitter glutamate (Weiland, 1992), and glutamate increases the release of free fatty acids

  444.                         (Kolko, et al., 1996). DHA (more strongly even than arachidonic acid) inhibits the uptake of the

  445.                         excitotoxic amino acid aspartate, and in some situations glutamate, prolonging their actions.

  446.                         Thymocytes are much more easily killed by stress than nerve cells, and they are easy to study.

  447.                         The PUFA kill them by increasing their intracellular calcium. The toxicity of DHA is greater

  448.                         than that of EPA, whose toxicity is greater than alpha-linolenic acid, and linoleic acid was the

  449.                         most potent (Prasad, et al., 2010). Excitotoxicity is probably an important factor in

  450.                         Alzheimer's disease (Danysz and Parsons, 2003).</span></span></span>

  451.         </blockquote>

  452.         <blockquote></blockquote>

  453.         <blockquote>

  454.             <span style="color: #222222"><span style="font-family: Helvetica"><span>When the brain is injured, DHA and

  455.                         arachidonic acid contribute to brain edema, weakening the blood-brain-barrier, increasing

  456.                         protein breakdown, inflammation, and peroxidation, while a similar amount of stearic acid in the

  457.                         same situation caused no harm (Yang, et al., 2007). In other situations, such as the important

  458.                         intestinal barrier, EPA and DHA also greatly increased the permeability (Dombrowsky, et al.,

  459.                         2011).</span></span></span>

  460.         </blockquote>

  461.         <blockquote></blockquote>

  462.         <blockquote>

  463.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The process by which excitotoxicity

  464.                         kills a cell is probably a foreshortened version of the aging process.&nbsp;</span></span></span

  465.             >

  466.         </blockquote>

  467.         <blockquote></blockquote>

  468.         <blockquote>

  469.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Excitotoxins (including endotoxin)

  470.                         increase the formation of neuroprostanes and isoprostanes (from n-3 and n-6 PUFA) (Milatovic, et

  471.                         al., 2005), and acrolein and other fragments, which inhibit the use of glucose and oxygen.&nbsp;

  472.                         DHA and EPA produce acrolein and HHE, which react with lysine groups in proteins, and modify

  473.                         nucleic acids, changing the bases in DNA.&nbsp;</span></span></span>

  474.         </blockquote>

  475.         <blockquote></blockquote>

  476.         <blockquote>

  477.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Increased intracellular calcium

  478.                         activates lipolysis (by phospholipases), producing more free fatty acids, as well as excitation

  479.                         and protein breakdown, and in the brain neurodegenerative diseases, calcium excess contributes

  480.                         to the clumping of synuclein (Wojda, et al., 2008), an important regulator of the cytoskeletal

  481.                         proteins. The reduced function of normal synuclein makes cells more susceptible to

  482.                         excitotoxicity (Leng and Chuang, 2006).</span></span></span>

  483.         </blockquote>

  484.         <blockquote></blockquote>

  485.         <blockquote>

  486.             <span style="color: #222222"><span style="font-family: Helvetica"><span>If the cells adapt to the increased

  487.                         calcium, rather than dying, their sensitivity is reduced. This is probably involved in the

  488.                         "defensive inhibition" seen in many types of cell. In the brain, DHA and arachidonic acid

  489.                         "brought the cells to a new steady state of a moderately elevated [intracellular calcium] level,

  490.                         where the cells became virtually insensitive to external stimuli. This new steady state can be

  491.                         considered as a mechanism of self-protection" (Sergeeva, et al., 2005). In the heart, the PUFAs

  492.                         decreased the sensitivity to stimulation (Coronel et al., 2007) and conduction velocity

  493.                         (Tselentakis, et al., 2006; Dhein, et al., 2005). Both DHA and EPA inhibit calcium-ATPase (which

  494.                         keeps intracellular calcium low to allow normal neurotransmission) in the cerebral cortex; this

  495.                         suggests "a mechanism that explains the dampening effect of omega-3 fatty acids on neuronal

  496.                         activity" (Kearns and Haag, 2002).</span></span></span>

  497.         </blockquote>

  498.         <blockquote></blockquote>

  499.         <blockquote>

  500.             <span style="color: #222222"><span style="font-family: Helvetica"><span>In normal aging, most processes are

  501.                         slowed, including nerve conduction velocity, and conduction velocity in the heart (Dhein and

  502.                         Hammerath, 2001). A similar "dampening" or desensitization is seen in sensory, endocrine, and

  503.                         immune systems, as well as in energy metabolism. Calorie restriction, by decreasing the

  504.                         age-related accumulation of PUFA (20:4, 22:4, and 22:5), can prevent the decrease of

  505.                         sensitivity, for example in lymphoid cells (Laganier and Fernandes, 1991). The known effects of

  506.                         the unsaturated fats on the organizational framework of the cell are consistent with the changes

  507.                         that occur in aging.</span></span></span>

  508.         </blockquote>

  509.         <blockquote></blockquote>

  510.         <blockquote>

  511.             <span style="color: #222222"><span style="font-family: Helvetica"><span>One of the essential protective

  512.                         functions that decline with aging is the liver's ability to detoxify chemicals, by combining

  513.                         them with glucuronic acid, making them water soluble so that they can be excreted in the urine.

  514.                         The liver (and also the intestine and stomach) efficiently process DHA by glucuronidation

  515.                         (Little, et al., 2002). Oleic acid, one of the fats that we synthesize ourselves, increases

  516.                         (about 8-fold) the activity of the glucuronidation process (Krcmery and Zakim, 1993; Okamura, et

  517.                         al., 2006). However, this system is inhibited by the PUFA, arachidonic acid (Yamashita, et al.,

  518.                         1997), and also by linoleic acid (Tsoutsikos, et al., 2004), in one of the processes that

  519.                         contribute to the accumulation of PUFA with aging.</span></span></span>

  520.         </blockquote>

  521.         <blockquote></blockquote>

  522.         <blockquote>

  523.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Animals that naturally have a

  524.                         relatively low level of the highly unsaturated fats in their tissues have the greatest

  525.                         longevity. For example, the naked mole rate has a life expectancy of more than 28 years, about 9

  526.                         times as long as other rodents of a similar size. Only about 2% to 6% of its phospholipids

  527.                         contain DHA, while about 27% to 57% of the phospholipids of mice contain DHA Mitchell, et al.,

  528.                         2007).&nbsp;</span></span></span>

  529.         </blockquote>

  530.         <blockquote></blockquote>

  531.         <blockquote>

  532.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The famously long-lived people of

  533.                         Azerbaijan eat a diet containing a low ratio of unsaturated to saturated fats, emphasizing

  534.                         fruits, vegetables, and dairy products (Grigorov, et al., 1991).</span></span></span>

  535.         </blockquote>

  536.         <blockquote>

  537.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Some of the clearest evidence of the

  538.                         protective effects of saturated fats has been published by A.A. Nanji's group, showing that they

  539.                         can reverse the inflammation, necrosis, and fibrosis of alcoholic liver disease, even with

  540.                         continued alcohol consumption, while fish oil and other unsaturated fats exacerbate the problem

  541.                         (Nanji, et al., 2001). Glycine protects against fat accumulation in alcohol-induced liver injury

  542.                         (Senthilkumar, et al., 2003), suggesting that dietary gelatin would complement the protective

  543.                         effects of saturated fats.</span></span></span>

  544.         </blockquote>

  545.         <blockquote></blockquote>

  546.         <blockquote>

  547.             <span style="color: #222222"><span style="font-family: Helvetica"><span>The least stable n-3 fats which

  548.                         accumulate with age and gradually reduce energy production also have their short term effects on

  549.                         endurance. Endurance was much lower in rats fed a high n-3 fat diet, and the effect persisted

  550.                         even after 6 weeks on a standard diet (Ayre and Hulbert, 1997). Analogous, but less extreme

  551.                         effects are seen even in salmon, which showed increased oxidative stress on a high n-3 diet (DHA

  552.                         or EPA), and lower mitochondrial cytochrome oxidase activity (Kjaer, et al., 2008).&nbsp;</span

  553.                     ></span></span>

  554.         </blockquote>

  555.         <blockquote></blockquote>

  556.         <blockquote>

  557.             <span style="color: #222222"><span style="font-family: Helvetica"><span>Maintaining a high rate of oxidative

  558.                         metabolism, without calorie restriction, retards the accumulation of PUFA, and a high metabolic

  559.                         rate is associated with longevity. An adequate amount of sugar maintains both a high rate of

  560.                         metabolism, and a high respiratory quotient, i.e., high production of carbon dioxide. Mole rats,

  561.                         bats, and queen bees, with an unusually great longevity, are chronically exposed to high levels

  562.                         of carbon dioxide. Carbon dioxide forms carbamino bonds with the amino groups of proteins,

  563.                         inhibiting their reaction with the reactive "glycating" fragments of PUFA.</span></span></span>

  564.         </blockquote>

  565.         <blockquote></blockquote>

  566.         <blockquote>

  567.             <span style="color: #222222"><span style="font-family: Helvetica"><span>To minimize the accumulation of the

  568.                         highly unsaturated fatty acids with aging, it's probably reasonable to reduce the amount of them

  569.                         directly consumed in foods, such as fish, but since they are made in our own tissues from the

  570.                         "essential fatty acids," linoleic and linolenic acids, it's more important to minimize the

  571.                         consumption of those (from plants, pork, and poultry, for example).</span></span></span>

  572.         </blockquote>

  573.         <blockquote>

  574.             <span style="color: #222222"><span style="font-family: Helvetica"><span>In the resting state, muscles

  575.                         consume mainly fats, so maintaining relatively large muscles is important for preventing the

  576.                         accumulation of fats.&nbsp;</span></span></span>

  577.         </blockquote>

  578.         <blockquote>

  579.             <span style="color: #222222"

  580.             >&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;</span>

  581.         </blockquote>

  582.         <blockquote>

  583.             <span style="color: #222222">&nbsp;&nbsp;&nbsp;&nbsp;<span style="font-family: Helvetica"><span><strong><h3>

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  1161.                         these pathologies."</span></span></span>

  1162.         </blockquote>

  1163.         <p>&nbsp;</p>

  1164. 

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