TweetPhosphatidylcholine
Source: DETOXXBOOK on PhosChol
January 06, 2003
One of the most important biochemical changes regarding aging, is a change in membrane phospholipid composition; the result being that we lose the active life giving highly fluid lipids and replace them with rigid stiff inactive ones. That is how it all comes to an end; how life slows down both in thought and in motion until it is no more and it all happens in the loss of control of the active lipids.
Phosphatidylcholine (PC) is the predominate head group in the outer leaflet of the membrane and is composed of two phospholipid groups opposing each other in a normal bilipid membrane array. PC also tends to incorporate a predominance of HUFAs (highly unsaturated fatty acids), especially arachidonic acid (AA) on the Sn2 position, thus the outer leaflet is composed of a grouping of higher energy lipids than the inner leaflet. In mammalian plasma membranes, the main variation occurs in the relative composition of phosphatidylcholine (PC), and both sphingomyelin (SM) and cholesterol. PC decreases with age while SM and cholesterol increases with age (Barenholz, Schacter 1983). The importance of this shift in the outer membrane is difficult to envision. It involves every cell of the body and every sensory neuron such as, touch, smell, taste, sight, hearing, skin, blood cells, brain neurons, endothelium, alveoli, immune cells, bone cells, etc. It involves the organelles within the cell, such as the mitochondria the peroxisomes and the nuclear membrane. The concept of aging and PC decline is a dramatic shift in the bodies homeostatic ability.
The changes in the relative amounts of PC and SM are especially great in tissues, which have a low phospholipid turnover. For example, plasma membranes associated with the aorta and arterial wall show a 6-fold decrease in PC/SM ratio with aging. SM also increases in several diseases, including atherosclerosis. The SM content can be as high as 70-80% of the total phospholipids in advanced aortic lesion (Barenholz 1982, 1984). Both sphingomyelin (SM) and cholesterol are structurally similar to saturated fats. They are rigid, with the concommittment decline in fluidity and lower metabolic performance. The loss of those dynamic double bonds of the high energy lipids could be the major cause of the aging disease.
Transition Temperatures: The most striking differences between PC and SM derived from biological membranes are (a) the phase transition temperature of the phospholipids and (b) the hydrogen-bonding character of the two phospholipids in a lipid bilayer. Most sphingomyelins have transition temperatures in the physiological temperature range between 30 and 40 Celsius, whereas most naturally occurring PC is well above its transition temperature of 37 C. (Barenholz 1980, 1982, 1984). SM and cholesterol contribute to rigidity of the membrane, while PC has a high affinity for HUFAs, especially AA, with much higher internal energy levels, which as discussed prior with reference to the higher energy of the double bonds, raises the transition temperature.
Heart Myocytes: The relative content of PC to SM in mammalian plasma membranes appears to affect cell functioning significantly. Researchers have recently reported on changes in the lipid composition and activity of primary rat heart myocytes in vitro over time. Measurements of PC and SM content in the cells showed a decline of PC/SM ratio from 5 to ~ 2 in the first three days in culture, and from 2 to ~ 1 over the next 14 days.
The phospholipid changes were accompanied by a dramatic change in heart cell activity, as measured by the beating rate of the cultured cells. Between days 7 and 12 in culture, the beats/minute fell from 160 to about 20, with significant increases in the activities of at least seven enzymes, expressed as Vmax/DNA. One of these enzymes was creatine phosphokinase (CPK), a major intracellular energy transport enzyme, and one which can serve as a PC level indicator.
Phospholipid Exchange: The ability to alter the lipid composition of biological cells by phospholipid exchange provides a means for studying the effect of phospholipid variation on cell function. For example, in the above-discussed myocyte culture system, in which a decline in PC/SM ratio over time is accompanied by a drop in beating frequency, the concerns are (a) whether the original phospholipid composition of the cells can be restored by an exchange of more favorable phospho-lipids, and (b) can the original cell function be restored, i.e. the initial higher beating rate.
There are a number of studies attempting to evaluate the premise of using phosphatidylcholine as a vehicle for phospholipid exchange within cellular membranes. The rat heart myocyte study specifically showed that by infusing PC, a phospholipid exchange increased both PC/SM and PC/cholesterol ratios, thus reversing the abnormal phospholipid composition which occurred in the cultured cells over time. (Yechiel 1985a, 1985b). Interestingly, phospholipid exchange restored cell-beating frequency to its original levels, with the beating frequency showing a jump from 20 to 160 within one day of cell exposure to phosphatidylcholine.
The same phospholipid exchange also led to a reduction in cellular enzymes, such as CPK, which normally increases over time. However, the experiments described were carried out in cell culture, whereby the cells are individually tested for their response to the various phospholipids. However, it is a bit presumptuous, based on in-vitro laboratory experiments that the use of phosphatidylcholine would necessarily lead to similar rates of rejuvenation in humans.
The present focus however, is with the use of phosphatidylcholine (PC) as either a medical intervention using IV therapy, or as a nutritional supplement, with the goal of changing fatty acid composition similar to components of the heart cells of subjects of a younger age. The intravenous administration of PC as a fast infusion, or the use of oral PC should be administered in a protocol sufficient to witness a significant drop in serum creatine phosphokinase (CPK). Both have been used either separately and together, with the oral supplementation as a means of maintaining levels of PC between IVs. IV administration is preferred, when possible, however oral has been documented in the literature to be efficacious. (Lipostabil, Rhone-Poulanc).
Atheroscerosis / Ischemia: An important aspect of the PC treatment program has been the recognition that essential phospholipids rich in phosphatidylcholine are able to reverse age-related changes in phospholipid composition of heart muscle cells in animals. In one series of tests, 18-month-old rats were treated with three doses, administered every three days for six days (three injections), and the animals were sacrificed three days after the final injection. The PC/SM and cholesterol content of heart muscle cells were compared from relatively young animals (three months old) and from untreated 18-month-old animals. The results show that the PC/SM ratio increased by more than twofold with an almost threefold decrease in cholesterol content, reversing the age related shift in both values, as would normally be the alterations experienced with age between three and eighteen months.
The three groups of animals were also tested for heart muscle and serum CPK levels. The changes in lipid composition, which normally occur between three and eighteen months (high SM and cholesterol), were accompanied by approximately threefold increases in both heart muscle cell and serum CPK. After nine days of treatment, heart cell CPK declined about threefold to levels normally seen in 3 month old animals, and serum CPK declined eightfold to a level substantially lower than that in 3 month old animals. The dramatic fall in serum CPK in treated animals thus provides a sensitive indicator of heart lipid changes occurring during treatment.
The above-noted changes in heart cell lipid composition were measured on whole heart homogenates, and therefore represent phospholipid contributions from both myocardial (heart) cells and connective tissue fibroblasts. To confirm that the observed change in phospholipids also reflects changes in myocardial cells, heart cells from three-month-old and eighteen-month-old animals were isolated, cultured under conditions which lead to myocardial reaggregates, then tested for lipid exchange with egg PC. The reaggregates originally showed a decrease in PC/SM ratio and an increase in cholesterol level, when comparing cells from three and eighteen month old animals. These age-related changes were substantially reversed by incubation with egg PC. The results indicate that the observed phospholipid effects seen in heart tissue in vivo are due at least in part to changes in myocardial membrane phospholipids. The effect of the PC treatment program on heart muscle phospholipid concentration is reflected in a number of other physiological changes readily observed in serum samples from the treated individual (animal or human).
Improved Respiratory Function: The use of the PC treatment program can also significantly enhance an animal's ability to withstand respiratory stress. As above, the use of the treatment can easily be monitored by changes in CPK or red blood cell properties. The animal's ability to withstand cardiac stress before and after treatment was measured by a standard lab procedure, in which an animal is placed in a defined-volume chamber, which does not allow gas exchange with the outside. During the course of the test, the depletion of oxygen and accumulation of carbon dioxide reduces the animal's blood pressure gradually to near zero levels. The ability to withstand respiratory stress is measured by the lapse in time in the chamber before the animal's blood pressure drops to near zero.
After three treatments (nine days after the first treatment), 18 month old male rats were able to maintain blood pressure about 50% longer than untreated rats. The treated rats also showed a much slower rate of increase of serum CPK during the test than untreated animals. Blood monitoring throughout the test period showed that both treated and untreated animals maintained comparable levels of blood oxygen and carbon dioxide, indicating that the better performance of treated animals was not merely a blood-gas content effect.
Increasing Longevity: Studies on laboratory animals indicate that treating relatively aged animals with PC infusion over an extended period increases an animals’ lifespan by an average of about 36%. 30-month-old rats were given an initial injection, followed by a second injection 1 week later, and maintenance injections every two months. A group of untreated rats died between ages 32 and 38 months, with an average age of death of about 34 months. The group of treated animals was sacrificed between ages 42 and 48 months.
It is interesting to note that longevity was extended in the treated animals, even though treatment was not begun until a relatively advanced age (32 to 38), actually within a few months of the time the animals would have normally died. This finding indicates that the treatment is effective in reversing age-related changes in lipid composition, even at an advanced age. The approximately 36% increase in longevity indicates that the alteration in lipid composition produced by treatment confers widespread physiological benefits (including, presumably, increased cardiac performance and arterial circulation) which are related to longevity. The increase in longevity, which is achievable in animals, could also result in increase of longevity in humans, assuming that a human lives on the average about 2 years for each month of a laboratory rat, treatment could result in a major increase of longevity equivalent to 25 years. Note: The 36% increase in longevity of the animal could have been improved by permitting a normal expiration period.
Another study examined the effect of treatment on animal longevity. The rats tested were 30-month-old male Sprague-Dawley rats. Since Sprague-Dawley rats normally die between the ages of 24-30 months, the rats tested exhibited some selection for longevity. A test group of six rats were each given PC SuVs, at a dose of between 0.5 and 1g phosphatidylcholine lipid through the tail vein, and similarly dosed after one week, and every two months thereafter, until the animal died of natural causes.
The animals were fed as much as they desired during the treatment period and the usual precautions were taken to avoid animal infection. A second control group of same-aged rats was similarly injected with sterile saline on the same dose schedule. Of the 6 animals in the control group, 2 died at 32 months (two months after the beginning of treatment), 3 died at 34 months, and 1 died at 40 months, giving an average age at death of about 34 months. Of the treated animals, 2 were sacrificed at 44 months, 1 at 45 months, and 3 at 48 months, giving a minimal average age at death of about 46 months.
Increased Male Fertility: Treating relatively old lab animals with this treatment reversed the near-complete loss of competence normally seen in the older male animals. The method is particularly useful for treating older breeding animals. 30 months and older rats received three doses over a 6 day period. Normally male rats at this age are unable to sire litters when placed in the same cage with younger fertile female rats. When untreated rats of this age were individually housed with three female rats, 5-6 months old, only two out of the three females had litters, and in each case the litter was smaller than the usual 10-13 animal litter sired by younger males. Treated rats, by contrast, showed normal male fertility. All of the rats sired litters in all three females, and all of the litter sizes were the normal 10-13 in size.
Difficulty With Animal Studies: It is difficult to extrapolate human reactivity from these animal studies. Rats have a more efficient FA metabolism regarding desaturase and elongase enzyme functions. To determine the final lipid composition of a rat after an infusion of IV PC, into the higher PUFAs and HUFAs, would be onerous to track. It is possible however, to determine the results of a variation in head groups of a PC exchange, but the PUFA lipids in the oral or IV PC are predominantly LA and would be readily metabolized to HUFAs in a rat, in effect, changing the performance relative to humans. In addition, the size of the bolus (1 gram IV) related to humans is in the order of 100:1. Using an IV equivalent would require an infusion of 50 to 100 grams of PC, which is 50 to 100 times the dosage recommended by the pharmaceutical manufacturer. Using an oral equivalent, and based on an absorption rate of oral PC at 20% to an infusion of PC at 100%, a ratio of 1:5, would require the ingestion of ~ 500 capsules at one time ( 900 mg ea.), which is certainly inadvisable.
The majority of the past 20 years of PC research on humans has focused on the positive effects on arteriosclerosis and improving liver enzymes and hepatitis B. The liver receives the first flush of PC from an infusion and receives 25% of the entire blood flow, therefore it was the first examined for potential benefits of a PC exchange. However, an exchange of lipids is systemic with every organ, every neuron and every cell sharing the increased PC and the higher performing lipids (HUFAs). It should be expected that improved metabolic performance would also be systemic.
Also, research has shown that the higher PC levels reached after a 3 month program of PC administration dissipates within 4 months of ceasing infusion or oral supplementation. The ability to maintain PC levels is therefore an energy related rate of change that equates with the higher metabolic rate of youth, but which some portion appears attainable at almost any age. To avail yourself of this exciting PC program, it is therefore necessary to consider a long term maintenance program of both IV and/or PC supplements, once optimum levels are attained from the initial program. The concept of altering an aging membrane is nothing short of exhilarating.