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Vitamin A: Anti-Cancer and Anti-Estrogen

Also see:
Hormonal profiles in women with breast cancer
Protect the Mitochondria
High Cholesterol and Metabolism
The Cholesterol and Thyroid Connection
Vitamin E Needs Increases with PUFA Consumption and Greater Unsaturation

Vitamin E and vitamin A also protect against lipid peroxidation, and vitamin A is specifically involved in progesterone synthesis. Vitamin A also has a variety of anti-estrogen functions, that are often considered to be relevant to protection against cancer. -Ray Peat, PhD

American Journal of Clinical Nutrition, Vol 5, 666-673
Relation of Vitamin A Deficiency and Estrogen to Induction of Keratinizing Metaplasia in the Uterus of the Rat
WALTER J. BO PH.D.
Metaplasia of the uterine epithelium of estrogen-treated rats begins as many independent centers that grow and coalesce to produce a keratinized stratified squamous epithelium which replaces the original uterine epithelium.

The origin of epithelial metaplasia produced by estrogen stimulation differs from the metaplasia which occurs in vitamin A deficiency in that in the former the change takes origin in the luminal epithehium and the latter in the endometrial glands. The epithelium produced by estrogen stimulation is thicker and more heavily keratinized than that produced by vitamin A deficiency.

Keratinizing metaplasia in the uterus of the rat was observed to occur only in intact animals on a vitamin A-deficient diet or in the ovariectomized, vitamin A-deficient rats treated with estrogen. The results demonstrate that estrogen has an important role in producing keratinized epithelium in avitaminosis A and the change cannot be considered to be due to only a local vitamin A deficiency.

From the present investigation it can be concluded that vitamin A deficiency is not the primary factor in producing keratinizing metaplasia in the uterus of the rat since estrogen plays a role in producing the change.

The mode of action of vitamin A in maintaining normal uterine epithelium is not known, but it seems that a balance may exist between estrogen and vitamin A in order to maintain the integrity of the uterine epithelium and when this is disrupted keratinizing metaplasia occurs.

The Journal of Steroid Biochemistry and Molecular Biology
Volume 39, Issue 4, Part 1, October 1991, Pages 455-460
Retinoic acid acts synergistically with 1,25-dihydroxyvitamin D3 or antioestrogen to inhibit T-47D human breast cancer cell proliferation
Masafumi Koga, Robert L. Sutherland
The abnormal cornification of the vagina that occurs in vitamin A deficiency of the rat was compared with the uterine changes and it was concluded that the two are not the same. In the vagina the change is more of a hyperplastic change while in the uterus it is a true metaplasia. Therefore, the conclusions drawn from the observations made on the vagina in avitaminosis A and between vitamin A and estrogen cannot be generalized to include the uterus.

Although retinoic acid has been shown to inhibit proliferation in human breast cancer cells, the mechanisms by which these effects are mediated are not known. Since several steroid hormones and their synthetic antagonists also inhibit proliferation of human breast cancer cells, we investigated the interactions between retinoic acid, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and antioestrogens in the control of human breast cancer cell proliferation in vitro. When T-47D cells, the most sensitive of six human breast cancer cell lines to the growth inhibitory effects of retinoic acid, were treated with retinoic acid and 1,25-(OH)2D3, a synergistic inhibitory effect on cell growth was observed. Retinoic acid also enhanced the growth inhibitory effect of various antioestrogens (4-hydroxytamoxifen, 4-hydroxyclomiphene or LY117018). However, retinoic acid did not affect oestradiol-induced growth stimulation. Measurement of the cellular receptors for 1,25-(OH)2D3 and oestrogen revealed no significant change in receptor levels following treatment with concentrations of retinoic acid which modulated growth.

These results indicate that retinoic acid not only has direct growth inhibitory effects on breast cancer cell proliferation but also augments the effects of some other known regulators of breast cancer cell replication including 1,25-(OH)2D3 and antioestrogens. Synergism appears to involve interactions with steroid hormone action distinct from changes in steroid hormone receptor levels.

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Gut Flora and Resistance to Endotoxin

J Exp Med. 1962 June 1; 115(6): 1149–1160.
THE FECAL FLORA OF VARIOUS STRAINS OF MICE. ITS BEARING ON THEIR SUSCEPTIBILITY TO ENDOTOXIN
Russell W. Schaedler and René J. Dubos
Adult mice from seven different colonies were studied with regard to (a) the numbers and types of bacteria that could be cultivated from their stools; (b) their resistance to the lethal effect of endotoxins prepared from three strains of Gram-negative bacilli. [See PDF for Structure] In six of the seven colonies, the stools yielded large numbers of various types of lactobacilli, enterococci, and Gram-negative bacilli. Most animals in these colonies died within 48 hours following injection of endotoxin. The other mouse colony (NCS) has been maintained for the past three years at the Rockefeller Institute under exacting sanitary conditions; it is free of many types of common mouse pathogens. The stool flora of NCS mice yielded very large numbers of viable lactobacilli (109 per gm), representing at least three different morphological types. In contrast, it contained only few enterococci and Gram-negative bacilli (less than 106 per gm). Moreover, E. coli, Proteus sp., and Pseudomonas sp. could not be recovered from the stools under normal conditions. NCS mice proved resistant to the lethal effect of endotoxins. These characteristics of the NCS colony prevailed whether the animals were housed continuously in individual cages on wire grids, or grouped continuously in large cages with wood shavings as litter. However, the composition of the bacterial flora could be rapidly and profoundly altered by a variety of unrelated disturbances such as sudden changes in environmental temperature, crowding in cages, handling of the animals, administration of antibacterial drugs, etc. The first effect of the change was a marked decrease in the numbers of lactobacilli and commonly an increase in the numbers of Gram-negative bacilli and enterococci. When tested 3 weeks after these disturbances some NCS animals were found to have become susceptible to the lethal effects of endotoxin.

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Exercise and Effect on Thyroid Hormone

Also see:
Exercise Induced Stress
Potential Adverse Cardiovascular Effects from Excessive Endurance Exercise
Exercise Induced Menstrual Disorders
Ray Peat, PhD: Quotes Relating to Exercise
Ray Peat, PhD and Concentric Exercise
Overtraining, Undereating & Self-Inflicted Hypothyrodism: Thresholds for Low T3 and High Reverse T3 Levels at 8% & 15% Reduced Energy Intake + Exercise After Only 4 Days!
Running on Empty

Clin Endocrinol (Oxf). 1984 Jun;20(6):657-69.
The thyroid function in young men during prolonged exercise and the effect of energy and sleep deprivation.
Opstad PK, Falch D, Oktedalen O, Fonnum F, Wergeland R.
Thyroid function has been investigated in 24 young military cadets participating in a 5 d ranger training course with heavy physical exercise, calorie deficiency and deprivation of sleep. The cadets were divided into three groups, each differing in the amount of sleep and food consumption. The serum levels of thyroid hormones (T4, FT4, T3, rT3) and TBG showed a biphasic pattern during the course. Initially there was an increased secretion concomitant with an increased deiodination of T4 to T3 and rT3 mainly due to physical exercise. When the activities lasted for several days without sufficient food supply the thyroid secretion decreased simultaneously with an alteration of the peripheral conversion of T4 to rT3 instead of T3. A significant correlation was found between the changes in total and free thyroxine (r = 0.9) and between the increase in rT3 and decrease in T3 (r = 0.6). TSH decreased during the first day of activities and remained low throughout the course. The TSH response to TRH stimulation was greatly reduced during the course due to physical exercise and calorie deficiency. The present investigation demonstrates that the thyroid function is strongly affected by prolonged physical exercise and a negative energy balance, whereas sleep deprivation does not have any significant influence. The results indicate that the alteration observed is not regulated just by the hypothalamo-pituitary-thyroid-axis alone.

Metabolism. 1981 Mar;30(3):237-41.
Thyroid hormones and lipolysis in physically trained rats.
Wirth A, Holm G, Lindstedt G, Lundberg PA, Björntorp P.
In rats a single bout of exercise resulted in increased triiodothyronine (T3), thyroxine (T4), and triiodothyronine/reverse triiodothyronine (T3/rT3) ratio 20 hr after exercise. The effect of norepinephrine on lipolysis in vitro was potentiated. In trained rats no changes were found in T4, T3, or rT3 concentrations. The T3/rT3 ratio as well as basal and stimulated TSH concentrations decreased in comparison with sedentary, freely eating rats. Moderate food restriction to produce a body weight similar to that of trained animals caused no changes in T4, T3, or rT3 concentrations but caused a decrease in T3/rT3 and in TSH levels. Training and moderate food restriction groups were not different. T3 in vitro caused a potentiation of catecholamine induced lipolysis in trained and food-restricted animals. With aging the serum concentration of T3 decreased and that of rT3 increased. Acute and chronic exercise both exert an effect on peripheral hormonal responses of lipolysis, while they have different and opposite effects on thyroid hormone concentrations. Physical training seems to have effects in this regard similar to those of moderate energy intake restriction. The results suggest that changes in peripheral effects of thyroid hormones during training should attract more attention.

J Physiol Pharmacol. 1998 Sep;49(3):457-66.
The effect of exercise training intensity on thyroid activity at rest.
Rosołowska-Huszcz D.
The influence of exercise training intensity on thyroid activity at rest was studied in male Wistar rats, weighting 114 g +/- 24 (mean +/- SD) at the beginning of the experiment. Animals were assigned to the following groups: untrained controls and rats trained on a treadmill at the speed of 20 m/min over a 5-week period with different intensities: 2 x 60 min weekly, 4 x 60 min, 6 x 20 min, 6 x 40 min and 6 x 60 min weekly. Thyroid peroxidase (TPO) and hepatic iodothyronine 5′-monodeiodinase (5’DI) activities as well as plasma thyroxine (T4), 3,3’5-triiodothyronine (T3) and 3,3′.5′-triiodothyronine (rT3) concentrations were determined. Training intensity was found to influence parameters under investigation. TPO activity was decreased in groups trained 240 min (4 x 60 min and 6 x 40 min) and 360 min (6 x 60 min) weekly in comparison to control, untrained group. Furthermore, a drop in T4 plasma concentration in all trained groups and a decrease in T3 plasma concentration in groups exercising for 120 min (2 x 60 min and 6 x 20 min) weekly, as compared to control, untrained rats, was found. Hepatic 5’DI activity and rT3 plasma concentration were not affected by training. Thus, exercise training in rats seems to elicit the fall in TPO activity and T4 plasma concentration at rest but without changing hepatic 5’DI activity and rT3 plasma concentrations. A decline in T3 plasma concentration, observed in rats trained with the lowest exercise intensities, could be regarded as transitional effect in adaptation to chronic exercise.

Eur J Appl Physiol. 2003 Jan;88(4-5):480-4. Epub 2002 Nov 22.
Resting thyroid and leptin hormone changes in women following intense, prolonged exercise training.
Baylor LS, Hackney AC.
This study examined whether free (f) triidothyronine (T3), f thyroxine (T4), thyroid stimulating hormone (TSH), and leptin concentrations at rest changed in response to 20 weeks of exercise-training. Two groups of women were recruited for participation in the study, collegiate athletes ( n=17) and sedentary controls (n=4). Exercise training consisted of daily athletic activity such as rowing, running, and weight lifting. Subjects were initially grouped into rowers and controls. However, earlier suggested criteria were further used to categorize hormone changes (percentages) in the subjects into (+) responders (increases), (-) responders (decreases), or non-responders (no changes). The fT3 results of the rowers revealed two distinct categories of responses, (-) responder (all decreases; n=10) and non-responder (no change; n=7) rowers. In the responders fT3 concentration decreased (P<0.05) from baseline (BL) during an intense training period [(mean SEM) at 5 weeks by -28.2 (6.2)% and at 10 weeks by -24.9 (7.9)%], then returned towards BL levels (20 weeks compared to BL, P>0.05). Similar changes (P<0.05), at comparable times, were noted for leptin and TSH concentrations in the (-) responder rowers. The non-responder rowers and control subjects displayed no significant (P>0.05) hormone changes over the 20 weeks. The hormone changes observed in the (-) responder rowers were not significantly (P>0.05) correlated with changes in body composition or hydration status during the study. The mechanism for the hormone changes in the (-) responder rowers is unclear. We speculate the decrease in concentrations of TSH and fT3 could be attributable to a lower hypothalamic-pituitary signaling action, and this is related to the decreased leptin concentrations, and could represent a possible means of energy conservation in these exercising women.

Metabolism. 1997 May;46(5):499-503.
Endurance training with constant energy intake in identical twins: changes over time in energy expenditure and related hormones.
Tremblay A, Poehlman ET, Despres JP, Theriault G, Danforth E, Bouchard C.
The effects of exercise training and of its interaction with the genotype on components of energy expenditure and related hormones were examined in young male monozygotic twins. Energy intake was maintained at the pretraining level for a 93-day training period. The estimated net energy deficit induced by training was 244 MJ and was associated with a 5-kg body weight loss that was almost entirely explained by body fat loss. Resting metabolic rate (RMR) was significantly decreased by 8% after training despite the preservation of fat-free mass (FFM). Accordingly, plasma norepinephrine (NE) concentrations, NE appearance rate, and plasma levels of triiodothyronine (T3), free T3, and total thyroxine (T4) were lower after training. The energy cost of standardized exercise was also reduced after the training program. A modest to significant within-twin-pair resemblance was observed for absolute changes in the RMR, thermic effect of food, energy cost of exercise, NE clearance, and plasma concentrations of thyroid hormones. These results suggest that when exercise training is associated with a substantial negative energy balance, energy expenditure and levels of related hormones are decreased, and this effect is partly accounted for by heredity.

Med Sci Sports Exerc. 1984 Jun;16(3):243-6.
Thyroidal changes associated with endurance training in women.
Boyden TW, Pamenter RW, Rotkis TC, Stanforth P, Wilmore JH.
The associations between endurance training, body composition, and the pituitary-thyroid axis were studied in 17 healthy, young women. Body composition and plasma concentrations of T4, T3, rT3, resin T3 uptake, TSH, and TRH-stimulated TSH were examined at baseline and after each subject’s weekly distance had increased 48 km (delta 48) and 80 km (delta 80) above baseline. Total body weight did not change at delta 48 or delta 80. Mean (+/- SE) lean weight in kg increased from 42.9 +/- 1.2 at baseline to 44.8 +/- 1.2 at delta 80 (P = 0.002). We have reported previously that at delta 48 the subjects had evidence of mild thyroidal impairment, which consisted of decreased T3 and rT3, and an exaggerated TSH response to TRH. With more prolonged training (delta 48 to delta 80) there were significant increases in T4, rT3, and unstimulated TSH, while the ratios of T4/rT3 and T3/rT3 and the TSH response to TRH decreased significantly. Some of the thyroidal changes that occurred between delta 48 and delta 80 are similar to those seen in other stressful non-thyroidal conditions.

J Sports Med Phys Fitness. 1991 Jun;31(2):142-6.
Serum thyroid hormones, thyrotropin and thyroxine binding globulin in elite athletes during very intense strength training of one week.
Pakarinen A, Häkkinen K, Alen M.
The effects of a one-week very intense strength training period on maximal strength and pituitary-thyroid function were investigated in eight elite male weight lifters. No statistically significant changes occurred in the maximal isometric leg extension force of the test subjects. Decreased serum concentrations of thyrotropin (TSH), thyroxine (T4) and triiodothyronine (T3) were found during the training period, but no statistically significant changes occurred in the levels of free thyroxine (fT4), reverse T3 (rT3) and thyroxine binding globulin (TBG). The results suggest that the training stress affects at the hypophyseal and/or hypothalamic level decreasing the secretion of TSH, which leads to slightly decreased function of the thyroid gland.

Eur J Appl Physiol Occup Physiol. 1988;57(4):394-8.
Serum thyroid hormones, thyrotropin and thyroxine binding globulin during prolonged strength training.
Pakarinen A, Alén M, Häkkinen K, Komi P.
The effects of progressive strength training for 24 weeks on maximal strength and pituitary-thyroid function were studied in 21 males during the training and during the following detraining period of 12 weeks. Maximal strength increased greatly (p less than 0.001) in the first 20 weeks, followed by a plateau phase in the last 4 weeks of training. Maximal strength decreased greatly (p less than 0.001) during the detraining period. The concentrations of serum total (T4) and free thyroxine (fT4) decreased (p less than 0.05 and less than 0.01, respectively) during the training period and they rose to pretraining levels during the detraining period. During the most intense training phase (the last 4 weeks) there was a positive correlation between the changes in serum fT4 concentrations and the changes in maximal force (r = 0.56; p less than 0.01). No statistically significant changes occurred in the levels of serum triiodothyronine, thyrotropin or thyroxine binding globulin. The results show that prolonged intensified strength training can slightly decrease the concentrations of serum total and free T4. These small changes cannot have any clinical significance, and even their physiological significance may be only marginal.

J Sports Sci. 1993 Dec;11(6):493-7.
Effects of prolonged training on serum thyrotropin and thyroid hormones in elite strength athletes.
Alén M, Pakarinen A, Häkkinen K.
The response of the pituitary-thyroid system was studied in 11 elite weight lifters before, during and after a strength training period of 1 year. During the overall 1 year training period, no systematic changes were found in the concentrations of serum thyrotropin (TSH), thyroxine (T4), free thyroxine (FT4), tri-iodothyronine (T3) and thyroxine binding globulin (TBG). During the pre-competition training period (weeks 15-18), there was a decreased volume of training which was accompanied by a gradual increase in serum T4, FT4 and T3 concentrations. When the intensity of training increased and volume decreased further before the main competition (weeks 19-20), the changes noted returned to their initial levels. It was concluded that in elite strength athletes, intensive training with one training session per day does not lead to major changes in pituitary-thyroid function, but only to minor physiological responses well within the normal range.

Med Sci Sports Exerc. 2003 Sep;35(9):1553-63.
Menstrual disturbances in athletes: a focus on luteal phase defects.
De Souza MJ.
Subtle menstrual disturbances that affect the largest proportion of physically active women and athletes include luteal phase defects (LPD). Disorders of the luteal phase, characterized by poor endometrial maturation as a result of inadequate progesterone (P4) production and short luteal phases, are associated with infertility and habitual spontaneous abortions. In recreational athletes, the 3-month sample prevalence and incidence rate of LPD and anovulatory menstrual cycles is 48% and 79%, respectively. A high proportion of active women present with LPD cycles in an intermittent and inconsistent manner. These LPD cycles are characterized by reduced follicle-stimulating hormone (FSH) during the luteal-follicular transition, a somewhat blunted luteinizing hormone surge, decreased early follicular phase estradiol excretion, and decreased luteal phase P4 excretion both with and without a shortened luteal phase. LPD cycles in active women are associated with a metabolic hormone profile indicative of a hypometabolic state that is similar to that observed in amenorrheic athletes but not as comprehensive or severe. These metabolic alterations include decreased serum total triiodothyronine (T3), leptin, and insulin levels. Bone mineral density in these women is apparently not reduced, provided an adequate estradiol environment is maintained despite decreased P4. The high prevalence of LPD warrants further investigation to assess health risks and preventive strategies.

J Clin Endocrinol Metab. 2003 Jan;88(1):337-46.
Luteal phase deficiency in recreational runners: evidence for a hypometabolic state.
De Souza MJ, Van Heest J, Demers LM, Lasley BL.
Exercising women with amenorrhea exhibit a hypometabolic state. The purpose of this study was to evaluate the relationship of luteal phase deficient (LPD) menstrual cycles to metabolic hormones, including thyroid, insulin, human GH (hGH), leptin, and IGF-I and its binding protein levels in recreational runners. Menstrual cycle status was determined for three consecutive cycles in sedentary and moderately active women. Menstrual status was defined as ovulatory or LPD. Subjects were either sedentary (n = 10) or moderately active (n = 20) and were matched for age (27.7 +/- 1.2 yr), body mass (60.2 +/- 3.3 kg), menstrual cycle length (28.4 +/- 0.9 d), and reproductive age (14.4 +/- 1.2 yr). Daily urine samples for the determination of estrone conjugates, pregnanediol 3-glucuronide, and urinary levels of LH were collected. Blood was collected on a single day during the follicular phase (d 2-6) of each menstrual cycle for analysis of TSH, insulin, total T3, total T4, free T4, leptin, hGH, IGF-I, and IGF binding protein (IGFBP)-1 and IGFBP-3. Among the 10 sedentary subjects, 28 of 31 menstrual cycles were categorized as ovulatory (SedOvul). Among the 20 exercising subjects, 24 menstrual cycles were included in the ovulatory category (ExOvul), and 21 menstrual cycles were included in the LPD category (ExLPD). TSH, total T4, and free T4 levels were not significantly different among the three categories of cycles. Total T3 was suppressed (P = 0.035) in the ExLPD (1.63 +/- 0.07 nmol/liter) and the ExOvul categories of cycles (1.75 +/- 0.8 nmol/liter) compared with the SedOvul category of cycles (2.15 +/- 0.1 nmol/liter). Leptin levels were lower (P < 0.001) in both the ExOvul (5.2 +/- 0.4 microg/liter) and the ExLPD categories of cycles (5.1 +/- 0.4 microg/liter) when compared with the SedOvul category of cycles (13.7 +/- 1.7 microg/liter). Insulin was lower (P = 0.009) only in the ExLPD category of cycles (31.9 +/- 2.8 pmol/liter) compared with the SedOvul (60.4 +/- 8.3 pmol/liter) and ExOvul (61.8 +/- 10.4 pmol/liter) categories of cycles. IGF-I, IGFBP-1, IGFBP-3, IGF-I/IGFBP-1, IGF-I/IGFBP-3, and hGH were comparable among the different categories of cycles. These data suggest that exercising women with LPD menstrual cycles exhibit hormonal alterations consistent with a hypometabolic state that is similar to that observed in amenorrheic athletes and other energy-deprived states, although not as comprehensive. These alterations may represent a metabolic adaptation to an intermittent short-term negative energy balance.

Neuro Endocrinol Lett. 2006 Feb-Apr;27(1-2):247-52.
The effect of exhaustion exercise on thyroid hormones and testosterone levels of elite athletes receiving oral zinc.
Kilic M, Baltaci AK, Gunay M, Gökbel H, Okudan N, Cicioglu I.
OBJECTIVES:
The present study aims to investigate how exhaustion exercise affects thyroid hormones and testosterone levels in elite athletes who are supplemented with oral zinc sulfate for 4 weeks.
METHODS:
The study included 10 male wrestlers, who had been licensed wrestlers for at least 6 years. Mean age of the wrestlers who volunteered in the study was 18.70 +/- 2.4 years. All subjects were supplemented with oral zinc sulfate (3 mg/kg/day) for 4 weeks in addition to their normal diet. Thyroid hormone and testosterone levels of all subjects were determined as resting and exhaustion before and after zinc supplementation.
RESULTS:
Resting TT3, TT4, FT3, FT4 and TSH levels of subjects were higher than the parameters measured after exhaustion exercise before zinc supplementation (p<0.05). Both resting and exhaustion TT3, TT4 and FT3 values after 4-week zinc supplementation were found significantly higher than both of the parameters (resting and exhaustion) measured before zinc supplementation (p<0.05). Resting total testosterone and free testosterone levels before zinc supplementation were significantly higher than exhaustion levels before zinc supplementation (p<0.05). Both resting and exhaustion total and free testosterone levels following 4-week zinc supplementation were found significantly higher than the levels (both resting and exhaustion) measured before zinc supplementation (p<0.05). CONCLUSION: Findings of our study demonstrate that exhaustion exercise led to a significant inhibition of both thyroid hormones and testosterone concentrations, but that 4-week zinc supplementation prevented this inhibition in wrestlers. In conclusion, physiological doses of zinc administration may benefit performance.

Neuro Endocrinol Lett. 2007 Oct;28(5):681-5.
Effect of fatiguing bicycle exercise on thyroid hormone and testosterone levels in sedentary males supplemented with oral zinc.
Kilic M.
OBJECTIVE:
The aim of this study was to determine how exercise affects thyroid hormones and testosterone levels in sedentary men receiving oral zinc for 4 weeks.
METHODS:
The study included 10 volunteers (mean age, 19.47+/-1.7 years) who did not exercise. All subjects received supplements of oral zinc sulfate (3 mg/kg/day) for 4 weeks and their normal diets. The thyroid hormone and testosterone levels of all subjects were determined at rest and after bicycle exercise before and after zinc supplementation.
RESULTS:
TT3, TT4, FT3, and total and free testosterone levels decreased after exercise compared to resting levels before supplementation (p<0.01). Both the resting and fatigue hormone values were higher after 4 weeks of supplementation than the resting and fatigue values before supplementation (p<0.05). CONCLUSION: The results indicate that exercise decreases thyroid hormones and testosterone in sedentary men; however, zinc supplementation prevents this decrease. Administration of a physiologic dose of zinc can be beneficial to performance.

Neuro Endocrinol Lett. 2007 Oct;28(5):708-12.
The effects of magnesium supplementation on thyroid hormones of sedentars and Tae-Kwon-Do sportsperson at resting and exhaustion.
Cinar V.
The effect of magnesium on thyroid hormones of sedentars and sportsperson in Tae-Kwon-Do, has been investigated in a 4-weeks training program. Group 1 consisted of sedentars receiving 10 mg/kg/day Mg for 4 weeks. Group 2 consisted of subjects receiving magnesium (Mg) supplement and practicing Tae-Kwon-Do for 90-120 min/day, for five days a week. Group 3 consisted of subjects practicing Tae-Kwon-Do but receiving Mg supplements. TSH levels increased with training and Mg supplementation (p<0.05). Mg increased FT3 values. (p<0.05). TT3 values of groups reduced in all groups (p<005). After supplementation, group 1 had higher TT4 values than groups 1 and 3 and the group 2 had higher TT4 values than the third group (p<005). Results of this research show that training until exhaustion causes reduction in thyroid hormone activity in sedentars and sportsperson. It has been established that Mg supplementation however, prevents reduction in thyroid hormone activity in sedentars and sportsperson.

Hormones (Athens). 2012 Jan-Mar;11(1):54-60.
Thyroid hormonal responses to intensive interval versus steady-state endurance exercise sessions.
Hackney AC, Kallman A, Hosick KP, Rubin DA, Battaglini CL.
OBJECTIVE:
To compare the thyroid hormonal responses to high-intensity interval exercise (IE) and steady-state endurance exercise (SEE) in highly trained males (n=15).
DESIGN:
The IE session consisted of repeated periods of 90-seconds treadmill running at 100-110% VO(2max) and 90-seconds active recovery at 40% VO(2max) for 42-47 minutes. The SEE session was a 45-minute run at 60-65% VO(2max). Total work output was equal for each session. A 45-minute supine rest control session (CON) was also performed. Pre-session (PRE), immediate post-session (POST), and 12-hours post-session (12POST) blood samples were collected and used to determine free (f) T₄, fT₃, reverse (r) T₃, and cortisol levels.
RESULTS:
All PRE hormone levels were within clinical norms and did not differ significantly between sessions. All POST IE and SEE hormone levels were significantly elevated compared to POST CON (p<0.001). At 12POST, no significant differences between CON and SEE hormonal levels were observed; however, fT₃ was significantly reduced and rT3 was significantly elevated in 12POST IE compared to 12POST SEE and CON (p=0.022). For IE, at 12POST a negative correlation (r(s) = -0.70, p<0.004) was found between fT₃ and rT₃. Also, for IE, a positive correlation (r(s) = 0.74, p<0.002) between cortisol POST and rT₃ 12POST was noted, and a negative correlation (r(s) = -0.72, p<0.003) between cortisol POST and fT₃ 12POST. CONCLUSION: IE results in a suppressed peripheral conversion of T₄ to T₃ implying that a longer recovery period is necessary for hormonal levels to return to normal following IE compared to SEE. These findings are useful in the implementation of training regimens relative to recovery needs and prevention of over-reaching-overtraining.

J Clin Endocrinol Metab. 2012 Jul;97(7):2489-96. doi: 10.1210/jc.2012-1444. Epub 2012 Apr 24.
Metabolic slowing with massive weight loss despite preservation of fat-free mass.
Johannsen DL, Knuth ND, Huizenga R, Rood JC, Ravussin E, Hall KD.
CONTEXT:
An important goal during weight loss is to maximize fat loss while preserving metabolically active fat-free mass (FFM). Massive weight loss typically results in substantial loss of FFM potentially slowing metabolic rate.
OBJECTIVE:
Our objective was to determine whether a weight loss program consisting of diet restriction and vigorous exercise helped to preserve FFM and maintain resting metabolic rate (RMR).
PARTICIPANTS AND INTERVENTION:
We measured body composition by dual-energy x-ray absorptiometry, RMR by indirect calorimetry, and total energy expenditure by doubly labeled water at baseline (n = 16), wk 6 (n = 11), and wk 30 (n = 16).
RESULTS:
At baseline, participants were severely obese (× ± SD; body mass index 49.4 ± 9.4 kg/m(2)) with 49 ± 5% body fat. At wk 30, more than one third of initial body weight was lost (-38 ± 9%) and consisted of 17 ± 8% from FFM and 83 ± 8% from fat. RMR declined out of proportion to the decrease in body mass, demonstrating a substantial metabolic adaptation (-244 ± 231 and -504 ± 171 kcal/d at wk 6 and 30, respectively, P < 0.01). Energy expenditure attributed to physical activity increased by 10.2 ± 5.1 kcal/kg.d at wk 6 and 6.0 ± 4.1 kcal/kg.d at wk 30 (P < 0.001 vs. zero). CONCLUSIONS: Despite relative preservation of FFM, exercise did not prevent dramatic slowing of resting metabolism out of proportion to weight loss. This metabolic adaptation may persist during weight maintenance and predispose to weight regain unless high levels of physical activity or caloric restriction are maintained.

Am J Physiol. 1994 Mar;266(3 Pt 2):R817-23.
Induction of low-T3 syndrome in exercising women occurs at a threshold of energy availability.
Loucks AB, Heath EM.
To investigate the relationship between energy availability (dietary energy intake minus energy expended during exercise) and thyroid metabolism, we studied 27 untrained, regularly menstruating women who performed approximately 30 kcal.kg lean body mass (LBM)-1.day-1 of supervised ergometer exercise at 70% of aerobic capacity for 4 days in the early follicular phase. A clinical dietary product was used to set energy availability in four groups (10.8, 19.0, 25.0, 40.4 kcal.kg LBM-1.day-1). For 9 days beginning 3 days before treatments, blood was sampled once daily at 8 A.M. Initially, thyroxine (T4) and free T4 (fT4), 3,5,3′-triiodothyronine (T3) and free T3 (fT3), and reverse T3 (rT3) were in the normal range for all subjects. Repeated-measures one-way analysis of variance followed by one-sided, two-sample post hoc Fischer’s least significant difference tests of changes by treatment day 4 revealed that reductions in T3 (16%, P < 0.00001) and fT3 (9%, P < 0.01) occurred abruptly between 19.0 and 25.0 kcal.kg LBM-1.day-1 and that increases in fT4 (11%, P < 0.05) and rT3 (22%, P < 0.01) occurred abruptly between 10.8 and 19.0 kcal.kg LBM-1.day-1. Changes in T4 could not be distinguished. If energy deficiency suppresses reproductive as well as thyroid function, athletic amenorrhea might be prevented or reversed by increasing energy availability through dietary reform to 25 kcal.kg LBM-1.day-1, without moderating the exercise regimen.

Am J Physiol. 1993 May;264(5 Pt 2):R924-30.
Induction and prevention of low-T3 syndrome in exercising women.
Loucks AB, Callister R.
To investigate the influence of exercise on thyroid metabolism, 46 healthy young regularly menstruating sedentary women were randomly assigned to a 3 x 2 experimental design of aerobic exercise and energy availability treatments. Energy availability was defined as dietary energy intake minus energy expenditure during exercise. After 4 days of treatments, low energy availability (8 vs. 30 kcal.kg body wt-1.day-1) had reduced 3,5,3′-triiodothyronine (T3) by 15% and free T3 (fT3) by 18% and had increased thyroxine (T4) by 7% and reverse T3 (rT3) by 24% (all P < 0.01), whereas free T4 (fT4) was unchanged (P = 0.08). Exercise quantity (0 vs. 1,300 kcal/day) and intensity (40 vs. 70% of aerobic capacity) did not affect any thyroid hormone (all P > 0.10). That is, low-T3 syndrome was induced by the energy cost of exercise and was prevented in exercising women by increasing dietary energy intake. Selective observation of low-T3 syndrome in amenorrheic and not in regularly menstruating athletes suggests that exercise may compromise the availability of energy for reproductive function in humans. If so, athletic amenorrhea might be prevented or reversed through dietary reform without reducing exercise quantity or intensity.

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High Blood Pressure and Hypothyroidism

Also see:
Ray Peat, PhD on High Blood Pressure
Thyroid Status and Cardiovascular Disease
High Cholesterol and Metabolism
The Cholesterol and Thyroid Connection
The Truth about Low Cholesterol
Inflammatory TSH
“Normal” TSH: Marker for Increased Risk of Fatal Coronary Heart Disease
The Cholesterol and Thyroid Connection
High Blood Pressure and Hypothyroidism
A Cure for Heart Disease
Hypothyroidism and A Shift in Death Patterns

“The speed of the pulse is partly determined by adrenaline, and many hypothyroid people compensate with very high adrenaline production. Knowing that hypothyroid people are susceptible to hypoglycemia, and that hypoglycemia increases adrenaline, I found that many people had normal (and sometimes faster than average) pulse rates when they woke up in the morning, and when they got hungry. Salt, which helps to maintain blood sugar, also tends to lower adrenalin, and hypothyroid people often lose salt too easily in their urine and sweat. Measuring the pulse rate before and after breakfast, and in the afternoon, can give a good impression of the variations in adrenalin. (The blood pressure, too, will show the effects of adrenaline in hypothyroid people. Hypothyroidism is a major cause of hypertension.)” -Ray Peat, PhD

“Thyroid hormone is necessary for respiration on the cellular level, and makes possible all higher biological functions. Without the metabolic efficiency which is promoted by thyroid hormone, life couldn’t get much beyond the single-cell stage. Without adequate thyroid, we become sluggish, clumsy, cold, anemic, and subject to infections, heart disease, headaches, cancer, and many other diseases, and seem to be prematurely aged, because none of our tissues can function normally. Besides providing the respiratory energy which is essential to life, thyroid hormones seem to stimulate and direct protein synthesis. In hypothyroidism there is little stomach acid, and other digestive juices (and even intestinal movement) are inadequate, so gas and constipation are common. Foods aren’t assimilated well, so even on a seemingly adequate diet there is ‘internal malnutrition.’ Magnesium is poorly absorbed, and a magnesium deficiency can lead to irritability, blood clots, vascular spasms and angina pectoris, and many other problems. Heart attacks, hardening of the arteries, and both high and low blood pressure can be caused by hypothyroidism.” -Ray Peat, PhD

“The hypo-osmolar blood of hypothyroidism, increasing the excitability of vascular endothelium and smooth muscle, is probably a mechanism contributing to the high blood pressure of hypothyroidism. The swelling produced in vascular endothelium by hypo-osmotic plasma causes these cells to take up fats, contributing to the development of atherosclerosis. The generalized leakiness affects all cells (see “Leakiness” newsletter), and can contribute to reduced blood volume, and problems such as orthostatic hypotension. The swollen endothelium is stickier, and this is suspected to support the metastasis of cancer cells. Inflammation-related proteins, including CRP, are increased by the hypothyroid hyperhydration. The heart muscle itself can swell, leading to congestive heart failure.” -Ray Peat, PhD

Endocrinol Metab Clin North Am. 1994 Jun;23(2):379-86.
Hypertension in thyroid disorders.
Saito I, Saruta T.
Hypertension is more common in hypothyroidic patients than in euthyroid controls in older age groups. Treatment of the thyroid deficiency alone lowers blood pressure in most patients. Hemodynamically, cardiac output is reduced and total peripheral resistance is elevated. The latter probably is secondary to an increase of sympathetic nervous tone and a relative increase in alpha-adrenergic response. In hyperthyroidism, elevation of diastolic blood pressure is uncommon. Systolic hypertension is more common in younger age groups. Treatment of the hyperthyroidism alone lowers systolic blood pressure in most patients. An increase in cardiac output and a decrease in total peripheral resistance accompany the hyperthyroidism. Potentiation of catecholamine action by an excess of thyroid hormone has been invoked as an explanation, because thyroid hormone excess is accompanied by increased beta-adrenergic receptors in some tissue, including heart.

Thyroid. 2002 May;12(5):421-5.
Risk factors for cardiovascular disease in women with subclinical hypothyroidism.
Luboshitzky R, Aviv A, Herer P, Lavie L.
Overt hypothyroidism may result in accelerated atherosclerosis and coronary heart disease (CHD) presumably because of the associated hypertension, hypercholesterolemia, and hyperhomocysteinemia. As many as 10%-15% of older women have subclinical hypothyroidism (SH) and thyroid autoimmunity. Whether SH is associated with risk for CHD is controversial. We examined 57 women with SH and 34 healthy controls. SH was defined as an elevated thyrotropin (TSH) (>4.5 mU/L) and normal free thyroxine (FT(4)) level (8.7-22.6 nmol/L). None of the patients had been previously treated with thyroxine. In all participants we determined blood pressure, body mass index (BMI), and fasting TSH, FT(4), antibodies to thyroid peroxidase and thyroglobulin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, folic acid, vitamin B(12), creatinine, and total plasma homocysteine levels. The SH and control groups did not differ in their total homocysteine values. Mean diastolic blood pressure was increased in SH patients versus controls (82 vs. 75 mm Hg; p < 0.01). Mean values of TC, HDL-C, LDL-C, triglycerides, TC/HDL-C, and LDL-C/HDL-C were not different in patients with SH compared with controls. Individual analysis revealed that the percentage of patients with SH having hypertension (20%), hypertriglyceridemia (26.9%), elevated TC/HDL-C (11.5%), and LDL-C/HDL-C (4%) ratios were higher than the percentages in controls. Hyperhomocysteinemia (> or = 10.98 micromol/L) was observed in 29.4% of SH and was not significantly different from the percentage in controls (21.4%). No significant correlation between TSH and biochemical parameters was detected. We conclude that subclinical hypothyroidism in middle-aged women is associated with hypertension, hypertriglyceridemia, and elevated TC/HDL-C ratio. This may increase the risk of accelerated atherosclerosis and premature coronary artery disease in some patients.

The Journal of Clinical Endocrinology & Metabolism May 1, 2002 vol. 87 no. 5 1996-2000
The Role of Thyroid Hormone in Blood Pressure Homeostasis: Evidence from Short-Term Hypothyroidism in Humans
Enza Fommei and Giorgio Iervasi
Arterial hypertension is known to be frequently associated with thyroid dysfunction, with a particularly high prevalence in chronic hypothyroidism. However, to our knowledge no comprehensive study addressed causal mechanisms possibly involved in this association. We here report the physiological relationships between blood pressure and neuro-humoral modifications induced by acute hypothyroidism in normotensive subjects. Twelve normotensive patients with previous total thyroidectomy were studied. Ambulatory 24-h blood pressure monitoring was performed, and free T3, free T4, TSH, PRA, aldosterone, cortisol, adrenaline, and noradrenaline were assayed 6 wk after oral L-T4 withdrawal (phase 1) and 2 months after resumption of treatment (phase 2). During the hypothyroid state (TSH, 68.1 ± 27.7 μIU/ml; mean ± SD), daytime arterial systolic levels slightly, but significantly, increased (125.5 ± 9.7 vs. 120.4 ± 10.8 mm Hg; P < 0.05), and daytime diastolic levels (84.6 ± 7.9 vs. 76.4 ± 6.8 mm Hg; P < 0.001), noradrenaline (2954 ± 1578 vs. 1574 ± 962 pmol/liter; P < 0.001), and adrenaline (228.4 ± 160 vs. 111.3 ± 46.1 pmol/liter; P < 0.05) also increased. PRA remained unchanged (0.49 ± 0.37 vs. 0.35 ± 0.21 ng/ml·h; P = NS), whereas both aldosterone (310.3 ± 151 vs. 156.9 ± 67.5 pmol/liter; P < 0.005) and cortisol (409.2 ± 239 vs. 250.9 ± 113 pmol/liter; P < 0.02) significantly increased. By using univariate logistic regression daytime arterial diastolic values, noradrenaline and aldosterone were found to be significantly related to the hypothyroid state (P < 0.02, P < 0.036, and P < 0.024, respectively). In conclusion, our data show that thyroid hormones participate in the control of systemic arterial blood pressure homeostasis in normotensive subjects. The observed sympathetic and adrenal activation in hypothyroidism, which is reversible with thyroid hormone treatment, may also contribute to the development of arterial hypertension in human hypothyroidism.

Vojnosanit Pregl. 2007 Nov;64(11):749-52.
[Cardiovascular risk factors in patients with subclinical hypothyroidism].
[Article in Serbian]
Pesić M, Antić S, Kocić R, Radojković D, Radenković S.
BACKGROUND/AIMS:
Overt hypothyroidism is disease associated with accelerated arteriosclerosis and coronary heart disease. Whether subclinical hypothyroidism (SH) is associated with increased cardiovascular risk is contraversial. As SH is a high prevalence thyroid dysfunction, specially in older women, it is important to evaluate cardiovascular risk factors in these patients and that was the aim of this study.
METHODS:
We examined 30 patients with SH and 20 healthy controls. Subclinical hypothireoidism was defined as an elevated thyrotropin (TSH) (> 4.5 mU/L) and normal free thyroxine (FT4) level. In all the participants we determined body mass index (BMI), blood pressure, TSH, FT4, antibodies to thyroid peroxidase, antibodies to thyroglobulin, total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglicerides, total cholesterol/HDL cholesterol ratio and LDL/HDL cholesterol ratio.
RESULTS:
Mean BMI in patients with SH was significantly higher (p < 0.05), as well as diastolic blood pressure (p < 0.01) compared with the controls. Average levels of total cholesterol (5.40 +/- 0.62 vs 5.06 +/- 0.19 mmol/l, p < 0.01) and triglycerides (2.16 +/- 0.56 vs 1.89 +/- 0.24 mmol/l, p < 0.05) were also significantly higher in the group with SH. Individual analysis revealed that the percentage of patients with SH having borderline elevated total cholesterol (63.33%), hypertrigliceridemia (43.33%) and elevated total cholesterol/HDL cholesterol ratio (26.67%) were significantly higher than the percentage in the controls. No significant correlation between TSH and lipid parameters was detected.
CONCLUSION:
Subclinical hypothyroidism was associated with higher BMI, diastolic hypertension, higher total cholesterol and triglicerides levels and higher total cholesterol/HDL cholesterols ratio. This might increase the risk of accelerated arteriosclerosis in patients with SH.

Endocrine. 2004 Jun;24(1):1-13.
Hypothyroidism as a risk factor for cardiovascular disease.
Biondi B, Klein I.
The cardiovascular risk in patients with hypothyroidism is related to an increased risk of functional cardiovascular abnormalities and to an increased risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid patients, even those with subclinical hypothyroidism, have impaired endothelial function, normal/depressed systolic function, left ventricular diastolic dysfunction at rest, and systolic and diastolic dysfunction on effort, which may result in poor physical exercise capacity. There is also a tendency to increase diastolic blood pressure as a result of increased systemic vascular resistance. All these abnormalities regress with L-T4 replacement therapy. An increased risk for atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. The “traditional” risk factors are hypertension in conjunction with an atherogenic lipid profile; the latter is more often observed in patients with TSH >10 mU/L. More recently, C-reactive protein, homocysteine, increased arterial stiffness, endothelial dysfunction, and altered coagulation parameters have been recognized as risk factors for atherosclerosis in patients with thyroid hormone deficiency. This constellation of reversible cardiovascular abnormalities in patient with TSH levels <10 mU/L indicate that the benefits of treatment of mild thyroid failure with appropriate doses of L-thyroxine outweigh the risk.

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Unsaturated Fats and Age Pigment

Also see:
Foods That Prevent Aging Skin by Emma Sgourakis

“An editorial by Pinckney in the June 1973 issue of the American Heart Journal reviews evidence that the unsaturated fats hasten aging of the skin, are toxic to the both animals and man, and furthermore, that use of such diets has not prevented heart attack.” -Broda & Charlotte Barnes

Quotes by Ray Peat, PhD:
“In the 1960s, Hartroft and Porta gave an elegant argument for decreasing the ratio of unsaturated oil to saturated oil in the diet (and thus in the tissues). They showed that the “age pigment” is produced in proportion to the ratio of oxidants to antioxidants, multiplied by the ratio of unsaturated oils to saturated oils. More recently, a variety of studies have demonstrated that ultraviolet light induces peroxidation in unsaturated fats, but not saturated fats, and that this occurs in the skin as well as in vitro. Rabbit experiments, and studies of humans, showed that the amount of unsaturated oil in the diet strongly affects the rate at which aged, wrinkled skin develops. The unsaturated fat in the skin is a major target for the aging and carcinogenic effects of ultraviolet light, though not necessarily the only one.”

“Lipofuscin, or age-pigment, is related to the oxidation of unsaturated fats, and has been proposed to be such a material, that progressively limits a cell’s adaptive capacity because of its physical and chemical properties.”

“Estrogen, at least when it is not opposed by a very large concentration of progesterone, creates all of the conditions known to be involved in the aging process. These effects of estrogen include interference with oxidative metabolism, formation of lipofuscin (the age-pigment), retention of iron, production of free radicals and lipid peroxides, promotion of excitotoxicity and death of nerve cells, impaired learning ability, increased tendency to form blood clots and to have vascular spasms, increased autoimmunity and atrophy of the thymus, elevated prolactin, atrophy of skin, increased susceptibility to a great variety of cancers, lowered body temperature, lower serum albumin, increased tendency toward edema, and many of the features of shock. In recent years, it has been found to be responsible even for neonatal masculinization and the masculinization of the polycystic ovary syndrome. Although the pharmaceutical industry has often referred to it as “the female hormone,” I don’t know of any competent scientist who has ever called it that.”

“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.”

“The lesions of atherosclerosis and cataracts contain some of the same oxidized lipids as the age pigment itself. When large deposits of age pigment become visible, it’s probably because the general reduction of metabolism and protein synthesis has interfered with the normal processes for removing debris. The age pigment contributes to degeneration by wasting energy and oxygen, weakening the antioxidation, antiglycation, and other defensive systems.”

“When I was studying the age pigment, lipofuscin, and its formation from polyunsaturated fatty acids, I saw the 1927 study in which a fat free diet practically eliminated the development of spontaneous cancers in rats (Bernstein and Elias). I have always wondered whether George and Mildred Burr were aware of that study in 1929, when they published their claim that polyunsaturated fats are nutritionally essential. The German study was abstracted in Biological Abstracts, and the Burrs later cited several studies from German journals, and dismissively mentioned two U.S. studies* that claimed animals could live on fat-free diets, so their neglect of such an important claim is hard to understand. (*Their bibliography cited, without further comment, Osborne and Mendel, 1920, and Drummond and Coward, 1921.)”

“Age pigment, lipofuscin, is produced in oxygen deprivation, apparently from reduced iron which attacks unsaturated fats. It has its own “respiratory” activity, acting as an NADH-oxidase. Melanin is produced by polymerization of amino acids, with copper as the catalyst. With aging, iron tends to replace copper. Melanin is an antioxidant. Thus, there is a sort of reciprocal relationship between the two types of pigment. A vitamin E deficiency relative to consumption of polyunsaturated fats, and an estrogen excess, accelerate the formation of lipofuscin.

A 47 year-old woman who had only a few “liver spots” on the backs of her hands began taking large amounts of estrogen, and within a few months the brown spots had darkened and spread until most of her skin was covered with spots. When she stopped using estrogen, and applied progesterone topically, the spots disappeared.”

“The unsaturated oils have been identified as a major factor in skin aging. For example, two groups of rabbits were fed diets containing either corn oil or coconut oil, and their backs were shaved, so sunlight could fall directly onto their skin. The animals that ate corn oil developed prematurely wrinkled skin, while the animals that ate coconut oil didn’t show any harm from the sun exposure. In a study at the University of California, photographs of two groups of people were selected, pairing people of the same age, one who had eaten an unsaturated fat rich diet, the other who had eaten a diet low in unsaturated fats. A panel of judges was asked to sort them by their apparent ages, and the subjects who consumed larger amounts of the unsaturated oils were consistently judged to be older than those who ate less, showing the same age-accelerating effects of the unsaturated oils that were demonstrated by the rabbit experiments.

While it is important to avoid overexposure to ultraviolet light, the skin damage that we identify with aging is largely a product of our diet.”

“The shorter chain fatty acids of coconut oil are more easily oxidized for energy than long chain fatty acids, and their saturation makes them resistant to the random oxidation produced by inflammation, so they don’t support their production of acrolein or age pigment; along with their reported antiinflammatory effect, these properties might be responsible for their beneficial effects that have been seen in Alzheimer’s disease.”

Adv Exp Med Biol. 1989;266:3-15.
Lipofuscin and ceroid formation: the cellular recycling system.
Harman D.
Lipofuscin, age pigment, is a dark pigment with a strong autofluorescence seen with increasing frequency with advancing age in the cytoplasm of postmitotic cells. By bright-field light microscopy lipofuscin appears as irregular yellow to brown granules ranging in size from 1-2 nm in diameter. The fluorescent spectra of lipofuscin in situ generally show excitation maxima at about 360 nm and a yellowish emission maxima at 540-650 nm. Ultrastructurally the granules, localized in residual body-type lysosomes, are extremely heterogeneous and vary from one cell type to another, and frequently within a single cell. The pigment granules usually contain numerous liquid droplets embedded in an electron-dense matrix. The granules stain positively for neutral lipids but are not soluble in polar or non-polar lipid solvents. Lipofuscin contains about 50 percent by weight of proteinaceous substances, a lesser fraction of lipid-like material, and probably less than one percent by weight fluorophore(s); it is enriched in metals such as Al, Cu, and Fe, and in dolichols. Free radical reactions and the proteolytic system are implicated in lipopigment formation. Thus the rate of lipopigment formation is increased by vitamin E deficiency and by increased intake of polyunsaturated fatty acids as well as by protease inhibitors such as leupeptin. Free radical reactions and proteolysis are involved in the continual turnover of cellular components. Cellular damage from free radical reactions, and others such as hydrolysis, has been present since the beginning of life. The evolution of more complex cells necessitated development of defenses – DNA repair processes, antioxidants, etc. – against damaging reactions as well as the removal and replacement of altered parts, and of those no longer needed by the cells. Proteins “marked” for disposal by oxidation damage, or other means such as conjugation with ubiquitin, are apparently rendered more hydrophobic so that they are “recognized” for degradation by the lysosomes and the proteinases and peptidases of the cytosol and mitochondria. Oxidatively altered lipids are removed by enzymes such as phospholipase A2. The products of the degradation processes are reused by the cells. Normally the recycling of damaged components works extremely well. There may be some slow slippage with advancing age as the rate of free radical damage increases while protease activity decreases. As a result a gradually increasing fraction of lysosomal “food” may be converted to non-digestible forms, lipofuscin, before it can be broken down to reusable components. Ceroid is apparently formed when the disposal system is “overloaded” or impaired.(ABSTRACT TRUNCATED AT 400 WORDS)

Ann Nutr Aliment. 1980;34(2):317-32.
[Polyunsaturated fatty acids and aging. Lipofuscins : structure, origin and development].
[Article in French]
Durand G, Desnoyers F.
In the last century, dense, pigmented bodies were observed on nerve cell sections, and the quantity of those pigments in the neurons was correlated to the age of the individual. Light microscopy has shown the presence of the pigments in the cells of most tissues and organs in both vertebrates and invertebrates, and they have also been seen in cultured cells. However, these commonly found cellular components have only have studied in detail since the last 25 years, using electron microscopic, histochemical and biochemical techniques to try to describe their nature, origin, development and possible physiological role. The comparable morphology, composition and physicochemical properties of these various pigments indicate that they are all produced by the same biochemical mechanism, including: 1) the peroxidation of the polyunsaturated fatty acids of cellular membranes by free radicals; 2) the reaction of lipid peroxidation end-products(s) with proteins, giving fluorescent polymerized compounds; 3) the combination of those polymerized elements and the peroxidized lipids. Different names have been used for these pigments, the most common of which in English are: “age pigment”, “ceroid” and “lipofuscins”. However, due to their common origin and their fluorescence, they are tended to be grouped under the term lipofuscins (in French: lipofuscines). Recent studies have confirmed that cellular lipofuscin concentration is definitely related to the physiological age of the individual. This concentration varies depending on the tissue and the organ; it is controlled by intrinsic regulatory factors, but also by environmental conditions, such as nutrition, physical activity, stress and hygienic conditions.

Adv Exp Med Biol. 1989; 266: 259-70; discussion 271.
Phospholipases and the molecular basis for the formation of ceroid in Batten Disease.
Dawson G, Dawson SA, Siakotos AN.
Lysosomal ceroid/lipofuscinosis storage in human, canine, and ovine forms of neuronal ceroidlipofuscinosis is predominantly in neurons and retinal pigment epithelial cells. Despite problems in identifying individual storage materials, it is believed that non-enzymic oxidation of unsaturated fatty acids in phospholipids and inhibition of lysosomal proteolysis, leading to massive deposition of autofluorescent pigment, is the cause of the disease. We have, therefore, studied cellular phospholipases and find a marked deficiency of lysosomal phospholipase A1 (PLA1) in canine NCL brain. Other lysosomal hydrolases, and cytosolic/mitochondrial forms of phospholipase A2 are completely normal. We believe that the PLA1 deficiency leads to transient lysosomal storage of phospholipids containing peroxy fatty acids which are then chemically converted to hydroxynonenal, a potent inhibitor of a thiol-dependent enzymes. Inhibition of proteases is believed to be intrinsic to the formation of lipofuscin. An inherited deficiency of a thiol protease (the lysosomal cathepsin H) in two siblings with NCL can also lead to build up of peptides which are then cross-linked and converted into ceroid-containing curvilinear bodies. Thus there is evidence for molecular and genetic heterogeneity in Batten disease.

Amino Acids. 2011 May;40(5):1297-303. doi: 10.1007/s00726-011-0850-1. Epub 2011 Mar 10.
Creatine in mouse models of neurodegeneration and aging.
Klopstock T, Elstner M, Bender A.
The supplementation of creatine has shown a marked neuroprotective effect in mouse models of neurodegenerative diseases (Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis). This has been assigned to the known bioenergetic, anti-apoptotic, anti-excitotoxic and anti-oxidant properties of creatine. As aging and neurodegeneration share pathophysiological pathways, we investigated the effect of oral creatine supplementation on aging in 162 aged wild-type C57Bl/6J mice. The median healthy life span of creatine-fed mice was 9% higher than in their control littermates, and they performed significantly better in neurobehavioral tests. In brains of creatine-treated mice, there was a trend toward a reduction of reactive oxygen species and significantly lower accumulation of the “aging pigment” lipofuscin. Expression profiling showed an upregulation of genes implicated in neuronal growth, neuroprotection, and learning. These data showed that creatine improves health and longevity in mice. Creatine may, therefore, be a promising food supplement to promote healthy human aging. However, the strong neuroprotective effects in animal studies of creatine have not been reproduced in human clinical trials (that have been conducted in Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis). The reasons for this translational gap are discussed. One obvious cause seems to be that all previous human studies may have been underpowered. Large phase III trials over long time periods are currently being conducted for Parkinson’s disease and Huntington’s disease, and will possibly solve this issue.

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Organ Donor and Transplantation – Effects of “EFA” Deficiency

Also see:
Protective “Essential Fatty Acid Deficiency”
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Anti-Inflammatory Omega -9 Mead Acid (Eicosapentaenoic acid)
Errors in Nutrition: Essential Fatty Acids
Arachidonic Acid’s Role in Stress and Shock
PUFA, Development, and Allergy Incidence
PUFA Accumulation & Aging
Metabolism, Brain Size, and Lifespan in Mammals
“Curing” a High Metabolic Rate with Unsaturated Fats
Glucocorticoids, Cytochrome Oxidase, and Metabolism
Fat Deficient Animals – Activity of Cytochrome Oxidase
Toxicity of Stored PUFA

Animals that have a diet free of polyunsaturated fats are good organ donors and recipients. -Ray Peat, PhD (personal correspondence)

Science. 1988 May 20;240(4855):1032-3.
Essential fatty acid depletion of renal allografts and prevention of rejection.
Schreiner GF, Flye W, Brunt E, Korber K, Lefkowith JB.
A central hypothesis in transplantation biology is that resident leukocytes expressing class II histocompatibility antigens may determine the immunogenicity of an organ. By means of a novel method to deplete the kidney of resident leukocytes, essential fatty acid deficiency (EFAD), this hypothesis was tested in an intact, vascular organ. Kidneys subjected to EFAD and thus depleted of resident Ia-positive macrophages survived and functioned when transplanted across a major histocompatibility antigen barrier in the absence of immunosuppression of the recipient. Control allografts were rejected promptly. Allografts from donors subjected to EFAD normalized their lipid composition and were repopulated with host macrophages by 5 days. Administration of Ia-positive cells at the time of transplantation established that the resident leukocyte depletion induced by EFAD was responsible for the protective effect. These observations may provide insights into the mechanisms underlying tissue immunogenicity and the population of normal tissues with resident leukocytes.

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Bowel Toxins Accelerate Aging

Also see:
Ray Peat, PhD on the Benefits of the Raw Carrot
Protective Cascara Sagrada and Emodin
Fermentable Carbohydrates, Anxiety, Aggression
Protective Bamboo Shoots
Endotoxin-lipoprotein Hypothesis
Endotoxin: Poisoning from the Inside Out
Protection from Endotoxin
PUFA Accumulation & Aging

Quotes by Ray Peat, PhD:
“Another process with potentially deadly results that increase with aging and stress, is the passage of bacteria from the intestines into the blood stream.”

“The intestine is source of toxins,, and some studies have found considerable life extension by keeping the intestine free of bacteria. At the beginning of the 20th century, Elie Metchnikof (The Nature of Man, 1894, Prolongation of Life; Optimistic Studies, 1907) believed, basing his ideas on comparative biology, that intestinal toxins caused aging by disrupting the immune and endocrine systems’ functions in tissue maintenance and renewal. He noticed that the intestine of short-lived herbivore such as rabbits had a strong odor of putrefaction and a great variety of bacterial species, but that the intestines of long-lived birds such as parrots and ravens had no unpleasant smell, even when he had fed the ravens with rotting meat, and contained only a few species of bacteria.

Metchnikof’s ideas about intestinal toxins as a source of sickness and aging were widely attacked in the US medical journals. In 1907 he wrote “Even at present there are critics who regard me as incapable of sane and logical reasoning.””

“The food industry is promoting the use of various gums and starches, which are convenient thickeners and stabilizers for increasing self-life, with the argument that the butyric acid produced when they are fermented by intestinal bacteria is protective. However, intestinal fermentation increases systemic and brain serotonin, and the short-chain fatty acids can produce a variety of inflammatory and cytotoxic effect. Considering the longevity and stress-resistance of germ-free animals, choosing foods (such as raw carrots or cooked bamboo shoots or cooked mushrooms) which accelerate peristalsis and speed transit through the bowel, which suppressing bacterial growth, seems like a convenient approach to increasing longevity.

In the years following the publication of Methnikof’s book in the US, there was a campaign in the medical journals to deny the validity of his idea of life-shortening “auto-intoxication” from the bowel. Warnings about the dangers of laxatives and enemas became common, and it was argued that a daily bowel movement wasn’t necessary. Max Gerson’s use of enemas in cacer therapy was ridiculed. Finally, the FDA banned the sale of cascara as a laxative. Recently, the kidney industry has been realizing that the bowel is the source of the major toxins of uremia, so there might be a gradual change of attitude toward the intestine in medicine generally.”

“Our innate immune system is perfectly competent for handling our normal stress induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats.”

“In aging, stress, and malnutrition, the barrier function of the intestine is weakened. Vitamin A and magnesium deficiencies allow macromolecules to enter the blood from the intestine.”

“Aging and stress increase some of the inflammatory mediators, tending to reduce the barrier function of the bowel, letting larger amounts of bacterial toxins enter the bloodstream, interfering with energy metabolism, creating inflammatory vicious circles of increasing leakiness and inflammation.”

“The gerontologist, V.V. Frolkis, recently found that mice lived 43% longer than animals on the standard diet when they periodically had activated charcoal added to their food. This is the clearest evidence I have seen that “bowel toxins” make a major contribution to the aging process.”

Biomater Artif Cells Artif Organs. 1989;17(3):341-51.
Effect of enterosorption on animal lifespan.
Frolkis VV, Nikolaev VG, Paramonova GI, Shchorbitskaya EV, Bogatskaya LN, Stupina AS, Kovtun AI, Sabko VE, Shaposhnikov VM, Muradian KK, et al.
Experiments were performed on Wistar male rats, starting from the 28th month of age. The effect of dietary sorbent (non coated nitrogen-containing carbon administered as 10 day courses at 1 month intervals in dosage of 10 ml/kg) on lifespan and a number of biological indices were studied. Enterosorption resulted in the increase of mean and maximal lifespan by 43 and 34% respectively. Analysis of the effect of enterosorption on activity of microsomal enzymes, intensity of total RNA and protein biosynthesis, lipid metabolism, formation of free radicals etc. showed that it produced a positive influence on the functional state of the studied systems and increased the organism’s adaptive capacities. Enterosorption was found to delay the rate of onset of age-related structural changes in the organs and tissues.

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Toxicity of Stored PUFA

Also see:
Fats, functions & malfunctions
Vitamin E Needs Increases with PUFA Consumption and Greater Unsaturation
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Israeli Paradox: High Omega -6 Diet Promotes Disease
Thigh and Buttock Fat Depots more Unsaturated than Abdominal Fat Depots
PUFA Accumulation & Aging
PUFA Promote Stress Response; Saturated Fats Suppress Stress Response
Ray Peat, PhD on Low Blood Sugar & Stress Reaction
Low Blood Sugar Basics
Unsaturated Fats and Longevity
Arachidonic Acid’s Role in Stress and Shock
Protective “Essential Fatty Acid Deficiency”
Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)
“Curing” a High Metabolic Rate with Unsaturated Fats
Fat Deficient Animals – Activity of Cytochrome Oxidase
Ray Peat, PhD Quotes on Therapeutic Effects of Niacinamide
Benefits of Aspirin
Saturated and Monousaturated Fatty Acids Selectively Retained by Fat Cells
PUFA Promote Cancer
Your MUFA + PUFA Intakes Determine Your True Vitamin E Requirements – N-3s are the Worst Offenders + Even MUFAs Need Buffering | Tool to Calculate Your Individual Needs
The Dangers of Fat Metabolism and PUFA: Why You Don’t Want to be a Fat Burner

Quotes by Ray Peat, PhD
“The half-life of fats in human adipose tissue is about 600 days, meaning that significant amounts of previously consumed oils will still be present up to four years after they have been removed from the diet.”

“Heavy drinking inhibits cellular respiration and sets up an inflammatory process, involving iron, which will still be harmful, but less so than in the presence of PUFA. If absolutely none of the dietary PUFA were in the body, no one really knows what that metabolic stress would do, maybe nothing cumulative.”

“When the polyunsaturated fats in the diet are reduced, the amount of them stored in the tissues decreases for about four years, making it progressively easier to keep the metabolic rate up, and stress hormones down.”

“The use of adequate protein and saturated fats during pregnancy will prevent many of the problems of pregnancy and infancy, but since the unsaturated fats remain stored in the tissues for many years, and are mobilized during stress, it’s important to eat correctly long before pregnancy. The requirement for vitamin E remains high for years after the diet has contained an excess of the polyunsatured fats. The diet which protects the developing fetus happens to be the diet that protects adults from all sorts of stress, and prevents many of the worst symptoms of aging.”

“The quantity of PUFA in the tissues strongly determines the susceptibility of the tissue to injury by radiation and other stresses. But a diet rich in PUFA will produce brain damage even without exceptional stressors, when there aren’t enough antioxidants, such as vitamin E and selenium, in the diet.”

“‎The larger the quantity of “toxic fat” stored in the body, the more careful the person must be about increasing metabolic and physical activity. Using more vitamin E, short-chain saturated fats, and other anti-lipid-peroxidation agents is important.”

“Although thyroid, progesterone, and a high quality protein diet will generally correct the epilepsy problem, it is important to mention that the involvement of unsaturated fats and free radicals in seizure physiology implies that we should minimize our consumption of the unsaturated fats. Even years after eliminating them from the diet, their release from tissue storage can prolong the problem, and during that time the use of vitamin E is likely to reduce the intensity and frequency of seizures.”

“But when tissues contain large amounts of polyunsaturated fats, every episode of fatigue and prolonged excitation leaves a residue of oxidative damage, and the adaptive mechanisms become progressively less effective.”

“It’s the stored PUFA, released by stress or hunger, that slow metabolism. Niacinamide helps to lower free fatty acids, and good nutrition will allow the liver to slowly detoxify the PUFA, if it isn’t being flooded with large amounts of them. A small amount of coconut oil with each meal will increase the ability to oxidize fat, by momentarily stopping the antithyroid effect of the PUFA. Aspirin is another thing that reduces the stress-related increase of free fatty acids, stimulating metabolism. Taking a thyroid supplement is reasonable until the ratio of saturated fats to PUFA is about 2 to 1.”

“The saturated fats protect against the body’s stored PUFA, and keeping the blood sugar up keeps the stored fats from being mobilized.”

“It was the body’s load of polyunsaturated fats which made it very susceptible to inflammation, stress, trauma, infection, radiation, hormone imbalance, and other fundamental problems, and drugs like aspirin and cortisone, which limit the activation of the stored “essential fatty acids,” gain their remarkable range of beneficial effects partly by the restraint they impose on those stored toxins.”

“Since stored fats are usually mostly polyunsaturated, the thyroid gland will keep being suppressed as long as weight is being lost, since the PUFA are being released into the blood stream. If a person has enough cholesterol, thyroid, and vitamin A, and keeps estrogen low, progesterone supplements shouldn’t be needed, but since adipose tissue is a source of estrogen synthesis when there’s inflammation, stress, or low thyroid, the need for progesterone is likely to recur. Aspirin helps to inhibit estrogen synthesis.”

“People with a significant amount of fat in their body, who have in the past eaten foods containing vegetable oils, are likely to draw unsaturated fats out of storage, with toxic effects unless vitamin E, thyroid, and coconut oil are used protectively until tissue stores of unsaturated fats are depleted. Typically, body stores of fat take four years to completely reflect the change to a different type of dietary fat.”

“Eliminating polyunsaturated fats from the diet is essential if the bystander effect is eventually to be restrained. Aspirin and salicylic acid can block many of the carcinogenic effects of the PUFA. Saturated fats have a variety of antiinflammatory and anticancer actions. Some of those effects are direct, others are the result of blocking the toxic effects of the PUFA. Keeping the stored unsaturated fats from circulating in the blood is helpful, since it takes years to eliminate them from the tissues after the diet has changed. Niacinamide inhibits lipolysis. Avoiding overproduction of lipolytic adrenaline requires adequate thyroid hormone, and the adjustment of the diet to minimize fluctuations of blood sugar.”

“In a young person, good food, sunlight, and a high altitude can often overcome severe and progressive inflammatory conditions. In an older person, whose tissues contain larger amounts of polyunsaturated fats and their breakdown products, it takes more environmental support to get out of the inflammatory pattern.”

“Sugars, if they are consumed in quantities beyond the ability to metabolize them (and that easily happens in the presence of PUFA) are converted into saturated fatty acids, which have antistress, antiinflammatory effects. Many propaganda experiments are set up, feeding a grossly excessive amount of polyunsaturated fat, causing sugar to form fat, specifically so they can publish their silly diet recommendations, which supposedly explain the obesity epidemic, but the government figures I cited show that vegetable fat consumption has increased, sugar hasn’t. My articles have a lot of information on the mechanisms, such as the so-called ‘Randle cycle,’ in which fatty acids shut down the ability to oxidize sugar. Polyunsaturated fats do many things that increase blood sugar inappropriately, and my articles review several of the major mechanisms. Several years ago, medical people started talking about the harmful effects of insulin, such as stimulating fat production, so ‘insulin resistance’ which keeps a high level of insulin from producing obesity would seem to be a good thing, but the medical obesity culture really isn’t thinking very straight. One factor in the ‘insulin resistance’ created by PUFA involves estrogen—chronic accumulation of PUFA in the tissues increases the production of estrogen, and the polyunsaturated free fatty acids intensify the actions of estrogen, which acts in several ways to interfere with glucose oxidation.”

“Our innate immune system is perfectly competent for handling our normal stress induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats. The brain has a very high concentration of complex fats, and is highly susceptible to the effects of lipid peroxidative stress, which become progressively worse as the unstable fats accumulate during aging.”

“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.

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)…

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…

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.

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.

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.

Saturated fatty acids terminate the stress reactions, polyunsaturated fatty acids amplify them.

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.

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.

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…

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.”

Am J Clin Nutr. 1980 Jan;33(1):81-5.
A mathematical relationship between the fatty acid composition of the diet and that of the adipose tissue in man.
Beynen AC, Hermus RJ, Hautvast JG.

Based on literature data, the hypothesis is advanced that in human subjects a direct mathematical relationship exists between the average fatty acid composition of the habitual diet and that of the lipid stores of subcutaneous adipose tissue. Since the half-life of adipose tissue fatty acids in man is in the order of 600 days, the fatty acid pattern of depot fat provides a qualitative measure of the fat intake over a period of 2 to 3 years. It is concluded that in long-term experimental and epidemiological nutritional surveys the adipose tissue fatty acid pattern of the subjects is a useful index of the average composition of their habitual dietary fat.

Adv Nutr November 2015 Adv Nutr vol. 6: 660-664, 2015
Increase in Adipose Tissue Linoleic Acid of US Adults in the Last Half Century
Stephan J Guyenet and Susan E Carlson
Linoleic acid (LA) is a bioactive fatty acid with diverse effects on human physiology and pathophysiology. LA is a major dietary fatty acid, and also one of the most abundant fatty acids in adipose tissue, where its concentration reflects dietary intake. Over the last half century in the United States, dietary LA intake has greatly increased as dietary fat sources have shifted toward polyunsaturated seed oils such as soybean oil. We have conducted a systematic literature review of studies reporting the concentration of LA in subcutaneous adipose tissue of US cohorts. Our results indicate that adipose tissue LA has increased by 136% over the last half century and that this increase is highly correlated with an increase in dietary LA intake over the same period of time.

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Ray Peat, PhD on Aspirin

Also see:
Aspirin and Exercise
Benefits of Aspirin
PUFA Promote Cancer
Arachidonic Acid’s Role in Stress and Shock
Sunburn, PUFA, Prostaglandins, and Aspirin
Phospholipases, PUFA, and Inflammation
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Toxicity of Stored PUFA
PUFA – Accumulation and Aging
Ray Peat, PhD Quotes on Therapeutic Effects of Niacinamide
Altitude Sickness: Therapeutic Effects of Acetazolamide and Carbon Dioxide
Carbonic Anhydrase Inhibitors as Cancer Therapy
Lab study: Daily aspirin could block growth of breast, other cancers

Screenshot 2016-01-22 at 6.22.56 AM

“When a drug such as caffeine or aspirin turns out to have a great variety of protective effects, it’s important to understand what it’s doing.

Because aspirin has been abused by pharmaceutical companies that have competing products to sell, as well as by the original efforts to promote aspirin itself, people can easily find reasons why they shouldn’t take it.

Early in the 20th century, people were told that fevers were very bad, and that aspirin should be used whenever there is a fever.

In the 1980s, there was a big publicity campaign warning parents that giving aspirin to a child with the flu could cause the potentially deadly Reye syndrome. Aspirin sales declined sharply, as sales of acetaminophen (Tylenol, etc.) increased tremendously. But in Australia, a study of Reye syndrome cases found that six times as many of them had been using acetaminophen as had used aspirin. (Orlowski, et al., 1987)

Until the 1950s and 1960s, when new products were being promoted, little was said about the possibility of stomach ulceration from aspirin. Lately, there has been more publicity about the damage it can do to the stomach and intestine, much of it in connection with the sale of the new “COX-2 inhibitors.” (These new drugs, rather than protecting the circulatory system as aspirin does, damage it.) Aspirin rapidly breaks down into acetic acid and salicylic acid (which is found in many fruits), and salicylic acid is protective to the stomach and intestine, and other organs. When aspirin was compared with the other common antiinflammatory drugs, it was found that the salicylic acid it releases protects against the damage done by another drug. (Takeuchi, et al, 2001; Ligumsky, et al., 1985.) Repeated use of aspirin protects the stomach against very strong irritants. The experiments in which aspirin produces stomach ulcers are designed to produce ulcers, not to realistically model the way aspirin is used.”

“Soon after vitamin E was discovered, tocopherol was defined as a brain-protective, pregnancy protective, male fertility protective, antithrombotic, antiestrogenic agent. But very soon, the estrogen industry made it impossible to present ideas that explained vitamin E, progesterone, vitamin A, or thyroid hormone in terms of the protection they provide against estrogenic substances. Since the polyunsaturated fats caused the same conditions that were caused by unopposed estrogen, vitamin E came to be known as an “antioxidant,” because it reduced their toxicity. (Vitamin E is now known to suppress COX-2, synergizing with aspirin and opposing estrogen.)”

“The competition between fatty acids and glucose, which has been called the “Randle cycle” for about 50 years, can be applied to the treatment of diabetes and other degenerative/stress problems by adjusting the diet, or by using supplements such as niacinamide and aspirin, which improve glucose oxidation by lowering the free fatty acids in the serum.”

“A few years later, aspirin was found to inactivate the enzyme that forms prostaglandins, by the transfer of the acetyl radical to the enzyme. This became the orthodox “explanation” for what aspirin does, though it neglected to explain that salicylic acid (lacking the acetyl radical) had been widely known in the previous century for its very useful antiinflammatory actions. The new theory did explain (at least to the satisfaction of editors of medical magazines) one of aspirin’s effects, but it distracted attention from all the other effects of aspirin and salicylic acid.

Aspirin is an antioxidant that protects against lipid peroxidation, but it also stimulates mitochondrial respiration. It can inhibit abnormal cell division, but promote normal cell division. It can facilitate learning, while preventing excitotoxic nerve injury. It reduces clotting, but it can decrease excessive menstrual bleeding. These, and many other strangely beneficial effects of aspirin, strongly suggest that it is acting on very basic biological processes, in a coherent way.

In explaining aspirin’s effects, as in explaining those of estrogen and progesterone, or polyunsaturated fats and vitamin E, I think we need concepts of a very broad sort, such as “stability and instability.””

“Aspirin activates both glycolysis and mitochondrial respiration, and this means that it shifts the mitochondria away from the oxidation of fats, toward the oxidation of glucose, resulting in the increased production of carbon dioxide. Its action on the glycolytic enzyme, GAPDH, is the opposite of estrogen’s.

The shift away from fat oxidation under the influence of aspirin doesn’t lead to an accumulation of free fatty acids in the circulation, since aspirin inhibits the release of fatty acids from both phospholipids and triglycerides. Estrogen has the opposite effects, increasing fat oxidation while increasing the level of circulating free fatty acids, since it activates lipolysis, as do several other stress-related hormones.

The polyunsaturated fatty acids, such as linolenic, linoleic, arachidonic, EPA, and DHA, have many directly toxic, antirespiratory actions, apart from the production of the prostaglandins or eicosanoids. Just by preventing the release of these fatty acids, aspirin would have broadly antiinflammatory effects.

Since the polyunsaturated fats and prostaglandins stimulate the expression of aromatase, the enzyme that synthesizes estrogen, aspirin decreases the production of estrogen. So many of aspirin’s effects oppose those of estrogen, it would be tempting to suggest that its “basic action” is the suppression of estrogen. But I think it’s more likely that both estrogen and aspirin are acting on some basic processes, in approximately opposite ways.

Bioelectrical functions, and the opposition between carbon dioxide and lactic acid, and the way water is handled in cells, are basic conditions that have a general or global effect on all of the other more specific biochemical and physiological processes. Originally, estrogen and progesterone were each thought to affect only one or a few biochemical events, but it has turned out that each has a multitude of different biochemical actions, which are integrated in globally meaningful ways. The salicylic acid molecule is much smaller and simpler than progesterone, but the range of its beneficial effects is similar. Because of aspirin’s medical antiquity, there has been no inclination to explain its actions in terms of an “aspirin receptor,” as for valium and the opiates, leaving its biochemistry, except for the inadequate idea of COX-inhibition, simply unexplained.”

“The competition between aspirin and salicylic acid, and other antiinflammatories, for the active site on the COX enzyme (Rao, et al., 1982), shows that the structural features of these molecules are in some ways analogous to those of the polyunsaturated fatty acids. Wherever there are phospholipids, free fatty acids, fatty acid esters, ethers, etc. (i.e., in mitochondria, chromosomes, cytoskeleton, collagen networks–essentially everywhere in and around the cell), the regulatory influence of specific fatty acids–or their surrogates–will be felt.

Although it would undoubtedly be best to grow up eating foods with relatively saturated fats, the use of aspirin preventively and therapeutically seems very reasonable under the present circumstances, in which, for example, clean and well ripened fruits are not generally available in abundance. Preventing blindness, degenerative brain diseases, heart and lung diseases, and cancer with aspirin should get as much support as the crazy public health recommendations are now getting from government and foundations and the medical businesses.

When people with cancer ask for my recommendations, they usually think I’m joking when I tell them to use aspirin, and very often they don’t take it, on the basis of what seems to be a very strong cultural prejudice. Several years ago, a woman whose doctors said it would be impossible to operate on her extremely painful “inflammatory breast cancer,” had overnight complete relief of the pain and swelling from taking a few aspirins. The recognized anti-metastatic effect of aspirin, and its ability to inhibit the development of new blood vessels that would support the tumor’s growth, make it an appropriate drug to use for pain control, even if it doesn’t shrink the tumor. In studies of many kinds of tumor, though, it does cause regression, or at least slows tumor growth. And it protects against many of the systemic consequences of cancer, including wasting (cachexia), immunosuppression, and strokes.

Opiates are the standard medical prescription for pain control in cancer, but they are usually prescribed in inadequate quantities, “to prevent addiction.” Biologically, they are the most inappropriate means of pain control, since they increase the release of histamine, which synergizes with the tumor-derived factors to suppress immunity and stimulate tumor growth.

It has recently become standard practice in most places to advise a person who is having a heart attack to immediately chew and swallow an aspirin tablet.

The same better-late-than-never philosophy can be applied to Alzheimer’s disease, Parkinson’s disease, and other degenerative nerve diseases. Aspirin protects against several kinds of toxicity, including excitotoxicity (glutamate), dopamine toxicity, and oxidative free radical toxicity. Since its effects on the mitochondria are similar to those of thyroid (T3), using both of them might improve brain energy production more than just thyroid. (By activating T3, aspirin can sometimes increase the temperature and pulse rate.) Magnesium, niacinamide, and other nerve protective substances work together.

In multiple organ failure, which can be caused by profound shock caused by trauma, infection, or other stress, aspirin is often helpful, but carbon dioxide and hypertonic glucose and sodium are more important.

Aspirin, like progesterone or vitamin E, can improve fertility, by suppressing a prostaglandin, and improving uterine circulation.

Although the animal studies that showed stomach damage from aspirin often used single doses equivalent to 10 or 100 aspirin tablets, the slight irritation produced by a normal dose of aspirin can be minimized by dissolving the aspirin in water. The stomach develops a tolerance for aspirin over a period of a few days, allowing the dose to be increased if necessary. And both aspirin and salicylic acid can be absorbed through the skin, so rheumatic problems have been treated by adding the drug to bath water.

The unsaturated (n-6 and n-3) fats that accumulate in our tissues, instead of being part of the system for reestablishing order and stability, tend to amplify the instability that is triggered by excitation, by estrogen, or by external stresses.

I think it’s important that we don’t allow the drug publicists to obscure the broad importance of substances such as aspirin, vitamin E, progesterone, and thyroid. For 60 years, a myth that was created to sell estrogen has harmed both science and the health of many people.”

“Aspirin protects against iron toxicity, clot formation, and reduces lipid peroxidation while blocking prostaglandin formation. Aspirin and other antiinflammatory drugs, taken for arthritis, have been clearly associated with a reduced incidence of Alzheimer’s disease. Aspirin reduces the formation of prostaglandins from arachidonic acid.”

“When I taught endocrinology, I annoyed my tidy-minded students by urging them to consider the potential hormone-like action of everything in the body, and to think of layers of control, ranging from sugar, salt, and carbon dioxide, through the “official hormones,” to complex nervous system actions such as expectancy, and biorhythms. Certain things that are active in very important processes deserve special attention as “signals,” but they still have to be understood in context. In this sense, we can think of Ca2+ as a signal substance, in its many contexts; it is strongly regulated by the cell’s energy charge. Magnesium and sodium antagonize it in certain situations. Linoleic acid, linolenic acid, arachidonic acid: Their toxicity is potentially prevented by the Mead acids, and their eicosanoid derivatives, which behave very differently from the familiar prostaglandins, as far as they have been compared; can be drastically reduced by dietary changes. Prostaglandins, prostacyclin, thromboxane: Formation is blocked by aspirin and other antiinflammatory drugs.”

“Aspirin’s antiinflammatory actions are generally important when the polyunsaturated fats are producing inflammatory and degenerative changes, and aspirin prevents many of the problems associated with diabetes, reducing vascular leakiness. It improves mitochondrial respiration (DeCristobal, et al., 2002) and helps to regulate blood sugar and lipids (Yuan, et al., 2001). Aspirin’s broad range of beneficial effects is probably analogous to vitamin E’s, being proportional to protection against the broad range of toxic effects of the polyunsaturated “essential” fatty acids.”

“Both preventively and therapeutically, the use of the antiinflammatory and antioxidative substances such as aspirin, caffeine, progesterone, and thyroid hormone would seem appropriate. Aspirin is coming to be widely accepted as an anticancer agent, and at moderate doses can cause cancer cells to die. It, like progesterone and thyroid, has a wide variety of anti-estrogenic effects. Especially when a tumor is painfully inflamed, aspirin’s effects can be quick and dramatic. However, people aren’t likely to be pleased if their cancer doctor tells them to “take aspirin and call me in six months.” Aspirin’s reputation for causing stomach bleeding causes people to avoid it, even when the alternative is something that’s seriously toxic to other organs, and it might just seem too ordinary to be considered as a powerful anticancer drug.”

“Aspirin protects against a variety of inflammatory processes, but it’s most famous for the inhibition of prostaglandins. While aspirin is often used to relieve pain in MS, and another inhibitor of prostaglandin synthesis, indomethacin, has been used therapeutically in MS, it would seem appropriate to investigate more carefully aspirin’s possible role in preventing or relieving MS.”

“Protein deficiency is an important cause of deranged calcium metabolism. Vitamins K, E, and A are important in regulating calcium metabolism, and preventing osteoporosis. Aspirin (with antiestrogenic and vitamin E-like actions) is protective against bone resorption and hypercalcemia.”

“If the physiology of shock has some relevance for eclampsia, so does the physiology of heart failure, since Meerson has shown that it is a consequence of uncompensated stress. The failing heart shifts from mainly glucose oxidation to the inefficient use of fatty acids, which are mobilized during stress, and with its decreased energy supply, it is unable to beat efficiently, since it remains in a partly contracted state. Estrogen (which is increased in men who have had heart attacks) is another factor which decreases the heart’s stroke volume, and estrogen is closely associated with the physiology of the free unsaturated fatty acids. The partly contracted state of the heart is effectively a continuation of the partly contracted state of the blood vessels that causes the hypertension, and reduced tissue perfusion seen in shock and eclampsia. Since shock can be seen as a generalized inflammatory state, and since aspirin has been helpful in protecting against heart disease, it’s reasonable that aspirin has been tried as a treatment in pre-eclampsia. It seems to protect the fetus against intrauterine growth retardation, an effect that I think relates to aspirin’s ability to protect in several ways against excesses of unsaturated fatty acids and of estrogen. But, since aspirin can interfere with blood clotting, its use around the time of childbirth can be risky, and it is best to correct the problem early enough that aspirin isn’t needed.”

“Some types of dementia, such as Alzheimer’s disease, involve a life-long process of degeneration of the brain, with an inflammatory component, that probably makes them comparable to osteoporosis and muscle-wasting. (In the brain, the microglia, which are similar to macrophages, and the astrocytes, can produce TNF.) The importance of the inflammatory process in Alzheimer’s disease was appreciated when it was noticed that people who used aspirin regularly had a low incidence of that dementia. Aspirin inhibits the formation of TNF, and aspirin has been found to retard bone loss. In the case of osteoporosis (A. Murrillo-Uribe, 1999), as in Alzheimer’s disease, the incidence is two or three times as high in women as in men. In both Alzheimer’s disease and osteoporosis, the estrogen industry is arguing that the problems are caused by a suddenly developing estrogen deficiency, rather than by prolonged exposure to estrogen.”

“Vitamin E, like progesterone and aspirin, acts within the cellular regulatory systems, to prevent
inflammation and inappropriate excitation. Since uncontrolled excitation causes destructive oxidations, these substances prevent those forms of oxidation.”

“Later, referring to the decades of hostility of the medical establishment to vitamin E, Dr. Shute said “…an obstetrician was unduly hardy and audacious to try it.” The spectrum of vitamin E’s protective effects (like those of aspirin) has been consistently misrepresented in the medical literature.”

“Abruptio placentae (premature detachment of the placenta) has often been blamed on the use of vitamin E, because of vitamin E’s reputation for preventing abnormal clotting, though the evidence tends to suggest instead that vitamin E (like aspirin) reduces the risk of pregnancy-related hemorrhaging.”

“But many very useful drugs that already existed, including cortisol and aspirin, were found to achieve some of their most important effects by inhibiting the formation of the prostaglandins. It was the body’s load of polyunsaturated fats which made it very susceptible to inflammation, stress, trauma, infection, radiation, hormone imbalance, and other fundamental problems, and drugs like aspirin and cortisone, which limit the activation of the stored “essential fatty acids,” gain their remarkable range of beneficial effects partly by the restraint they impose on those stored toxins.”

“Inflammation activates beta-glucuronidase, and antiinflammatory substances such as aspirin reduce many of estrogen’s effects.”

“Both the excitatory amino acids and a peptide that promotes inflammation, tumor necrosis factor (TNF), activate the enzyme which makes estrogen, aromatase. Estrogen, by activating NF kappaB, increases the formation of TNF, which in itself can promote the growth and metastasis of cancer. Various antiinflammatory agents, including aspirin, progesterone, testosterone, saturated fats, and glycine, can inhibit the production of NF kappaB.”

“The use of aspirin, which reduces inflammation and inhibits the formation of neurotoxic prostaglandins, is known to be associated with a lower incidence of Alzheimer’s disease, and in other contexts, it offers protection against estrogen. Naloxone, the antiendorphin, has been found to reverse some of the cumulative effects of stress, restoring some pituitary and ovarian function, and it promotes recovery after brain injury; in a variety of ways, it corrects some of estrogen’s toxic effects.”

“People who take aspirin, drink coffee, and use tobacco, have a much lower incidence of Alzheimer’s disease than people who don’t use those things. Caffeine inhibits brain phospholipase, making it neuroprotective in a wide spectrum of conditions. In recent tests, aspirin has been found to prevent the misfolding of the prion protein, and even to reverse the misfolded beta sheet conformation, restoring it to the harmless normal conformation. Nicotine might have a similar effect, preventing deposition of amyloid fibrils and disrupting those already formed (Ono, et al., 2002). Vitamin E, aspirin, progesterone, and nicotine also inhibit phospholipase, which contributes to their antiinflammatory action. Each of the amyloid-forming proteins probably has molecules that interfere with its toxic accumulation.”

“Aspirin protects cells in many ways, interrupting excitotoxic processes by blocking nitric oxide and prostaglandins, and consequently it inhibits cell proliferation, and in some cases inhibits glycolysis, but the fact that it can inhibit FAS (Beynen, et al., 1982) is very important in understanding its role in cancer.

There are several specific signals produced by lactate that can promote growth and other features of cancer, and it happens that aspirin antagonizes those: HIF, NF-kappaB, the kinase cascades, cyclin D1, and heme oxygenase.”

“The pituitary hormones, especially prolactin and TSH, are pro-inflammatory, and darkness increases TSH along with prolactin, so to compensate for a light deficiency, the pituitary should be well-suppressed by adequate thyroid. Armour thyroid or Thyrolar or Cynoplus, Cytomel, would probably be helpful. (Eye-drops containing T3 might be a way to restore metabolic activity more quickly.) Limiting water intake (or using salt generously) helps to inhibit prolactin secretion. The saturated fats protect against the body’s stored PUFA, and keeping the blood sugar up keeps the stored fats from being mobilized. Aspirin (or indomethacin) is generally protective to the retina, analogously to its protection against sunburn. Adequate vitamin E is extremely important. There are several prescription drugs that protect against serotonin excess, but thyroid and gelatin (or glycine, as in magnesium glycinate) are protective against the serotonin and melatonin toxicities.”

“In aspirin, it has been found that it is the acetyl group which (by a free radical action) blocks an enzyme involved in prostaglandin synthesis.”

“Carbon dioxide, high altitude, thyroid, progesterone, caffeine, aspirin, and decreased tryptophan consumption protect against excessive serotonin release. When sodium intake is restricted, there is a sharp increase in serotonin secretion. This accounts for some of the antiinflammatory and diuretic effects of increased sodium consumption–increasing sodium lowers both serotonin and adrenalin.”

“Aspirin, by inhibiting prostaglandin synthesis (and maybe other mechanisms) often lowers free radical production.”

“Antiinflammatory and anticoagulant things, especially aspirin and vitamin E, protect against the accelerated turnover of fibrinogen/fibrin caused by estrogen and the various inflammatory states.”

“I have known adults and children who were diagnosed as diabetic, and given insulin (and
indoctrinated with the idea that they had a terminal degenerative disease) on the strength of a single test showing excessive glucose. When I taught at the naturopathic medical school in Portland, I tried to make it clear that “diabetes” (a term referring to excessive urination) is a function, and that a high level of glucose in the blood or urine is also a function, and that the use of insulin should require a greater diagnostic justification than the use of aspirin for a headache does, because insulin use itself constitutes a serious health problem. (And we seldom hear the idea that “diabetes” might have a positive side [Robinson and Johnston], for example that it reduces the symptoms of asthma [Vianna and Garcialeme], which get worse when insulin is given. Normal pregnancy can be considered “diabetic” by some definitions based on blood sugar. I got interested in this when I talked to a healthy “diabetic” woman who had a two year old child whose IQ must have been over 200, judging by his spontaneous precocious hobbies. Old gynecologists told me that it was common knowledge that “diabetic” women had intellectually precocious children.)”

“Despite the nutritional value of those vitamins, fish oils are generally much more immunosuppressive than the seed oils, and the early effects of fish oil on the “immune system” include the suppression of prostaglandin synthesis, because the more highly unsaturated long chain fats interfere with the conversion of linoleic acid into arachidonic acid and prostaglandins. The prostaglandins are so problematic that their suppression is helpful, whether the inhibition is caused by aspirin or vitamin E, or by fish oil.”

“For a long time, gelatin’s therapeutic effect in arthritis was assumed to result from its use in repairing the cartilage or other connective tissues around joints, simply because those tissues contain so much collagen. (Marketers suggest that eating cartilage or gelatin will build cartilage or other collagenous tissue.) Some of the consumed gelatin does get incorporated into the joint cartilage, but that is a slow process, and the relief of pain and inflammation is likely to be almost immediate, resembling the antiinflammatory effect of cortisol or aspirin.”

“In aspirin, it has been found that it is the acetyl group which (by a free radical action) blocks an enzyme involved in prostaglandin synthesis.”

“(Chen, Y, et al., 1999: BRCA represses the actions of estrogen and its receptor, and, like progesterone, activates the p21 promoter, which inhibits cell proliferation. Aspirin and vitamin D also act through p21.)”

“Aspirin, which stimulates bone formation, has other thyroid-like actions, including activation of mitochondrial respiration and energy production, with an increase of cytochrome C oxidase (Cai, et al., 1996), and it lowers serotonin (Shen, et al., 2011). It also apparently protects against calcification of the soft tissues, (Vasudev, et al., 2000), \ though there has been surprisingly little investigation of that. “Aspirin can promote trabecular bone remodeling, improve three-dimensional structure of trabecular bone and increase bone density of cancellous in osteoporotic rats by stimulating bone formation. It may become a new drug for the treatment of osteoporosis,” Chen, et al., 2011.”

“Defensive aggression is probably a response intermediate between fearful giving up and confident achievement. When a rat is restrained, held down on its back, it quickly develops ulcers, but if it has a stick to bite, it is very resistant to the formation of the ulcers. The ability to do something with a defensive meaning prevents the excessive production of serotonin and its consequences, such as increased production of cortisol and other stress hormones, and disturbance of circulation and energy production. Endotoxin and prostaglandins activate these same systems, and progesterone and aspirin are among the protective factors that can oppose those effects.”

“In 1927, Bernstein and Elias found that rats eating a fat free diet had almost no spontaneous cancer, and many studies since then in animals and people have shown a close association between polyunsaturated fatty acids and cancer. The polyunsaturated fatty acids in themselves, and their breakdown products, are excitatory and destabilizing to normal cells, but by modifying the sensitivity and energy production of cells, they limit cells’ ability to respond to stimulation and destabilizing influences. Although they aren’t essential for wound healing (Porras-Reyes, et al., 1992), they and their metabolites, the prostaglandins, are very conspicuous in wounds and tumors, and their proportion generally increases with aging. The prostaglandins are involved in several vicious cycles, including that with HIF mentioned above. This makes the PUFA and prostaglandins important to consider in relation to optimizing wound healing, and decreasing cancerization. Aspirin’s protective and therapeutic effects in cancer are starting to be recognized, but there are several other things that can synergize with aspirin to reduce the circulation of free fatty acids and their conversion to prostaglandins. Niacinamide, progesterone, sugar, carbon dioxide, and red light protect against both free fatty acids and prostaglandins.”

“Increasing carbon dioxide lowers the intracellular pH, as well as inhibiting lactic acid formation, and restoring the oxidation of glucose increases CO2. Inhibiting carbonic anhydrase, to allow more CO2 to stay in the cell, contributes to intracellular acidification, and by systemically increasing carbon dioxide this inhibition has a broad range of protective anti-excitatory effects. The drug industry is now looking for chemicals that will specifically inhibit the carbonic anhydrase enzymes that are active in tumors. Existing carbonic anhydrase inhibitors, such as acetazolamide, will inhibit those enzymes, without harming other tissues. Aspirin has some effect as an inhibitor of carbonic anhydrase (Bayram, et al., 2008). Since histamine, serotonin (Vullo, et al., 2007), and estrogen (Barnett, et al., 2008; Garg, 1975) are carbonic anhydrase activators, their antagonists would help to acidify the hypoxic cells. Testosterone (Suzuki, et al., 1996) and progesterone are estrogen antagonists that inhibit carbonic anhydrase.”

“The foods that nourish the patient well enough to support healing while permitting energy reserves to be built up are also the foods that don’t interfere with the hormones, that don’t cause spurious excitation of the tissues. The polyunsaturated fats directly stimulate the stress hormones, activate the excitatory amino acid signals, and directly excite cells, while the saturated fats have opposite effects, and are anti-inflammatory, and also don’t interfere with mitochondrial function. When we eat more carbohydrate than can be oxidized, some of it will be turned into saturated fats and omega-9 fats, and these will support mitochondrial energy production. Carbohydrates in the diet also help to decrease the mobilization of fatty acids from storage; niacinamide and aspirin support that effect. Sugars are probably more favorable than starches for the immune system (Harris, et al., 1999), and failure of the immune system is a common feature of cancer. Polyunsaturated fats are generally known to suppress the immune system. Foods that provide generous amounts of sodium, calcium, magnesium, and potassium, help to minimize stress. Trace minerals and vitamins are important, but can be harmful if used excessively–iron excess is important to avoid.”

“While lactic acidosis causes bone loss, acidosis caused by increased carbonic acid doesn’t; low bicarbonate in the body fluids seems to remove carbonate from the bone (Bushinsky, et al., 1993), and also mineral phosphates (Bushinsky, et al., 2003). The parathyroid hormone, which removes calcium from bone, causes lactic acid to be formed by bone cells (Nijweide, et al., 1981; Lafeber, et al., 1986). Lactic acid produced by intense exercise causes calcium loss from bone (Ashizawa, et al., 1997), and sodium bicarbonate increases calcium retention by bone. Vitamin K2 (Yamaguchi, et al., 2003) blocks the removal of calcium from bone caused by parathyroid hormone and prostaglandin E2, by completely blocking their stimulation of lactic acid production by bone tissues. Aspirin, which, like vitamin K, supports cell respiration and inhibits lactic acid formation, also favors bone calcification. Vitamin K2 stimulates the formation of two important bone proteins, osteocalcin and osteonectin (Bunyaratavej, et al., 2009), and reduces the activity of estrogen by oxidizing estradiol (Otsuka, et al, 2005).”

“Aspirin, which is antilipolytic, decreasing the release of free fatty acids, as well as inhibiting their conversion to prostaglandins, lowers the production of stressed induced aldosterone, and helps to lower blood pressure, if it’s taken during the night. Aspirin increases insulin sensitivity.”

“Aspirin and vitamin E are protective against toxic radiation, and the consequent inflammatory processes.”

“Antioxidant, antiinflammatory, and antiestrogenic substances are protective against radiation damage. Aspirin, vitamin e, progesterone, saturated fats, and thyroid have these functions.”

“In recent years inflammation’s role in cancer and heart disease has been acknowledged to some extent, and simple antiinflammatory treatments such as aspirin have been more widely accepted in prevention and treatment of both heart disease and cancer. I think the next step is to recognize the importance of preventing all sorts of inflammation during the reproductive years, to protect the brains of the unborn, and the inheritance of future generations.”

“Aspirin and niacin help to prevent fatigue symptoms, and to prevent many of the harmful systemic oxidative after-effects. (Both are antilipolytic; aspirin uncouples mitochondria.)”

“Uncoupling of mitochondrial oxidative metabolism from ATP production helps to consume the sugar which otherwise would be diverted into lactic acid, and converts it into carbon dioxide instead…Aspirin and thyroid (T3) increase uncoupling. A drug that used to be used for weight reduction, DNP, also uncouples mitochondrial metabolism, and, surprisingly, it has some of the beneficial effects of thyroid and aspirin. It stimulates the consumption of lactic acid and the formation of carbon dioxide.”

“The “treatment” for intracellular fatigue consists of normalizing thyroid and steroid metabolism, and eating a diet including fruit juice, milk, some eggs, liver, and gelatin, assuring adequate calcium, potassium, sodium, and magnesium, and using supplements of niacinamide, aspirin, and carbon dioxide when necessary.”

“The excitatory metabolite glutamate, and nitric oxide, are both inhibited by aspirin (Moro, et al., 2000).”

“Aspirin and saturated fats can also be protective when applied topically.”

“Aspirin, increased levels of carbon dioxide (Ni Chonghaile, et aI., 2005), and progesterone (Deroo and Archer, 2002; Kelly, et al., 2001; Allport, et al., 2001; van der Burg and van der Saag, 1996; Caldenhoven, et aI., 1995) inhibit NF kappa-B, and NF kappa-B inhibits the synthesis of both testosterone (Hong, et aI., 2004) and progesterone (Allport, et aI., 2001).”

“Salicylic acid, which occurs naturally in many fruits, as well as in aspirin, is unlike the other antiinflammatory drugs so vaguely classified with it as “nonsteroidal,” in having a broad spectrum of antiinflammatory effects, inhibiting the prostaglandins and NF kappa-B, TNF, and IL-6, besides contributing to the inhibition of estrogen synthesis and actions.”

“Other things that protect against excessive polyamines are procaine and other local anesthetics (Yuspa, et al., 1980), magnesium, niacin, vitamin A, aspirin, and, in some circumstances, caffeine.”

“The amounts needed seem large if niacinamide is thought of as “vitamin B3,” but it should be considered as a factor that compensates for our unphysiological exposure to inappropriate fats. Aspirin and vitamin E are other natural substances that are therapeutic in “unnaturally” large amounts because of our continual exposure to the highly unsaturated plant-derived n-3 and n-6 fats.”

“Aspirin has a very broad spectrum of antiinflammatory actions, and is increasingly being recommended for preventing complications of diabetes. One of the consequences of inflammation is hyperglycemia, and aspirin helps to correct that (Yuan, et al., 2001), while protecting proteins against oxidative damage (Jafarnejad, et al, 2001).”

“The contractile ability of smooth muscle, that’s impaired by swelling and inflammation, can be restored by antiinflammatory agents, for example aspirin (or other inhibitor of prostaglandin synthesis) or antihistamines. This applies to the muscles of lymphatic vessels (Wu, et al., 2005, 2006; Gosling, 2000), that must function to reduce edema, as well as to the bowel muscles that cause peristalsis.”

“Another kind of adaptogen resembles the body’s intrinsic defensive substances, but isn’t produced in significant quantities in our bodies. This type includes caffeine and the anthraquinones (such as emodin) and aspirin and other protective substances from plants. These overlap in functions with some of our intrinsic regulatory substances, and can also complement each other’s effects.”

“This makes the PUFA and prostaglandins important to consider in relation to optimizing wound healing, and decreasing cancerization. Aspirin’s protective and therapeutic effects in cancer are starting to be recognized, but there are several other things that can synergize with aspirin to reduce the circulation of free fatty acids and their conversion to prostaglandins. Niacinamide, progesterone, sugar, carbon dioxide, and red light protect against both free fatty acids and prostaglandins.”

“The drug industry is now looking for chemicals that will specifically inhibit the carbonic anhydrase-enzymes that are active in tumors. Existing carbonic anhydrase inhibitors, such as acetazolamide, will inhibit those enzymes, without harming other tissues. Aspirin has some effect as an inhibitor of carbonic anhydrase (Bayram, et al., 2008).”

“When we eat more carbohydrate than can be oxidized, some of it will be turned into saturated fats and omega-9 fats, and these will support mitochondrial energy production. Carbohydrates in the diet also help to decrease the mobilization of fatty acids from storage; niacinamide and aspirin support that effect.”

“Many of the things that can be achieved by vaccination and treatment with safe antiinflammatories such as aspirin could be done better by long-term changes of diet, and by taking into account the interactions of the hormones, especially progesterone, estrogen, and thyroid, with nutrients and stressors. But much more than that is needed: The nature of the relationships between environmental factors and the body’s reactions has to be clarified, so that the processes of healing and regeneration can more closely resemble the prenatal condition, possibly even continuing in adulthood the “pedomorphic” process, realizing human potentials that haven’t previously been seen.”

“The continuing accumulation of polyunsaturated fats in the tissues is undoubtedly important in the changing relationship between the pancreas and the adrenal glands in aging. Aspirin, which is antilipolytic, decreasing the release of free fatty acids, as well as inhibiting their conversion to prostaglandins, lowers the production of stress induced aldosterone, and helps to lower blood pressure, if it’s taken in the evening, to prevent the increase of free fatty acids during the night. Aspirin increases insulin sensitivity. A low salt diet increases the free fatty acids, leading to insulin resistance, and contributing to atherosclerosis (Prada, et al., 2000; Mroka, et aI., 2000; Catanozi, et al., 2003; Garg, et al., 2011).”

“Recognizing causal connections between premature birth and respiratory distress and retinopathy of prematurity, it would be obvious that the greatest effort should be made to prevent the problems by improving the health of pregnant women. Hospitals, however, are invested in high technology systems for treating these problems, and even though their results are dismal, they can’t make money by getting pregnant women to eat enough protein to prevent preeclampsia, which is a major cause of premature birth, or by treating the problems with salt, magnesium, progesterone, thyroid, and aspirin when the women haven’t had a good diet.”

“The saturated fats protect against the body’s stored PUFA, and keeping the blood sugar up keeps the stored fats from being mobilized. Aspirin (or indomethacin) is generally protective to the retina, analogously to its protection against sunburn.”

“Since polyunsaturated fatty acids become integrated into all types of cell, and cause so many types of damage when they are released, everything which inhibits their release is protective. Niacinamide, Benadryl, aspirin (Yu, et aI., 2003), and procaine help to reduce the release of free fatty acids.”

“Aspirin’s similarity to benzoate and phenylacetate suggests that it might sometimes help to remove ammonia. The safest procedure is to use foods, such as fruit juices, that regulate nitrogen metabolism in varied ways.”

“Aspirin protects against some of the worst stressors, including the polyunsaturated fats, so despite its mild toxicity, long term studies usually show that it decreases sickness and mortality.”

“Aspirin, by inhibiting the production of estrogen, of carbon monoxide, and of several cytokines and toxic lipid products, and by supporting normal respiration, helping to correct hyperglycemia, and suppressing lactate production, is an especially valuable therapy. Sacca et aI., have recently (October, 2004) demonstrated that aspirin’s anticancer effect appears to involve the inhibition of heme oxygenase.”

“Caffeine, by inhibiting FAS and sparing glucose, and inhibiting many of the toxic lipid inflammatory mediators, additive effects when products and other should have at least combined with aspirin.

Vitamin D, by its antiestrogenic and antiinflammatory actions, and by suppressing FAS, parallels the effects of aspirin and caffeine in several ways.”

“The prostaglandins were discovered in prostatic fluid, where they occur in significant concentrations. They are so deeply involved with the development of cancers of all sorts that aspirin and other prostaglandin inhibitors should be considered as a basic part of cancer therapy.”

“The PUFA (especially the omega -3 fatty acids) spontaneously decompose into a variety of toxins, and arachidonate is also enzymically converted into prostaglandins, some of which exacerbate the excitatory damage (Pepicelli, et aI., 2005); aspirin’s neuroprotective effect (Riepe, et aI., 1997) is probably partly caused by inhibiting prostaglandin synthesis. Besides the prostaglandins, other mediators of inflammation including nitric oxide and interleukins are produced by excessive excitation, as cells lose their ability to retain magnesium, and to control excitatory intracellular calcium.”

“Inhibitors of estrogen synthesis are being considered for use in controlling epilepsy (Reddy, 2007), but aspirin and progesterone and thyroid can produce similar results.”

“It’s the stored PUFA, released by stress or hunger, that slow metabolism. Niacinamide helps to lower free fatty acids, and good nutrition will allow the liver to slowly detoxify the PUFA, if it isn’t being flooded with large amounts of them. A small amount of coconut oil with each meal will increase the ability to oxidize fat, by momentarily stopping the antithyroid effect of the PUFA. Aspirin is another thing that reduces the stress-related increase of free fatty acids, stimulating metabolism. Taking a thyroid supplement is reasonable until the ratio of saturated fats to PUFA is about 2 to 1.”

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