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Niacinamide and the Skin

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A year of treatment with nicotinamide, a form of vitamin B3, significantly lowered the risk of common, non-melanoma skin cancer in high-risk patients, according to University of Sydney research published in the New England Journal of Medicine.

J Cosmet Dermatol. 2004 Apr;3(2):88-93.
Nicotinic acid/niacinamide and the skin.
Gehring W.
Nicotinic acid (also generally known as niacin) and niacinamide (also known as nicotinamide) are similarly effective as a vitamin because they can be converted into each other within the organism. The blanket term vitamin B(3) is used for both. Niacinamide is a component of important coenzymes involved in hydrogen transfer. Here, the two codehydrogenases, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are of central importance. Topical application of niacinamide has a stabilizing effect on epidermal barrier function, seen as a reduction in transepidermal water loss and an improvement in the moisture content of the horny layer. Niacinamide leads to an increase in protein synthesis (e.g. keratin), has a stimulating effect on ceramide synthesis, speeds up the differentiation of keratinocytes, and raises intracellular NADP levels. In ageing skin, topical application of niacinamide improves the surface structure, smoothes out wrinkles and inhibits photocarcinogenesis. It is possible to demonstrate anti-inflammatory effects in acne, rosacea and nitrogen mustard-induced irritation. Because of its verifiable beneficial effects, niacinamide would be a suitable component in cosmetic products for use in disorders of epidermal barrier function, for ageing skin, for improving pigmentary disorders and for use on skin prone to acne.

N Engl J Med 2015; 373:1618-1626October 22, 2015DOI: 10.1056/NEJMoa1506197
A Phase 3 Randomized Trial of Nicotinamide for Skin-Cancer Chemoprevention
Andrew C. Chen, M.B., B.S., Andrew J. Martin, Ph.D., Bonita Choy, M.Med., Pablo Fernández-Peñas, Ph.D., Robyn A. Dalziell, Ph.D., Catriona A. McKenzie, M.B., B.S., Richard A. Scolyer, M.D., Haryana M. Dhillon, Ph.D., Janette L. Vardy, M.D., Anne Kricker, Ph.D., Gayathri St. George, M.Sc.Med., Niranthari Chinniah, M.B., B.S., Gary M. Halliday, D.Sc., and Diona L. Damian, Ph.D.
BACKGROUND
Nonmelanoma skin cancers, such as basal-cell carcinoma and squamous-cell carcinoma, are common cancers that are caused principally by ultraviolet (UV) radiation. Nicotinamide (vitamin B3) has been shown to have protective effects against damage caused by UV radiation and to reduce the rate of new premalignant actinic keratoses.
METHODS
In this phase 3, double-blind, randomized, controlled trial, we randomly assigned, in a 1:1 ratio, 386 participants who had had at least two nonmelanoma skin cancers in the previous 5 years to receive 500 mg of nicotinamide twice daily or placebo for 12 months. Participants were evaluated by dermatologists at 3-month intervals for 18 months. The primary end point was the number of new nonmelanoma skin cancers (i.e., basal-cell carcinomas plus squamous-cell carcinomas) during the 12-month intervention period. Secondary end points included the number of new squamous-cell carcinomas and basal-cell carcinomas and the number of actinic keratoses during the 12-month intervention period, the number of nonmelanoma skin cancers in the 6-month postintervention period, and the safety of nicotinamide.
RESULTS
At 12 months, the rate of new nonmelanoma skin cancers was lower by 23% (95% confidence interval [CI], 4 to 38) in the nicotinamide group than in the placebo group (P=0.02). Similar differences were found between the nicotinamide group and the placebo group with respect to new basal-cell carcinomas (20% [95% CI, −6 to 39] lower rate with nicotinamide, P=0.12) and new squamous-cell carcinomas (30% [95% CI, 0 to 51] lower rate, P=0.05). The number of actinic keratoses was 11% lower in the nicotinamide group than in the placebo group at 3 months (P=0.01), 14% lower at 6 months (P<0.001), 20% lower at 9 months (P<0.001), and 13% lower at 12 months (P=0.001). No noteworthy between-group differences were found with respect to the number or types of adverse events during the 12-month intervention period, and there was no evidence of benefit after nicotinamide was discontinued. CONCLUSIONS Oral nicotinamide was safe and effective in reducing the rates of new nonmelanoma skin cancers and actinic keratoses in high-risk patients. (Funded by the National Health and Medical Research Council; ONTRAC Australian New Zealand Clinical Trials Registry number, ACTRN12612000625875.)

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By Team FPS – April 7, 2012

The AIDS Debate That Isn’t

WALL STREET JOURNAL, 2/26/88
Copyright Dow Jones & Co. Inc.
By Katie Leishman
SOURCE

Last week the Presidential Commission on the Human Immunodeficiency Virus Epidemic held hearings in New York.

Among the witnesses was Peter Duesberg, a professor of virology at the University of California at Berkeley, who is one of the world s foremost retrovirologists and a member of the National Academy of Sciences. Mr. Duesberg explained why he does not believe, with the majority of AIDS researchers, that the disease is caused by HIV, a retrovirus discovered in 1983.

According to Mr. Duesberg the viral model for AIDS contradicts too many principles of virology. HIV is said to destroy T4 cells, which are footsoldiers in the body’s immune system. But retroviruses, Mr. Duesberg counters, do not destroy cells. Moreover, he argues, HIV infects fewer than one in 10,000 to 100,000 cells, a number easily replaced by the body in a day. When the virus is most active it triggers no AIDS symptoms, whereas when AIDS symptoms arise, the virus is, paradoxically, inactive. Mr. Duesberg observes that no other virus, indeed no other infectious agent, is known to cause disease in this way.

In the year since Mr. Duesberg first advanced his theories in a paper in Cancer Research, leading AIDS investigators have been unanimous in their refusal to rebut him, despite requests from universities and press forums like the “MacNeil/Lehrer NewsHour.” They have been willing, however, to justify their silence at length. Anthony Fauci, coordinator of AIDS research at the National Institutes of Health, recently explained on National Public Radio, “Critiquing a dubious theory would take time away from more productive efforts.” A proposed White House seminar (“How Does HIV Cause AIDS? “) in which Mr. Duesberg was to participate was abruptly canceled when no AIDS researcher from the National Institutes would agree to attend. Mr. Duesberg has kept his views alive through occasional radio interviews, university addresses and a brief appearance on CNN. Mr. Duesberg was asked to speak by the Presidential Commission, although a member of one commissioner s staff readily acknowledged that Mr. Duesberg “was invited to discredit him.” Nowhere was this clearer than in his treatment by Commissioner Frank Lilly, chairman of the department of genetics at the Albert Einstein College of Medicine. At the conclusion of Mr. Duesberg s testimony, Mr. Lilly remarked: “You ve made your usual very charming presentation…I would like to recommend that perhaps you could sit through our graduate course on animal virology.”

That opening shot raised expectations that Mr. Lilly was about to put Mr. Duesberg away. Yet Mr. Lilly s reply to Mr. Duesberg s arguments contained several strange assertions. (His claim that the causative role of the polio virus was only proved by the discovery of its vaccine drew stares from the audience, which included physicians and research scientists as well as gay activists. An animal model of infection existed long before the vaccine.) Mr. Lilly noted that hepatitis virus, although inactive following that disease’s course, could cause liver cancer up to 20 years later. Mr. Duesberg asked if he might reply to that point and was told that he could not. In fact, the relationship between the virus and cancer remains entirely speculative.

Mr. Lilly conceded that scientists have offered no definitive mechanism by which HIV destroys the immune system and that retroviruses classically do not kill cells. In the middle of his summation he said: “You may be right. There is a slight possibility that HIV does not cause AIDS. The evidence to date is in fact circumstantial.”

This striking admission did not prevent another commission member, William Walsh, president of Project Hope, from joining in the scolding. He admonished Mr. Duesberg to confine his opinions to professional circles and to have “the scientific integrity” to resist appearing on television programs “until you have something more substantial to say.”

Dr. Walsh added: “Don’t confuse the public. Don’t confuse the poor people suffering from this disease.” Whether Mr. Duesberg is right or wrong, there is nothing confusing about his contentions. Moreover, the suggestion that the public and patients must be protected from confusion is not merely condescending but faintly sinister. America is spending a billion dollars in research on the assumption that HIV causes AIDS, and treating patients with AZT — one of the most toxic yet hastily approved drugs ever released. The commission heard testimony concerning AZT’s use as a prophylactic measure in HIV-infected but still healthy individuals, a practice that Mr. Duesberg believes verges on the irresponsible.

AZT works by blocking production of DNA in the cell, both viral DNA and cellular DNA. Yet, as Mr. Duesberg told the commission, no one has been able to detect viral DNA production in any AIDS patient. All that is known for certain about the drug’s activity is that it is killing healthy cells.

The only subject about which the public needs to be spared confusion is behavioral risk factors for AIDS, which Mr. Duesberg s questions do not concern. As for confusing the patients, clearly their medical “right to know” should include the right to any information that might affect their choice of treatment.

Mr. Duesberg is frequently challenged, “If HIV isn’t the cause, what is? ” He responds that his expertise permits him to suggest only what AIDS is not. He is often asked about the growing epidemiological evidence linking syphilis and AIDS.

Venereal-disease clinics in several major cities are reporting increases in the incidence of syphilis in heterosexuals of nearly 100% in a one-year period — after a 20-year decline. The syphilis being seen is distinctively aggressive, and many public-health officials are speculating about the new outbreak and its relationship to the emergence of AIDS in the syphilis-ridden gay community of nearly a decade ago.

Mr. Duesberg allows that syphilis may play a key role in many cases of AIDS. But, as he testified, he doubts that any single pathogen could explain all the conditions embraced in the Centers for Disease Control’s definition of AIDS.

It is unsettling to be offered Mr. Duesberg’s hypothesis seven years into the epidemic, but that seems no excuse for the disdainful treatment it has received. AIDS research is based on the assumption that all that remains to be found is a cure. But this urgency to put all resources behind what appear to be promising solutions has created an instant orthodoxy, which resists review.

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By Team FPS – April 7, 2012

Soy and Behavior

Br Poult Sci. 2001 Mar;42(1):33-42.
Development of pecking damage in layer pullets in relation to dietary protein source.
McKeegan DE, Savory CJ, MacLeod MG, Mitchell MA.
1. In recent years, the UK egg industry has become increasingly dependent on plant protein sources, in particular soyabean meal, and it has been suggested that this trend (and/or the concomitant absence of animal protein in layer diets) might be causally related to increased feather pecking and cannibalism. 2. This study examined the development of pecking damage in relation to dietary protein source, by rearing 12 groups of 12 layer pullets to 24 weeks of age on diets based on ‘animal’ (fishmeal) or ‘plant’ (soyabean meal) protein. 3. Damaging pecking began at 6 weeks of age, in three groups (one plant and two animal). Injurious pecking began at 18 weeks of age, and affected four groups (two plant and two animal). 4. Greater numbers of vigorous pecks/pulls were observed in plant protein groups throughout the experiment, although they were significantly higher only between 13 to 16 weeks of age. Pecking damage scores did not differ between treatments. 5. Dietary protein source did not affect plasma oestradiol, progesterone or egg production. 6. These results do not support the notion that inclusion of fishmeal in laying hen diets prevents or alleviates feather pecking and cannibalism.

Horm Behav. 2004 Apr;45(4):278-84.
Increased aggressive behavior and decreased affiliative behavior in adult male monkeys after long-term consumption of diets rich in soy protein and isoflavones.
Simon NG, Kaplan JR, Hu S, Register TC, Adams MR.
Estrogen produced by aromatization of gonadal androgen has an important facilitative role in male-typical aggressive behavior that is mediated through its interaction with estrogen receptors (ER) in the brain. Isoflavones found in soybeans and soy-based dietary supplements bind ER and have dose- and tissue-dependent effects on estrogen-mediated responses. Yet, effects of isoflavone-rich diets on social and aggressive behavior have not been studied. We studied the effects of long-term (15 months) consumption of diets rich in soy isoflavones on spontaneous social behavior among adult male cynomolgus macaques (Macaca fascicularis) (n = 44) living in nine stable social groups. There were three experimental conditions which differed only by the source of dietary protein: casein and lactalbumin (no isoflavones), soy protein isolate containing 0.94 mg isoflavones/g protein, and soy protein isolate containing 1.88 mg isoflavones/g protein. In the monkeys fed the higher amount of isoflavones, frequencies of intense aggressive (67% higher) and submissive (203% higher) behavior were elevated relative to monkeys fed the control diet (P’s < 0.05). In addition, the proportion of time spent by these monkeys in physical contact with other monkeys was reduced by 68%, time spent in proximity to other monkeys was reduced 50%, and time spent alone was increased 30% (P's < 0.02). There were no effects of treatment on serum testosterone or estradiol concentrations or the response of plasma testosterone to exogenous gonadotropin-releasing hormone (GnRH). The results indicate that long-term consumption of a diet rich in soy isoflavones can have marked influences on patterns of aggressive and social behavior.

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By Team FPS – April 6, 2012

Check Your Labels – Guar Gum

Also see:
Fermentable Carbohydrates, Anxiety, Aggression
Carrageenan, Inflammation, Cancer, ImmunityRay Peat, PhD on the Benefits of the Raw Carrot
Estrogen, Serotonin, and Aggression
Endotoxin: Poisoning from the Inside Out
Scanning Electron Microscope (SEM) images of plant cell microparticles in urine sediment
THE PHENOMENON OF PERSORPTION: PERSORPTION, DISSEMINATION, AND ELIMINATION OF MICROPARTICLES

“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, while suppressing bacterial growth, seems like a convenient approach to increasing longevity. -Ray Peat, PhD

Proc Soc Exp Biol Med. 1986 Dec;183(3):299-310.
Relationship between dietary fiber and cancer: metabolic, physiologic, and cellular mechanisms.
Jacobs LR.
The relationships between fiber consumption and human cancer rates have been examined, together with an analysis of the effects of individual dietary fibers on the experimental induction of large bowel cancer. The human epidemiology indicates an inverse correlation between high fiber consumption and lower colon cancer rates. Cereal fiber sources show the most consistent negative correlation. However, human case-control studies in general fail to confirm any protective effect due to dietary fiber. Case-control studies indicate that if any source of dietary fiber is possibly antineoplastic then it is probably vegetables. These results may mean that purified fibers alone do not inhibit tumor development, whereas it is likely that some other factors present in vegetables are antineoplastic. Experiments in laboratory animals, using chemical induction of large bowel cancer, have in general shown a protective effect with supplements of poorly fermentable fibers such as wheat bran or cellulose. In contrast, a number of fermentable fiber supplements including pectin, corn bran, oat bran, undegraded carageenan, agar, psyllium, guar gum, and alfalfa have been shown to enhance tumor development. Possible mechanisms by which fibers may inhibit colon tumorigenesis include dilution and adsorption of any carcinogens and/or promoters contained within the intestinal lumen, the modulation of colonic microbial metabolic activity, and biological modification of intestinal epithelial cells. Dietary fibers not only bind carcinogens, bile acids, and other potential toxins but also essential nutrients, such as minerals, which can inhibit the carcinogenic process. Fermentation of fibers within the large bowel results in the production of short chain fatty acids, which in vivo stimulate cell proliferation, while butyrate appears to be antineoplastic in vitro. Evidence suggests that if dietary fibers stimulate cell proliferation during the stage of initiation, then this may lead to tumor enhancement. Fermentation also lowers luminal pH, which in turn modifies colonic microbial metabolic acidity, and is associated with increased epithelial cell proliferation and colon carcinogenesis. Because dietary fibers differ in their physiochemical properties it has been difficult to identify a single mechanism by which fibers modify colon carcinogenesis. Clearly, more metabolic and physiological studies are needed to fully define the mechanisms by which certain fibers inhibit while others enhance experimental colon carcinogenesis.

J Nutr. 1996 Aug;126(8):1979-91.
Dietary guar gum alters colonic microbial fermentation in azoxymethane-treated rats.
Weaver GA, Tangel C, Krause JA, Alpern HD, Jenkins PL, Parfitt MM, Stragand JJ.
To assess the effects of guar gum on colonic microbial fermentation and cancer development, azoxymethane-treated rats were fed a partially hydrolyzed guar or control diet. Anaerobic fecal incubations were conducted at 8-wk intervals, either without added substrate or with cornstarch or hydrolyzed guar as substrates. Short-chain fatty acids in colonic contents and colonic carcinoma areas were measured at 27 wk. Fecal in vitro fermentation rates were higher for guar-fed rats than for control rats [three-way ANOVA (diet, time, in vitro substrates), P = 0.002]. Fecal in vitro butyrate production was greater for guar-fed rats than for control rats after 3-11 weeks of diet treatment (three-way ANOVA, P = 0.027). Butyrate concentrations of colonic contents at 27 wk were higher in guar-fed than in control rats and higher in the cecum than in the post-cecal colon (two-way ANOVA, P = 0.0001). A regression equation predicting colonic carcinoma area (r2 = 0.279) using propionate and butyrate concentrations of the contents of the post-cecal colon showed propionate as a positive predictor (P < 0.001) and butyrate as a negative predictor (P = 0.033). Our results show that patterns of short-chain fatty acid production may affect the results of fiber-carcinogenesis experiments. Dietary addition of hydrolyzed guar is associated with fecal fermentation low in propionate and high in butyrate; short-chain fatty acid concentrations are greater proximally than distally. These results suggest that butyrate protects against colonic neoplasia, whereas propionate enhances it, and demonstrate that colonic microbiota adapt to produce more butyrate if given time and the proper substrate.

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By Team FPS – April 6, 2012

Carbohydrates and Bone Health

Also see:
Sugar (Sucrose) Restrains the Stress Response
Calcium Paradox
Thumbs Up: Fructose
Intestinal Serotonin and Bone Loss
Bone Health and Vitamin K
Parmigiano Reggiano cheese and bone health
Calcium Paradox
Estrogen Dominance and Magnesium Deficiency
Benefits of Aspirin

Picture 5

Ann Nutr Aliment. 1975;29(4):305-12.
[Effects of administering diets with starch or sucrose basis on certain parameters of calcium metabolism in the young, growing rat].
[Article in French]
Artus M.
The important role of many carbohydrates on calcium metabolism has been demonstrated by FOURNIER and DUPUIS. Starch, however, neither influences the absorption nor the retention of calcium. Less is known about the effects of sucrose. In this study the influence of starch on calcium metabolsim has been compared with that of sucrose. Male weanling Wistar rats were divided into three groups according to their diets. The first group received a refined and well-balanced diet (except for the absence of vitamin D), containing 68 p. 100 of starch. The second group received the same diet except sucrose was substituted for the starch. The third group received the same diet as Group 1, with the addition of vitamin D. Plasma calcium citrate and urinary citrate and calcium were determined. At the age of 2 months after one night of fasting, each group of rats was injected intraperitoneally with a 1 ml, aqueous solution containing 1 mg calcium and 0, 6 mu Ci45Ca. Twenty-four hours later the animals were sacrificed and the calcium femur percentage, radioactivity p. 1,000 of the injected dose of 45Ca, and specific radioactivity were determined. When performance data from Group 3 were compared to Group 1 and Group 2, the following results were obtained: —Group 1 (starch diet without vitamin D) had very low plasma calcium levels; urinary calcium, plasma citrate and urinary citrate levels were lowered, and the calcium femur percentage was smaller. Bone avidity for calcium was found. –Group 2 (sucrose diet without vitamin D) had normal plasma calcium levels. Urinary calcium and citrate and plasma citrate did not show significant differences from those of animals receiving vitamin D. No significant differences were found in the specific radioactivity and radioactivity p. 1,000 of the administered dose. Contrary to starch, sucrose maintained calcium homeostasis, and apparently, normal ossification, although the femur was lighter than those of animals receiving vitamin D. Further work is necessary to determine whether the fructose component of the sucrose molecule is responsible for the increased calcium utilization and, if so, what levels of ingestion are necessary for this activity.

Bone. 2008 May;42(5):960-8. Epub 2008 Feb 15.
The effect of feeding different sugar-sweetened beverages to growing female Sprague-Dawley rats on bone mass and strength.
Tsanzi E, Light HR, Tou JC.
Consumption of sugar beverages has increased among adolescents. Additionally, the replacement of sucrose with high fructose corn syrup (HFCS) as the predominant sweetener has resulted in higher fructose intake. Few studies have investigated the effect of drinking different sugar-sweetened beverages on bone, despite suggestions that sugar consumption negatively impacts mineral balance. The objective of this study was to determine the effect of drinking different sugar-sweetened beverages on bone mass and strength. Adolescent (age 35d) female Sprague-Dawley rats were randomly assigned (n=8-9/group) to consume deionized distilled water (ddH2O, control) or ddH2O containing 13% w/v glucose, sucrose, fructose or high fructose corn syrup (HFCS-55) for 8weeks. Tibia and femur measurements included bone morphometry, bone turnover markers, determination of bone mineral density (BMD) and bone mineral content (BMC) by dual energy X-ray absorptiometry (DXA) and bone strength by three-point bending test. The effect of sugar-sweetened beverage consumption on mineral balance, urinary and fecal calcium (Ca) and phosphorus (P) was measured by inductively coupled plasma optical emission spectrometry. The results showed no difference in the bone mass or strength of rats drinking the glucose-sweetened beverage despite their having the lowest food intake, but the highest beverage and caloric consumption. Only in comparisons among the rats provided sugar-sweetened beverage were femur and tibia BMD lower in rats drinking the glucose-sweetened beverage. Differences in bone and mineral measurements appeared most pronounced between rats drinking glucose versus fructose-sweetened beverages. Rats provided the glucose-sweetened beverage had reduced femur and tibia total P, reduced P and Ca intake and increased urinary Ca excretion compared to the rats provided the fructose-sweetened beverage. The results suggested that glucose rather than fructose exerted more deleterious effects on mineral balance and bone.

Am J Clin Nutr. 1989 Jun;49(6):1290-4.
Dietary fructose or starch: effects on copper, zinc, iron, manganese, calcium, and magnesium balances in humans.
Holbrook JT, Smith JC Jr, Reiser S.
A balance study was conducted to assess the effects of consuming low-copper diets, high in fructose or cornstarch. The study involved 19 apparently healthy males, aged 21-57 y. The two experimental diets averaged 0.35 mg Cu/1000 kcal and provided 20% of the calories from fructose or cornstarch. Cu, zinc, calcium, magnesium, and iron balances were determined 1 wk before the study (pretest) when the subjects consumed self-selected diets and after consuming the experimental diets for 6 wk. No major differences in mineral balances were evident between the two groups during the pretest study when the subjects ate self-selected diets. In contrast, when fed the test diets, the group consuming the low-Cu fructose diet had significantly more positive balances for all minerals studied than the group fed the low-Cu cornstarch diet. The results indicate that dietary fructose enhances mineral balance.

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By Team FPS – April 6, 2012

Arachidonic Acid’s Role in Stress and Shock

Also see:
Resuscitation: Benefits of ATP, Glucose, and Sodium
Trauma & Resuscitation: Toxicity of Lactated Ringer’s Solution
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
Brain Swelling Induced by Polyunsaturated Fats (PUFA)
Fish Oil Toxicity
Estrogen’s Role in Asthma
PUFA Decrease Cellular Energy Production
Benefits of Aspirin
Protective “Essential Fatty Acid Deficiency”
Anti-Inflammatory Omega -9 Mead Acid (Eicosatrienoic acid)
Unsaturated Fats and Lung Function

“In adults, prostaglandins are known to be involved in many of the harmful effects of inflammation. They are formed from the polyunsaturated fats, linoleic acid and arachidonic acid, which we are unable to synthesize ourselves, so the adult’s exposure to the prostaglandins is influenced by diet.” -Ray Peat, PhD

“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…” -Ray Peat, PhD

Adv Shock Res. 1981;6:83-91.
Implications for thromboxane A2 in the pathogenesis of endotoxic shock.
Wise WC, Cook JA, Halushka PV.
During endotoxemia there is increased synthesis of arachidonic-acid-derived metabolites. We investigated the potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A2, an arachidonic acid metabolite, in the endotoxic shocked rat. Plasma levels of thromboxane B2, the stable metabolite of thromboxane A2, 6-keto-PGF1 alpha, the stable metabolite of PGI2, and PGE were measured via radioimmunoassay. We also investigated the therapeutic efficacy of the fatty acid cyclo-oxygenase imidazole and 7(1-imidazolyl)-heptanoic acid (7-IHA), in endotoxic shocked rats. Thirty minutes after intravenous (IV) administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma immunoreactive thromboxane B2 (TxB2) was increased from nondetectable levels (less than 200 pg/ml) in normal nonshocked rats to 2207 +/- 282 pg/ml (N = 16). The 6-keto-PGF1 alpha level was increased from nondetectable levels to 840 +/- 59 pg/ml (N = 8), and prostaglandin E rose from 146 +/- 33 to 2160 +/- 606 pg/ml (N = 5). Ibuprofen (3.75 mg/kg) or indomethacin (10 mg/kg) administered IV 30 min prior to endotoxin (20 mg/kg) improved the survival rate to 81% (N = 15, P less than 0.001) and 78% (N = 17, P less than 0.001), respectively, compared to the 24-hr survival of 8% (N = 26) in the vehicle-treated rats. Ibuprofen also inhibited the endotoxin-induced elevation of TxB2, 6-keto-PGF1 alpha, and fibrinogen/fibrin degradation products. Imidazole (30 mg/kg) or 7-IHA (30 mg/kg), IV, 30 min prior to endotoxin improved survival 65% (N = 11) and 81% (N = 15), respectively. These drugs also inhibited endotoxin-induced elevations in TxB2 and fibrinogen/fibrin degradation products, but did not inhibit endotoxin-induced elevations in plasma PGE. These results are consistent with the suggestion that TxA2 plays a role in the pathogenesis of endotoxic shock.

J Clin Invest. 1980 Jan;65(1):227-30.
Elevated thromboxane levels in the rat during endotoxic shock: protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency.
Cook JA, Wise WC, Halushka PV.
The potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A(2), in endotoxic shock was investigated in rats. Plasma thromboxane A(2) was determined by radioimmunoassay of its stable metabolite thromboxane B(2). After intravenous administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma thromboxane B(2) levels increased from nondetectable levels (<375 pg/ml) in normal control rats to 2,054+/-524 pg/ml (n = 8), within 30 min to 2,071+/-429 at 60 min, and decreased to 1,119+/-319 pg/ml, at 120 min. Plasma levels of prostaglandin E also increased from 146+/-33 pg/ml in normal controls (n = 5) to 2,161+/-606 pg/ml 30 min after endotoxin (n = 5). In contrast to shocked controls, rats pretreated with imidazole, a thromboxane synthetase inhibitor, or essential fatty acid-deficient rats, which are deficient in arachidonate and its metabolites, did not exhibit significant elevations in plasma levels of thromboxane B(2). Imidazole did not however inhibit endotoxin-induced elevations in plasma prostaglandin E. Essential fatty acid deficiency significantly reduced mortality to lethal endotoxic shock. This refractoriness could be duplicated in normal rats pretreated with the fatty acid cyclo-oxygenase inhibitor, indomethacin (10 mg/kg), intravenously 30 min before endotoxin injection. Imidazole (30 mg/kg) administered intraperitoneally 1 h before or intravenously 30 min before endotoxin, also significantly (P < 0.01) reduced mortality from lethal endotoxin shock to 40% compared to a control mortality of 95% at 24 h. Likewise pretreatment with 13-azaprostanoic acid (30 mg/kg), a thromboxane antagonist, reduced mortality from endotoxic shock at 24 h from 100% in control rats to only 50% (P < 0.01). The results suggest that endotoxin induces increased synthesis of thromboxane A(2) that may contribute to the pathogenesis of endotoxic shock.

Adv Shock Res. 1981;6:93-105.
Essential fatty acid deficient rats: a new model for evaluating arachidonate metabolism in shock.
Cook JA, Wise WC, Knapp DR, Halushka PV.
Essential fatty acid deficient (EFAD) rats are significantly more resistant to the lethal effects of S. enteritidis endotoxin (20 mg/kg, IV) than normal control rats. Compared to endotoxin-treated normal rats, EFAD rats also manifested less severe alterations of hepatic and lysosomal integrity and became less hypoglycemic. Administration of the ethyl ester of the essential fatty acid, arachidonic acid (100 mp, IP) two days prior to challenge with S. enteritidis endotoxin (20 mg/kg) in EFAD rats restored their sensitivity to endotoxin, as denoted by a 100% mortality compared to a 24% mortality (P less than 0.01) in EFAD rats.Treatment of EFAD rats with the fatty acid docosahexaenoic acid, a non-prostaglandin and thromboxane precursor, (100 mg, IP) produced significantly less (less than 0.01) mortality than ethyl-arachidonate-treated groups (ie, 40% vs 100%). The arachidonate metabolite, thromboxane B2 (TxB2), increased from nondetectable plasma levels (less than 200 pg/ml) to 2285 +/- 449 pg/ml (N = 10) at 30 min and remained elevated for 180 minutes after endotoxin administration in nondeficient rats. However, plasma TxB2 was not detectable in endotoxin-treated EFAD rats and was only slightly elevated in groups supplemented with docosahexaenoic acid (273 +/- 104 pg/ml, N = 6) after 30 minutes. In ethyl arachidonate (100 mg, IP) supplemented EFAD rats, plasma TxB2 rose to 873 +/- 204 pg/ml (N = 8), 30 min after endotoxin. Pretreatment of the ethyl-arachidonate-supplemented EFAD group with a specific thromboxane synthetase inhibitor, 7-(1-imidazolyl)-heptanoic acid (30 mg/kg, IV), significantly reduced mortality 100% to 50% (P less than 0.05) from endotoxic shock. These observations suggest a deleterious role for arachidonic acid and its conversion to TxA2 in the pathogenesis of endotoxic shock.

Circ Shock. 1990 Jun;31(2):159-70.
Resistance of essential fatty acid-deficient rats to endotoxin-induced increases in vascular permeability.
Li EJ, Cook JA, Spicer KM, Wise WC, Rokach J, Halushka PV.
Resistance to endotoxin in essential fatty acid-deficient (EFAD) rats is associated with reduced synthesis of certain arachidonic acid metabolites. It was hypothesized that EFAD rats would manifest decreased vascular permeability changes during endotoxemia as a consequence of reduced arachidonic acid metabolism. To test this hypothesis, changes in hematocrit (HCT) and mesenteric localization rate of technetium-labeled human serum albumin (99mTc-HSA) and red blood cells (99mTc-RBC) were assessed in EFAD and normal rats using gamma-camera imaging. Thirty minutes after Salmonella enteritidis endotoxin, EFAD rats exhibited less hemoconcentration as determined by % HCT than normal rats (47 +/- 2% vs. 54 +/- 1% respectively, P less than 0.01). Endotoxin caused a less severe change in permeability index in the splanchnic region in EFAD rats than in normal rats (1.2 +/- 0.6 x 10(-3)min-1 vs. 4.9 +/- 1.7 x 10(-3)min-1 respectively, P less than 0.05). In contrast to 99mTc-HSA, mesenteric localization of 99mTc-RBC was not changed by endotoxin in control or EFAD rats. Supplementation with ethyl-arachidonic acid did not enhance susceptibility of EFAD rats to endotoxin-induced splanchnic permeability to 99mTc-HSA. Leukotrienes have been implicated as mediators of increased vascular permeability in endotoxin shock. Since LTC3 formation has been reported to be increased in EFA deficiency, we hypothesized that LTC3 may be less potent than LTC4. Thus the effect of LTC3 on mean arterial pressure and permeability was compared to LTC4 in normal rats. LTC3-induced increases in peak mean arterial pressure were less than LTC4 at 10 micrograms/kg (39 +/- 5 mm Hg vs. 58 +/- 4 mm Hg respectively, P less than 0.05) and at 20 micrograms/kg (56 +/- 4 mm Hg vs. 75 +/- 2 mm Hg respectively, P less than 0.05). LY171883 (30 mg/kg), an LTD4/E4 receptor antagonist, attenuated the pressor effect of LTC4, LTD4, and LTC3. Infusion of LTC4 (4 micrograms/kg/min) in normal rats induced a rise in HCT from 44 +/- 1% to 51 +/- 1% (P less than 0.01), which was greater (P less than 0.05) than the rise induced by LTC3 (47 +/- 1% to 49 +/- 1%). The results showing that EFAD rats are resistant to endotoxin-induced increases in HCT and vascular permeability raise the possibility that this may, in part, be a result of preferential LTC3 production that is less potent than LTC4.

Journal of Applied Physiology August 1989 vol. 67 no. 2 811-816
Essential fatty acid-deficient rats are resistant to oleic acid-induced pulmonary injury
H. A. Ball, J. A. Cook, K. M. Spicer, W. C. Wise, and P. V. Halushka
Because leukotrienes and prostaglandins are inflammatory mediators derived from arachidonic acid, their potential role in oleic acid-induced lung injury was evaluated in control and in essential fatty acid-deficient (EFAD) rats depleted of arachidonic acid substrate. In control rats, oleic acid (0.06 ml/kg iv) increased the pulmonary permeability index (measured by scintigraphy) from -10 +/- 13 x 10(-6) s-1 to 217 +/- 20 x 10(-6) s-1 and 118 +/- 13 x 10(-6) s-1 at 5 and 50 min (P less than 0.05), respectively. It also caused arterial hypoxemia at 30 min (P less than 0.05). Compared with saline controls, oleic acid increased bronchoalveolar lavage fluid levels of immunoreactive (i) LTC4/D4, iLTB4, (P less than 0.01), and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) (P less than 0.05). In EFAD rats, oleic acid failed to significantly increase the lung permeability index at 5 and 50 min. In contrast to control rats, oleic acid failed to cause hypoxemia in the EFAD rats. Bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha after oleic acid in EFAD rats were lower compared with oleic acid controls, whereas iLTC4/D4 in the oleic acid EFAD group was not decreased. Treatment with intraperitoneal ethyl arachidonate (400 mg over 2 wk) reversed the resistance of EFAD rats such that the pulmonary edema (P less than 0.05) was evident after oleic acid. This latter group also manifested a significant (P less than 0.05) rise in the bronchoalveolar lavage levels of iLTB4 and i6-keto-PGF1 alpha. These results suggest that arachidonic acid metabolites contribute to oleic acid-induced pulmonary permeability.

INTENSIVE CARE MEDICINE Volume 12, Number 3, 116-126
Role of thromboxane, prostaglandins and leukotrienes in endotoxic and septic shock
H. A. Ball, J. A. Cook, W. C. Wise and P. V. Halushka
Intravenous bolus endotoxin elicits a marked but transient increase in plasma TxB2 and 6-keto-PGF1 in a large number of species. A smaller, delayed and more prolonged increase in TxB2 and 6-keto-PGF1 are reported in animals with septic shock, i.e., those with fecal peritonitis or cecal ligation. Thromboxane synthetase inhibitors or antagonists attenuate endotoxin-induced acute cardiopulmonary changes, the delayed increase in serum lysosomal enzymes, fibrin/fibrinogen degradation products and the thrombocytopenia in a number of species. While these drugs increase survival of rats or mice following endotoxin they do not alter survival of rats in septic shock. These results support the hypothesis that TxA2 exerts a pathophysiologic effect in shock following bolus endotoxin. In contrast, nonsteroidal antiinflammatory drugs (NSAID) and dietary essential fatty acid deficiency increase survival of rats subjected to endotoxin shock, and survival time in models of septic shock. These results also suggest that some other cyclooxygenase product(s) is involved in septic shock due to fecal peritonitis or cecal ligation. Preliminary experimental studies indicate salutary effects of leukotriene inhibitors and antagonists in endotoxin shock and in models of acute pulmonary injury. Clinical studies have demonstrated elevated plasma TxB2 and 6-keo-PGF1 concentrations in patients with septic shock, and elevated LTD4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. In view of these clinical and experimental results, clinical trials of NSAID and/or leukotriene inhibitors/antagonists should be considered.

Am J Vet Res. 2008 Feb;69(2):199-207.
Roles of thromboxane A2 and 5-hydroxytryptamine in endotoxin-induced digital vasoconstriction in horses.
Menzies-Gow NJ, Sepulveda MF, Bailey SR, Cunningham FM, Elliott J.
OBJECTIVE:
To evaluate the roles of 5-hydroxytryptamine (5-HT), thromboxane A2 (TxA2), and platelet-activating factor (PAF) in endotoxin-induced digital hypoperfusion in horses.
ANIMALS:
6 healthy adult Thoroughbreds.
PROCEDURES:
Horses were treated with IV administration of saline (0.9% NaCl) solution (control treatment) or the 5-HT 1B/D selective antagonist, GR55562 (0.3 mg/kg), prior to tryptamine infusion (1.6 microg/kg/min for 30 minutes) to establish an effective GR55562 dose. In a crossover study, horses were treated with IV administration of saline solution (control treatment), aspirin (4 mg/kg, 2 hours or 4 days before lipopolysaccharide [LPS] infusion), GR55562 (0.3 mg/kg), the PAF antagonist WEB2086 (3 mg/kg), or aspirin plus GR55562 prior to LPS infusion (30 ng/kg for 30 minutes). Digital blood flow was measured by use of Doppler ultrasonography. Concomitant measurements of hoof wall and coronary band surface temperatures were made. Serial blood samples were collected and plasma 5-HT and TxA2 concentrations determined.
RESULTS:
GR55562 abolished tryptamine-induced digital hypoperfusion. Neither WEB2086 nor GR55562 affected LPS-induced alterations in digital perfusion or plasma mediator concentrations. Aspirin given 2 hours before LPS administration abolished the increase in plasma TxA2 concentration and significantly attenuated LPS-induced digital hypoperfusion. Aspirin given 4 days before LPS significantly attenuated the increase in plasma TxA2 concentration and digital hypothermia. Aspirin plus GR55562 had a greater effect on LPS-induced digital hypothermia than aspirin alone.
CONCLUSIONS AND CLINICAL RELEVANCE:
Thromboxane A2 and 5-HT played a role in mediating LPS-induced digital hypoperfusion in horses. Platelet-activating factor appeared unimportant in mediating LPS-induced 5-HT or TxA2 release or digital hypoperfusion.

Prostaglandins, Leukotrienes and Medicine Volume 11, Issue 2, June 1983, Pages 179–188
Protective effects of thromboxane A2 on endotoxin shock
Sumio Fukumoto, Kenzo Tanaka
To elucidate the role of thromboxane A2 in the development of endotoxin shock following administration of endotoxin, the effects of three thromboxane A2 synthetase inhibitors, (E)-3-(4-(l-imidazolyl)phenyl)-2-propenoic acid hydrochloride monohydrate (OKY-046), sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methylacrylate (OKY-1581) and imidazole were examined. Intravenous administration of E. Coli endotoxin (3 mg/kg) produced shock and all rats died within ten hours. Pretreatment with thromboxane A2 synthetase inhibitors markedly improved the survival rates. The untreated endotoxin shock group showed marked increase in thromboxane B2 levels in the venous blood, while no such changes were seen in the pretreated groups. There were no statistically significant differences in 6-keto prostaglandin F1α levels in the venous blood. In the untreated shock group, micrathrombi were observed in 64 % of the glomeruli in the kidneys two hours after endotoxin injection. In the groups pretreated with OKY-046, OKY-1581 and imidazole, microthrombi were seen only in 22, 19 and 24%, respectively. Thus, thromboxane A2 plays an important role in the development of endotoxin shock and thromboxane A2 synthetase inhibitors, in particular OKY-046 and -1581, are prophylactic.

Am J Physiol. 1989 Oct;257(4 Pt 2):H1192-9.
Lung injury caused by cobra venom factor is reduced in rats raised on an essential fatty acid-deficient diet.
Morganroth ML, Schoeneich SO, Till GO, Pickett W, Ward PA.
Arachidonate metabolites appear to be involved in lung injury caused by cobra venom factor (CVF)-induced complement and polymorphonuclear leukocyte (PMN) activation. These studies were designed to assess the effects of a dietary-induced deficiency of arachidonic acid on CVF-induced lung injury. Rats raised on an essential fatty acid-deficient (EFAD) diet exhibited the expected changes in fatty acid composition including decreased plasma levels of arachidonic acid and increased levels of 5,8,11-eicosatrienoic acid. In intact rats raised on the EFAD diet, CVF-induced lung injury was attenuated. When blood and excised lungs from rats raised on the normal diet were used, CVF caused pulmonary vascular constriction and acute lung injury, as evidenced by increased 125I-labeled bovine serum albumin accumulation in lung parenchyma and alveolar lavage fluid. The CVF-induced pulmonary artery pressor response and lung injury were reduced when blood perfusate or blood perfusate and excised lungs were obtained from rats raised on the EFAD diet. The pulmonary vascular constriction and lung injury were not attenuated when the blood perfusate was obtained from rats raised on the normal diet, irrespective of whether the excised lungs were obtained from rats raised on the normal or EFAD diet. PMNs obtained from rats raised on the EFAD diet demonstrated decreased superoxide production as well as impaired random migration and chemotaxis in vitro. In contrast, beta-glucuronidase release was quantitatively similar to PMNs from control rats. These data indicate that the EFAD diet-induced attenuation of CVF-induced pulmonary hypertension and acute lung injury is due to defective effector cells in blood rather than modified pulmonary target tissue.

Kidney Int. 1992 May;41(5):1245-53.
Essential fatty acid deficiency normalizes function and histology in rat nephrotoxic nephritis.
Takahashi K, Kato T, Schreiner GF, Ebert J, Badr KF.
The central lipid abnormality in essential fatty acid deficiency (EFAD) is the lack of availability of arachidonic acid. To examine the role of total eicosanoid’s biosyntheses in the pathology and pathophysiology of glomerulonephritis, EFAD was induced in weanling rats, which were then subjected to antiglomerular basement membrane antibody (NTS)-induced injury in adulthood. Glomerular dynamics (as assessed by micropuncture), quantitative histology, and eicosanoid generation rates were measured at two hours and two weeks post-NTS, and compared to those of standard diet-fed (STD) controls. Two hours post-NTS, and despite the occurrence of proteinuria in both EFAD and STD animals, glomerular dynamics were essentially normal in EFAD rats, whereas STD animals had reduced values for glomerular filtration rate (GFR) and renal plasma flow rate (RPF). At two weeks, severe histologic changes were observed in STD animals including mesangial and stalk hypercellularity, moderate sclerosis, and interstitial nephritis, coupled with heavy proteinuria and reduced GFR and RPF. In dramatic contrast, EFAD rats displayed totally normal glomerular structures and functions. In parallel, glomerular generation rates of prostaglandin E2 and thromboxane A2 were suppressed markedly in EFAD rats. Thus, EFAD confers complete protection against the histopathologic and functional sequelae of immune-initiated injury in the glomerulus. The data suggest that the initial wave of complement-induced neutrophil infiltration (with resultant proteinuria) is not sufficient to perpetuate injury into the more destructive chronic phases. The results provide strong impetus for the design of more specific interventional therapies targeting the various enzymes and products of arachidonic acid metabolism in the attempts to control glomerular inflammation.

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By Team FPS – April 3, 2012

Protective Carbon Dioxide, Exercise, and Performance

Also see:
Protective Altitude
Synergistic Effect of Creatine and Baking Soda on Performance
Ray Peat, PhD on Carbon Dioxide, Longevity, and Regeneration
Exercise Induced Stress
Exercise and Effect on Thyroid Hormone
Lactate Paradox: High Altitude and Exercise
Carbohydrate Lowers Exercise Induced Stress
Exercise Induced Menstrual Disorders
Aspirin and Exercise
Bicarbonate For Strength Athletes: 25g of Baking Soda Up Your Squat (+27%) & Bench Press (+6%) Within 60 Min
How Measuring My Urine pH Got Me to Love Working Out Again

1026140808a

EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY AND OCCUPATIONAL PHYSIOLOGY
Volume 57, Number 1, 45-48, DOI: 10.1007/BF00691236
Induced metabolic alkalosis and its effects on 400-m racing time
Jo Goldfinch, Lars Mc Naughton and Peter Davies
Six trained male athletes who competed regularly in 400 metre races, were studied under control, alkalotic (NaHCO3) and placebo (CaCO3) conditions to study the effect of induced metabolic alkalosis on 400 m racing time. Pre and post exercise blood samples in the three conditions were analysed for pH, bicarbonate and base excess. Following ingestion of NaHCO3, pre-exercise pH, bicarbonate and base excess levels were significantly higher than either control or placebo conditions. In the alkalotic condition the subjects ran significantly (p<0.005) faster (1.52 s) than either the control of placebo conditions. The post-exercise pH, bicarbonate and base excess levels were all lower in the alkalotic condition than in the others. The results suggest that NaHCO3 can be used as an effective ergogenic aid and support the speculation that the increased extracellular buffering afforded by NaHCO3 ingestion facilitated efflux of H+ from the working tissues, thus decreasing intracellular pH and hence offsetting fatigue.

J Strength Cond Res. 2014 May;28(5):1358-66. doi: 10.1519/JSC.0000000000000277.
The effect of sodium bicarbonate ingestion on back squat and bench press exercise to failure.
Duncan MJ, Weldon A, Price MJ.
Duncan, MJ, Weldon, A, and Price, MJ. The effect of sodium bicarbonate ingestion on back squat and bench press exercise to failure. J Strength Cond Res 28(5): 1358-1366, 2014-This study examined the acute effects of NaHCO3 ingestion on repetitions to failure and rating of perceived exertion in the back squat and bench press in trained men. Eight resistance-trained men took part in this double-blind, randomized crossover experimental study whereby they ingested NaHCO3 (0.3 g·kg body mass) or placebo (sodium chloride NaCl: 0.045 g·kg body mass) solution 60 minutes before completing a bout of resistance exercise (3 sets of bench press and back squat exercise to failure at an intensity of 80% 1 repetition maximum). Experimental conditions were separated by at least 48 hours. Participants completed more repetitions to failure in the back squat after NaHCO3 ingestion (p = 0.04) but not for bench press (p = 0.679). Mean ± SD of total repetitions was 31.3 ± 15.3 and 24.6 ± 16.2 for back squat and 28.7 ± 12.2 and 26.7 ± 10.2 for bench press in NaHCO3 and placebo conditions, respectively. Repetitions to failure decreased as set increased for the back squat and bench press (p = 0.001, both). Rating of perceived exertion significantly increased with set for the back squat and bench press (p = 0.002, both). There was no significant change in blood lactate across time or between conditions. There were however treatment × time interactions for blood pH (p = 0.014) and blood HCO3 concentration (p = 0.001). After ingestion, blood pH and HCO3 (p = 0.008) concentrations were greater for the NaHCO3 condition compared with the placebo condition (p < 0.001). The results of this study suggest that sodium bicarbonate ingestion can enhance resistance exercise performance using a repetition to failure protocol in the first exercise in a resistance exercise session.

J Sports Sci. 1992 Oct;10(5):415-23.
Bicarbonate ingestion: effects of dosage on 60 s cycle ergometry.
McNaughton LR.
Nine healthy male subjects who were all participating in athletic events volunteered to take part in this study, the aim of which was to determine whether there are specific dosages of sodium bicarbonate (HCO3-) that are useful as an ergogenic aid as far as anaerobic performance times are concerned. A control, placebo (CaCO3 500 mg kg-1) and five dosages of bicarbonate (100, 200, 300, 400 and 500 mg kg-1) were used. The anaerobic test consisted of pedalling a Repco Exertech cycle ergometer for 1 min during which total work (kJ) and peak power (W) were measured. The subjects completed more work in the 200 (P < 0.05), 300, 400 and 500 mg kg-1 (P < 0.005) trials with most work being undertaken in the 300 mg kg-1 trial (41.9 kJ min-1). Peak power was not significantly different from the control until the 300 mg kg-1 dose, and there were no further changes from this with increasing doses of HCO3-. The highest level of peak power achieved was 1295 +/- 72.8 W at the 300 mg kg-1 dosage. Blood pH indicated that after ingestion of all but the 100 mg kg-1 dose, a state of alkalosis was achieved (P < 0.005), and this was also indicated by changes in base excess. Bicarbonate levels increased post-ingestion in all but the 100 mg kg-1 dose, with these changes reflecting the changes that occurred in the work output. Blood lactate (BLa) levels increased post-exercise (P < 0.0001). The BLa level during ingestion of 200mg kg-1 does was higher than the control, placebo, or 100 mg kg-1 dose (P<0.05), and this was also true for the three remaining doses (P<0.01). In conclusion, it is suggested that the optimal dose of bicarbonate for anaerobic performance of 1 min is 300mg kg-1. Further doses showed no greater increase in work and there was increased gastrointestinal disturbance.

Int J Sports Med. 2010 Nov;31(11):797-802. Epub 2010 Aug 11.
Metabolic alkalosis, recovery and sprint performance.
Siegler JC, McNaughton LR, Midgley AW, Keatley S, Hillman A.
Pre-exercise alkalosis and an active recovery improve the physiological state of recovery through slightly different mechanisms (e. g. directly increasing extracellular bicarbonate (HCO3 (-)) vs. increasing blood flow), and combining the two conditions may provide even greater influence on blood acid-base recovery from high-intensity exercise. Nine subjects completed four trials (Placebo Active ( PLAC A), sodium bicarbonate (NaHCO3) Active ( BICARB A), Placebo Passive ( PLAC P) and NaHCO3 Passive ( BICARB P)), each consisting of three, 30-s maximal efforts with a three min recovery between each effort. Pre-exercisealkalosis was evident in both NaHCO3 conditions, as pH and HCO3 (-) were significantly higher than both Placebo conditions (pH: 7.46 ± 0.04 vs. 7.39 ± 0.02; HCO3 (-): 28.8 ± 1.9 vs. 23.2 ± 1.4  mmol·L (-1); p<0.001). In terms of performance, significant interactions were observed for average speed (p<0.05), with higher speeds evident in the BICARB A condition (3.9 ± 0.3 vs. 3.7 ± 0.4  m·s (-1)). Total distance covered was different (p=0.05), with post hoc differences evident between the BICARB A and PLAC P conditions (368 ± 33 vs. 364 ± 35 m). These data suggest that successive 30-s high intensity performance may be improved when coupled with NaHCO3 supplementation.

Int J Sports Med. 2008 Jul;29(7):545-51. Epub 2007 Nov 14.
Pre-exercise alkalosis and acid-base recovery.
Siegler JC, Keatley S, Midgley AW, Nevill AM, McNaughton LR.
The aim of this study was to observe the influence of pre-exercise sodium bicarbonate (NaHCO3) ingestion and varying recovery modes on acid-base recovery from a single bout of supramaximal exercise. Nine male subjects completed four separate, randomized cycle ergometer exercise trials to volitional fatigue at 120% maximum power output, under the following conditions: 0.3 g.kg(-1) BW NaHCO3 ingestion with passive recovery (BICARB P), 0.3 g.kg (-1) BW NaHCO3 ingestion with active recovery (BICARB A), placebo ingestion with passive recovery (PLAC P) and placebo ingestion with active recovery (PLAC A). Capillary blood samples were obtained every minute for 15 min during recovery. Significant main effects for pH were observed for time (F = 42.1, p < 0.001), intervention (BICARB and PLAC) (F = 1117.3, p < 0.001) and recovery condition (F = 150.0, p < 0.001), as the BICARB condition reduced acid-base perturbation. Significant interaction effects were observed between conditions (BICARB and PLAC) for active and passive recovery modes (F = 29.1, p < 0.001) as the active recovery facilitated H+ removal better than the passive condition. Pre-exercise alkalosis attenuates blood acid-base perturbations from supramaximal exercise to exhaustion, regardless of whether the recovery mode is active or passive. These findings suggest that individuals may benefit from introducing a pre-exercise alkalotic condition while including passive recovery during high-intensity training protocols.

Int J Sports Med. 2008 Jun;29(6):519-23. Epub 2007 Nov 14.
Sodium bicarbonate improves swimming performance.
Lindh AM, Peyrebrune MC, Ingham SA, Bailey DM, Folland JP.
Sodium bicarbonate ingestion has been shown to improve performance in single-bout, high intensity events, probably due to an increase in buffering capacity, but its influence on single-bout swimming performance has not been investigated. The effects of sodium bicarbonate supplementation on 200 m freestyle swimming performance were investigated in elite male competitors. Following a randomised, double blind counterbalanced design, 9 swimmers completed maximal effort swims on 3 separate occasions: a control trial (C); after ingestion of sodium bicarbonate (SB: NaHCO3 300 mg . kg (-1) body mass); and after ingestion of a placebo (P: CaCO3 200 mg . kg (-1) body mass). The SB and P agents were packed in gelatine capsules and ingested 90 – 60 min prior to each 200 m swim. Mean 200 m performance times were significantly faster for SB than C or P (1 : 52.2 +/- 4.7; 1 : 53.7 +/- 3.8; 1 : 54.0 +/- 3.6 min : ss; p < 0.05). Base excess, pH and blood bicarbonate were all elevated pre-exercise in the SB compared to C and P trials (p < 0.05). Post-200 m blood lactate concentrations were significantly higher following the SB trial compared with P and C (p < 0.05). It was concluded that SB supplementation can improve 200 m freestyle performance time in elite male competitors, most likely by increasing buffering capacity.

J Strength Cond Res. 2010 Nov;24(11):3105-11.
Sodium bicarbonate ingestion and repeated swim sprint performance.
Siegler JC, Gleadall-Siddall DO.
The purpose of the present investigation was to observe the ergogenic potential of 0.3 g·kg-1 of sodium bicarbonate (NaHCO3) in competitive, nonelite swimmers using a repeated swim sprint design that eliminated the technical component of turning. Six male (181.2 ± 7.2 cm; 80.3 ± 11.9 kg; 50.8 ± 5.5 ml·kg-1·min-1 VO2max) and 8 female (168.8 ± 5.6 cm; 75.3 ± 10.1 kg; 38.8 ± 2.6 ml·kg-1·min-1 VO2max) swimmers completed 2 trial conditions (NaHCO3 [BICARB] and NaCl placebo [PLAC]) implemented in a randomized (counterbalanced), single blind manner, each separated by 1 week. Swimmers were paired according to ability and completed 8, 25-m front crawl maximal effort sprints each separated by 5 seconds. Blood acid-base status was assessed preingestion, pre, and postswim via capillary finger sticks, and total swim time was calculated as a performance measure. Total swim time was significantly decreased in the BICARB compared to PLAC condition (p = 0.04), with the BICARB condition resulting in a 2% decrease in total swim time compared to the PLAC condition (159.4 ± 25.4 vs. 163.2 ± 25.6 seconds; mean difference = 4.4 seconds; 95% confidence interval = 8.7-0.1). Blood analysis revealed significantly elevated blood buffering potential preswim (pH: BICARB = 7.48 ± 0.01, PLAC = 7.41 ± 0.01) along with a significant decrease in extracellular K+ (BICARB = 4.0 ± 0.1 mmol·L-1, PLAC = 4.6 ± 0.1 mmol·L-1). The findings suggest that 0.3 g·kg-1 NaHCO3 ingested 2.5 hours before exercise enhances the blood buffering potential and may positively influence swim performance.

J Strength Cond Res. 2010 Jan;24(1):103-8.
Sodium bicarbonate ingestion and boxing performance.
Siegler JC, Hirscher K.
Boxing is a sport that consists of multiple high-intensity bouts separated by minimal recovery time and may benefit from a pre-exercise alkalotic state. The purpose of this study was to observe the ergogenic potential of sodium bicarbonate (NaHCO3) ingestion on boxing performance. Ten amateur boxers volunteered to participate in 2 competitive sparring bouts. The boxers were prematched for weight and boxing ability and consumed either 0.3 g.kg(-1) body weight (BW) of NaHCO3 (BICARB) or 0.045 g.kg(-1) BW of NaCl placebo (PLAC) mixed in diluted low calorie-flavored cordial. The sparring bouts consisted of four 3-minute rounds, each separated by 1-minute seated recovery. Blood acid-base (pH, bicarbonate [HCO3(-)], base excess [BE]), and performance (rates of perceived exertion [RPE], heart rate [HR] [HR(ave) and HR(max)], total punches landed successfully) profiles were analyzed before (where applicable) and after sparring. The results indicated a significant interaction effect for HCO3(-) (p < or = 0.001) and BE (p < 0.001), but not for pH (p = 0.48). Post hoc analysis revealed higher presparring HCO3(-) and BE for the BICARB condition, but no differences between the BICARB and PLAC conditions postsparring. There was a significant increase in punches landed during the BICARB condition (p < 0.001); however, no significant interaction effects for HRave (p = 0.15), HRmax (p = 0.32), or RPE (p = 0.38). The metabolic alkalosis induced by the NaHCO3 loading elevated before and after sparring blood buffering capacity. In practical application, the findings suggest that a standard NaHCO3 loading dose (0.3 g.kg(-1)) improves punch efficacy during 4 rounds of sparring performance.

Eur J Appl Physiol Occup Physiol. 1988;58(1-2):171-4.
Sodium bicarbonate ingestion improves performance in interval swimming.
Gao JP, Costill DL, Horswill CA, Park SH.
In an effort to determine the effects of bicarbonate (NaHCO3) ingestion on exercise performance, ten male college swimmers were studied during five different trials. Each trial consisted of five 91.4 m (100-yd) front crawl swims with a two-minute rest interval between each bout. The trials consisted of two NaHCO3 treatments, two placebo trials and one test with no-drink. One hour before the onset of swimming, the subjects were given 300 ml of citric acid flavored solution containing either 17 mmol of NaCl (placebo) or 2.9 mmol of NaHCO3.kg-1 body weight (experimental), or received no drink (no-drink). Performance times for each 91.4 m swim were recorded. Blood samples were obtained before and one hr after treatment, two min after warmup, and two min after the final 91.4 m sprint. Blood pH, lactate, standard bicarbonate (SBC) and base excess (BE) were measured. No differences were found for performance or the blood measurements between the placebo and no-drink trials. Bicarbonate feedings, on the other hand, produced a significant (P less than 0.05) improvement in performance on the fourth and fifth swimming sprints. Blood lactate, pH, SBC and BE were significantly higher (P less than 0.05) at post-exercise in NaHCO3 treatments. These data are in agreement with previous findings that during repeated bouts of exercise pre-exercise administration of NaHCO3 improves performance, possibly by facilitating the efflux of hydrogen ions from working muscles and thereby delaying the onset of fatigue.

Journal of Sports Sciences Volume 13, Issue 5, 1995
The effect of sodium bicarbonate ingestion on 1500‐m racing time
S.R. Birda, J. Wiles & J. Robbins
Twelve athletes, all of whom regularly participated in middle‐ or long‐distance running races at club to national standard, competed in simulated 1500‐m races under three conditions: following ingestion of 300 mg sodium bicarbonate per kg of body mass (B); following ingestion of a placebo (100 mg sodium chloride per kg of body mass and 200 mg calcium carbonate per kg of body mass) (P); and following ingestion of neither (C). A double‐blind protocol was used between the B and P trials. Each condition was replicated so that the athletes competed in six races. Ten of the athletes completed all the races. The athletes’ average times for trials B, P and C were 253.9, 256.8 and 258.0 s, respectively. The data were analysed using a two‐way ANOVA with replicates and Tukey tests. This revealed a difference between trial B and trials P and C (P < 0.05), but no difference between trials P and C. These findings, therefore, indicate that sodium bicarbonate can have an ergogenic effect upon 1500‐m running.

Journal of Sports Science and Medicine (2009) 8, 45 – 50
EFFECTS OF SODIUM BICARBONATE INGESTION ON SWIM PERFORMANCE IN YOUTH ATHLETES
Adam Zajac, Jaroslaw Cholewa, Stanislaw Poprzecki, Zbigniew Waskiewicz and Jozef Langfort
The purpose of this study was to evaluate the effect of oral administration of sodium bicarbonate (300 mg·kg-1 b.w.) on swim performance in competitive, (training experience of 6.6 ± 0.6 years) youth, (15.1 ± 0.6 years) male swimmers. The subjects completed a test trial, in a double blind fashion, on separate days, consisting of 4 x 50m front crawl swims with a 1st minute passive rest interval twice, on two occasions: after ingestion of bicarbonate or placebo, 72 hours apart, at the same time of the day. Blood samples were drawn from the finger tip three times during each trial; upon arrival to the laboratory, 60 min after ingestion of placebo or the sodium bicarbonate solution and after the 4 x 50m test, during the 1st min of recovery. Plasma lactate concentration, blood pH, standard bicarbonate and base excess were evaluated. The total time of the 4 x 50 m test trial improved from 1.54.28 to 1.52.85s, while statistically significant changes in swimming speed were recorded only during the first 50m sprint (1.92 vs. 1.97 m·s-1, p < 0.05). Resting blood concentration of HCO-3 increased following the ingestion of sodium bicarbonate from 25.13 to 28.49 mM (p < 0.05). Sodium bicarbonate intake had a statistically significant effect on resting blood pH (7.33 vs. 7.41, p < .05) as well as on post exercise plasma lactate concentration (11.27 vs. 13.06 mM, p < 0.05)). Collectively, these data demonstrate that the ingestion of sodium bicarbonate in youth athletes is an effective buffer during high intensity interval swimming and suggest that such a procedure can be used in youth athletes to increase training intensity as well as swimming performance in competition at distances from 50 to 200 m.

J Appl Physiol. 1997 Aug;83(2):333-7.
Effect of ingested sodium bicarbonate on muscle force, fatigue, and recovery.
Verbitsky O, Mizrahi J, Levin M, Isakov E.
The influence of acute ingestion of NaHCO3 on fatigue and recovery of the quadriceps femoris muscle after exercise was studied in six healthy male subjects. A bicycle ergometer was used for exercising under three loading conditions: test A, load corresponding to maximal oxygen consumption; test B, load in test A + 17%; test C, load in test B but performed 1 h after acute ingestion of NaHCO3. Functional electrical stimulation (FES) was applied to provoke isometric contraction of the quadriceps femoris. The resulting knee torque was monitored during fatigue (2-min chronic FES) and recovery (10-s FES every 10 min, for 40 min). Quadriceps torques were higher in the presence of NaHCO3 (P < 0.05): with NaHCO3 the peak, residual, and recovery (after 40 min) normalized torques were, respectively, 0.68 +/- 0.05 (SD), 0.58 +/- 0.05, and 0.73 +/- 0.05; without NaHCO3 the values were 0.45 +/- 0.04, 0.30 +/- 0.06, and 0.63 +/- 0.06. The increased torques obtained after acute ingestion of NaHCO3 indicate the possible existence of improved nonoxidative glycolysis in isometric contraction, resulting in reduced fatigue and enhanced recovery.

Med Sci Sports Exerc. 1983;15(4):277-80.
Effect of acute induced metabolic alkalosis on 800-m racing time.
Wilkes D, Gledhill N, Smyth R.
Six trained middle-distance runners wer studied under alkalotic (NaHCO3 ingestion), placebo (CaCO3 ingestion), and control conditions to determine the effect of an acute induced metabolic alkalosis on time to run an 800-m race. Pre-exercise, following NaHCO3 ingestion, pH and standard [HCO3-] were significantly higher. In the alkalotic condition, subjects ran faster (2.9 s) and the corresponding post-exercise values for blood [lactate] and extracellular H+ were higher than in the control and placebo conditions, suggesting an increased anaerobic energy contribution. These results support the speculation that the increase in extracellular buffering following NaHCO3 ingestion facilitated H+ efflux from the cells of working muscle, thereby delaying the decrease in intracellular pH and postponing fatigue. It is concluded that the ingestion of NaHCO3 by trained middle-distance runners prior to an 800-m race has an ergogenic benefit.

J Sports Sci. 1992 Oct;10(5):425-35.
Sodium bicarbonate ingestion and its effects on anaerobic exercise of various durations.
McNaughton LR.
Four groups of male subjects participated in anaerobic testing on a Repco EX10 cycle ergometer to determine the effectiveness of sodium bicarbonate (0.3 g kg-1 body mass) as an ergogenic aid during exercise of 10, 30, 120 and 240 s duration. Blood was collected 90 min prior to ingestion of sodium bicarbonate (NaHCO3), after ingestion of NaHCO3 and immediately post-exercise from a heated (43-46 degrees C) fingertip and analysed immediately post-collection for pH, base excess, bicarbonate and lactate. The total work undertaken (kJ) and peak power achieved during the tests were also obtained via a Repco Work Monitor Unit. Blood bicarbonate levels were again increased above the control and placebo conditions (P < 0.001) and blood lactate levels were also increased following the bicarbonate trials. The pH levels fell significantly (P < 0.05) below the control and placebo conditions in all trials. The results indicate that NaHCO3 at this dosage has no ergogenic benefit for work of either 10 or 30 s duration, even though blood bicarbonate levels were significantly increased (P < 0.05) following ingestion of NaHCO3. For work periods of 120 and 240 s, performance was significantly increased (P < 0.05) above the control and placebo conditions following NaHCO3 ingestion.

Br J Sports Med. 1989 March; 23(1): 41–45.
Effect of sodium bicarbonate ingestion upon repeated sprints.
G Lavender and S R Bird
The purpose of the study was to assess the effect of sodium bicarbonate ingestion upon repeated bouts of intensive short duration exercise. Twenty-three subjects participated in the investigation (8 females and 15 males, age 21.4 +/- 2.3, mean +/- sd). Subjects completed six trials; three following the ingestion of sodium bicarbonate (300 mg/kg body weight) and three following the ingestion of a placebo (8 g sodium chloride). Each trial consisted of ten ten-second sprints on a cycle ergometer with 50 seconds recovery between each sprint. ‘Peak power’ and ‘average power output’ during each ten second sprint was measured from the flywheel of the ergometer using a light-sensitive monitor (Cranlea) linked to a BBC microcomputer. The power outputs recorded during each ten-second sprint of the bicarbonate trials were then compared with those recorded during the corresponding sprint of the placebo trials. The bicarbonate trials produced higher mean ‘average power’ outputs in all ten of the ten-second sprints, with the difference in ‘average power’ output being statistically significant in eight of these (p less than 0.05). The results also revealed that the difference in the ‘average power’ outputs attained during the bicarbonate and placebo trials increased as the number of sprint repetitions increased (p less than 0.01). ‘Peak power’ output was also greater in the bicarbonate trials with it being significantly higher (p less than 0.001) during the final ten-second sprint. It was concluded that during exercise consisting of repeated, short-duration sprints, power output was enhanced following the ingestion of sodium bicarbonate, (300 mg/kg body weight).

Boll Soc Ital Biol Sper. 1984 Mar 30;60(3):617-23.
[Acid-base equilibrium, blood lactic acid and pyruvic acid in albino rats after muscular exertion under conditions of normal oxygen, hypoxia and hypoxia-hypercapnia].
[Article in Italian]
Quatrini U, Licciardi A.
Albino rats of the Wistar family were subjected at three subsequent equal trials of muscular work: the first in normoxyc conditions; the second in hypoxic normobaric conditions; the third in hypoxic-hypercapnic normobaric conditions. The modifications of the lactacidemia, pyruvicemia and acid-base balance were greatest at the end of hypoxic trial. Added CO2 (2%) sensitively reduced the acidificant effects of the muscular work on the acid-base balance.

Rev Pneumol Clin. 1986;42(5):238-41.
Acid-base balance and blood lactate and pyruvate levels in albino rats bred under normobaric hypoxia or normoxia, after muscular work in a hypoxic or hypoxic-hypercapnic environment.
Quatrini U, Licciardi A.
Albino rats, Wistar family, have been raised since birth in normobaric hypoxic environment (10-12% O2). This hypoxic animal group and a normoxic animal group were subjected to muscular fatigue by forced march within revolving room. Normoxic animals were subjected to 3 spaced trials: in normoxic environment; in hypoxic normobaric environment; in the same hypoxic normobaric environment with about 2% CO2 added. Hypoxic animals were subjected to 2 spaced trials: in hypoxic normobaric environment; in the same hypoxic environment with about 2% CO2 added. At the end of every single trial, lactatemia, blood pyruvate, acid-base balance and the erythrocytic number were examined. Albino rats raised in hypoxic environment since birth, subjected to muscular work in hypoxic environment showed a smaller increase of lactatemia and a moderate variation of the acid-base balance, compared to normoxic animals in the same conditions. CO2 added to the respired hypoxic mixture during muscular work, attenuated in both animal groups, the observed modifications. Finally we found that the erythrocytes per mm3 of blood increased from the second drawing of blood.

Cor Vasa. 1981;23(5):359-65.
Heart rhythm disturbances in the inhabitants of mountainous regions.
Mirrakhimov MM, Meimanaliev TS.
The authors studied 513 males, permanently living in the high-mountain regions of Tian Shan and the Pamirs (2800 – 4000 m above sea level). A control group consisted of 404 males permanently living at low altitudes (780-900 m above sea level) in the Kemin District, Kirghiz SSR. The probands’ ages were 30-59 years. In all of them the resting electrocardiograms were recorded; 110 exercise tests were made in the high mountains, and 35 tests, at the low altitudes. The prevalence of heart rhythm disturbances was statistically significantly higher in the inhabitants of the high-mountain regions (12.1%) than in the low-altitude inhabitants (2.9%; p less than 0.0001). The most frequent disturbance was the 1st-degree a-v block (6 per cent). In the high mountains cardiac arrhythmias are usually associated with right ventricular hypertrophy, caused by high-altitude hypoxia. During exercise heart arrhythmias appeared conspicuously less frequently in the high mountain than in the low altitude inhabitants.

N Engl J Med. 1977 Mar 17;296(11):581-5.
Reduction in mortality from coronary heart disease in men residing at high altitude.
Mortimer EA Jr, Monson RR, MacMahon B.
In New Mexico, where inhabited areas vary from 914 to over 2135 m above sea level, we compared age-adjusted mortality rates for arteriosclerotic heart disease for white men and women for the years 1957-1970 in five sets of counties, grouped by altitude in 305-m (1000-foot) increments. The results show a serial decline in mortality from the lowest to the highest altitude for males but not for females. Mortality rates for males residing in the county groups higher than 1220 m in order of ascending altitude were 98, 90, 86 and 72 per cent of that for the county group below 1220-m altitude (P less than 0.0001). The results do not appear to be explained by artifacts in ascertainment, variations in ethnicity or urbanization. A possible explanation of the trend is that adjustment to residence at high altitude is incomplete and daily activities therefore represent greater exercise than when undertaken at lower altitudes.

J. Appl Physiol 1991 Apr;70(4):1720-30.
Metabolic and work efficiencies during exercise in Andean natives.
Hochachka PW, Stanley C, Matheson GO, McKenzie DC, Allen PS, Parkhouse WS
Maximum O2 and CO2 fluxes during exercise were less perturbed by hypoxia in Quechua natives from the Andes than in lowlanders. In exploring how this was achieved, we found that, for a given work rate, Quechua highlanders at 4,200 m accumulated substantially less lactate than lowlanders at sea level normoxia (approximately 5-7 vs. 10-14 mM) despite hypobaric hypoxia. This phenomenon, known as the lactate paradox, was entirely refractory to normoxia-hypoxia transitions. In lowlanders, the lactate paradox is an acclimation; however, in Quechuas, the lactate paradox is an expression of metabolic organization that did not deacclimate, at least over the 6-wk period of our study. Thus it was concluded that this metabolic organization is a developmentally or genetically fixed characteristic selected because of the efficiency advantage of aerobic metabolism (high ATP yield per mol of substrate metabolized) compared with anaerobic glycolysis. Measurements of respiratory quotient indicated preferential use of carbohydrate as fuel for muscle work, which is also advantageous in hypoxia because it maximizes the yield of ATP per mol of O2 consumed. Finally, minimizing the cost of muscle work was also reflected in energetic efficiency as classically defined (power output per metabolic power input); this was evident at all work rates but was most pronounced at submaximal work rates (efficiency approximately 1.5 times higher than in lowlander athletes). Because plots of power output vs. metabolic power input did not extrapolate to the origin, it was concluded 1) that exercise in both groups sustained a significant ATP expenditure not convertible to mechanical work but 2) that this expenditure was downregulated in Andean natives by thus far unexplained mechanisms.

J Appl Physiol. 1991 May;70(5):1963-76.
Skeletal muscle metabolism and work capacity: a 31P-NMR study of Andean natives and lowlanders.
Matheson GO, Allen PS, Ellinger DC, Hanstock CC, Gheorghiu D, McKenzie DC, Stanley C, Parkhouse WS, Hochachka PW.
Two metabolic features of altitude-adapted humans are the maximal O2 consumption (VO2max) paradox (higher work rates following acclimatization without increases in VO2max) and the lactate paradox (progressive reductions in muscle and blood lactate with exercise at increasing altitude). To assess underlying mechanisms, we studied six Andean Quechua Indians in La Raya, Peru (4,200 m) and at low altitude (less than 700 m) immediately upon arrival in Canada. The experimental strategy compared whole-body performance tests and single (calf) muscle work capacities in the Andeans with those in groups of sedentary, power-trained, and endurance-trained lowlanders. We used 31P nuclear magnetic resonance spectroscopy to monitor noninvasively changes in concentrations of phosphocreatine [( PCr]), [Pi], [ATP], [PCr]/[PCr] + creatine ([Cr]), [Pi]/[PCr] + [Cr], and pH in the gastrocnemius muscle of subjects exercising to fatigue. Our results indicate that the Andeans 1) are phenotypically unique with respect to measures of anaerobic and aerobic work capacity, 2) despite significantly lower anaerobic capacities, are capable of calf muscle work rates equal to those of highly trained power- and endurance-trained athletes, and 3) compared with endurance-trained athletes with significantly higher VO2max values and power-trained athletes with similar VO2max values, display, respectively, similar and reduced perturbation of all parameters related to the phosphorylation potential and to measurements of [Pi], [PCr], [ATP], and muscle pH derivable from nuclear magnetic resonance. Because the lactate paradox may be explained on the basis of tighter ATP demand-supplying coupling, we postulate that a similar mechanism may explain 1) the high calf muscle work capacities in the Andeans relative to measures of whole-body work capacity, 2) the VO2max paradox, and 3) anecdotal reports of exceptional work capacities in indigenous altitude natives.

Eur J Appl Physiol Occup Physiol. 1999 Jun;80(1):64-9.
Sodium bicarbonate can be used as an ergogenic aid in high-intensity, competitive cycle ergometry of 1 h duration.
McNaughton L, Dalton B, Palmer G.
The aim of this study was to determine whether a dose of 300-mg x kg(-1) body mass of sodium bicarbonate would effect a high-intensity, 1-h maximal cycle ergometer effort. Ten male, well-trained [maximum oxygen consumption 67.3 (3.3) ml x kg(-1) x min(-1), mean (SD)] volunteer cyclists acted as subjects. Each undertook either a control (C), placebo (P), or experimental (E) ride in a random, double-blind fashion on a modified, air-braked cycle ergometer, attached to a personal computer to which the work and power data was downloaded at 10 Hz. Fingertip blood was sampled at 10-min intervals throughout the exercise. Blood was also sampled at 1, 3, 5, and 10 min post-exercise. Blood was analysed for lactate, partial pressure of Carbon dioxide and oxygen, pH and plasma bicarbonate (HCO-) concentration. Randomly chosen pairs of subjects were asked to complete as much work as possible during the 60-min exercise periods in an openly competitive situation. The sodium bicarbonate had the desired effect of increasing blood HCO3- prior to the start of the test. The subjects in E completed 950.9 (81.1) kJ of work, which was significantly more (F(2,27) = 5.28, P < 0.01) than during either the C [835.5 (100.2) kJ] or P [839.0 (88.6) kJ] trials. No differences were seen in peak power or in the power:mass ratio between these three groups. The results of this study suggest that sodium bicarbonate may be used to offset the fatigue process during high-intensity, aerobic cycling lasting 60 min.

Med Sci Sports Exerc. 2003 Aug;35(8):1303-8.
Effects of sodium bicarbonate ingestion on prolonged intermittent exercise.
Price M, Moss P, Rance S.
PURPOSE:
The aim of this study was to determine the effects of sodium bicarbonate ingestion on prolonged intermittent exercise and performance.
METHODS:
Eight healthy male subjects (mean +/- SD: age 25.4 +/- 6.4 yr, mass 70.9 +/- 5.1 kg, height 179 +/- 7 cm, VO(2max) 4.21 +/- 0.51 L.min-1) volunteered for the study, which had received ethical approval. Subjects undertook two 30-min intermittent cycling trials (repeated 3-min blocks; 90 s at 40% VO(2max), 60 s at 60% VO(2max), 14-s maximal sprint, 16-s rest) after ingestion of either sodium bicarbonate (NaHCO(3); 0.3 g.kg-1) or sodium chloride (NaCl; 0.045 g x kg(-1). Expired air, blood lactate (BLa), bicarbonate (HCO(3)-), and pH were measured at rest, 30 and 60 min postingestion, and during the 40% VO(2max) component of exercise (4, 10, 16, and 29 min).
RESULTS:
After ingestion, pH increased from rest to 7.46 +/- 0.03 and 7.40 +/- 0.01 for NaHCO(3) and NaCl, respectively (main effect for time and trial; P < 0.05). Values decreased at 15 min of exercise to 7.30 +/- 0.07 and 7.21 +/- 0.06, respectively, remaining at similar levels until the end of exercise. BLa peaked at 15 min (12.03 +/- 4.31 and 10.00 +/- 2.58 mmol.L-1, for NaHCO(3) and NaCl, respectively; P > 0.05) remaining elevated until the end of exercise (P < 0.05). Peak power expressed relative to sprint 1 demonstrated a significant main effect between trials (P < 0.05). Sprint 2 increased by 11.5 +/- 5% and 1.8 +/- 9.5% for NaHCO(3) and NaCl, respectively. During NaHCO(3), sprint 8 remained similar to sprint 1 (0.2 +/- 17%), whereas a decrease was observed during NaCl (-10.0 +/- 16.0%).
CONCLUSION:
The results of this study suggest that ingestion of NaHCO(3) improves sprint performance during prolonged intermittent cycling.

Med Sci Sports Exerc. 2004 Jul;36(7):1239-43.
Effects of ingestion of bicarbonate, citrate, lactate, and chloride on sprint running.
Van Montfoort MC, Van Dieren L, Hopkins WG, Shearman JP.
PURPOSE:
Ingestion of sodium bicarbonate is known to enhance sprint performance, probably via increased buffering of intracellular acidity. The goal was to compare the effect of ingestion of sodium bicarbonate with that of other potential buffering agents (sodium citrate and sodium lactate) and of a placebo (sodium chloride) on sprinting.
METHODS:
In a double-blind randomized crossover trial, 15 competitive male endurance runners performed a run to exhaustion 90 min after ingestion of each of the agents in the same osmolar dose relative to body mass (3.6 mosmol x kg) on separate days. The agents were packed in gelatin capsules and ingested with 750 mL of water over 90 min. During each treatment we assayed serial finger-prick blood samples for lactate and bicarbonate. A familiarization trial was used to set a treadmill speed for each runner’s set of runs. We converted changes in run time between treatments into changes in a time trial of similar duration using the critical-power model, and we estimated likelihood of practical benefit using 0.5% as the smallest worthwhile change in time-trial performance.
RESULTS:
The mean run times to exhaustion for each treatment were: bicarbonate 82.3 s, lactate 80.2 s, citrate 78.2 s, and chloride 77.4 s. Relative to bicarbonate, the effects on equivalent time-trial time were lactate 1.0%, citrate 2.2%, and chloride 2.7% (90% likely limits +/- 2.1%). Ingested lactate and citrate both appeared to be converted to bicarbonate before the run. There were no substantial differences in gut discomfort between the buffer treatments.
CONCLUSION:
Bicarbonate is possibly more beneficial to sprint performance than lactate and probably more beneficial than citrate or chloride. We recommend ingestion of sodium bicarbonate to enhance sprint performance.

J Appl Physiol. 2006 Sep;101(3):918-25. Epub 2006 Apr 20.
Effects of chronic NaHCO3 ingestion during interval training on changes to muscle buffer capacity, metabolism, and short-term endurance performance.
Edge J, Bishop D, Goodman C.
This study determined the effects of altering the H(+) concentration during interval training, by ingesting NaHCO(3) (Alk-T) or a placebo (Pla-T), on changes in muscle buffer capacity (beta m), endurance performance, and muscle metabolites. Pre- and posttraining peak O(2) uptake (V(O2 peak)), lactate threshold (LT), and time to fatigue at 100% pretraining V(O2 peak) intensity were assessed in 16 recreationally active women. Subjects were matched on the LT, were randomly placed into the Alk-T (n = eight) or Pla-T (n = eight) groups, and performed 8 wk (3 days/wk) of six to twelve 2-min cycle intervals at 140-170% of their LT, ingesting NaHCO(3) or a placebo before each training session (work matched between groups). Both groups had improvements in beta m (19 vs. 9%; P < 0.05) and V(O2 peak) (22 vs. 17%; P < 0.05) after the training period, with no differences between groups. There was a significant correlation between pretraining beta m and percent change in beta m (r = -0.70, P < 0.05). There were greater improvements in both the LT (26 vs. 15%; P = 0.05) and time to fatigue (164 vs. 123%; P = 0.05) after Alk-T, compared with Pla-T. There were no changes to pre- or postexercise ATP, phosphocreatine, creatine, and intracellular lactate concentrations, or pH(i) after training. Our findings suggest that training intensity, rather than the accumulation of H(+) during training, may be more important to improvements in beta m. The group ingesting NaHCO(3) before each training session had larger improvements in the LT and endurance performance, possibly because of a reduced metabolic acidosis during training and a greater improvement in muscle oxidative capacity.

J Strength Cond Res. 2004 May;18(2):306-10.
Combined creatine and sodium bicarbonate supplementation enhances interval swimming.
Mero AA, Keskinen KL, Malvela MT, Sallinen JM.
This study examined the effect of simultaneous supplementation of creatine and sodium bicarbonate on consecutive maximal swims. Sixteen competitive male and female swimmers completed, in a randomized order, 2 different treatments (placebo and a combination of creatine and sodium bicarbonate) with 30 days of washout period between treatments in a double-blind crossover procedure. Both treatments consisted of placebo or creatine supplementation (20 g per day) in 6 days. In the morning of the seventh day, there was placebo or sodium bicarbonate supplementation (0.3 g per kg body weight) during 2 hours before a warm-up for 2 maximal 100-m freestyle swims that were performed with a passive recovery of 10 minutes in between. The first swims were similar, but the increase in time of the second versus the first 100-m swimming time was 0.9 seconds less (p < 0.05) in the combination group than in placebo. Mean blood pH was higher (p < 0.01-0.001) in the combination group than in placebo after supplementation on the test day. Mean blood pH decreased (p < 0.05) similarly during the swims in both groups. Mean blood lactate increased (p < 0.001) during the swims, but there were no differences in peak blood lactate between the combination group (14.9 +/- 0.9 mmol.L(-1)) and placebo (13.4 +/- 1.0 mmol.L(-1)). The data indicate that simultaneous supplementation of creatine and sodium bicarbonate enhances performance in consecutive maximal swims.

Int J Sport Nutr Exerc Metab. 2008 Apr;18(2):116-30.
Effects of sodium bicarbonate, caffeine, and their combination on repeated 200-m freestyle performance.
Pruscino CL, Ross ML, Gregory JR, Savage B, Flanagan TR.
The purpose of this study was to investigate the effects of sodium bicarbonate (NaHCO(3)), caffeine, and their combination on repeated 200-m freestyle performance. Six elite male freestyle swimmers ingested NaHCO(3) (0.3 g/kg; B), caffeine (6.2 +/- 0.3 mg/kg; C), a combination of both (B+C), and placebo (P) on 4 separate occasions before completing 2 maximal 200-m freestyle time trials (TT1 and TT2) separated by 30 min. No significant differences (p = .06) were observed for performance in TT1 (B 2:03.01 +/- 0:03.68 min, C 2:02.42 +/- 0:03.17 min, B+C 2:01.69 +/- 0:03.19 min, P 2:03.77 +/- 0:03.21 min) or TT2 (B 2:02.62 +/- 0:04.16 min, C 2:03.90 +/- 0:03.58 min, B+C 2:01.70 +/- 0:02.84 min, P 2:04.22 +/- 0:03.75 min). The drop-off in performance time from TT1 to TT2, however, was significantly greater when C was ingested than with B (-1.5%, p = .002) or B+C (-1.2%, p = .024). This is likely because of the lower blood pH and slower recovery of blood HCO(3) post-TT1 after C ingestion. These findings suggest that the ergogenic benefit of taking C alone for repeated 200-m swimming performance appears limited. When combined with NaHCO(3), however, its negative impact on repeated maximal exercise performance is reversed.

J Appl Physiol. 1977 Dec;43(6):959-64.
Effect of pH on cardiorespiratory and metabolic responses to exercise.
Jones NL, Sutton JR, Taylor R, Toews CJ.
Five male subjects performed exercise at 33, 66, and 95% of their maximum power output on three occasions in random order. Each study was preceded by a 3-h period in which capsules were taken by mouth, containing either CaCO3 (control, NH4Cl (acidosis), or NaHCO3 (alkalosis) in a dose of 0.3 g/kg body wt; preexercise blood pH was 7.38 +/- 0.015, 7.21 +/- 0.033, and 7.43 +/- 0.029, respectively. Exercise was continuous and maintained for 20 min at the two lower power outputs and for as long as possible at the highest. Compared with control (270 +/- 13 s), endurance time at the highest power output was reduced in acidosis (160 +/- 22 s) and increased in alkalosis (438 +/- 120 s). No differences were observed for central cardiovascular changes in exercise (cardiac output, frequency, or stroke volume). The respiratory changes expected from changes in blood pH were observed, with a higher alveolar ventilation in acidosis. At all power outputs arterialized venous lactate was lowest in acidosis and highest in alkalosis. Plasma glycerol and free fatty acids were lowest in acidosis. Changes in blood [HCO3-] and pH were shown to have major effects on metabolism in exercise which presumably were responsible for impaired endurance.

Int J Sport Nutr Exerc Metab. 2011 Jun;21(3):189-94.
Effect of sodium bicarbonate on [HCO3-], pH, and gastrointestinal symptoms.
Carr AJ, Slater GJ, Gore CJ, Dawson B, Burke LM.
CONTEXT:
Sodium bicarbonate (NaHCO₃) is often ingested at a dose of 0.3 g/kg body mass (BM), but ingestion protocols are inconsistent in terms of using solution or capsules, ingestion period, combining NaHCO₃ with sodium citrate (Na₃C₆H₅O₇), and coingested food and fluid.
PURPOSE:
To quantify the effect of ingesting 0.3 g/kg NaHCO₃ on blood pH, [HCO₃-], and gastrointestinal (GI) symptoms over the subsequent 3 hr using a range of ingestion protocols and, thus, to determine an optimal protocol.
METHODS:
In a crossover design, 13 physically active subjects undertook 8 NaHCO₃ experimental ingestion protocols and 1 placebo protocol. Capillary blood was taken every 30 min and analyzed for pH and [HCO₃-]. GI symptoms were quantified every 30 min via questionnaire. Statistics used were pairwise comparisons between protocols; differences were interpreted in relation to smallest worthwhile changes for each variable. A likelihood of >75% was a substantial change.
RESULTS:
[HCO₃-] and pH were substantially greater than in placebo for all other ingestion protocols at almost all time points. When NaHCO3 was coingested with food, the greatest [HCO₃-] (30.9 mmol/kg) and pH (7.49) and lowest incidence of GI symptoms were observed. The greatest incidence of GI side effects was observed 90 min after ingestion of 0.3 g/kg NaHCO₃ solution.
CONCLUSIONS:
The changes in pH and [HCO₃-] for the 8 NaHCO₃-ingestion protocols were similar, so an optimal protocol cannot be recommended. However, the results suggest that NaHCO₃ coingested with a high-carbohydrate meal should be taken 120-150 min before exercise to induce substantial blood alkalosis and reduce GI symptoms.

Strength & Conditioning Journal: August 2012 – Volume 34 – Issue 4 – p 21
Sodium Bicarbonate Supplementation: It’s Worth Another Chance
Koziris, Lymperis (Perry)
SUMMARY: THE BENEFIT TO RISK RATIO OF SODIUM BICARBONATE BUFFER PROTOCOLS MAY BE OPTIMIZED BY REDUCING THE RISK OF GASTROINTESTINAL SIDE EFFECTS. THIS CAN BE ACHIEVED BY COINGESTING A SMALL CARBOHYDRATE MEAL AND ALLOWING ENOUGH TIME FOR INITIAL SIDE EFFECTS TO DECLINE FROM THEIR PEAK.

J Strength Cond Res. 2012 Jul;26(7):1953-8. doi: 10.1519/JSC.0b013e3182392960.
Sodium bicarbonate supplementation and ingestion timing: does it matter?
Siegler JC, Marshall PW, Bray J, Towlson C.
Although a considerable amount of literature exists on the ergogenic potential of ingesting sodium bicarbonate (NaHCO3) before short-term, high-intensity exercise, very little exists on optimal loading times before exercise. The purpose of this study was to determine the influence of NaHCO3 supplementation timing on repeated sprint ability (RSA). Eight men completed 3 (randomized and counterbalanced) trials of ten 10-second sprints separated by 50 seconds of active recovery (1:5 work-to-rest) on a nonmotorized treadmill. Before each trial, the subjects ingested 0.3 g·kg(-1) body weight of NaHCO3 at 60 (H1), 120 (H2), or 180 (H3) minutes before exercise. Additionally, the subjects were assessed for any side effects (gastrointestinal [GI] discomfort) from the NaHCO3 ingestion via a visual analog scale (VAS). Blood buffering was assessed using a 2-way analysis of variance (ANOVA) with repeated measures, whereas repeated sprint performance and GI discomfort were assessed via a 1-way ANOVA with repeated measures. Blood-buffering capacity was not different at preexercise times (HCO3(-) [millimoles per liter] H1: 30.2 ± 0.4, H2: 30.9 ± 0.6, H3: 31.2 ± 0.6; p > 0.74). Average speed, average power, and total distance covered progressively declined over the 10 sprints; however, there was no difference between conditions (p > 0.22). The incidence of GI discomfort was significantly higher (p < 0.05) from preingestion at all time points with the exception of 180 minutes, whereas severity was only different between 90 and 180 minutes. Ingestion times (between 60 and 180 minutes) did not influence the blood buffering or the ergogenic potential of NaHCO3 as assessed by RSA. However, VAS scores indicated that at 180 minutes postingestion, an individual is less prone to experiencing significant GI discomfort.

Eur J Appl Physiol. 2013 Jan;113(1):127-34. doi: 10.1007/s00421-012-2419-4. Epub 2012 May 19.
The physiological stress response to high-intensity sprint exercise following the ingestion of sodium bicarbonate.
Peart DJ, Kirk RJ, Hillman AR, Madden LA, Siegler JC, Vince RV.
The purpose of this study was to investigate the effects of pre-exercise alkalosis on the physiological stress response to high-intensity exercise. Seven physically active males (age 22 ± 3 years, height 1.82 ± 0.06 m, mass 81.3 ± 8.4 kg and peak power output 300 ± 22 W) performed a repeated sprint cycle exercise following a dose of 0.3 g kg(-1) body mass of sodium bicarbonate (NaHCO(3)) (BICARB), or a placebo of 0.045 g kg(-1) body mass of sodium chloride (PLAC). Monocyte-expressed heat shock protein 72 (HSP72) and plasma thiobarbituric acid reactive substances (TBARS) were significantly attenuated in BICARB compared to PLAC (p = 0.04 and p = 0.039, respectively), however total anti-oxidant capacity, the ratio of oxidised to total glutathione, cortisol, interleukin 6 and interleukin 8 were not significantly induced by the exercise. In conclusion, monocyte-expressed HSP72 is significantly increased following high-intensity anaerobic exercise, and its attenuation following such exercise with the ingestion of NaHCO(3) is unlikely to be due to a decreased oxidative stress.

Sodium bicarbonate taken before strenuous exercise reduces the expression of heme oxygenase (Kirk, et al, 2012) and improves endurance. -Ray Peat, PhD

Amino Acids. 2013 Mar;44(3):903-10. doi: 10.1007/s00726-012-1419-3. Epub 2012 Oct 23.
The influence of exogenous carbohydrate provision and pre-exercise alkalosis on the heat shock protein response to prolonged interval cycling.
Peart DJ, Kirk RJ, Madden LA, Siegler JC, Vince RV.
The aim of this study was to observe the intracellular heat shock protein 72 (HSP72) and heme oxygenase-1 (HSP32) response to prolonged interval cycling following the ingestion of carbohydrates (CHO) and sodium bicarbonate (NaHCO(3)). Six recreationally active males (mean ± SD; age 23.2 ± 2.9 years, height 179.5 ± 5.5 cm, body mass 76.5 ± 6.8 kg, and peak power output 315 ± 36 W) volunteered to complete a 90 min interval cycling exercise on four occasions. The trials were completed in a random and blinded manner following ingestion of either: placebo and an artificial sweetener (P-P), NaHCO(3) and sweetener (B-P), placebo and CHO (P-CHO), and NaHCO(3) and CHO (B-CHO). Both HSP72 and HSP32 were significantly increased in monocytes and lymphocytes from 45 min post-exercise (p ≤ 0.039), with strong relationships between both cell types (HSP72, r = 0.83; HSP32, r = 0.89). Exogenous CHO had no influence on either HSP72 or HSP32, but the ingestion of NaHCO(3) significantly attenuated HSP32 in monocytes and lymphocytes (p ≤ 0.042). In conclusion, the intracellular stress protein response to 90 min interval exercise is closely related in monocytes and lymphocytes, and HSP32 appears to be attenuated with a pre-exercise alkalosis.

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By Team FPS – April 3, 2012

Fats and AGEs: PUFAs Are Even Worse than Fructose

Source

Olive oil is mostly monounsaturated fat.
Olive oil is mostly monounsaturated fat. (Photo by Splat Worldwide)
While the exact role AGEs play in aging is still unclear, it seems that reducing their accumulation in the body is a useful goal. And if for no other reason, how about being superficial: liver spots, for example, are a visible sign of AGEs in the skin. If you want to look youthful, glycation is not the way to go. 

The question of how to avoid AGEs has proven to be more difficult than one might think, however. If it was merely a matter of reducing the formation of advanced glycation end-products during cooking, we could just cook our foods at lower heat and use water instead of frying at high temperatures. But as we’ve seen, the AGEs we get directly from food may not be as important as the AGEs that form inside our body as a result of internal glycation.

The term ‘advanced glycation end-product’ is somewhat misleading in the sense that they are not formed only by glycation, which refers to glucose molecules binding to protein or lipid molecules, but also by fructation, which is essentially the same thing but this time with fructose. In fact, fructose is much more prone to form these products than glucose. Since there’s no such term as ‘advanced fructation end-product’, they’re also referred to as AGEs (other sugars like galactose go through a similar process too; more on that in another post).

To complicate this further, similar products are also formed during cooking when fats alone are exposed to high heat and air. This process is known as lipid peroxidation. The end results of lipid peroxidation are referred to as either AGEs or ALEs, short for advanced lipoxidation end-products. For the sake of simplicity, I will refer to all of them as AGEs, unless the difference is important.

So we now have several different ways to accumulate AGEs: eating cooked foods that contain sugars heated with protein or fats, eating uncooked foods that contain sugars, or eating oxidized fats. And, like glycation, lipid peroxidation can also happen endogenously. That is, even if the fats you eat do not contain any AGEs, they can still form AGEs inside the body if they are unstable and prone to oxidation.

The bad news is that not only does lipid peroxidation lead to AGEs, it appears to do so more rapidly than glycation does. CML, a product of the oxidative degradation of glycated protein anda common measure of AGE levels, is actually formed through the oxidation of arachidonic acid in much higher quantities than from glycation (link). CML is a handy way to compare things, because it can be formed through glycation, fructation or lipid peroxidation.

The reason you should keep your fish oil and flax seed oil in the fridge is precisely because they, like other highly unsaturated fats, are easily oxidized (link). Cooking with these oils is a really bad idea. Through lipid peroxidation, polyunsaturated fats or PUFAs are more prone to form AGEs. Below is a comparison of CML formation from three different fatty acids and glucose (link):

AGE formation from glucose and lipids
The left graph shows that arachidonic acid forms CML at about twice the rate as linoleic acid. The formation of CML from oleic acid is close to zero. Compared to glucose in the right graph, the two PUFAs here are at least 10 times as prone to AGE formation – very much like fructose, except that if you look at the fructose graphs, the 10-fold increase is not seen as early as it is in these graphs.

The explanation for the differences is that lipid peroxidation increases exponentially as a function of the number of double bonds (link), i.e. the degree of unsaturation. Arachidonic acid is a 20-carbon chain PUFA with four double bonds and linoleic acid is an 18-carbon chain PUFA with two double bonds. Oleic acid, like all MUFAs, has one double bond. Note that this equation makes the omega-3 fatty acids DHA and EPA (with their 6 and 5 double bonds, respectively) the worst offenders.

So oils high in PUFAs seem to have the ability to raise the AGE burden much more than glucose, or even fructose. This could potentially explain some of the differences in AGE levels between omnivores and vegetarians – maybe vegetarians eat more vegetable oils than omnivores, since glucose and fructose intakes alone are insufficient to explain the results. The authors of the paper state:

Oxidation of fatty acid is clearly a more efficient source of CML, despite the fact that the glucose is in solution throughout the course of the experiment, while the PUFA are only progressively solubilized. Further, after 6 days of incubation, a large fraction of the arachidonate was oxidized based on its solubilization in the aqueous phase, while less than 2% of the glucose is oxidized during this same time period.

In the same study, arachidonic acid produced more than 10 times the amount glyoxal than it did CML. Glyoxal is another inflammatory compound, which in food is created by heating unstable (i.e. polyunsaturated) oils to high temperatures but which, again, can also be formed inside the body. Some of this glyoxal goes on to form AGEs, but the rest that doesn’t isn’t exactly life elixir either.

Unfortunately, the problems don’t end with CML. Polyunsaturated fats also quite easily form other AGEs, such as malondialdehydelysine (MDA-lys) and carboxyethyllysine (CEL). Indeed, rats fed a diet high in PUFAs have over twice the level of MDA-lys in their brains compared to rats fed a diet high insaturated fat diet (link). Their levels of CEL and CML in the brain and MDA-lys in the liver are also significantly higher (although CEL and CML are lower in the liver). Unsurprisingly, MDA and CML deposits in the brain are implicated in Alzheimer’s disease (link).

As I mentioned before, simply avoiding cooking with oils rich in PUFAs is probably not enough, because exposing them to high heat and air in the frying pan isn’t the only thing that causes them to form AGEs. Reactive species such as radicals, transition metals, other electrophiles, and enzymes can also cause their oxidation inside the body (link).

In fact, it’s not certain based on the studies mentioned here just how bad food-derived ALEs are. Perhaps ALEs from food are less important than ALEs formed endogenously. Endogenous AGEs certainly appear to play a bigger role than exogenous AGEs, although consuming excess amounts of AGEs is probably not a good idea either.

Personally, I’m trying to limit both endogenous and exogenous AGEs and ALEs by avoiding cooking at high temperatures and using saturated fats for frying. Stay tuned for more posts on the issue. Meanwhile, see these posts on glycation and fats:

AGE Content of Foods
The 7 Types of Aging Damage That End up Killing You
Green Tea Reduces the Formation of AGEs
Should Saturated Fat Be Avoided in Low-Carb Diets?

 

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By Team FPS – April 3, 2012

“Curing” a High Metabolic Rate with Unsaturated Fats

Also see:
Fat Deficient Animals – Activity of Cytochrome Oxidase
Errors in Nutrition: Essential Fatty Acids
Thumbs Up: Fructose
Cardiolipin, Cytochrome Oxidase, Metabolism, & Aging
Medium Chain Fats from Saturated Fat – Weight Management Friendly
Toxicity of Stored PUFA
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Israeli Paradox: High Omega -6 Diet Promotes Disease
PUFA Accumulation & Aging
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)

Some of the discoveries listed in the studies below were made by the same researcher (George Burr) who discovered the “essential fatty acids.” With a different perspective, we can conclude that the “EFA” lower the metabolic rate of animals that are “deficient” in these fats.

The implications of this change in perspective is noteworthy. It points out the longevity depressing characteristics of “EFA” and also suggests their non essentiality since the “EFA” cured the skin disease of fat deficient rats only by lowering their metabolic rate and thus their exceedingly high nutritional requirements.

Through misinterpretation, we are poisoning ourselves with fats meant for lower temperatured organisms. Organisms with a high body temperature can consume saturated fats with no harmful side effects. The accumulation of unsaturated fats in the tissues of warm-blooded animals progressively lowers the metabolic rate, increases damage from the toxic form of oxidation (lipid peroxidation), damages the heart, lungs, and liver, promotes diabetes, cancer and immunosuppression, lowers our resistance to stress and shock, and harms development.

Also see this blog in relation to the “EFA’s” effect on cytochrome oxidase, a crucial respiratory enzyme.

Quotes by Ray Peat, PhD:
“The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzyme in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome oxidase.”

“Burr didn’t understand that it was his rats’ high sugar diet, freed of the anti-oxidative unsaturated fatty acids, that caused their extremely high metabolic rate, but since that time many experiments have made it clear that it is specifically the fructose component of sucrose that is protective against the antimetabolic fats.

Although Brown, et al., weren’t focusing on the biological effects of sugar, their results are important in the history of sugar research because their work was done before the culture had been influenced by the development of the lipid theory of heart disease, and the later idea that fructose is responsible for increasing the blood lipids.”

“By l950, then, it was established that unsaturated fats suppress the metabolic rate, apparently creating hypothyroidism. Over the next few decades, the exact mechanisms of that metabolic damage were studied. Unsaturated fats damage the mitochondria, partly by suppressing the repiratory enzyme, and partly by causing generalized oxidative damage. The more unsaturated the oils are, the more specifically they suppress tissue response to thyroid hormone, and transport of the hormone on the thyroid transport protein.”

“The choice of foods which have less unsaturated fat tends to reinforce the achievements of evolution.”

“The fetus produces saturated fats such as palmitic acid, and the monounsaturated fat, oleic acid, which can be turned into the Mead acid, ETrA (5,8,11-eicosatrienoic acid), and its derivatives, which are antiinflammatory, and some of which act on the “bliss receptor,” or the cannibinoid receptor.

At birth, the baby’s mitochondria contain a phospholipid, cardiolipin, containing palmitic acid, but as the baby eats foods containing polyunsaturated fatty acids, the palmitic acid in cardiolipin is replaced by the unsaturated fats. As the cardiolipin becomes more unsaturated, it becomes less stable, and less able to support the activity of the crucial respiratory enzyme, cytochrome oxidase.”

“The respiratory activity of the mitochondria declines as the polyunsaturated oils replace palmitic acid, and this change corresponds to the life-long decline of the person’s metabolic rate.”

Exp Biol Med May 1934 vol. 31 no. 8 911-912
METABOLISM STUDIES WITH EATS SUFFERING FROM FAT DEFICIENCY
GEORGE O. BURR AND A J. BEBER
…The results show clearly that fat-deficient rats are very different from stock animals and that fat-deficient rats which have been cured with small doses of fats return to a much more nearly normal gas exchange. The most marked differences shown by the fat-deficient rats are higher basal rate, higher specific dynamic action of food, and higher respiratory quotients. These results are of especial interest since the runs were made over long periods of time under normal conditions. The respiratory quotients of the fat-deficient rats remain above unity for as long as 12 hours out of 24. They, therefore, synthesize every day large amounts of fat, but this synthetic fat does not prevent the fat deficiency.

Summary
Fat-deficient rats may synthesize much fat each day as indicated by high respiratory quotients. The fat synthesized from carbohydrate does not contain appreciable quantities of the essential fatty acids since these must be added to the diet to prevent decline and death. Although much smaller, the rats have a higher metabolic rate than their controls. Consequently, they have a much higher rate calculated as calories per square meter of surface. A normal diurnal activity is shown for all groups, which is independent of light and food.

J. Biol. Chem., vol. 91, pp. 525-539.
The metabolic rate and respiratory quotients of rats on a fat-deficient diet.
WESSON, L. G., AND G. O. BURR 1931
1. The metabolic rate and respiratory quotients following a
carbohydrate test meal have been determined in the case of rats
maintained for some time on a fat-deficient diet, and are compared
with those obtained on normal rats and under approximately the
same conditions.
2. The respiratory quotients in the 1st hours following the
carbohydrate feeding are in many cases well above unity, definitely
indicating the formation of fat from carbohydrate by these rats in
various stages of the fat-deficiency disease.
3. The fact that no relief is obtained from the symptoms of the
fat-deficiency disease by the fat thus formed from carbohydrate
indicates that the curative linolic and linolenic acids are not
formed by the rat from the carbohydrate or from the fat.
4. The basal and assimilatory metabolic rate in the case of rats
showing the early symptoms of the fat-deficiency disease was well
above the normal value, while the metabolic rate in the later
stages of the disease was normal or subnormal.
5. The possible relationship of thyroid activity to several phases
of the fat-deficiency disease is discussed.

Additional sources portraying the high metabolic rate of animals of “EFA” deficient animals:
Arch Int Physiol Biochim. 1990 Aug;98(4):193-9.
Non-shivering thermogenesis and brown adipose tissue activity in essential fatty acid deficient rats.
Goubern M, Yazbeck J, Senault C, Portet R.
The effects of essential fatty acid (EFA) deficiency on energetic metabolism and interscapular brown adipose tissue (BAT) activity were examined in the cold acclimated rat. Weanling male Long-Evans rats were fed on a low fat semipurified diet (control diet, 2% sunflower oil; EFA deficient diet, 2% hydrogenated coconut oil) for 9 weeks. They were exposed at 5 degrees C for the last 5 weeks. In EFA deficient rats, compared to controls, growth retardation reached 22% at sacrifice. Caloric intake being the same in the two groups, it follows that food efficiency was decreased by 40%. Resting metabolism in relation to body surface area was 25% increased. Calorigenic effect of norepinephrine (NE) in vivo (test of non-shivering thermogenesis) underwent a marked decrease of 34%. BAT weight was 21% decreased but total and mitochondrial protein content showed no variation. A 26% increase in purine nucleotide binding per BAT (taken as an index of thermogenic activity) was observed, suggesting that the enhancement in resting metabolism observed was mainly due to increased BAT thermogenesis. However, BAT mitochondria respiratory studies which are more direct functional tests showed a marked impairment of maximal O2 consumption of about 30% with palmitoyl-carnitine or acetyl-carnitine (both in presence of malate) or with alpha-glycerophosphate as substrate. It is likely that this impaired maximal BAT oxidative capacity may explain the impaired NE calorigenic effect in vivo. A possible increase in mitochondrial basal permeability is also discussed.

J Nutr. 1988 May;118(5):627-32.
Effect of dietary linoleic acid and essential fatty acid deficiency on resting metabolism, nonshivering thermogenesis and brown adipose tissue in the rat.
Rafael J, Patzelt J, Elmadfa I.
Rats were fed a diet either deficient (0.05%) in essential fatty acids (EFA), or providing 4% (control) and 10% (surplus) of the total energy intake in the form of linoleic acid. All diets were isoenergetic and provided 13.9% of the energy as fat. The rats were kept at 29 or 5 degrees C. Growth and food intake of rats fed linoleic acid surplus at either temperature for 10 wk were not different from that of controls; basal metabolism, norepinephrine-induced nonshivering thermogenesis (NST) and thermogenic variables in the brown adipose tissue (amount of mitochondria and mitochondrial uncoupling protein) also were not different. The effects of EFA deficiency were drastically enhanced in the cold: After 10 wk of consuming a diet low in EFA at 5 degrees C, the body weight of rats was 75% of that of controls (87% at 29 degrees C); the food intake was 135% of controls at 5 degrees C (120% at 29 degrees C). The resting respiration in deficient rats was 125% of controls at 5 degrees C (110% at 29 degrees C); body temperatures as low as 35.1 degrees C were measured in deficient rats after 3 wk at 5 degrees C; the cold tolerance of the rats was significantly diminished (30% died within 3 wk at 5 degrees C), thus emphasizing the essential role of dietary EFA during cold stress. Norepinephrine-induced NST and the thermogenic parameters in brown fat were not influenced by EFA deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Comp Biochem Physiol A Comp Physiol. 1989;94(2):273-6.
The effects of essential fatty acid deficiency on brown adipose tissue activity in rats maintained at thermal neutrality.
Yazbeck J, Goubern M, Senault C, Chapey MF, Portet R.
1. The consequences of essential fatty acid (EFA) deficiency on the resting metabolism, food efficiency and brown adipose tissue (BAT) thermogenic activity were examined in rats maintained at thermal neutrality (28 C). 2. Weanling male Long-Evans rats were fed a hypolipidic semi-purified diet (control diet: 2% sunflower oil; EFA-deficient diet: 2% hydrogenated coconut oil) for 9 weeks. 3. They were kept at 28 C for the last 5 weeks. Compared to controls, in EFA-deficient rats the growth shortfall reached 21% at killing. 4. As food intake was the same in EFA-deficient and control rats, food efficiency was thus decreased by 40%. 5. Resting metabolism expressed per surface unit was 15% increased. 6. Non-renal water loss was increased by 88%. 7. BAT weight was 28% decreased but total and mitochondrial proteins were not modified. 8. Heat production capacity, tested by GDP binding per BAT was 69% increased in BAT of deficient rats. 9. The stimulation of BAT was established by two other tests: GDP inhibition of mitochondrial O2 consumption and swelling of mitochondria. 10. It is suggested that the observed enhancement of resting metabolism in EFA-deficient rats is, in part, due to an activation of heat production in BAT.

J Nutr. 1984 Feb;114(2):255-62.
The effect of essential fatty acid deficiency on basal respiration and function of liver mitochondria in rats.
Rafael J, Patzelt J, Schäfer H, Elmadfa I.
Rats were fed a diet poor (0.05%) in essential fatty acids (EFA) with hydrogenated coconut oil as fat component, or a control diet containing 4% of the total energy intake in the form of linoleic acid. Effects of dietary EFA deficiency were investigated during a period of 2-30 weeks. Growth retardation becomes significant after 4 weeks of deficiency and attains about 25% when the deficiency is maintained for longer than 12 weeks. Respiration, body weight and age of EFA-deficient rats and controls are in a nonlinear relationship. Basal respiration in relation to the body weight is significantly increased by EFA deficiency; it is unchanged when related to total animals under the employed experimental conditions. Oxidative phosphorylation in isolated liver mitochondria is unaffected by EFA deficiency, i.e., the increased metabolic rate of EFA-deficient rats, related to the body weight, cannot be explained from impaired functional integrity of the inner mitochondrial membrane. Respiratory chain enzyme activities in mitochondria from heart and skeletal muscle and specific amounts of mitochondria in these tissues are unchanged by EFA deficiency.

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By Team FPS – April 3, 2012

Fat Deficient Animals – Activity of Cytochrome Oxidase

Also see:
“Curing” a High Metabolic Rate with Unsaturated Fats
Cardiolipin, Cytochrome Oxidase, Metabolism, & Aging
Errors in Nutrition: Essential Fatty Acids
Thumbs Up: Fructose
PUFA Accumulation & Aging
Toxicity of Stored PUFA
Dietary PUFA Reflected in Human Subcutaneous Fat Tissue
Israeli Paradox: High Omega -6 Diet Promotes Disease
PUFA Accumulation & Aging
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)
Copper: The Forgotten Essential Nutrient

Quotes by Ray Peat, PhD:
“A crucial enzyme in the mitochondrion is cytochrome oxidase, which reacts directly with oxygen, completing (or beginning) the process of chemical respiration. It is this enzyme (which is most sensitive to cyanide) which appears to be a “choke point” for energy production in various situations. Learning how to preserve and promote the activity of this enzyme is an important issue for everything having to do with biological energy…Kunkel and Willians (J. Biol. Chem., 1951) found that the very high respiratory rate of animals fed a diet lacking polyunsaturated fats was caused primarily by a great increase in the activity of cytochrome oxidase, and that adding an “essential fatty acid” strongly inhibited this enzyme’s activity.”

“Burr didn’t understand that it was his rats’ high sugar diet, freed of the anti-oxidative unsaturated fatty acids, that caused their extremely high metabolic rate, but since that time many experiments have made it clear that it is specifically the fructose component of sucrose that is protective against the antimetabolic fats.

Although Brown, et al., weren’t focusing on the biological effects of sugar, their results are important in the history of sugar research because their work was done before the culture had been influenced by the development of the lipid theory of heart disease, and the later idea that fructose is responsible for increasing the blood lipids.”

“As early as 1951, it was known (Kunkel and Williams, J. BioI. Chern.) that the polyunsaturated fatty acids strongly inhibit the crucial respiratory enzyme, cytochrome oxidase, and that inhibition of this enzyme has a very important effect on the whole animal suppressing its metabolic rate, reducing the number of calories it can burn. It is now known that polyunsaturated fats interfere with thyroid hormone in just about every conceivable way.”

“Cytochrome oxidase is one of the enzymes damaged by stress and by blue light, and activated or restored by red light, thyroid, and progesterone.”

“A crucial enzyme in the mitochondrion is cytochrome oxidase, which reacts directly with oxygen, completing (or beginning) the process of chemical respiration. It is this enzyme (which is most sensitive to cyanide) which appears to be a “choke point” for energy production in various situations. Learning how to preserve and promote the activity of this enzyme is an important issue for everything having to do with biological energy.”

“The suppressive effects of unsaturated fats on mitochondrial energy production have been widely investigated, since it is that effect that makes animal fattening with PUFA so economical. Rather than interpreting that as a toxic effect, using the innate structure and function of the mitochondrion as a point of reference from which to evaluate dietary components, the consumption of “good” oils is being used as the reference point from which to evaluate the meaning of metabolism (“efficiency is good,” “low oxygen consumption is good”). Building on the idea that the oils are health-promoters which increase metabolic efficiency, the never-viable “rate of aging” theory was resuscitated: The anti-respiratory effect of PUFA is used (illogically) to return to the idea that aging occurs in proportion to the amount of oxygen consumed, because animals which lack the supposedly essential nutrients (“defective animals”) consume oxygen rapidly–burning calories rapidly, they are supposed to be like a candle that won’t last as long if it burns intensely. The old theory is simply resuscitated to explain why the anti-respiratory action of PUFA might be beneficial, justifying further promotion of their use as food and drugs.”

“The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzymes in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome c oxidase.

The enzyme is dependent on the thyroid hormone is inhibited by nitric oxide, carbon monoxide, estrogen, polyunsaturated fatty acids, serotonin, excess or free iron, ionizing radiation, and many toxins, including bacterial endotoxin. Red light, which passes easily through the tissues, reactivates the enzyme, which slowly loses its function during darkness.”

“When mitochondria are functioning fully, either glucose or saturated fats can safely
provide energy. Some glucose or saturated fat can be converted to polyunsaturated fats, that can be used as regulators or signals, for example to activate the formation of stem cells. But those PUFA don’t create disruptive cascades of increasing excitation or inflammation or excessive growth, and, from the evidence of animals that are fed fat free diets, or diets lacking omega -3 and omega -6 fatty acids, they aren’t toxic to mitochondria.”

“Increased estrogen exposure, decreased thyroid hormone, an increased ratio of iron to copper, and lack of light, are other factors that impair the cytochrome oxidase enzyme.”


Source: Danny Roddy

J Biol Chem. 1951 Apr;189(2):755-61.
The effects of fat deficiency upon enzyme activity in the rat.
KUNKEL HO, WILLIAMS JN Jr.
The activity of the cytochrome oxidase, however, is markedly increased in fat deficiency…In each case the activity of livers from rats fed the basal diet was 38 per cent greater than from the linoleate-supplemented animals or from the animals receiving corn oil. This is particularly interesting in view of the observation of Burr and Beeber (8) and Wesson and Burr (9) that fat-deficient rats had a markedly increased metabolic rate. The latter authors reported that the basal and assimilatory metabolic rates of fat-deficient animals were 25 per cent greater than the rates of the control animals. Thus the liver cytochrome oxidase activity appears to parallel the metabolic rate in fat deficiency. This increased cytochrome oxidase activity in liver and perhaps other tissues may account in a large part for the increased metabolic rate.

Summary
A fat deficiency in the rat causes a marked increase in liver cytochrome oxidase activity, a slight increase in choline oxidase activity, and a marked decrease in endogenous respiration. The activity of the succinic oxidase system is not altered by this deficiency condition. Supplementation with 100 mg. of methyl linoleate per rat per day reduced the cytochrome oxidase to the level of that produced by a 5 percent corn oil diet.

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By Team FPS – April 3, 2012