|A Peek Inside|
|How To Order|
|Illnesses and Conditions|
of Pharma Drugs
|Zulma Nonfiction Novel|
Don’t Be Conned
By The Resveratrol Scam
by Dr Raymond Peat
A year ago GlaxoSmithKline bought Sirtris, a company focusing on the biological effects of resveratrol, for $720,000,000. Harvard Medical School’s website, and broadcasts by Barbara Walters and Morley Safer have publicized resveratrol as a longevity-increasing drug, and millions of people are spending large amounts of money for resveratrol capsules.
The main claim being made about resveratrol is that it can mimic the anti-aging effects of calorie restriction, without having to restrict food consumption. This involves silencing genes, blocking their production of RNA and protein.
The mass media and some medical journals aren’t giving a balanced description of the biological effects of resveratrol, but many biologists are being influenced too, by the same simple arguments that the television reporters summarized. The academic biology culture, the medical culture, and the basic American culture itself, are all permeated by the idea of genetic determinism, so when a DNA molecule in yeast is identified as the “anti-aging gene,” and a molecule is found that activates it, that molecule, or something similar, seems to them clearly to be an anti-aging drug.
Part of the cultural framework that makes it easy to sell that idea is the old “rate of living” theory of aging, the idea that we have only so many heartbeats in a lifetime, that we can use only so many calories and so much oxygen in a lifetime, and that organisms with a low metabolic rate therefore live longer than those with a high metabolic rate. The rate of living theory is closely related to the “wear and tear” theory of aging, that our bodies are (except for our germ cells) made up of “post-mitotic cells,” unable to continue dividing once growth is complete, and so must die when those cells are “worn out.” By the middle of the 20th century, those ideas had been disproved in many ways, but in the 1960s Leonard Hayflick renewed for a time the doctrine of aging as the wearing out of unrenewable cells, with his doctrine that somatic cells (non-germ cells) have an absolute limit of 50 replications. Producing cloned animals from somatic cells, and the subsequent excitement about stem cells, made that theory obsolete (again).
The “longevity gene,” named Sir2 in yeasts, worms, and flies (its equivalent in mammals is called SirT1), is activated by restricting calories, and caloric restriction is known to extend lifespan (though the restriction of certain nutrients can similarly increase longevity, without restricting calories). Both semi-starvation and increased activity of the Sir2 gene can prevent obesity, and obesity has some harmful effects. The promoters of the theory suggest that a resveratrol-like drug will be able to prevent obesity and cure type-2 diabetes. They are also suggesting that it could slow aging and increase longevity.
Talking about the “aging” of a single-celled organism such as yeast, and drawing conclusions about the aging of multicellular organisms and humans, from events in the life of yeast, is meaningful only to people who subscribe to the Hayflick doctrine, and who deny the reality of stem cells in mammals and other complex organisms. They are actually talking about the “fertility,” the reproductive growth capacity, of the yeasts. The study of yeast metabolism and growth developed mostly in relation to the needs of the wine and beer industries, and that has biased ideas about the ways yeast adapts to changing ecosystems. Yeasts adapt their reproductive strategy to the perceived adequacy of their environment. An individual yeast cell coordinates its physiology with the surrounding cells, in ways analogous to the ways individual cells in an animal participate in the coherence of the organism.
As in higher organisms, stress can accelerate the reproductive process in yeast. In animals, stress can cause precocious puberty, as if they were being exposed to an excess of estrogen. Resveratrol is a defensive fungicidal antibiotic, or phytoalexin, so it’s reasonable that it would be perceived as a stressor by yeast. It is also a phytoestrogen, and for many years yeasts have been known to be responsive to estrogenic substances. To the brewing industry, these effects of phytoestrogens are known to influence the biomass, but when the rate of growth is considered to represent aging, then increased biomass is equivalent to increased longevity.
Anyone familiar with the last 40 years of yeast research would presumably know that phenolic phytoalexins are estrogenic, and that the growth of yeast is influenced by estrogenic substances, and also that estrogenic substances such as resveratrol could be very dangerous if consumed in exaggeratedly large amounts.
Resveratrol is a stilbene, similar in structure to diethylstilbestrol, DES, the famously toxic-carcinogenic pharmaceutical. Estrogens affect all of the systems affected by resveratrol, and for 67 years, the estrogen industry has been telling the public that whatever estrogen does is beneficial---more than 200 medical conditions have been benefited by estrogen treatment, according to the medical literature/pharmaceutical advertising.
Many people have been asserting that the reason calorie restriction can extend life is that it activates “the antiaging gene, Sir2.” A recent publication (Carrano, et al., 2009) from the Salk institute proposes that two other genes are responsible for calorie-restriction longevity in the roundworm, C. elegans.
But restricting calories has a multitude of effects--Sir2 is only one of hundreds of genes that function differently in hunger-stressed animals. Calorie restriction is stressful, but the nature of that stress and the response to it depends on the whole situation, just as in any other challenging situation.
One problem with the Sirtris scheme is that increased Sir2 activity shortens the actual chronological lifespan of non-dividing yeast (Kennedy, et al., 2005; Fabrizio, et al., 2005). In animals, increasing the activity of SirT1 might contribute to the development of cancer (Liu, et al., 2009). It might also be involved in Alzheimer’s disease, and the replacement of nerve cells in the brain with astrocytes or other glial cells. Gliosis can occur in normal aging, but inflammation can produce extreme degrees of fibrosis of the brain or spongy encephalopathy. Estrogens also have this effect of accelerating stem cell production of glial cells.
In a recent study, to determine whether resveratrol would slow the heart rate and lower the body temperature in mice (as expected according to the rate of aging doctrine), those metabolic indicators were depressed by resveratrol for one day, but then returned to normal. However, the endurance of the mice on a treadmill was reduced by the resveratrol treatment (Mayers, et al., 2009).
Going beyond the Sir2 gene-based argument, many researchers have examined resveratrol’s effects on various other genes. Too often, it seems that the authors reason that whatever resveratrol does to those genes must be good for the organism. These arguments seem to be following the reasoning that has been systematically used to promote estrogen and polyunsaturated fats.
If we consider the effects of resveratrol in the context of the well established facts about the metabolic processes associated with long life, we will notice many things that should lead to skepticism about the claims being made by the advertisers.
A little stress can make an organism more resistant to subsequent stresses. However, resveratrol fails to extend the lifespan of normal mice, being effective only in a strain of mice that becomes abnormally fat on a normal diet.
About 40 years ago, when people first began promoting fish oil as a longevity factor, Alex Comfort watched the rats that were being given the fish oil in their food. The food smelled bad, and the rats ate it only when they were very hungry, so they ate less and were leaner than the animals that were getting the standard diet. Their increased longevity was the result of avoiding obesity.
In a long-term study at NIH, rhesus monkeys are being studied to learn whether calorie restriction extends the lifespan of primates, as it does certain (genetically fat) rodents. The monkeys are kept in small cages. Confinement causes severe stress. Rats that are allowed to bite something while restrained suffer less physical stress, fewer ulcers, and are more able to maintain normal body temperature. Restraint normally lowers body temperature, lowering thyroid and increasing cortisol.
Eating in response to stress ameliorates some of the hormonal changes, but the monkeys that are permitted to eat as much as they want during their life of confinement have become very obese. They look much less agitated than the low calorie monkeys, and their body temperatures are higher.
The rate-of-living doctrine causes the researchers to reason that the low-calorie diet is slowing the rate of aging by lowering their body temperature. However, their metabolic rate, per gram of non-fat tissue, hasn’t decreased.
An important difference that has been observed is that the chromosomes of the calorie deprived monkeys have more defects.
Nitric oxide, which is promoted by resveratrol, according to numerous publications (Klinge, et al., 2008; Gresele, et al. 2008; Gan, et al., 2009), and estrogens (acting partly through nitric oxide), including some phytoestrogens, causes chromosomal damage (Banerjee and Banerjee, 1994; Kulling, et al., 1999) which contributes to cancer and possibly to birth defects. Nitric oxide has been proposed to be a major factor in causing the degenerative diseases of aging.
If these monkey experiments have any relevance to human biology, it is to demonstrate that prolonged torture by confinement and food restriction causes bodily damage, in the form of chromosomal abnormalities. But unless the next generation of monkeys is examined for birth defects and other problems, the full meaning of the experiment won’t be apparent.
In some of the publications claiming that resveratrol increases lifespan, it was reported that niacinamide had the opposite effect, suppressing Sir2, the longevity gene, and shortening the organism’s lifespan. To put their claims into context, it’s helpful to look at a variety of experiments involving treatment with niacinamide.
It protects nerves, vascular cells, insulin-producing cells in the pancreas, and a variety of other types of cell from cell death produced by lack of oxygen, excitotoxicity, endotoxin, and a variety of stressors and toxins. (Niacinamide acts in many ways as a negation of resveratrol; for example, resveratrol interferes with the ability of the beta cells to secrete insulin [Szkudelski, 2007]).
Niacinamide protects mitochondrial respiration from many of the age-related factors that can damage mitochondria and decrease energy production. Lipopolysaccharide, the bacterial endotoxin, increases the production of the free radical nitric oxide, leading to the secretion of inflammatory mediators and the suppression of energy production by the mitochondria. These effects are blocked by niacinamide (Fukuzawa, et al., 1997). Calorie restriction also protects mitochondrial respiration, in yeasts (Lin, et al., 2002) and rats (Broderick, et al., 2002)
The “replicative lifespan” of human cells in vitro is extended by treatment with niacinamide (Kang, et al., 2006).
In an experiment with human keratinocytes in vitro, resveratrol had the opposite effect, reducing their ability to divide (Blander, et al., 2009). By the definitions of “aging” used by the advocates of the rate-of-living theory, this experiment suggests that resveratrol causes premature aging. Estrogen has a similar effect on keratinocytes. Resveratrol, nitric oxide, and estrogen, unlike niacinamide, suppress mitochondrial respiration. Resveratrol inhibits the formation of progesterone (Chen, et al., 2007), which is synthesized in mitochondria.
The NIH researchers reported that the food deprived monkeys (contrary to their expectation) didn’t have a lower rate of metabolism, but many experiments done with a variety of very different animals through much of the last century found that a higher metabolic rate corresponded to increased longevity. Within a given species of bird or mammal, the higher rate of metabolism is often associated with a higher body temperature,
But when different types of animal of very different sizes are compared, smaller animals may have a higher rate of metabolism, but a shorter lifespan, than a larger animal, as in the case of mice and elephants. This example was used recently by an endocrinologist, Martin Surks, to argue against treating “subclinical hypothyroidism.” He suggests that hypothyroid people, who have a lower rate of metabolism than euthyroid people, are likely to live longer, because their metabolism is analogous to the slow metabolism of elephants, rather than the fast metabolism of mice.
Comparing animals of different species, such as birds, monkeys, and rodents, of similar sizes, those with the highest metabolic rate are likely to have the longest average and maximum lifespans.
The smaller an organism is, the more easily it loses heat to the environment. Most of a mouse’s metabolic energy is spent simply maintaining its body temperature. Large animals have less surface area in proportion to their mass, so they spend relatively little energy in temperature regulation.
One of the ideas deeply associated with the rate-of-living theory of aging is that our metabolic energy is spent mainly for regulating the concentration of salts and other substances in cells, with a small amount used for secretion, movement, and--a relatively recent admission--for thought.
Gilbert Ling has demonstrated the falsity of the idea that “membrane pumps” regulate the concentratons of dissolved materials, and showed that the amount of energy needed to operate them constantly is much greater than the metabolic capacity of any organism.
The fact that those “membrane-based” energy consuming processes don’t exist leaves a lot of energy to be accounted for. One of the main energy-consuming activities of a cell is just being alive, that is, adapting, sensing, responding, anticipating, orienting itself to its environment. Except in very special circumstances, the substance of a cell is in constant motion, and the molecules are being consumed and reconstructed, in a process of continuous renewal. These intracellular streams of renewal of molecules and organelles are paralleled on the scale of tissues and organs by a process of renewal, in which new cells are born and unnecessary cells are dissolved.
Part of the “rate of living” relates to the rate of renewal of the organism. Another part relates to issues such as the loss of heat, that makes life shorter and harder for very small animals.
The end product of respiration is carbon dioxide, and it is an essential component of the life process. The ability to produce and retain enough carbon dioxide is as important for longevity as the ability to conserve enough heat to allow chemical reactions to occur as needed.
Carbon dioxide protects cells in many ways. By bonding to amino groups, it can inhibit the glycation of proteins during oxidative stress, and it can limit the formation of free radicals in the blood; inhibition of xanthine oxidase is one mechanism (Shibata, et al., 1998). It can reduce inflammation caused by endotoxin/LPS, by lowering the formation of tumor necrosis factor, IL-8 and other promoters of inflammation (Shimotakahara, et al., 2008). It protects mitochondria (Lavani, et al., 2007), maintaining (or even increasing) their ability to respire during stress.
The “replicative lifespan” of a cell can be shortened by factors like resveratrol or estrogen that interfere with mitochondrial production of carbon dioxide. Both of those chemicals cause skin cells, keratinocytes, to stop dividing, to take up calcium, and to begin producing the horny material keratin, that allows superficial skin cells to form an effective barrier. This process normally occurs as these cells differentiate from the basal (stem) cells and, by multiplying, move farther outward away from the underlying blood vessels that provide the nutrients that are oxidized to form carbon dioxide, and as they get farther from the blood supply, they get closer to the external air, which contains less than 1% as much CO2 as the blood. This normally causes their eventual hardening into the keratin cells, but when conditions are optimal, numerous layers of moist, translucent cells that give the skin the characteristic appearance of youth, will be retained between the basal cells and the condensed surface layers. (Wilke, et al., 1988)
In other types of tissue, a high level of carbon dioxide has a similar stabilizing effect on cells, preserving stem cells, limiting stress and preventing loss of function. In the lining of the mouth, where the oxygen tension is lower, and carbon dioxide higher, the cells don’t form as much keratin as the skin cells do. In the uterus, the lining cells would behave similarly, except that estrogen stimulates keratinization. A vitamin A deficiency mimics an estrogen excess, and can cause excessive keratinization of membrane cells.
Yeasts adapt their physiology and life cycle to their particular ecological situation. The cells within an animal behave analogously, but that is likely to be forgotten or denied, because of the culture of genetic determinism.
The cells in each organ and tissue of the body are arranged in ways that allow them to make their contribution to the function of the organism, while receiving oxygen, glucose, and regulatory substances in the blood, and maintaining and renewing themselves. Except for the skin, their situation amid other cells assures that they will live in a high concentration of carbon dioxide.
There are proteins (uncoupling proteins, UCP) that cause the mitochondria to increase their consumption of oxygen without increasing their synthesis of ATP. The synthesis of ATP is usually thought of as the main reason for the consumption of oxygen, so the UCP have been assumed to exist to increase heat production. The formation of carbon dioxide is usually thought of as just an unavoidable consequence. UCP proteins, however, exist in situations in which heat production doesn’t seem appropriate (Borecký & Vercesi, 2005; Aguilera, et al., 2005; Gnanalingham, et al., 2005). For example, fasting or calorie restriction increases UCP, tending to cause tissues to consume energy more rapidly. Stress and hypoxia also can increase UCP, suggesting that these enzymes have protective functions.
Increasing the formation of carbon dioxide seems to me to be the essential function of the UCP. Thyroid hormone (T3) increases UCP, and UCP increases the formation of new mitochondria. Increased activity of the UCP is closely associated with increased lifespan. A decreased amount of T3 in tissues during aging corresponds to decreasing mitochondrial functon.
Increased CO2 inhibits the formation of lactate, decreases the lipolytic effect of adrenaline, and the lowered energy charge produced by the UCP would prevent the diversion of glucose into other uses.
According to the rate-of-living theory of aging, the “post-mitotic” organism ages and degenerates in proportion to the rate at which it metabolizes. Leonard Hayflick, to demonstrate that it is cell division, not the passage of time, that ages cells, put some cells in a freezer, while others, from the same batch, were kept in a warm incubator and allowed to go through their allotted number of divisions. When the warm, growing cells had approached 50 replications and began dying “of old age,” the other cells were taken out of the freezer, and they were able to divide as well as they had before being frozen. The implication was that slowing metabolism was the only way to extend the lifespan.
These beliefs have allowed people to view the metabolism, the turnover of substance and cells, of a tissue such as bone, as indicating breakdown, weakening, and loss. For many years, it was impossible to show any beneficial effect of estrogen on the bones of experimental animals or people, but then it was discovered that it could slow the metabolism of the osteoclasts, reducing the rate of turnover in the bones. This was propagandistically effective.
The estrogen industry’s funding greatly reinforced the rate-of-living theory of aging, and metabolic markers of bone turnover began to be used to measure the effects of treatment. Thyroid hormone (the active T3 hormone) increases the rate of turnover of all tissues, including bone, so by reference to the “bone protective effects of estrogen,” the argument was made that thyroid supplementation should be reduced, to prevent osteoporosis (despite animal studies showing that T3 increases bone development). Since hypothyroidism usually involves increased thyroid stimulating hormone, TSH, the argument was extended by showing that TSH lowers bone turnover.
One factor involved in the increased production of TSH in hypothyroidism is that the low metabolic rate allows estrogen to accumulate, leading to increased serotonin production. Serotonin stimulates both TSH and prolactin. Serotonin and prolactin both happen to cause bone loss. They increase nitric oxide, which inhibits mitochondrial respiration. Serotonin increases a cytokine, osteoprotegerin, that inhibits osteoclasts, reducing bone turnover. However, serotonin’s other antimetabolic effects outweigh that effect, and it is a major factor in causing osteoporosis. The antimetabolic factors that slow the rate of living also slow the rate of renewal, and on balance lead to tissue atrophy, fibrosis, inflammation, and degeneration. Several decades after estrogen-induced prolactin might have been recognized as a cause of bone loss in aging, a few people are mentioning the mechanism in specific situations (Horner, 2009; Horner, et al., 2007).
With aging, metabolic activity and the turnover of biological substance decrease. Organelles such as mitochondria are renewed every day or two, much of the brain substance has a similarly fast rate of turnover, and other parts of the body are renewed more slowly. When conditions are optimal, the new structures are flawless, but under the wrong conditions, faulty repairs can accumulate, producing the degenerative problems of aging.
Our culture’s understanding of biology has been shaped by a series of ideologies, and currently the drug industry is the main force shaping those ideologies, creating an attitude that’s receptive to their products.
The huge marketing campaign for resveratrol will have direct effects on people’s health, probably extending beyond the generation that uses it, but it is also polluting the culture by reinforcing the doctrine that torpor, slowing the life process, is beneficial.
FEMS Yeast Res. 2005 Apr;5(6-7):579-93. Physiological and genome-wide transcriptional responses of Saccharomyces cerevisiae to high carbon dioxide concentrations. Aguilera J, Petit T, de Winde JH, Pronk JT.
Eur J Appl Physiol. 2006 May;97(2):210-5. Increased expired NO and roles of CO2 and endogenous NO after venous gas embolism in rabbits. Agvald P, Adding LC, Nilsson KF, Gustafsson LE, Linnarsson D.
Nat Rev Neurosci. 2005 Nov;6(11):829-40. Mitochondrial uncoupling proteins in the CNS: in support of function and survival. Andrews ZB, Diano S, Horvath TL. “Recent evidence indicates that UCP family proteins are also present in selected neurons , . .”
Mutat Res. 1994 Dec 1;311(2):191-7. Induction of chromosome aberrations in Syrian hamster renal cortical cells by various estrogens. Banerjee SK, Banerjee S, Li SA, Li JJ.
J Invest Dermatol. 2009 Jan;129(1):41-9. Epub 2008 Jun 19. SIRT1 promotes differentiation of normal human keratinocytes. Blander G, Bhimavarapu A, Mammone T, Maes D, Elliston K, Reich C, Matsui MS, Guarente L, Loureiro JJ.
FASEB J. 2001 Jan;15(1):13-15. Triiodothyronine-mediated up-regulation of UCP2 and UCP3 mRNA expression in human skeletal muscle without coordinated induction of mitochondrial respiratory chain genes. Barbe P, Larrouy D, Boulanger C, Chevillotte E, Viguerie N, Thalamas C, Oliva Trastoy M, Roques M, Vidal H, Langin D.
Biosci Rep. 2005 Jun-Aug;25(3-4):271-86. Plant uncoupling mitochondrial protein and alternative oxidase: energy metabolism and stress. Borecký J, Vercesi AE.
Free Radic Res. 2009 Mar;43(3):206-13. Serotonin binds to purified neuronal nitric oxide synthase: a possible explanation for ROS production induced by 5HT in the presence of nNOS. Bréard M, Grillon C.
Mol Cell Biochem. 2002 Apr;233(1-2):119-25. Effects of chronic caloric restriction on mitochondrial respiration in the ischemic reperfused rat heart. Broderick TL, Belke T, Driedzic WR.
Biogerontology. 2004;5(4):211-22. Ageing studies on bats: a review. Brunet-Rossinni AK, Austad SN.
Mech Ageing Dev. 2004 Jan;125(1):11-20. Reduced free-radical production and extreme longevity in the little brown bat (Myotis lucifugus) versus two non-flying mammals. Brunet-Rossinni AK.
Brain Res Bull. 2005 Apr 15;65(3):219-23. Effects of dietary phytoestrogens on core body temperature during the estrous cycle and pregnancy. Bu LH, Lephart ED.
Vascul Pharmacol. 2006 Apr;44(4):231-7. Epub 2006 Feb 10. Resveratrol decreases calcium sensitivity of vascular smooth muscle and enhances cytosolic calcium increase in endothelium. Buluc M, Demirel-Yilmaz E.
Mol Nutr Food Res. 2005 May;49(5):396-404. Trans- and cis-resveratrol increase cytoplasmic calcium levels in A7r5 vascular smooth muscle cells. Campos-Toimil M, Elíes J, Orallo F.
Salk Institute (2009, June 24) ScienceDaily. Retrieved June 24, 2009, from http://www.sciencedaily.com. Why A Low Calorie Diet Extends Lifespans: Critical Enzyme Pair Identified. Carrano AC, Dillon A, Hunter T.
J Endocrinol. 2007 Mar;192(3):527-37. Effects of genistein, resveratrol, and quercetin on steroidogenesis and proliferation of MA-10 mouse Leydig tumor cells. Chen YC, Nagpal ML, Stocco DM, Lin T.
J Leukoc Biol. 2002 Apr;71(4):603-10. Ambient pCO2 modulates intracellular pH, intracellular oxidant generation, and interleukin-8 secretion in human neutrophils. Coakley RJ, Taggart C, Greene C, McElvaney NG, O'Neill SJ.
Am J Physiol Regul Integr Comp Physiol. 2000 Dec;279(6):R2048-56. Anticipatory changes in liver metabolism and entrainment of insulin, glucagon, and corticosterone in food-restricted rats. Díaz-Muñoz M, Vázquez-Martínez O, Aguilar-Roblero R, Escobar C.
Cell. 2005 Nov 18;123(4):655-67. Sir2 blocks extreme life-span extension. Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, McGrew K, Longo VD.
J Cell Biol. 2004 Sep 27;166(7):1055-67. Superoxide is a mediator of an altruistic aging program in Saccharomyces Cerevisiae. Fabrizio P, Battistella L, Vardavas R, Gattazzo C, Liou LL, Diaspro A, Dossen JW, Gralla EB, Longo VD.
Immunol Lett. 1997 Oct;59(1):7-11. Inhibitory effect of nicotinamide on in vitro and in vivo production of tumor necrosis factor-alpha. Fukuzawa M, Satoh J, Muto G, Muto Y, Nishimura S, Miyaguchi S, Qiang XL, Toyota T.
Hypertens Res. 2009 May 15. Improvement of neovascularization capacity of bone marrow mononuclear cells from diabetic mice by ex vivo pretreatment with resveratrol. Gan L, Matsuura H, Ichiki T, Yin X, Miyazaki R, Hashimoto T, Cui J, Takeda K, Sunagawa K.
J Comp Physiol B. 1991;161(6):590-7. The effect of unsaturated and saturated dietary lipids on the pattern of daily torpor and the fatty acid composition of tissues and membranes of the deer mouse Peromyscus maniculatus. Geiser F.
Am J Physiol Endocrinol Metab. 2005 Sep;289(3):E456-65. Epub 2005 Apr 26. Chronic umbilical cord compression results in accelerated maturation of lung and brown adipose tissue in the sheep fetus during late gestation. Gnanalingham MG, Giussani DA, Sivathondan P, Forhead AJ, Stephenson T, Symonds ME, Gardner DS.
J Neurosci. 2008 Nov 5;28(45):11500-10. Nicotinamide restores cognition in Alzheimer's disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, LaFerla FM.
J Nutr. 2008 Sep;138(9):1602-8. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. Gresele P, Pignatelli P, Guglielmini G, Carnevale R, Mezzasoma AM, Ghiselli A, Momi S, Violi F.
Mech Ageing Dev. 2008 Mar;129(3):129-37. Epub 2007 Nov 17. Intra-specific variation in resting metabolic rate in MF1 mice is not associated with membrane lipid desaturation in the liver. Haggerty C, Hoggard N, Brown DS, Clapham JC, Speakman JR.
Hear Res. 2009 Jun;252(1-2):56-60. The effect of sex hormones on bone metabolism of the otic capsule--an overview. Horner KC.
Am J Physiol Endocrinol Metab. 2007 Nov;293(5):E1224-32. Experimental estrogen-induced hyperprolactinemia results in bone-related hearing loss in the guinea pig. Horner KC, Cazals Y, Guieu R, Lenoir M, Sauze N.
J Biol Chem. 2009 Feb 6;284(6):3823-32. Epub 2008 Dec 15. Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? Jung-Hynes B, Nihal M, Zhong W, Ahmad N.
Aging Cell. 2006 Oct;5(5):423-36. Epub 2006 Aug 25. Nicotinamide extends replicative lifespan of human cells. Kang HT, Lee HI, Hwang ES.
J Cardiovasc Pharmacol. 2007 Sep;50(3):333-42. Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin. Kao SJ, Liu DD, Su CF, Chen HI.
Cell. 2005 Nov 18;123(4):548-50. The enigmatic role of Sir2 in aging. Kennedy BK, Smith ED, Kaeberlein M. “In contrast to measurements of aging for mitotic cells, cell survival in the nonmitotic state is decreased by Sir2 activity under conditions that mimic calorie restriction.”
J Biol Chem. 2005 Mar 4;280(9):7460-8. Epub 2004 Dec 22. Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors alpha and beta in endothelial cells. Klinge CM, Blankenship KA, Risinger KE, Bhatnagar S, Noisin EL, Sumanasekera WK, Zhao L, Brey DM, Keynton RS.
Biull Eksp Biol Med. 1983 Dec;96(12):37-40. [Regulation of oxidative phosphorylation as a possible method of normalizing cerebral metabolism] Kresiun VI. “During the stage of excess catabolism, stress was demonstrated to dramatically inhibit and dissociate oxidative phosphorylation. This led to the impairment of macroerg synthesis and to the reduction of the brain macroerg content. Prophylactic administration of the derivatives of nicotinic acid and GABA markedly stimulated oxidative phosphorylation making it return to the initial level.” “It has been demonstrated that energy metabolism of the brain may return to normal at the expense of stimulation of oxidative phosphorylation.”
Arch Toxicol. 1999 Feb;73(1):50-4. The phytoestrogens coumoestrol and genistein induce structural chromosomal aberrations in cultured human peripheral blood lymphocytes. Kulling SE, Rosenberg B, Jacobs E, Metzler M.
Crit Care Med. 2007 Jul;35(7):1709-16. Altering CO2 during reperfusion of ischemic cardiomyocytes modifies mitochondrial oxidant injury. Lavani R, Chang WT, Anderson T, Shao ZH, Wojcik KR, Li CQ, Pietrowski R, Beiser DG, Idris AH, Hamann KJ, Becker LB, Vanden Hoek TL.
Cell Metab. 2008 Jul;8(1):38-48. SirT1 inhibition reduces IGF-I/IRS-2/Ras/ERK1/2 signaling and protects neurons. Li Y, Xu W, McBurney MW, Longo VD.
Cell Cycle. 2009 Jun 15;8(12):1877-82. Epub 2009 Jun 14. The pro-apoptotic action of stilbene-induced COX-2 in cancer cells: convergence with the anti-apoptotic effect of thyroid hormone. Lin HY, Davis PJ, Tang HY, Mousa SA, Luidens MK, Hercbergs AH, Davis FB.
Nature. 2002 Jul 18;418(6895):344-8. Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration. Lin SJ, Kaeberlein M, Andalis AA, Sturtz LA, Defossez PA, Culotta VC, Fink GR, Guarente L.
Neuromolecular Med. 2009;11(1):28-42. Epub 2009 Mar 14. Nicotinamide prevents NAD+ depletion and protects neurons against excitotoxicity and cerebral ischemia: NAD+ consumption by SIRT1 may endanger energetically compromised neurons. Liu D, Gharavi R, Pitta M, Gleichmann M, Mattson MP.
Cancer Res. 2009 Mar 1;69(5):1702-5. Epub 2009 Feb 24. The critical role of the class III histone deacetylase SIRT1 in cancer. Liu T, Liu PY, Marshall GM.
Nat Rev Genet. 2005 Nov;6(11):866-72. Programmed and altruistic ageing. Longo VD, Mitteldorf J, Skulachev VP.
Exp Gerontol. 2009 Jan-Feb;44(1-2):70-4. Epub 2008 Jun 24. Linking sirtuins, IGF-I signaling, and starvation. Longo VD.
Horm Metab Res. 2001 Jun;33(6):343-7. Mitochondrial respiration and triiodothyronine concentration in liver from postpubertal and adult rats. Lossa S, Lionetti L, Mollica MP, Crescenzo R, Botta M, Liverini G. “The purpose of this study was to investigate the decline in rat liver mitochondria respiration found in adult rats compared to younger ones, and to find a link between this respiratory impairment and a tissue hypothyroidism state.” “In addition, we found that in state 4 condition, mitochondria from adult rats consumed less oxygen than mitochondria from young rats. Finally, we found a decrease in liver triiodothyronine concentration in adult rats.”
Mol Cell Biochem. 2007 Aug;302(1-2):99-109. Resveratrol-induced mitochondrial dysfunction and apoptosis are associated with Ca2+ and mCICR-mediated MPT activation in HepG2 cells. Ma X, Tian X, Huang X, Yan F, Qiao D.
Eur Surg Res. 2001;33(2):71-6. Effect of CO2 pneumoperitoneum on the systemic and peritoneal cytokine response in a LPS-induced sepsis model. Matsumoto T, Dolgor B, Ninomiya K, Bandoh T, Yoshida T, Kitano S.
FASEB J. 2009 Apr;23(4):1032-40. Resveratrol treatment in mice does not elicit the bradycardia and hypothermia associated with calorie restriction. Mayers JR, Iliff BW, Swoap SJ.
Proc Soc Exp Biol Med. 1999 Sep;221(4):386-90. 5-hydroxytryptamine evokes endothelial nitric oxide synthase activation in bovine aortic endothelial cell cultures. McDuffie JE, Coaxum SD, Maleque MA.
Aging Cell. 2008 Dec;7(6):920-3. Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic model. Miwa S, Lawless C, von Zglinicki T. “We estimated the actual liver mitochondrial half life as only 1.83 days, and this decreased to 1.16 days following 3 months of dietary restriction, supporting the hypothesis that this intervention might promote mitochondrial turnover as a part of its beneficial effects.”
Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):4024-9. Elevated CO2 levels affect development, motility, and fertility and extend life span in Caenorhabditis elegans. Sharabi K, Hurwitz A, Simon AJ, Beitel GJ, Morimoto RI, Rechavi G, Sznajder JI, Gruenbaum Y.
Am J Respir Crit Care Med. 1998 Nov;158(5 Pt 1):1578-84. Hypercapnic acidosis may attenuate acute lung injury by inhibition of endogenous xanthine oxidase. Shibata K, Cregg N, Engelberts D, Takeuchi A, Fedorko L, Kavanagh BP.
Surg Endosc. 2008 Aug;22(8):1813-7. Carbon dioxide directly suppresses spontaneous migration, chemotaxis, and free radical production of human neutrophils. Shimotakahara A, Kuebler JF, Vieten G, Kos M, Metzelder ML, Ure BM.
Endocrinology. 2005 Jul;146(7):2920-32. Epub 2005 Mar 24. Adult-onset growth hormone and insulin-like growth factor I deficiency reduces neoplastic disease, modifies age-related pathology, and increases life span. Sonntag WE, Carter CS, Ikeno Y, Ekenstedt K, Carlson CS, Loeser RF, Chakrabarty.
Aging Cell. 2004 Jun;3(3):87-95. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Speakman JR, Talbot DA, Selman C, Snart S, McLaren JS, Redman P, Krol E, Jackson DM, Johnson MS, Brand MD.
Nature. 2001 Oct 18;413(6857):739-43. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Steffan JS, Bodai L, Pallos J, Poelman M, McCampbell A, Apostol BL, Kazantsev A, Schmidt E, Zhu YZ, Greenwald M, Kurokawa R, Housman DE, Jackson GR, Marsh JL, Thompson LM.
Am J Physiol Endocrinol Metab. 2007 Oct;293(4):E901-7. Resveratrol-induced inhibition of insulin secretion from rat pancreatic islets: evidence for pivotal role of metabolic disturbances. Szkudelski T.
Nan Fang Yi Ke Da Xue Xue Bao. 2006 Jul;26(7):910-3. [Resveratrol promotes Ca2+-induced Ca2+ release from rat liver cell mitochondria mediated by Ca2+] [Article in Chinese] Tian XM, Ma XD, Yan F.
PLoS Genet. 2009 May;5(5):e1000467. Epub 2009 May 8. Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension. Wei M, Fabrizio P, Madia F, Hu J, Ge H, Li LM, Longo VD.
Shock. 1998 Dec;10(6):436-41. Acetazolamide treatment prevents in vitro endotoxin-stimulated tumor necrosis factor release in mouse macrophages. West MA, LeMieur TL, Hackam D, Bellingham J, Claire L, Rodriguez JL.
JNatl Cancer Inst. 1988 Oct 19;80(16):1299-304. Ability of normal human keratinocytes that grow in culture in serum-free medium to be derived from suprabasal cells. Wilke MS, Edens M, Scott RE.
Cell. 1999 Jul 9;98(1):115-24. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM.