test your knowledge
How the world got lost on
the road to an anti-aging pill
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September 21, 2010: by Bill Sardi
Niacinamide (form of vitamin B3) is also known as nicotinamide. You read in the following abstract that depletion of nicotinamide is sufficient to activate the SIR2 gene (which is akin to the SIRTUIN1 gene in humans) and therefore regulate longevity. Since vitamin B3 is ubiquitous in food, starvation (calorie restriction) would deplete this essential vitamin and send a survival signal by upregulating SIRTUIN1 (SIR2 in lower life forms). [see Ref. #1 below] Of course, niacin is essential for life, a frank deficiency resulting in the vitamin deficiency disease called pellagra. So it would not be desirable to deplete niacin, nor starve oneself, to achieve longevity, though limited-calorie (CR) diets that border on starvation are employed by a few longevity seekers (Calorie Restriction Society). The idea of employing resveratrol is to create the same survival signal without having to deprive oneself of food. Biologists face a roadblock here because CR produces lean bodies, whereas resveratrol has only been shown to do this in animals at extreme doses (14,000 mg human equivalent dose in rodents, which is a potentially toxic dose). [Ref. #2 below] However, it has become apparent that low doses of resveratrol work better than high doses [Ref. #3], and when combined with other small molecules such as those provided in red wine (quercetin, ferulic acid, etc.), exerts even greater biological activity and influence over the genome. More important, when resveratrol is combined with other small molecules such as quercetin, the two molecules inhibit fat cell (adipocyte) activity. [See Refs #4 & #5 below] Longevinex was compared to a CR diet and plain resveratrol in a head-to-head study. Whereas it takes life-long adherence to a CR diet to significantly differentiate 832 genes, Longevinex differentiated nearly twice as many longevity genes (1711) in the short-term. For comparison, short-term CR only exerted influence over 198 genes and plain resveratrol 225 genes. This suggests that short-term supplementation with plain resveratrol would have to continue for decades to achieve the same effect as a CR diet, whereas Longevinex produced a similar gene expression profile as CR in the short-term. Since many people don’t have decades of life ahead of them, the full benefits of resveratrol supplementation may not be achieved. This is not to say resveratrol is not beneficial, but it may not mimic the longevity of CR with short-term use.
Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Sinclair DA.
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Calorie restriction extends lifespan in a broad range of organisms, from yeasts to mammals. Numerous hypotheses have been proposed to explain this phenomenon, including decreased oxidative damage and altered energy metabolism. In Saccharomyces cerevisiae, lifespan extension by calorie restriction requires the NAD+-dependent histone deacetylase, Sir2 (ref. 1). We have recently shown that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide. Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. We also identify PNC1 as a longevity gene that is responsive to all stimuli that extend lifespan. We provide evidence that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms.
Dal-Pan A, Blanc S, Aujard F.
Mécanismes Adaptatifs et Evolution, UMR 7179 Centre National de la Recherche Scientifique, Muséum National d’Histoire Naturelle, Paris, France.
BACKGROUND: Resveratrol, a natural polyphenolic compound, was shown to protect rodents against high-fat-diet induced diabesity by boosting energy metabolism. To the best of our knowledge, no data is yet available on the effects of resveratrol in non-human primates. Six non-human heterotherm primates (grey mouse lemurs, Microcebus murinus) were studied during four weeks of dietary supplementation with resveratrol (200 mg/kilogram/day, or 14,000 mg for a 160-lb human) during their winter body-mass gain period. Body mass, spontaneous energy intake, resting metabolic rate, spontaneous locomotor activity and daily variations in body temperature were measured. In addition, the plasma levels of several gut hormones involved in satiety control were evaluated.
RESULTS: Resveratrol reduced the seasonal body-mass gain by concomitantly decreasing energy intake by 13% and increasing resting metabolic rate by 29%. Resveratrol supplementation inhibited the depth of daily torpor, an important energy-saving process in this primate. The daily amount of locomotor activity remained unchanged. Except for an increase in the glucose-dependent insulinotropic polypeptide, a gut hormone known to promote mobilization of fat stores, no major change in satiety hormone plasma levels was observed under resveratrol supplementation.
CONCLUSIONS: These results suggest that in a non-human primate, resveratrol reduces body-mass gain by increasing satiety and resting metabolic rate, and by inhibiting torpor expression. The measured anorectic gut hormones did not seem to play a major role in these observations.
Barger JL, Weindruch R, Prolla TA.
LifeGen Technologies, LLC, Madison, Wisconsin, United States of America.
Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg(-1) day(-1)), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.
Yang JY, Della-Fera MA, Rayalam S, Ambati S, Hartzell DL, Park HJ, Baile CA.
Department of Animal and Dairy Science, University of Georgia, Athens, GA 30602-2771, USA.
Certain flavonoids have been shown to have specific effects on biochemical and metabolic functions of adipocytes. In this study, we investigated the effects of combinations of resveratrol and quercetin on adipogenesis and apoptosis in 3T3-L1 cells. In maturing preadipocytes resveratrol and quercetin at 25 microM individually suppressed intracellular lipid accumulation by 9.4+/-3.9% (p<0.01) and 15.9+/-2.5%, respectively, (p<0.001). The combination of resveratrol and quercetin at the same dose, however, decreased lipid accumulation by 68.6+/-0.7% (p<0.001). In addition, combinations of resveratrol and quercetin at 25 microM significantly decreased the expression of peroxisome proliferators-activated receptor gamma (PPAR gamma) and CCAAT/enhancer-binding protein (C/EBP)alpha, both of which act as key transcription factors. In mature adipocytes resveratrol and quercetin at 100 microM individually decreased viability by 18.1+/-0.6% (p<0.001) and 15.8+/-1% (p<0.001) and increased apoptosis (100 microM) by 120.5+/-8.3% (p<0.001) and 85.3+/-10% (p<0.001) at 48 h, respectively. Combinations of resveratrol and quercetin further decreased viability (73.5+/-0.9%, p<0.001) and increased apoptosis (310.3+/-9.6%, p<0.001) more than single compounds alone. The combination of resveratrol and quercetin at 100 muM increased release of cytochrome c from mitochondria to cytosol and decreased ERK 1/2 phosphorylation. Taken together, our data indicate that combinations of resveratrol and quercetin can exert potential anti-obesity effects by inhibiting differentiation of preadipocytes and inducing apoptosis of mature adipocytes.
Andersen C, Rayalam S, Della-Fera MA, Baile CA.
Department of Veterinary Disease Biology, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark.
Obesity is an increasing health problem all over the world. Phytochemicals are potential agents to inhibit differentiation of preadipocytes, stimulate lipolysis, and induce apoptosis of existing adipocytes, thereby reducing the amount of adipose tissue. Flavonoids and stilbenoids represent the most researched groups of phytochemicals with regards to their effect on adipogenesis, but there are also a number of in vitro and in vivo studies with phenolic acids, alkaloids, and vitamins, as well as other plant compounds. Although phytochemicals like epigallocatechin-3-gallate, genistein, and resveratrol reduce lipid accumulation and induce adipocyte apoptosis in vitro and reduce body weight and adipose tissues mass in animal models of diet-induced obesity, well-conducted clinical trials are lacking. Pharmacological doses are often used in vitro and when applied in physiological doses in animals or humans, the phytochemicals are often ineffective in affecting adipogenesis. However, by combining several phytochemicals or using them as templates for synthesizing new drugs, there is a large potential in targeting adipogenesis using phytochemicals. (c) 2010 International Union of Biochemistry and Molecular Biology, Inc.
Barger JL, Kayo T, Pugh TD, Prolla TA, Weindruch R.
LifeGen Technologies, LLC, Madison, WI 53719, USA. email@example.com
An active area of aging research is focused on identifying compounds having the ability to mimic the effects of caloric restriction (CR). From 2 to 5 months of age, we fed male B6C3F(1) mice either a 40% CR diet, a control diet supplemented with a commercially available nutraceutical mixture (NCM) containing resveratrol, quercetin and inositol hexaphosphate, or a diet supplemented with an equivalent dose of chemical-grade resveratrol (RES; 1.25 mg resveratrol kg(-1) day(-1)) from 2 to 5 months of age. Cardiac gene expression profiles were generated for the three groups of treated mice and compared to age-matched control (CO) mice. All three treatments were associated with changes in several cytoskeletal maintenance pathways, suggesting that RES and NCM are able to mimic short-term CR. CR uniquely affected several immune function pathways while RES uniquely affected multiple stress response pathways. Pathway analysis revealed that NCM (but not CR or RES) regulated multiple metabolic pathways that were also changed by long-term CR, including glucose and lipid metabolism, oxidative phosphorylation and chromatin assembly. Examination of key genes and pathways affected by NCM suggests that Foxo1 is a critical upstream mediator of its actions.