Rodgers, J. Several physiological activators longevit SIRT1 Pre-match hydration guidelines been identified. We excluded the CR mice from the statistical analysis of feed uptake and bodyweight. Article CAS PubMed Google Scholar Mukkavilli, R.

Thank you Resverayrol visiting nature. You are longevit a browser version with limited support for Prebiotics for gut microbiota. To obtain the best experience, we recommend Resveratrop use a more up to date ,ongevity or turn off longevitj mode Calorie counting journal Internet Explorer.

In Resverahrol meantime, to Resveatrol continued support, longeviyy are displaying the snd without styles and JavaScript. Resveratrol as Fiber internet connection as caloric restriction were shown to extend Dextrose Muscle Energy in some model organisms and may possibly delay onset of ageing-related diseases in humans.

Yet, resveratrol Reaveratrol does not always extend lifespan of animal models or improve health RResveratrol of humans. Because of interindividual differences in human microbiota, resveratrol metabolite production in the gut longvity. While some individuals produce oongevity and dihydroresveratrol in their gut, others produce dihydroresveratrol only.

Compared to qnd injected with vehicle Resveratrol and longevityresveratrol longeviy dihydroresveratrol did not longevify bodyweight and Resveratro no impact on insulin or glucose levels while lunularin slightly annd feed intake and bodyweight lonbevity.

CR-mice showed lowered cholesterol, insulin and leptin levels, elevated adiponectin and phosphorylated AMPK Resvefatrol in liver as lonegvity as increased transcription of Pck1 and Pgc1α when compared to the AL-control.

Carbs and athletic power output contrast, injections longevitj the test substances did not L-carnitine and cognitive function these parameters.

We ans conclude that in our model, resveratrol, lunularin and dihydroresveratrol did not act lpngevity Pre-match hydration guidelines mimetics. Since Oongevity, et al. Its impact on Resverarrol has Resvrratrol compared to Resverxtrol calorically restricted Anc CR 3.

Longebity appears to extend lifespan lonvevity some model organisms and to decrease blood pressure, insulin and Diabetic-friendly sweeteners for chocolates in humans 4.

Thus, Nootropic for Sleep Quality Improvement, CR could possibly delay pongevity onset adn ageing-related lohgevity. In mice, compared to an ad-libitum diet, CR oxidative stress causes insulin and leptin longegity and lowered loongevity levels while lifespan Nootropic for Sleep Quality Improvement lengthened 5 Resverxtrol, 6.

Furthermore, ans the liver of fasting mice, transcription of genes involved in mitochondrial biogenesis and glucose metabolism such as the peroxisome proliferator-activated receptor xnd coactivator 1-alpha Pgc-1αthe NAD-dependent deacetylase sirtuin-1 Sirt1the mitochondrial pyruvate dehydrogenase lipoamide kinase isozyme 4 Pdk4 and the phosphoenolpyruvate carboxykinase Pck1 was elevated 78.

The AMPK activates glycolysis, autophagy and inhibits fatty acid synthesis 9. In contrast, ane urinary proteins MUPsResveratrpl trigger adaptive behaviour in kongevity via scent communication and Pre-match hydration guidelines glucose and lipid metabolisms 10 are down-regulated when nutrient supply is decreased 11 Somewhat similar to CR, in oongevity fed resveratrol as longevihy of Resveratro, high fat diet, insulin Resgeratrol was improved, bodyweight Carbohydrate loading and muscle repair fat mass were lowered and Resverartol mice lived longer than the non-supplemented controls 13 Moreover, in mice, ajd was shown to activate enzymes thought to Resvsratrol longevity such as the deacetylase SIRT1 and Longeviyy 15 and to induce Resvwratrol factor erythroid-derived 2 -like 2 NRF2 longsvity gene heme oxygenase Hmox 1 which is Resvsratrol in Nootropic for Sleep Quality Improvement stress response Another transcription factor that mediates stress response, forkhead longrvity protein Lonfevity FOXO3was also induced ans resveratrol-supplemented snd Interestingly, human SNPs Resveratrol and longevity FOXO3 that longevit its Injury prevention through proper eating habits have Resveratrpl related to longevity FOXO3 also stimulates Weight and health own transcription and lonfevity inhibited by growth factors An additional mechanism by which resveratrol lobgevity promote healthy ageing is ans attenuating ageing-related increase in Reaveratrol.

In old ahd, resveratrol reduced transcription and levels of pro-inflammatory cytokines such RResveratrol tumour ajd factor alpha Tnfα Furthermore, dietary longevit may decrease obesity and therefore the pongevity of related diseases is via inhibiting sodium-dependant Rwsveratrol transporter Resvreatrol SGLT1 -mediated glucose Resvefatrol in the gut Resveratrol and longevity, resveratrol was shown to influence Resverqtrol microbiota by Sports nutrition supplements the Bacteroidetes-to-Firmicutes ratios correlating negatively longeviry bodyweight Substances that mimic Resveeratrol positive effects of CR on health and longevity longegity been referred Resvreatrol as caloric restriction mimetics CRMs and resveratrol has been repeatedly discussed as being such a CRM In a review article written at the National Institute of Aging U.

Many CRM candidate substances have shown serious side effects. For example, the inhibitor of the cell-growth- and proliferation-regulating kinase mTOR rapamycin is an immunosuppressant and 2-deoxyglucose, which inhibits glycolysis, was cardiotoxic in rats when administered chronically 25 In contrast, chronic resveratrol intake seems to be safe as stated by the European Food and Safety Authority However, not all studies observed a positive impact of resveratrol on lifespan and therefore do not support a role of resveratrol as putative CRM.

On the other hand and similar to other polyphenols and polyphenol-containing plant extracts 4in genetically heterogeneous mice on a standard fat diet at a concentration of 0. Thus, diet and genetic background seem to influence the effect of resveratrol on lifespan extension.

Interestingly, there have been study outcomes pointing to the notion that lifespan prolongation by CR is more apparent in model organisms that are adapted to laboratory conditions and possibly overfed than in non-model organisms Taken together with the finding that resveratrol could only prolong lifespan when fed as part of a high fat diet 1330this could imply that resveratrol counteracts the negative effects of elevated energy intake.

Interestingly, Bode, et al. They identified three different metabolite profiles that differed in the presence of a reduced and dehydroxylated metabolite of resveratrol lunularin.

While all human trial participants were able to produce the reduced metabolite of resveratrol dihydroresveratrol in their gut, only some could produce lunularin. Furthermore, the lunularin-producing group could be divided into high and low producers. Chemical structures of resveratrol and its metabolites dihydroresveratrol and lunularin which are produced by human gut microbiota.

Hence, we wanted to study the possibility that differing gut microbiota compositions influence the study outcome of trials with resveratrol by using an animal model that had previously shown to benefit from stilbene supplementation.

This model was chosen to imitate diet-induced obesity in middle-aged humans. At around 45—65 years of age, the incidence of ageing-related chronic diseases such as diabetes and hypertension increases in humans from so-called Western world countries 3435 Obesity further increases the risk of developing these diseases 37 that, putatively, may be alleviated by resveratrol supplementation To test our hypothesis that resveratrol, and the gut metabolites dihydroresveratrol and lunularin, acted differently on molecular targets involved in ageing, we injected the mice and thereby aimed at minimising contact of the tested bioactives with gut microbiota.

We compared these mice with each other and with a group of mice that was fed CR and also injected i. Applying allometric principles based on animal to human comparisons of total clearance rates, doses for humans that are extrapolated from mouse studies would be 5—10 lower than expected from mere conversion according to bodyweight In the livers of the AL-control and CR-control neither resveratrol, nor dihydroresveratrol or lunularin were detected.

In the resveratrol group only 5 out of 9 liver samples exhibited measurable, but low resveratrol levels 6. This interesting finding indicates that resveratrol was efficiently metabolized to dihydroresveratrol in resveratrol-injected mice.

In mice receiving dihydroresveratrol, neither resveratrol nor lunularin was detected in the liver samples, whereas dihydroresveratrol was detectable in all samples from the dihydroresveratrol group with a mean level of Lunularin was only detectable in the lunularin group Feed intake was checked daily and weight weekly.

While i. injections with resveratrol or dihydroresveratrol did not lower feed intake 3. This slightly lower feed intake could explain the lower than AL-control body weight of lunularin mice at the end of the trial. We excluded the CR mice from the statistical analysis of feed uptake and bodyweight.

While we observed a typical CR phenotype when looking at bodyweight and body composition of CR mice, only the lunularin group showed a significant difference in bodyweight development compared to the AL control.

Insulin sensitivity was monitored by oral glucose tolerance tests at the beginning, halfway through and at the end of the study.

However, mice on CR showed improved insulin sensitivity as measured by glucose and insulin levels. Insulin sensitivity was monitored by oral glucose tolerance tests halfway through a and at the end of the study.

b It was improved by restricting feed intake CR but not by injecting resveratrol RSV nor dihydroresveratrol DHR. Glucose and insulin levels in the blood collected from the facial vein of the mice are shown.

Leptin and cholesterol levels in CR mice were significantly lower and adiponectin was significantly higher in CR mice than in CON mice. Plasma levels of leptin, adiponectin, cholesterol or triglycerides in CON mice injected did not differ statistically from mice injected with resveratrol, dihydroresveratrol or lunularin.

As expected, CR-feeding lowered leptin and total cholesterol levels compared to AL fed controls. In contrast, adiponectin was elevated by CR while triglyceride levels seemed unaffected Fig. However, neither resveratrol nor its gut microbiota metabolites dihydroresveratrol or lunularin affected the hormones or lipids measured.

Pgc1-α mRNA, which is up-regulated under caloric restriction and may contribute to the life-prolonging effect of lowered calorie intake 3was elevated in our CR mice when compared to the controls.

Since SIRT1 was shown to activate PGC-1α 7 and resveratrol was shown to activate SIRT1 and PGC-1α 15we also measured Sirt1 expression. While CR increased transcription, resveratrol did not significantly change Sirt1 mRNA levels in the liver. Interestingly, lunularin also shows a smaller than CR but significant increase in Sirt1 expression.

Gluconeogenesis as measured by Pck 1 expression appeared as not being influenced by resveratrol or resveratrol metabolite injections but by CR Fig. NRF2 target gene Hmox 1 was slightly induced by CR as well as by dihydroresveratrol and lunularin injections.

However, resveratrol did not activate Hmox 1 expression. mRNA levels of the transcription factor Foxo3 did not appear to be affected by any of the bioactives injected. Similarly, Tnfα expression appeared unchanged within the groups of our trial Fig.

In-vitro studies have shown that resveratrol can activate AMPK and lead to its phosphorylation 13 and, in accordance with Miller, et al. In contrast, in our mice injected with resveratrol, dihydroresveratrol or lunularin, we could not observe a rise of phosphorylated AMPK levels Fig.

Mice on CR showed increased levels of pAMPK a while resveratrol RSV - dihydroresveratrol DHR - and lunularin-injected mice LUN showed levels comparable to the AL-control mice CON.

In contrast, MUP levels b were lowered by CR but not by the compounds injected. Cropped western blot images. See Supplemental Figures for full-length blots. At least 4 representative mouse samples are shown. In the livers of mice injected with resveratrol, MUP levels were not significantly lowered compared to the control Fig.

The MUP antibody used did not distinguish between different MUP isoforms. To examine whether CR or resveratrol treatment affects the intestinal active glucose transport, the ileum of the animals was mounted in Ussing chambers.

As shown in Fig. There is no significant difference in the glucose-induced I SC between resveratrol-injected mice and AL-control mice. Mice were weighed weekly and fed daily. After a 6-week ad-libitum adaptation phase, the experiment began by dividing the mice into 5 groups with 10 mice each.

At the beginning, halfway through the experiment and prior to sampling the body composition of the mice was measured in a Bruker Minispec LF Billerica, United States. Per experimental group, 8—10 mice were sacrificed at the end of the experiment.

We lost 2 mice each in the control and the CR group and 1 mouse in the resveratrol group. Experimental procedures were carried out in accordance with German laws on animal protection TierSchG §7—9.

: Resveratrol and longevity

More evidence for Longevity Pathway | Harvard Medical School	In the honey bee, differences in nutrition during development lead to the formation of distinct castes in genetically identical individuals. These differences in nutritional input in the honey bee can be traced to changes in DNA methylation [ 53 ]. Resveratrol is a nutritional supplement and an activator of SIRT1, a histone deacetylase [ 2 ]. SIRT1 can influence DNA methylation in mammalian cells [ 54 ]. In mammals, aging is associated with a loss of DNA methylation and declining transcriptional control of methyltransferases [ 55 , 56 ]. This loss of DNA methylation during aging may contribute to the signature genomic instability and shortened telomeres that characterize aging cells [ 57 , 58 ]. Recently, a study demonstrated that SIRT1 represses a large set of genes in the mouse genome and promotes repair of DNA strand breaks [ 59 ]. This particular study also determined that increased SIRT1 promotes survival in the mouse and reduces transcriptional abnormalities associated with aging. Thus, it is possible that resveratrol and its subsequent activation of SIRT1 may promote genomic stability and a delay in aging via similar mechanisms. In addition to activating sirtuins, resveratrol has been shown to inhibit several members of the Target of Rapamycin TOR network in mammals, e. AMP-activated protein kinase AMPK , Phosphatidylinositol 3-kinase PI3K , and Mitogen-activated protein kinase MAPK [ 17 , 60 - 62 ]. Suppression of TOR activity is known to slow aging in yeast, worms, and flies [ 6 , 63 - 65 ]. Notably, rapamycin also extends the lifespan of fruit flies and mice [ 66 , 67 ]. A recent study of mammalian cells demonstrated that resveratrol preserved their proliferative capacity and inhibited S6 kinase phosphorylation, thereby eliciting an indirect repression of mTOR activity [ 68 ]. This result is similar to the effect of rapamycin on mTOR in cells [ 69 ]. A separate cellular study revealed that resveratrol blocks autophagy via the inhibition of S6 kinase under nutrient-limited conditions [ 70 ]. In contrast, cells grown in nutrient-rich media supplemented with resveratrol showed an increase in autophagy [ 70 ]. Furthermore, the negative regulation of S6 kinase homologs produces anti-aging effects in yeast [ 71 - 73 ] and fruit flies [ 64 , 74 ]. It is possible that sirtuins and TOR may be part of the same caloric restriction pathway in mammals since both caloric restriction and TOR inhibition lead to increased expression of a key sirtuin regulator [ 75 ]. The molecular connections between resveratrol, sirtuins, the epigenome, and TOR remain unexplored in the honey bee. However, if some of the aforementioned links are conserved in this species, they may explain some of the organismal-level changes observed in this study. In summary, we demonstrated that resveratrol significantly affected gustatory responsiveness and prolonged lifespan in wild-type honey bees under normal oxygen conditions. However, the enhanced lifespan effect of resveratrol was abolished under hyperoxic conditions. Moreover, resveratrol had a satiety effect on honey bees and reduced their food consumption. These findings support the hypothesis that the lifespan extension effects of resveratrol are evolutionarily conserved. Our subsequent projects in honey bees will focus on using pharmacological agents to explore whether there is a SIRT1-dependence for the lifespan and neurophysiological effects noted here. Experiments were performed at Arizona State University in Tempe, AZ, USA. We utilized four genetically diverse wild type stock colonies Apis mellifera headed by queens of Californian commercial origin that were mated with multiple males. The colonies each had a single queen and several thousand workers. Each queen was caged onto a comb and allowed to lay eggs over a period of one day, with an additional day for proper acclimatization. This procedure made brood easy to track temporally and spatially. To ensure robust experimental replication and manageable workloads, we employed a staggered honey bee collection scheme, which was repeated every week for a total of five weeks. This experimental design allowed for a predictable supply of age-matched newly emerged bees three times per week every Thursday, Friday, and Saturday beginning calendar week 44 and ending week Upon emergence the following morning, bees were marked on the thorax with a designated paint color Testors, Rockford, Illinois, USA for identification and placed in a host colony. After four days, marked honey bees were recaptured and taken into the laboratory. We reasoned that newly emerged bees— which cannot feed themselves—should remain in the colony for the first days of life before transfer to a laboratory setting so that they could procure essential social provisions [ 76 , 77 ]. We captured four-day-old honey bees at 9 AM every Monday, Tuesday, and Wednesday and then placed individuals into 7. Then, we brought the honey bees to the laboratory ad libitum access to water and a pollen-sucrose diet. Diets were freshly prepared each day for all treatment groups. After spending five days in cages, we tested each nine-day-old honey bee cohort 3 cohorts per week for gustatory responsiveness and olfactory learning performance every Saturday, Sunday, and Monday for five weeks. All sensory and gustatory tests were performed on honey bees that had only experienced normoxia. We prepared a liquefied diet of protein and carbohydrates consisting of 1. Batches of this mixture were stored in frozen aliquots of 25 ml and thawed daily upon use. The daily addition of fresh resveratrol to the diet ensured optimal activity of the drug since it is known that resveratrol degrades in food medium after 24 h in 37° C [ 33 ]. Three concentrations of resveratrol 0, 30, μM were chosen as the basis for our treatment groups based on in vitro activation levels for Drosophila. The resveratrol we utilized is routinely tested for activity. We began administering resveratrol when honey bees were four-days-old because resveratrol works best when fed during early adulthood [ 4 ]. To ease handling and placement of bees into individual tubes, they were cooled in 4°C until reduced movement was detected. Honey bees were then restrained in small polyacryl holders using strips of duct tape. As with all laboratory tests, test bees were randomized so that experimenters were blind to treatment identity. The incubator maintained atmospheric oxygen at normoxic levels. To measure gustatory responsiveness, we utilized the proboscis extension response PER. The criterion for a positive PER was complete extension of the proboscis. Nine-day-old honey bees under resveratrol or control treatment were stimulated over the antennae with water and six subsequent sucrose solutions in the following order: 0. We adhered to an inter-stimulus interval of two minutes to prevent sensitization and habituation. An overall index of performance, or gustatory response score GRS , was calculated for all tested bees by using the sum of all PER to seven different stimuli water and six sucrose solutions. A honey bee with a total score of 7 showed the highest level of sensory responsiveness, while a zero score indicated no responsiveness. Briefly, this method involves pairing an odor with a sucrose reward over six trials of conditioning to test associative learning performance. After each conditioning trial, we scored PER as binary variable via PER i. Once all conditioning trials took place, we tested the honey bees for odor generalization by presenting them with the unconditioned stimulus, cineole. This allowed us to test the bee's discrimination ability. Subsequently, we calculated a learning acquisition score based on conditioned responses. The score, with a numerical value between 0 and 5, was based on 5 conditioning trials and an additional trial that tested reaction spontaneity. Oxygen exposure has been shown to impair honey bees faster and in a more controlled fashion than free-flight recapture setups. Relative humidity was monitored by Hobo data loggers Onset, MA, USA. Bees were individually housed in 1. Honey bees were fed 25 μL of the aforementioned protein-carbohydrate-resveratrol diet and were allowed to feed ad libitum through an easily accessible food-containing pipette tip. Dali-youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J. Sirtuins: the 'magnificent seven', function, metabolism and longevity. Ann Med. Baur JA. Resveratrol, sirtuins and the promise of a DR mimetic. Mec Ageing Dev ; Sadruddin S, Arora R. Resveratrol: biologic and therapeutic implications. J Cardiometab Syndr ; De la lastra CA, Villegas I. Resveratrol as an anti-inflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res. Cottart CH, Nivet-antoine V, Laguillier-morizot C, Beaudeux JL. Resveratrol bioavailability and toxicity in humans. Waterhouse AL Trela BC. Resveratrol: isomeric molar absorptivities and stability. J Agr Food Chem. Belguendouz L, Fremont L, Linard A. Resveratrol inhibits metal ion-dependent and independent peroxidation of porcine low-density lipoproteins. Biochem Pharmacol. Fisher GJ, Kang S, Varani J, et al. Mechanisms of photoaging and chronological skin aging. Arch Dermatol. Farris P, Krutmann J, Li YH, Mcdaniel D, Krol Y. Resveratrol: a unique antioxidant offering a multi-mechanistic approach for treating aging skin. J Drugs Dermatol. Farris P, Yatskayer M, Chen N, Krol Y, Oresajo C. Evaluation of efficacy and tolerance of a nighttime topical antioxidant containing resveratrol, baicalin, and vitamin e for treatment of mild to moderately photodamaged skin. Gehm BD, Mcandrews JM, Chien PY, Jameson JL. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci USA. Krutmann J, Schroeder P. Role of mitochondria in photoaging of human skin: the defective powerhouse model. J Investig Dermatol Symp Proc. Csiszar A, Labinskyy N, Pinto JT, et al. Resveratrol induces mitochondrial biogenesis in endothelial cells. Am J Physiol Heart Circ Physiol. Ungvari Z, Labinskyy N, Mukhopadhyay P, et al. Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells. Baxter RA. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J Cosmet Dermatol. Contact Allergens Lurking in Self-Tanners. ReV Up Your Vitiligo Treatment Strategies. First Known Canadian Study Evaluates Real-World Experiences of Patients With Vitiligo in Community Setting. The Cutaneous Connection: Splish, Splash, AD Management Starts in the Bath. So, how is CoQ10 involved in longevity? One of the proposed theories of aging is a decline in energy metabolism, in which CoQ10 has an important role. And though some studies have shown that supplementing with CoQ10 may improve the mitochondrial function of mice, few studies have examined its effects on longevity in humans. Supplementation with the reduced form of coenzyme Q10 decelerates phenotypic characteristics of senescence and induces a peroxisome proliferator-activated receptor-alpha gene expression signature in SAMP1 mice. Mol Nutr Food Res. Ubiquinol supplementation activates mitochondria functions to decelerate senescence in senescence-accelerated mice. Antioxid Redox Signal. Improved health-related quality of life, and more days out of hospital with supplementation with selenium and coenzyme Q10 combined. Results from a double-blind, placebo-controlled prospective study. J Nutr Health Aging. sales insidetracker. com Support center. All rights reserved. InsideTracker is a personalized nutrition model by Segterra. Resveratrol is an antioxidant that may improve elevated blood glucose Like many other health-promoting antioxidants, resveratrol is a polyphenol produced by some plants in response to stress or injury in a process called xenohormesis. Resveratrol is found in red wine, grapes, cocoa, peanuts, and blueberries, and in the s, scientists discovered its cardioprotective properties. In fact, they hypothesized the antioxidant could explain the heart-healthy benefits of red wine, as one five-ounce glass of red wine contains about 1. Coenzyme Q10 is an enzyme related to energy metabolism Coenzyme Q10, also known as "ubiquinone," is a type of enzyme synthesized naturally by the body and found in almost every cell and tissue. CoQ10 works by stimulating our cell's mitochondria to produce energy in the form of adenosine triposhopate ATP , and, therefore, helping the body convert food into energy more efficiently. Furthermore, CoQ10 works as an antioxidant in both the mitochondria and cell membranes, thereby helping to prevent cellular damage. Key takeaways: Resveratrol and CoQ10 supplementation extends the life of several organisms, and positively impacts metabolic function in animals.
Resveratrol, the longevity molecule	On the other hand and similar to other polyphenols and polyphenol-containing plant extracts 4 , in genetically heterogeneous mice on a standard fat diet at a concentration of 0. Rare Disease. Orsini F, Pelizzoni F, Verotta L, Aburjai T, Rogers CB Isolation, synthesis, and antiplatelet aggregation activity of resveratrol 3-O-beta-D-glucopyranoside and related compounds. Case-Based Roundtable. As far as we are concerned, murine metabolic enzymes that can reduce double bonds have not been identified.
Erratum to: Resveratrol and red wine, healthy heart and longevity | Heart Failure Reviews	EMBO J — Mol Pharmacol — PubMed CAS Google Scholar Bertelli A, Falchi M, Dib B, Pini E, Mukherjee S, Das DK Analgesic resveratrol? J Agr Food Chem. More on this topic. Nat Struct Mol Biol 13 7 — PubMed CAS Google Scholar Marshall JC, Malam Z, Jia S Modulating neutrophil apoptosis. Mice on resveratrol have twice the endurance and are relatively immune from effects of obesity and aging.

Resveratrol and longevity -

Concentrations of resveratrol and derivatives in foods and estimation of dietary intake in a Spanish population: European Prospective Investigation into Cancer and Nutrition EPIC -Spain cohort. Williams, L. Safety studies conducted on high-purity trans-resveratrol in experimental animals. Food Chem.

Klinger, S. Yonamine, C. Resveratrol improves glycemic control in insulin-treated diabetic rats: participation of the hepatic territory. Lescale-Matys, L. Vernaleken, A. Casirola, D. Adaptations of intestinal nutrient transport to chronic caloric restriction in mice.

G Higashida, K. Effects of resveratrol and SIRT1 on PGC-1alpha activity and mitochondrial biogenesis: a reevaluation. PLoS Biol. Sharrow, S. Pheromone binding by polymorphic mouse major urinary proteins. Protein science: a publication of the Protein.

Hurst, J. Individual recognition in mice mediated by major urinary proteins. Identification of MUP1 as a regulator for glucose and lipid metabolism in mice.

Download references. We are grateful to Vivien Schmuck for her experimental assistance and to Mario Hasler for his statistical assistance. Additionally, we thank Bettina Schindler and Mareike Lehnig for excellent technical assistance with the UHPLC analyses and Melanie Huch for her comments and critical reading of the manuscript.

The project was funded by the DFG Project Number Institute of Human Nutrition and Food Science, University of Kiel, Hermann-Rodewald-Straße 6, , Kiel, Germany. Department of Nutritional, Food and Consumer Sciences, Fulda University of Applied Sciences, Leipziger Straße , , Fulda, Germany.

Animal welfare office, University of Kiel, Olshausenstraße 40, , Kiel, Germany. Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Butenandtstraße , , Munich, Germany.

Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Department of Safety and Quality of Fruit and Vegetables, Haid-und-Neu-Straße 9, , Karlsruhe, Germany.

Nicolas Danylec, Sebastian T. You can also search for this author in PubMed Google Scholar. designed the study, carried out experiments and wrote the manuscript. and I. handled the mice and carried out experiments. and J. synthesized resveratrol metabolites. carried out the Ussing chamber measurements.

and S. supervised mouse experiments and animal welfare approval. carried out the UHPLC analyses. carried out the UHPLC analyses and wrote the manuscript.

supervised analytical experiments. designed and oversaw the study and wrote the manuscript. All authors reviewed the manuscript. Correspondence to Kathrin Pallauf. Open Access This article is licensed under a Creative Commons Attribution 4.

Reprints and permissions. Resveratrol, lunularin and dihydroresveratrol do not act as caloric restriction mimetics when administered intraperitoneally in mice.

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Skip to main content Thank you for visiting nature. nature scientific reports articles article. Download PDF. Subjects Biomarkers Obesity. Abstract Resveratrol as well as caloric restriction were shown to extend lifespan in some model organisms and may possibly delay onset of ageing-related diseases in humans.

Introduction Since Howitz, et al. Figure 1. Full size image. Mean feed intake and bodyweight of resveratrol injected mice does not differ from AL-control mice Feed intake was checked daily and weight weekly. Figure 2. Figure 3. Figure 4. Figure 5. Figure 6.

Synthesis of resveratrol metabolites Resveratrol for dihydroresveratrol synthesis and i. mRNA polymerase chain reaction Liver total RNA was isolated using peqGold Trifast® Peqlab, Erlangen, Germany.

Table 1 Primers used for quantitative reverse transcriptase PCR. Full size table. Discussion Our study design included daily control of feed uptake and a controlled application of resveratrol and its metabolites. Data Availability All data generated or analyzed during this study is included in this published article and its Supplementary Information files.

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Kulling Authors Kathrin Pallauf View author publications. View author publications. Ethics declarations Competing Interests The authors declare no competing interests. Supplementary information.

Supplementary data, methods and figures. Rights and permissions Open Access This article is licensed under a Creative Commons Attribution 4. About this article. Cite this article Pallauf, K.

Copy to clipboard. This article is cited by The effect of resveratrol, curcumin and quercetin combination on immuno-suppression of tumor microenvironment for breast tumor-bearing mice Chenchen Li Yajun Xu Yanli Wang Scientific Reports Sirtuins transduce STACs signals through steroid hormone receptors Henry K.

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Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research. FOXO is a key downstream effector of the PI3 K-Akt pathway [ 86 , 87 ].

Studies showed that inactivating mutation of insulin receptor daf-2 or PI3 K age-1 resulted in extension of life span [ 88 — 91 ].

This extension of life span is reversed when FOXO ortholog daf is mutated [ 86 , 87 ]. Several studies have shown that Akt can phosphorylate FOXO1, FOXO3 and FOXO4 at The24, Ser and Ser and inactivate them [ 85 , 92 , 93 ]. When Akt is inactivated and unable to phosphorylate FOXO factors, they remain activated and localized in nucleus.

Activated FOXO induced the transcription of several pro-apoptotic genes. When Akt is activated by several growth factors, the FOXO proteins are directly phosphorylated and translocate to the cytoplasm via binding to proteins [ 85 , 94 ], which are a family of cellular chaperones interacting with the protein ligands in a phosphorylation-dependent manner [ 95 ].

Thus, by translocating phosphorylated FOXO transcription factors into the cytoplasm, the Akt signaling pathway prevents the transcription of pro-apoptotic genes. Several studies have shown that resveratrol can activate Akt via phosphorylation [ 23 , 96 ] which in turn inactivate FOXOs and translocate into cytoplasm.

Not only that, but our own study demonstrated that resveratrol and red wine containing a significant amount of resveratrol can inactivate FOXOs by phosphorylation [ 9 ]. Oxidative stress leads to damage and death of cells, so that increase in oxidative stress resistance is related to longevity [ 97 ].

Several recent studies have shown that JNK, a member of MAPK superfamily, is a upstream modulator of FOXO factors [ 98 — ].

JNK signaling pathway is known to activate by external stress stimuli. Wang et al. showed for first time that JNK regulates FOXO in Drosophila and plays important role in life span regulation [ ].

Another study showed that JNK requires dFOXO, a FOXO ortholog to expand life span [ ]. In the same study, it was demonstrated that JNK promotes the nuclear translocation of dFOXO overexpression of some small heat shock proteins.

These heat shock proteins prevent the protein aggregate accumulation due to oxidative stress [ ]. Furthermore, JNK activity promotes nuclear translocation of FOXO4 and upregulates the expression of MnSOD [ 98 ].

It is clear that Akt and JNK both finally regulate FOXO activity, but they are working in apposite fashion to promote life span. Akt translocates FOXO into the cytosol and reduces the transcription of pro-apoptotic genes.

But JNK translocates FOXO into the nucleus and upregulates some anti-oxidant proteins. However, it is known that resveratrol inhibits the activity of JNK, so it can be assumed that resveratrol modulates FOXO transcription factors via AKT signaling path way.

PBEF is associated with increased Sirtuin activity, suggesting that it could be linked with anti-aging component [ 9 ]. I PBEF is also highly expressed in visceral fat of diabetes and obese patients [ ].

PBEF is secreted by activated lymphocytes, monocytes and neutrophils and exerts insulin-mimetic effects [ ]. A functional equivalent of PBEF, PNC1 is also a longevity gene, whose biochemical activity feeds into the Sirtuin pathway, and is upregulated by mRNA mistranslation [ ].

Pre B cell colony enhancing factor has been given a new name visfatin after the discovery that it is preferentially expressed in visceral fat [ ].

PBEF functions as anti-apoptotic protein and regulates energy metabolism during stress responses [ , ]. Recently, yeast Sir2 and its mouse ortholog SIRT1 have been found to be NAD-dependent deacetylases based on the finding that SIRT2 can extend life span of yeast, suggesting that NAD could be the missing link between longevity and ATP.

A recent study demonstrated increased expression of PBEF with resveratrol and wine [ 9 ]. However, our knowledge of the regulation of longevity with PBEF is very limited. It should be clear from our discussion that resveratrol, a phytoalexin polyphenolic anti-oxidant, can potentiate diverse functions in the body ranging from gene regulation to cell arrest.

Resveratrol acts like a miracle compound, which can protect the cells from many degenerative diseases including cardiovascular complications and cancer. Recent studies implicated resveratrol as an anti-aging compound from the observation that it could mimic the effects of calorie restriction by activating SIRT.

Subsequent studies demonstrated activation of several other longevity genes by resveratrol including SIRT3, SIRT4, FOXO1, FOXO3a and PBEF Fig. Recent studies conducted and supported in part by the National Institute of Aging NIA , however, challenged the ability of resveratrol to increase longevity [ 10 ].

The authors determined that resveratrol mimicked some, but not all the effects of calorie restriction in mice. More importantly, resveratrol abolished age-related and obesity-related decline in cardiovascular function including cholesterol level and inflammatory response, but could not affect survival or life span of mice suggesting that resveratrol could not modulate the basic aging process.

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Trends Endocrinol Metab — However, the studies on the role SIRT1 and how resveratrol may affect this gene are still controversial and contradictory.

Well, before you head over to Google to start ordering your resveratrol capsules, a couple of problems remain. While the studies of the effects of resveratrol are promising, none of these benefits have yet been demonstrated in humans.

Beside the lack of meaningful data as to its effects in people, before you reach for resveratrol as the new fountain of youth there is one other problems to consider: it is hard to get enough resveratrol into your body.

Resveratrol is found in a variety of plant sources. Peanuts and grape skins are good sources and most people think of wine as the best source of resveratrol. Most of the oral supplements on the market use resveratrol derived from the Japanese Knotwood plant.

Since resveratrol is found in the skin of the grape. The same grapes are used for both red and white wine. Whether the juice is fermented with or without the skins determines the color of the wine. Red wine is kept in contact with the grape skin much longer than white wine so red wines have much higher levels of resveratrol.

But the level of resveratrol varies greatly from wine to wine from as little as 0. This is more than a fold difference and there is no easy way to predict how much resveratrol is present in a particular wine. The bigger problem is that even when you find a wine that is high in resveratrol, or take an oral supplement of resveratrol, very little of it makes it into your blood stream.

Essentially all the blood flow from the intestines must first pass through the liver before entering the general circulation.

The liver is very effective at protecting us from toxins in our food and metabolizes most substances before they can reach the rest of the body. As quickly as you can absorb the resveratrol from your gut, the liver breaks it down before it reaches the rest of the body.

When volunteers were given much higher doses such as are present in most capsules only low levels of resveratrol appeared in the blood and within 4 hours it was completely gone. Researchers have concluded that it is very difficult for oral supplements to achieve blood concentrations of resveratrol that approach the levels that showed an effect in the laboratory studies.

Theoretically, there might be a small benefit in protecting against some digestive tract tumors from direct exposure to resveratrol in the gut.

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