Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 Al Pater wrote: > Hi All, > > Is it not current " wisdom " that taking more calories from alcoholic drinks > predisposes weight gain due to taking in the extra calories? It depends on why CR works. If it is the lower weight and fat, then this would work, but if it is a lowered metabolism, then the cost of digesting the alcohol, which may be why there is no weight gain, is counter productive to CR. Positive Dennis Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 Al Pater wrote: > Hi All, > > Is it not current " wisdom " that taking more calories from alcoholic drinks > predisposes weight gain due to taking in the extra calories? It depends on why CR works. If it is the lower weight and fat, then this would work, but if it is a lowered metabolism, then the cost of digesting the alcohol, which may be why there is no weight gain, is counter productive to CR. Positive Dennis Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 --- Dennis De Jarnette <positivedennis@...> wrote: > Al Pater wrote: > > > Hi All, > > > > Is it not current " wisdom " that taking more calories from alcoholic drinks > > predisposes weight gain due to taking in the extra calories? > > It depends on why CR works. If it is the lower weight and fat, then this > would work, but if it is a lowered metabolism, then the cost of > digesting the alcohol, which may be why there is no weight gain, is > counter productive to CR. Hi All, " However, the red wine didn't modify the fed efficiency 0.012 +/- 0.001 g/KJ for HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). " Al Pater, PhD; email: old542000@... __________________________________________________ Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 --- Dennis De Jarnette <positivedennis@...> wrote: > Al Pater wrote: > > > Hi All, > > > > Is it not current " wisdom " that taking more calories from alcoholic drinks > > predisposes weight gain due to taking in the extra calories? > > It depends on why CR works. If it is the lower weight and fat, then this > would work, but if it is a lowered metabolism, then the cost of > digesting the alcohol, which may be why there is no weight gain, is > counter productive to CR. Hi All, " However, the red wine didn't modify the fed efficiency 0.012 +/- 0.001 g/KJ for HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). " Al Pater, PhD; email: old542000@... __________________________________________________ Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 Al Pater wrote:> > > It depends on why CR works. If it is the lower weight and fat, then > this > > would work, but if it is a lowered metabolism, then the cost of > > digesting the alcohol, which may be why there is no weight gain, is > > counter productive to CR. > > Hi All, > > " However, the red wine didn't modify the fed efficiency 0.012 +/- > 0.001 g/KJ for > HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). " > > Al Pater, PhD; email: old542000@... But it would seem to me that the calories from wine must go somewhere. Where? Positive Dennis Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 Al Pater wrote:> > > It depends on why CR works. If it is the lower weight and fat, then > this > > would work, but if it is a lowered metabolism, then the cost of > > digesting the alcohol, which may be why there is no weight gain, is > > counter productive to CR. > > Hi All, > > " However, the red wine didn't modify the fed efficiency 0.012 +/- > 0.001 g/KJ for > HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). " > > Al Pater, PhD; email: old542000@... But it would seem to me that the calories from wine must go somewhere. Where? Positive Dennis Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 Re: [ ] Red wine for CR? Al Pater wrote:>> > It depends on why CR works. If it is the lower weight and fat, then > this> > would work, but if it is a lowered metabolism, then the cost of> > digesting the alcohol, which may be why there is no weight gain, is> > counter productive to CR.>> Hi All,>> "However, the red wine didn't modify the fed efficiency 0.012 +/- > 0.001 g/KJ for> HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080).">> Al Pater, PhD; email: old542000@...But it would seem to me that the calories from wine must go somewhere. Where? --Flirting, bad jokes, and sloppy, inefficient manipulation of the TV remote come to mind. Anonymous Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 Re: [ ] Red wine for CR? Al Pater wrote:>> > It depends on why CR works. If it is the lower weight and fat, then > this> > would work, but if it is a lowered metabolism, then the cost of> > digesting the alcohol, which may be why there is no weight gain, is> > counter productive to CR.>> Hi All,>> "However, the red wine didn't modify the fed efficiency 0.012 +/- > 0.001 g/KJ for> HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080).">> Al Pater, PhD; email: old542000@...But it would seem to me that the calories from wine must go somewhere. Where? --Flirting, bad jokes, and sloppy, inefficient manipulation of the TV remote come to mind. Anonymous Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 Red wine is probably the highest natural source of resveratrol (a sirtuin activating compound, or STAC), plus anthocyanins, I think, indicated by the red color. I know that STACs " turn on " the same gene that is activated by CR, but I wondered, do these compounds influence how our bodies store fat? I thought I had read something about this in the past. I found this article: Gene and grape antioxidant slice obesity away? 09/07/2004 - Progress towards tackling the obesity epidemic comes from a new study that finds a compound commonly found in red wine boosts the activity of an identified gene that cuts the growth of new fat cells. link to full article: http://www.nutraingredients.com/news/ng.asp?id=53448 Dave > > > > > It depends on why CR works. If it is the lower weight and fat, then > > this > > > would work, but if it is a lowered metabolism, then the cost of > > > digesting the alcohol, which may be why there is no weight gain, is > > > counter productive to CR. > > > > Hi All, > > > > " However, the red wine didn't modify the fed efficiency 0.012 +/- > > 0.001 g/KJ for > > HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). " > > > > Al Pater, PhD; email: old542000@y... > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 26, 2005 Report Share Posted September 26, 2005 Red wine is probably the highest natural source of resveratrol (a sirtuin activating compound, or STAC), plus anthocyanins, I think, indicated by the red color. I know that STACs " turn on " the same gene that is activated by CR, but I wondered, do these compounds influence how our bodies store fat? I thought I had read something about this in the past. I found this article: Gene and grape antioxidant slice obesity away? 09/07/2004 - Progress towards tackling the obesity epidemic comes from a new study that finds a compound commonly found in red wine boosts the activity of an identified gene that cuts the growth of new fat cells. link to full article: http://www.nutraingredients.com/news/ng.asp?id=53448 Dave > > > > > It depends on why CR works. If it is the lower weight and fat, then > > this > > > would work, but if it is a lowered metabolism, then the cost of > > > digesting the alcohol, which may be why there is no weight gain, is > > > counter productive to CR. > > > > Hi All, > > > > " However, the red wine didn't modify the fed efficiency 0.012 +/- > > 0.001 g/KJ for > > HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). " > > > > Al Pater, PhD; email: old542000@y... > Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 27, 2005 Report Share Posted September 27, 2005 The body can use extra energy to raise "metabolism". Like sometimes you can be hotter or at least feel hotter. Regards. Re: [ ] Red wine for CR? Al Pater wrote:>> > It depends on why CR works. If it is the lower weight and fat, then > this> > would work, but if it is a lowered metabolism, then the cost of> > digesting the alcohol, which may be why there is no weight gain, is> > counter productive to CR.>> Hi All,>> "However, the red wine didn't modify the fed efficiency 0.012 +/- > 0.001 g/KJ for> HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080).">> Al Pater, PhD; email: old542000@...But it would seem to me that the calories from wine must go somewhere. Where?Positive Dennis Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 27, 2005 Report Share Posted September 27, 2005 The body can use extra energy to raise "metabolism". Like sometimes you can be hotter or at least feel hotter. Regards. Re: [ ] Red wine for CR? Al Pater wrote:>> > It depends on why CR works. If it is the lower weight and fat, then > this> > would work, but if it is a lowered metabolism, then the cost of> > digesting the alcohol, which may be why there is no weight gain, is> > counter productive to CR.>> Hi All,>> "However, the red wine didn't modify the fed efficiency 0.012 +/- > 0.001 g/KJ for> HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080).">> Al Pater, PhD; email: old542000@...But it would seem to me that the calories from wine must go somewhere. Where?Positive Dennis Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 27, 2005 Report Share Posted September 27, 2005 --- Dave <davemaddux@...> wrote: > Red wine is probably the highest natural source of resveratrol (a > sirtuin activating compound, or STAC), plus anthocyanins, I think, > indicated by the red color. > > I know that STACs " turn on " the same gene that is activated by CR, but > I wondered, do these compounds influence how our bodies store fat? I > thought I had read something about this in the past. > > I found this article: > > > Gene and grape antioxidant slice obesity away? > > 09/07/2004 - Progress towards tackling the obesity epidemic comes > from a new study that finds a compound commonly found in red wine > boosts the activity of an identified gene that cuts the growth of new > fat cells. > > link to full article: > > http://www.nutraingredients.com/news/ng.asp?id=53448 > > > Dave > > > > > > > > > > It depends on why CR works. If it is the lower weight and fat, then > > > this > > > > would work, but if it is a lowered metabolism, then the cost of > > > > digesting the alcohol, which may be why there is no weight gain, is > > > > counter productive to CR. > > > > > > Hi All, > > > > > > " However, the red wine didn't modify the fed efficiency 0.012 +/- > > > 0.001 g/KJ for > > > HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). " Hi All, Below is the final discussion of the text of the review on how fats may be involved in the effects of aging. Most of the article documents much of what is known regarding the role of genetics of the lipidology of aging and these are available in the full-test available pdf. Sirt is again discussed regarding its controlling during CR of lipid metabolism. Unfortunately, the CR model for starvation is an overnight fast, in the reference, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\ ct & list_uids=15175761 The pdf of the review is available, the two Nature references from it are pdf-available and the third J Clin Invest paper is pdf-available free. Ordovas JM, Mooser V. Genes, lipids and aging: is it all accounted for by cardiovascular disease risk? Editorial review. Curr Opin Lipidol. 2005 Apr;16(2):121-6. No abstract available. PMID: 15767851 ... From gene variants to life-extending therapeutic interventions ... So far, the only intervention that has been shown to prolong life in model organisms from yeast to rodents is caloric restriction. One molecular mechanism linking potentially caloric restriction with longevity has recently been elucidated and appears to be closely related to the PPAR[gamma] pathway and possibly lipid metabolism. Picard et al. [45••] have shown that Sirt1 (sirtuin 1), the mammalian SIR2 orthologue, promotes fat mobilization in white adipocytes by repressing PPAR[gamma]. In yeast, the SIR2 gene mediates the life-extending effects of caloric restriction. These investigators demonstrate that Sirt1 activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and represses genes controlled by PPAR[gamma], including those genes mediating fat storage. Thus, the mobilization of fatty acids from white adipocytes upon fasting was impaired in Sirt1+/- mice. The investigators propose that Sirt1 represses PPAR[gamma] by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). As a reduction in fat is sufficient to extend murine lifespan, these results provide a possible molecular pathway connecting calorie restriction to life extension in mammals. Incidentally, red wine, which is known to raise plasma HDL-C, contains resveratrol, a potent activator of Sir2 in yeast [46••]. Interestingly enough, in Caenorhabditis elegans, the extension of lifespan by Sir2 requires the presence of daf-16, which is the only C. elegans homologue of the FOXO family of forkhead transcription factors. In rodents, it was recently demonstrated that viral delivery of forkhead box 01 (FOXO1) increases the expression of APOC3 [47••]. In these experiments, the investigators delivered FOXO1 cDNA to hepatocytes by adenovirus-mediated gene transfer. Foxo1 stimulated hepatic APOC3 expression by binding to its consensus site in the APOC3 promoter. Deletion or mutation of the Foxo1-binding site abolished insulin response and Foxo1-mediated stimulation. Similar findings were observed in enterocytes. Furthermore, elevated FOXO1 production in liver augmented hepatic APOC3 expression, which resulted in increased plasma triglyceride levels in mice. These data suggest that FOXO1 provides a molecular link between insulin deficiency or resistance and aberrant APOC3 production in the pathogenesis of diabetic hypertriglyceridemia. To summarize, data accumulated so far illustrate that a variety of genes involved in lipoprotein metabolism are associated with cardiovascular disease and, to a certain extent, with longevity. Although thus far tenuous, recent studies are providing clues to indicate that there is a crosstalk between genes involved in longevity and those involved in lipid metabolism and that lipid homeostasis could be involved in longevity beyond its effects on the cardiovascular system. Future directions Understanding the molecular basis of aging is one of the major challenges now facing the biomedical sciences. Genetics has shown to be a valuable tool. However, a large proportion of studies published so far have been limited by their design (i.e. cross-sectional design, small sample size, limited SNP coverage of small candidate genes, inter-ethnic differences). To benefit fully from the contribution of genetics, large prospective studies need to be designed, fully supported by extensive genotyping and analytical capacities. Numerous genes which have not been examined so far need to be interrogated (e.g. APOJ, SIRT1, etc.). Data from a variety of new genetically manipulated mouse models that are on the horizon and which shall contribute substantially to better understanding of the contribution of new pathways (like the Sirt1) to longevity and senescence need to be integrated with genetics. Even more importantly, a reliable intermediate phenotype for aging is urgently needed, both for genetic studies and for therapeutic interventions. ... 45•• Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004 Jun 17;429(6993):771-6. Epub 2004 Jun 2. PMID: 15175761 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\ ct & list_uids=15175761 http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0406 & L=crsociety & P=R5497 & X=\ 4E51A46A74251AE17D & Y=old542000 ... Addition of resveratrol greatly stimulated the release of FFA triggered by adrenalin (Fig. 2d) [3-4-fold for 10 and 50 microM] ... ... As yeast Sir2 is important during calorie restriction, we assayed by ChIP the recruitment of Sirt1 to PPAR--binding sites in the aP2 and PPAR- promoters in WAT of mice that were either fed or fasted. In mice fed ad libitum, Sirt1 was not bound to aP2 or PPAR- promoter sequences (Fig. 4c). However, Sirt1 was bound to these sequences after overnight food deprivation, showing that Sirt1 is recruited to PPAR- DNA-binding sites upon fasting. As a test of the effect of Sirt1 on fatty acid mobilization in adipocytes, we next addressed whether fatty acid release from WAT upon fasting was altered in Sirt1+/- mice. Heterozygous gene ablation was associated with a 40–45% lowering in circulating FFA levels in the blood after overnight food deprivation compared with wild type (Fig. 4d, P<0.05). To verify that these effects of Sirt1 genotype were due to differences in fat release from WAT and not re-uptake of FFA from the blood by oxidative tissues, we cultured the same number of white adipocytes from Sirt1+/+ and Sirt1+/- mice, challenged them with adrenalin, and measured the release of FFA. Again, FFA release was reduced in the Sirt1+/- cells compared with the Sirt1+/+ cells (Fig. 4e). Here we show that the mammalian Sir2 orthologue, Sirt1, is activated by food deprivation to trigger fat mobilization in WAT. The pharmacological activation of Sirt1 also elicits the lipolysis of triglycerides and the release of FFA. Because a reduction in fat storage in WAT is a primary way by which calorie restriction extends lifespan in mammals, our results provide a possible mechanism for understanding the regulation of mammalian lifespan by diet. Sirt1 represses WAT by inhibiting the nuclear receptor PPAR-13, 19. Starvation of animals causes Sirt1 to interact with PPAR- DNA-binding sites and thereby repress target genes that drive fat storage19. We do not yet know whether Sirt1 is activated upon fasting by a change in the NAD/NADH ratio, as has been proposed in yeast22, or by other metabolic changes. It is also uncertain whether Sirt1 deacetylates PPAR-, histones at target genes, or both. The pathway of regulation described here may impact on age-related diseases. The accumulation of WAT during ageing is associated with several adverse complications, such as insulin resistance, type 2 diabetes and atherosclerosis23. Given the impact of Sirt1 on PPAR- activity and because PPAR- activity helps determine age-related insulin resistance24, Sirt1 may have an important role in metabolic diseases and link the effects of food consumption to body fat mass and diseases of ageing. It is likely that calorie restriction exerts other effects on mammals to increase longevity, besides reducing WAT, as longevity in mice with reduced fat is not as great as animals on a long-term calorie restriction regimen. Tissues that metabolize fat and carbohydrate may also be important in delivering some of the benefit of calorie restriction, and it will be of interest to determine whether Sirt1 upregulates metabolism upon food reduction to round out an optimal profile for long life. 46•• Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24. PMID: 12939617 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\ ct & list_uids=12939617 47•• Altomonte J, Cong L, Harbaran S, Richter A, Xu J, Meseck M, Dong HH. Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Invest. 2004 Nov;114(10):1493-503. PMID: 15546000 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\ ct & list_uids=15546000 http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & pubmedid=1554600\ 0 Al Pater, PhD; email: old542000@... __________________________________ - PC Magazine Editors' Choice 2005 http://mail. Quote Link to comment Share on other sites More sharing options...
Guest guest Posted September 27, 2005 Report Share Posted September 27, 2005 --- Dave <davemaddux@...> wrote: > Red wine is probably the highest natural source of resveratrol (a > sirtuin activating compound, or STAC), plus anthocyanins, I think, > indicated by the red color. > > I know that STACs " turn on " the same gene that is activated by CR, but > I wondered, do these compounds influence how our bodies store fat? I > thought I had read something about this in the past. > > I found this article: > > > Gene and grape antioxidant slice obesity away? > > 09/07/2004 - Progress towards tackling the obesity epidemic comes > from a new study that finds a compound commonly found in red wine > boosts the activity of an identified gene that cuts the growth of new > fat cells. > > link to full article: > > http://www.nutraingredients.com/news/ng.asp?id=53448 > > > Dave > > > > > > > > > > It depends on why CR works. If it is the lower weight and fat, then > > > this > > > > would work, but if it is a lowered metabolism, then the cost of > > > > digesting the alcohol, which may be why there is no weight gain, is > > > > counter productive to CR. > > > > > > Hi All, > > > > > > " However, the red wine didn't modify the fed efficiency 0.012 +/- > > > 0.001 g/KJ for > > > HFRWD group versus 0.013 +/- 0.001 g/KJ for the HFD one (P=.080). " Hi All, Below is the final discussion of the text of the review on how fats may be involved in the effects of aging. Most of the article documents much of what is known regarding the role of genetics of the lipidology of aging and these are available in the full-test available pdf. Sirt is again discussed regarding its controlling during CR of lipid metabolism. Unfortunately, the CR model for starvation is an overnight fast, in the reference, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\ ct & list_uids=15175761 The pdf of the review is available, the two Nature references from it are pdf-available and the third J Clin Invest paper is pdf-available free. Ordovas JM, Mooser V. Genes, lipids and aging: is it all accounted for by cardiovascular disease risk? Editorial review. Curr Opin Lipidol. 2005 Apr;16(2):121-6. No abstract available. PMID: 15767851 ... From gene variants to life-extending therapeutic interventions ... So far, the only intervention that has been shown to prolong life in model organisms from yeast to rodents is caloric restriction. One molecular mechanism linking potentially caloric restriction with longevity has recently been elucidated and appears to be closely related to the PPAR[gamma] pathway and possibly lipid metabolism. Picard et al. [45••] have shown that Sirt1 (sirtuin 1), the mammalian SIR2 orthologue, promotes fat mobilization in white adipocytes by repressing PPAR[gamma]. In yeast, the SIR2 gene mediates the life-extending effects of caloric restriction. These investigators demonstrate that Sirt1 activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and represses genes controlled by PPAR[gamma], including those genes mediating fat storage. Thus, the mobilization of fatty acids from white adipocytes upon fasting was impaired in Sirt1+/- mice. The investigators propose that Sirt1 represses PPAR[gamma] by docking with its cofactors NCoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors). As a reduction in fat is sufficient to extend murine lifespan, these results provide a possible molecular pathway connecting calorie restriction to life extension in mammals. Incidentally, red wine, which is known to raise plasma HDL-C, contains resveratrol, a potent activator of Sir2 in yeast [46••]. Interestingly enough, in Caenorhabditis elegans, the extension of lifespan by Sir2 requires the presence of daf-16, which is the only C. elegans homologue of the FOXO family of forkhead transcription factors. In rodents, it was recently demonstrated that viral delivery of forkhead box 01 (FOXO1) increases the expression of APOC3 [47••]. In these experiments, the investigators delivered FOXO1 cDNA to hepatocytes by adenovirus-mediated gene transfer. Foxo1 stimulated hepatic APOC3 expression by binding to its consensus site in the APOC3 promoter. Deletion or mutation of the Foxo1-binding site abolished insulin response and Foxo1-mediated stimulation. Similar findings were observed in enterocytes. Furthermore, elevated FOXO1 production in liver augmented hepatic APOC3 expression, which resulted in increased plasma triglyceride levels in mice. These data suggest that FOXO1 provides a molecular link between insulin deficiency or resistance and aberrant APOC3 production in the pathogenesis of diabetic hypertriglyceridemia. To summarize, data accumulated so far illustrate that a variety of genes involved in lipoprotein metabolism are associated with cardiovascular disease and, to a certain extent, with longevity. Although thus far tenuous, recent studies are providing clues to indicate that there is a crosstalk between genes involved in longevity and those involved in lipid metabolism and that lipid homeostasis could be involved in longevity beyond its effects on the cardiovascular system. Future directions Understanding the molecular basis of aging is one of the major challenges now facing the biomedical sciences. Genetics has shown to be a valuable tool. However, a large proportion of studies published so far have been limited by their design (i.e. cross-sectional design, small sample size, limited SNP coverage of small candidate genes, inter-ethnic differences). To benefit fully from the contribution of genetics, large prospective studies need to be designed, fully supported by extensive genotyping and analytical capacities. Numerous genes which have not been examined so far need to be interrogated (e.g. APOJ, SIRT1, etc.). Data from a variety of new genetically manipulated mouse models that are on the horizon and which shall contribute substantially to better understanding of the contribution of new pathways (like the Sirt1) to longevity and senescence need to be integrated with genetics. Even more importantly, a reliable intermediate phenotype for aging is urgently needed, both for genetic studies and for therapeutic interventions. ... 45•• Picard F, Kurtev M, Chung N, Topark-Ngarm A, Senawong T, Machado De Oliveira R, Leid M, McBurney MW, Guarente L. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature. 2004 Jun 17;429(6993):771-6. Epub 2004 Jun 2. PMID: 15175761 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\ ct & list_uids=15175761 http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0406 & L=crsociety & P=R5497 & X=\ 4E51A46A74251AE17D & Y=old542000 ... Addition of resveratrol greatly stimulated the release of FFA triggered by adrenalin (Fig. 2d) [3-4-fold for 10 and 50 microM] ... ... As yeast Sir2 is important during calorie restriction, we assayed by ChIP the recruitment of Sirt1 to PPAR--binding sites in the aP2 and PPAR- promoters in WAT of mice that were either fed or fasted. In mice fed ad libitum, Sirt1 was not bound to aP2 or PPAR- promoter sequences (Fig. 4c). However, Sirt1 was bound to these sequences after overnight food deprivation, showing that Sirt1 is recruited to PPAR- DNA-binding sites upon fasting. As a test of the effect of Sirt1 on fatty acid mobilization in adipocytes, we next addressed whether fatty acid release from WAT upon fasting was altered in Sirt1+/- mice. Heterozygous gene ablation was associated with a 40–45% lowering in circulating FFA levels in the blood after overnight food deprivation compared with wild type (Fig. 4d, P<0.05). To verify that these effects of Sirt1 genotype were due to differences in fat release from WAT and not re-uptake of FFA from the blood by oxidative tissues, we cultured the same number of white adipocytes from Sirt1+/+ and Sirt1+/- mice, challenged them with adrenalin, and measured the release of FFA. Again, FFA release was reduced in the Sirt1+/- cells compared with the Sirt1+/+ cells (Fig. 4e). Here we show that the mammalian Sir2 orthologue, Sirt1, is activated by food deprivation to trigger fat mobilization in WAT. The pharmacological activation of Sirt1 also elicits the lipolysis of triglycerides and the release of FFA. Because a reduction in fat storage in WAT is a primary way by which calorie restriction extends lifespan in mammals, our results provide a possible mechanism for understanding the regulation of mammalian lifespan by diet. Sirt1 represses WAT by inhibiting the nuclear receptor PPAR-13, 19. Starvation of animals causes Sirt1 to interact with PPAR- DNA-binding sites and thereby repress target genes that drive fat storage19. We do not yet know whether Sirt1 is activated upon fasting by a change in the NAD/NADH ratio, as has been proposed in yeast22, or by other metabolic changes. It is also uncertain whether Sirt1 deacetylates PPAR-, histones at target genes, or both. The pathway of regulation described here may impact on age-related diseases. The accumulation of WAT during ageing is associated with several adverse complications, such as insulin resistance, type 2 diabetes and atherosclerosis23. Given the impact of Sirt1 on PPAR- activity and because PPAR- activity helps determine age-related insulin resistance24, Sirt1 may have an important role in metabolic diseases and link the effects of food consumption to body fat mass and diseases of ageing. It is likely that calorie restriction exerts other effects on mammals to increase longevity, besides reducing WAT, as longevity in mice with reduced fat is not as great as animals on a long-term calorie restriction regimen. Tissues that metabolize fat and carbohydrate may also be important in delivering some of the benefit of calorie restriction, and it will be of interest to determine whether Sirt1 upregulates metabolism upon food reduction to round out an optimal profile for long life. 46•• Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6. Epub 2003 Aug 24. PMID: 12939617 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\ ct & list_uids=12939617 47•• Altomonte J, Cong L, Harbaran S, Richter A, Xu J, Meseck M, Dong HH. Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. J Clin Invest. 2004 Nov;114(10):1493-503. PMID: 15546000 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstra\ ct & list_uids=15546000 http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & pubmedid=1554600\ 0 Al Pater, PhD; email: old542000@... __________________________________ - PC Magazine Editors' Choice 2005 http://mail. Quote Link to comment Share on other sites More sharing options...
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