In Vino Veritas: A Tale of Two Sirt1s?
2006; Cell Press; Volume: 127; Issue: 6 Linguagem: Inglês
10.1016/j.cell.2006.11.034
ISSN1097-4172
Autores Tópico(s)Genetics, Aging, and Longevity in Model Organisms
ResumoResveratrol increases life span in lower organisms by activating the NAD+-dependent histone deacetylase Sirt1. Studies by Lagouge et al., 2006Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. et al.Cell. 2006; (this issue. Published online November 22, 2006)https://doi.org/10.1016/j.cell.2006.11.013Abstract Full Text Full Text PDF PubMed Scopus (3065) Google Scholar and Baur et al., 2006Baur J.A. Pearson K.J. Price N.L. Jamieson H.A. Lerin C. Kalra A. Prabhu V.V. Allard J.S. Lopez-Lluch G. Lewis K. et al.Nature. 2006; 444: 337-342Crossref PubMed Scopus (3430) Google Scholar now show that resveratrol promotes longevity and improves glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the transcriptional coactivator PGC-1α. Resveratrol increases life span in lower organisms by activating the NAD+-dependent histone deacetylase Sirt1. Studies by Lagouge et al., 2006Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. et al.Cell. 2006; (this issue. Published online November 22, 2006)https://doi.org/10.1016/j.cell.2006.11.013Abstract Full Text Full Text PDF PubMed Scopus (3065) Google Scholar and Baur et al., 2006Baur J.A. Pearson K.J. Price N.L. Jamieson H.A. Lerin C. Kalra A. Prabhu V.V. Allard J.S. Lopez-Lluch G. Lewis K. et al.Nature. 2006; 444: 337-342Crossref PubMed Scopus (3430) Google Scholar now show that resveratrol promotes longevity and improves glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the transcriptional coactivator PGC-1α. During the 15th century, the Venetian nobleman Luigi Cornaro documented the beneficial effects of caloric restriction (he survived to the age of 102) in a treatise entitled "On the Sober Life." Everyone has a different measure of sobriety—Cornaro's daily diet included 14 oz. of red wine. Indeed, resveratrol, a polyphenolic flavonoid enriched in the skins of red grapes, has been shown to increase life span in lower organisms by binding to and enhancing the activity of the nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase Sirt1 (Blander and Guarente, 2004Blander G. Guarente L. Annu. Rev. Biochem. 2004; 73: 417-435Crossref PubMed Scopus (1235) Google Scholar). First identified as a transcriptional silencer in yeast, Sirt1 modulates the activity of a number of transcriptional regulators in mammals, most notably PGC-1α, a nuclear hormone receptor coactivator that promotes mitochondrial biogenesis in skeletal muscle and brown adipose tissue (Figure 1). Two new studies by Auwerx (Lagouge et al., 2006Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. et al.Cell. 2006; (this issue. Published online November 22, 2006)https://doi.org/10.1016/j.cell.2006.11.013Abstract Full Text Full Text PDF PubMed Scopus (3065) Google Scholar) and Sinclair (Baur et al., 2006Baur J.A. Pearson K.J. Price N.L. Jamieson H.A. Lerin C. Kalra A. Prabhu V.V. Allard J.S. Lopez-Lluch G. Lewis K. et al.Nature. 2006; 444: 337-342Crossref PubMed Scopus (3430) Google Scholar) demonstrate that resveratrol improves energy balance and increases mitochondrial function in mice by stimulating the Sirt1-mediated deacetylation of PGC-1α. The results have important implications for the treatment of type II diabetes and perhaps other diseases associated with aging. Obesity is a major risk factor in the development of insulin resistance, which is characterized by reduced glucose utilization in skeletal muscle. Chronic hyperglycemia, a hallmark of insulin resistance in the diabetic state, increases the production of reactive oxygen species, promotes mitochondrial damage, and impairs oxygen consumption in peripheral tissues. During fasting and caloric restriction, by contrast, elevations in cellular NAD+ are thought to protect against oxidative stress and to promote cell survival by stimulating Sirt1 activity. Because it increases the affinity of Sirt1 for NAD+, resveratrol would be predicted to improve metabolic function in the setting of obesity, where cellular NAD+ levels are low. The Auwerx and Sinclair groups tested this idea on mice that were fed a high-fat diet, which commonly promotes insulin resistance. Both groups saw beneficial effects of resveratrol on circulating glucose and insulin levels; but the apparent mechanisms of insulin sensitization were quite different. Using oral doses 10- to 20-fold higher than the Sinclair group, Auwerx and colleagues found that short-term (15 week) resveratrol treatment protected young (4- to 8-week-old) male mice against obesity induced by a high-fat diet (Lagouge et al., 2006Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. et al.Cell. 2006; (this issue. Published online November 22, 2006)https://doi.org/10.1016/j.cell.2006.11.013Abstract Full Text Full Text PDF PubMed Scopus (3065) Google Scholar). Indeed, amounts of adipose tissue were significantly reduced in these mice, due in part to increased fat burning by the mitochondria-enriched brown adipose tissue. In keeping with the role of brown fat in adaptive thermogenesis, core body temperatures were elevated in resveratrol-treated mice following cold exposure. The health benefits here are uncertain, however, as increases in core body temperature are thought to correlate with a reduced life span (Conti et al., 2006Conti B. Sanchez-Alavez M. Winsky-Sommerer R. Morale M.C. Lucero J. Brownell S. Fabre V. Huitron-Resendiz S. Henriksen S. Zorrilla E.P. et al.Science. 2006; 314: 825-828Crossref PubMed Scopus (269) Google Scholar). Rather, lowering core body temperature has been show to increase survival in mice. Although they gain more weight than wild-type animals, such "cool mice" are apparently protected from oxidative damage in peripheral tissues because of reduced energy expenditure. In addition to its effects on adiposity, resveratrol also improved muscle function; resveratrol-treated mice were less prone to exercise-induced fatigue due to an increase in the proportion of slow-twitch/oxidative muscle fibers relative to fast-twitch/glycolytic fibers. Consistent with these changes, resveratrol increased the expression of mitochondrial genes and genes involved in oxidative phosphorylation. This is an important finding because expression of genes involved in oxidative phosphorylation is often reduced in skeletal muscle from individuals with type II diabetes (Mootha et al., 2003Mootha V.K. Lindgren C.M. Eriksson K.F. Subramanian A. Sihag S. Lehar J. Puigserver P. Carlsson E. Ridderstrale M. Laurila E. et al.Nat. Genet. 2003; 34: 267-273Crossref PubMed Scopus (5034) Google Scholar, Patti et al., 2003Patti M.E. Butte A.J. Crunkhorn S. Cusi K. Berria R. Kashyap S. Miyazaki Y. Kohane I. Costello M. Saccone R. et al.Proc. Natl. Acad. Sci. USA. 2003; 100: 8466-8471Crossref PubMed Scopus (1546) Google Scholar). But how does resveratrol stimulate expression of these genes? Enter PGC-1α, a nuclear hormone receptor coactivator previously shown to increase the proportion of slow-twitch fibers to fast-twitch fibers and to increase mitochondrial biogenesis in both muscle and brown adipose tissue (Lin et al., 2005Lin J. Handschin C. Spiegelman B.M. Cell Metab. 2005; 1: 361-370Abstract Full Text Full Text PDF PubMed Scopus (1514) Google Scholar). Auwerx found that resveratrol increased PGC-1α activity in muscle by promoting its deacetylation by Sirt1 (Lagouge et al., 2006Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. et al.Cell. 2006; (this issue. Published online November 22, 2006)https://doi.org/10.1016/j.cell.2006.11.013Abstract Full Text Full Text PDF PubMed Scopus (3065) Google Scholar). Consistent with this idea, resveratrol had no effect on the expression of PGC-1α target genes in cells deficient in Sirt1 or in myotubes expressing a mutant PGC-1α protein that could not be acetylated. Extending their studies to humans, the Auwerx group found that asymptomatic offspring of type II diabetic patients with single nucleotide polymorphisms (SNPs) in the Sirt1 gene exhibit abnormal energy expenditure relative to controls (Lagouge et al., 2006Lagouge M. Argmann C. Gerhart-Hines Z. Meziane H. Lerin C. Daussin F. Messadeq N. Milne J. Lambert P. Elliott P. et al.Cell. 2006; (this issue. Published online November 22, 2006)https://doi.org/10.1016/j.cell.2006.11.013Abstract Full Text Full Text PDF PubMed Scopus (3065) Google Scholar). The studies were performed on a relatively small patient population; if confirmed in other groups, however, these SNPS may have prognostic value in identifying individuals at higher risk of developing type II diabetes. Taken together, these studies support the idea that resveratrol improves energy balance under conditions of a high-fat diet by triggering the SirT1:PGC-1α pathway and thereby stimulating mitochondrial function. Using an older (1-year-old) cohort of mice compared to the Auwerx study, the Sinclair group found that chronic (1+ years) treatment with resveratrol at one-tenth the dose of the Auwerx group not only improved insulin sensitivity but, remarkably, increased life span in mice fed a high-fat diet (Baur et al., 2006Baur J.A. Pearson K.J. Price N.L. Jamieson H.A. Lerin C. Kalra A. Prabhu V.V. Allard J.S. Lopez-Lluch G. Lewis K. et al.Nature. 2006; 444: 337-342Crossref PubMed Scopus (3430) Google Scholar). As opposed to the Auwerx group, the Sinclair study observed no effect of resveratrol on weight gain, adiposity, or core body temperature. Rather they found that resveratrol improved glucose and lipid metabolism specifically in liver. Perhaps the most striking observation was the ability of resveratrol to protect mice against development of hepatic steatosis or fatty liver, a condition commonly associated with obesity and insulin resistance. In contrast, the Auwerx group found no changes in liver histology between resveratrol-treated and control groups, which might reflect the shorter time course of resveratrol treatment or the younger cohort of mice they employed. Sinclair and colleagues also found that, at doses comparable to the Auwerx study, resveratrol administration increased amounts of deacetylated and therefore active PGC-1α in liver (Baur et al., 2006Baur J.A. Pearson K.J. Price N.L. Jamieson H.A. Lerin C. Kalra A. Prabhu V.V. Allard J.S. Lopez-Lluch G. Lewis K. et al.Nature. 2006; 444: 337-342Crossref PubMed Scopus (3430) Google Scholar). However, the induction of PGC-1α by resveratrol in liver is difficult to reconcile with the fact that PGC-1α triggers the gluconeogenic program and increases hepatic glucose production following its deacetylation by Sirt1 in fasted mice (Rodgers et al., 2005Rodgers J.T. Lerin C. Haas W. Gygi S.P. Spiegelman B.M. Puigserver P. Nature. 2005; 434: 113-118Crossref PubMed Scopus (2352) Google Scholar). Rather, Sinclair and colleagues attribute the lowering of glucose with resveratrol treatment to the activation of the stress- and energy-sensing Ser/Thr kinase AMPK, a potent inhibitor of gluconeogenesis. Because it increases fatty-acid oxidation through phosphorylation and inhibition of acetyl coA carboxylase (the rate-limiting enzyme in fatty-acid synthesis), AMPK may also protect mice treated with resveratrol against development of a fatty liver. However, whether resveratrol increases AMPK activity via Sirt1 is unclear; other polyphenols, which are not known to activate Sirt1, are also capable of stimulating AMPK (Zang et al., 2006Zang M. Xu S. Maitland-Toolan K.A. Zuccollo A. Hou X. Jiang B. Wierzbicki M. Verbeuren T.J. Cohen R.A. Diabetes. 2006; 55: 2180-2191Crossref PubMed Scopus (540) Google Scholar). Indeed, some of the insulin-sensitizing effects of resveratrol in the Auwerx study may also reflect AMPK activation. What could explain the apparent differences between the two studies? Following oral administration, resveratrol is rapidly glucuronidated and presumably inactivated in the liver (Gescher and Steward, 2003Gescher A.J. Steward W.P. Cancer Epidemiol. Biomarkers Prev. 2003; 12: 953-957PubMed Google Scholar). The 10- to 20-fold higher dose of resveratrol used in the Auwerx study may be sufficient to promote its accumulation and to trigger Sirt1 activation in brown fat and muscle. As well, potential off-target effects of resveratrol on AMPK and other pathways may be more pronounced at these higher doses. Age-specific effects may also factor in. Amounts of brown adipose tissue have been shown to decline with age in rodents (McDonald and Horwitz, 1999McDonald R.B. Horwitz B.A. J. Bioenerg. Biomembr. 1999; 31: 507-516Crossref PubMed Scopus (51) Google Scholar); and impairments in the function of brown adipose tissue may explain why resveratrol did not increase core body temperature or protect older mice from obesity induced by a high-fat diet in the Sinclair study. Further work on mice with muscle- and liver-specific knockouts of Sirt1 and PGC-1α should reveal the extent to which resveratrol modulates energy homeostasis via these effectors. Taken together, the two studies point to an interesting parallel between the AMPK and Sirt1 signaling pathways. Both pathways are energy sensing (AMP and NAD+), are triggered in response to fasting, and are capable of extending life span. In mammals, AMPK and Sirt1 also increase insulin sensitivity by improving glucose utilization, apparently via a mechanism that is dependent on PGC-1α. Future biochemical studies may reveal the extent to which these two pathways converge on PGC-1α and perhaps other regulators of glucose and lipid metabolism. Whatever the result, the Auwerx and Sinclair papers have provided new insight into the remarkable effects of a natural compound on life span and metabolism in mammals. As we await the development of more potent resveratrol analogs, perhaps we are best advised to heed Cornaro's advice that "men should live up to the simplicity dictated by nature, which teaches us to be content with little…." Resveratrol Improves Mitochondrial Function and Protects against Metabolic Disease by Activating SIRT1 and PGC-1αLagouge et al.CellDecember 15, 2006In BriefDiminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1α acetylation and an increase in PGC-1α activity. Full-Text PDF Open Archive
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