Previews when the life-span defect of SIR2 deletion is suppressed by deletion of a second gene, FOB1, mother cells respond robustly to dietary restriction and live substantially longer than wild-type cells (Kaeberlein et al., 2004). What makes the study by Li et al. particularly interesting is the observation that SirT1 inhibition causes some phenotypes more consistent with a slower rate of aging. For example, they show that SirT1 inhibition leads to increased IRS-2 acetylation, decreased IGF-1 signaling, and decreased Ras/ERK signaling. Decreased Ras signaling increases life span in yeast, and reduced insulin/IGF-1-like signaling is associated with increased life span in worms, flies, and mice. Supporting the idea that inhibition of SirT1 may slow aspects of aging in mice, Li et al. proceed to show enhanced resistance to oxidative stress in neuronal cells after SirT1 knockdown and reduced oxidation of proteins and lipids in brains of SirT1 knockout animals. Taken together, these data may indicate that inhibition of SirT1 can be neuroprotective in aging animals and that some features of aging are slowed rather than accelerated in SirT1 knockout animals. So what’s the ‘‘take-home message’’ from all this? Is more SirT1 good, or is less SirT1 good? The answer, as is often
the case in biology, is that there’s no simple answer. Activating SirT1 is probably a good thing in some cells under some conditions and is probably a bad thing in other cells under other conditions. SirT1 activators may be good for diabetes but may cause cancer due to p53 inhibition, SirT1 inhibitors may protect against cancer but cause metabolic disease, and there is evidence supporting the idea that both activators and inhibitors of SirT1 can confer protection against neurodegeneration in different contexts. The one thing that seems clear is that sirtuin activators are unlikely to be a ‘‘magic bullet’’ for aging. A more realistic hope is that, as we continue to unravel the complexities of sirtuin biology, targeted activation or inhibition of SirT1—and perhaps other sirtuins as well—will prove therapeutically useful toward a subset of age-associated diseases. Such an achievement would be a huge step forward in the transition of aging-related science from the laboratory to the clinic, and we eagerly await the next chapter in the unfolding saga that is sirtuin biology.
Baur, 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. (2006). Nature 444, 337–342. Baur, J.A., and Sinclair, D.A. (2006). Nat. Rev. Drug Discov. 5, 493–506. Fabrizio, P., Gattazzo, C., Battistella, L., Wei, M., Cheng, C., McGrew, K., and Longo, V.D. (2005). Cell 123, 655–667. Guarente, L., and Picard, F. (2005). Cell 120, 473– 482. Haigis, M.C., and Guarente, L.P. (2006). Genes Dev. 20, 2913–2921. Kaeberlein, M., Kirkland, K.T., Fields, S., and Kennedy, B.K. (2004). PLoS Biol. 2, E296. Kaeberlein, M., McDonagh, T., Heltweg, B., Hixon, J., Westman, E.A., Caldwell, S.D., Napper, A., Curtis, R., Distefano, P.S., Fields, S., et al. (2005). J. Biol. Chem. 280, 17038–17045. Kaeberlein, M., and Powers, R.W., 3rd. (2007). Ageing Res. Rev. 6, 128–140. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., et al. (2006). Cell 127, 1109–1122. Li, Y., Xu, W., Wei, M., Fabrizio, P., Parrella, E., and Longo, V.D. (2008). Cell Metab. 8, this issue, 38–48.
REFERENCES Bass, T.M., Weinkove, D., Houthoofd, K., Gems, D., and Partridge, L. (2007). Mech. Ageing Dev. 128, 546–552.
Longo, V.D., and Kennedy, B.K. (2006). Cell 126, 257–268.
Diabetes Risk Begins In Utero Melissa Woo1 and Mary-Elizabeth Patti1,* 1Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA *Correspondence: [email protected]
Both intrauterine and postnatal environments contribute to diabetes risk. A recent paper highlights epigenetic mechanisms underlying b cell dysfunction associated with intrauterine growth retardation, including repressive histone modification and DNA methylation during postnatal life. Thus, intrauterine stress can initiate a disturbing epigenetic cascade of progressive transcriptional repression linked to b cell failure. The prevalence of childhood obesity and type 2 diabetes (DM) has increased dramatically in the past 50 years. While overnutrition and a sedentary lifestyle clearly contribute to these findings, the intrauterine and early postnatal environment are also key contributors to obesity
and DM risk. A recent paper (Park et al., 2008) highlights epigenetic mechanisms linking intrauterine growth retardation to b cell dysfunction and diabetes risk. The association between low birth weight and adult disease was first reported by David Barker (Barker et al.,
1989). Barker accessed the records of 15,000 men and women born before 1930 whose medical history was meticulously documented by nurses in Hertfordshire, England. Using this information, he made a landmark observation: Birth weight is inversely correlated with the risk
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Previews of cardiovascular disease in adulthood. This observation spurred subsequent epidemiological studies in multiple countries that revealed a strong association between fetal growth retardation, low birth weight, and increased risk of DM and cardiovascular disease (Barker et al., 1993). In addition to low birth weight, rapid postnatal weight gain is also associated with increased susceptibility to obesity and DM. Thus, individuals who are both small at birth and have accelerated early postnatal (‘‘catchup’’) growth are at very high risk for central obesity and DM. Rapid weight gain later in childhood and early timing of adiposity rebound (minimum BMI during early childhood) also predict adult disease risk (Barker et al., 2005). Experimentally, prevention of postnatal catchup growth normalizes both glucose intolerance and obesity (Jimenez-Chillaron et al., 2006). Together, such data have led to the formulation of the developmental origins of adult disease hypothesis, which proposes that nutritional or environmental stimuli, acting during critical windows in development, can have a lasting impact on cellular structure and function and on patterns of adult disease (Barker et al., 1989). Thus, early life stressors such as maternal undernutrition, maternal obesity, corticosteroid therapy, uteroplacental insufficiency, or hypoxia, particularly when followed by accelerated postnatal growth and/or positive caloric balance, may ‘‘program’’ metabolic adaptations that favor survival initially, but are ultimately detrimental to adult health. Interestingly, some phenotypes associated with low birth weight can also be transmitted to a second generation, initiating a vicious cycle of DM risk (Drake and Walker, 2004). The molecular mechanisms mediating risk associated with a suboptimal intrauterine and early postnatal environment have not been fully elucidated. However, several lines of evidence indicate that epigenetic modification may be a key unifying mechanism. First, disruption of physiologic responses and functional capacity is observed in multiple tissues of LBW animals and humans, including muscle, adipose, pancreatic b cells, liver, and CNS (Jensen et al., 2007; Jimenez-Chillaron et al., 2005; Fu et al., 2004). These tissue effects may be related to altered gene expression, in turn potentially mediated by histone modification and DNA
methylation effects on chromatin structure. DNA methylation, although typically relatively stable during adult life, can be altered by the early-life nutrient/metabolic environment (Waterland and Jirtle, 2003). Histone modification is a more dynamic regulatory process, but can also be altered by the intrauterine and postnatal milieu (Fu et al., 2004). Finally, both epigenetic modification and phenotypes linked to early nutrition can be transmitted to subsequent generations and may contribute to ‘‘intergenerational programming’’ of obesity and DM risk (Drake and Walker, 2004). The recent publication of Park et al. (2008) further expands our knowledge of the epigenetic patterns associated with adult metabolic phenotypes resulting from intrauterine stress. Simmons and colleagues have previously developed a rat model of intrauterine growth retardation (IUGR) produced by uterine artery ligation; IUGR offspring develop impaired b cell mass, insulin secretory dysfunction, and DM with aging. A consistent finding in this model is progressive reduction in expression of PDX1, a key transcription factor regulating pancreatic development and function (Stoffers et al., 2003); during fetal life, expression of PDX1 is reduced by 50% in IUGR fetuses and by 80% in adult rats with a history of IUGR. Notably, these changes precede the onset of b cell dysfunction, suggesting a primary pathogenic role. The PDX promoter is a target for epigenetic modification, as it contains a conserved CpG island (potential site of altered DNA methylation) and is associated with high levels of histone acetylation. Park and colleagues asked whether alterations in histone modification may mediate reduced activity of the PDX promoter. Interestingly, binding of both acetylated histone H3/H4 and the transcription factor USF1 was abolished in IUGR fetuses. By 2 weeks of age, these changes were accompanied by reduced binding of the activating H3K4me3, increased binding of the repressive H3K9me2, and increased binding of HDAC1 and mSin3A. These patterns increased by 6 months of age, in parallel with progressive loss of b cell function in IUGR rats. Park and colleagues also evaluated PDX1 promoter methylation patterns using pyrosequencing of bisulfite-treated DNA. While there was 50% methylation at multiple CpGs in IUGR
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adults, in association with binding of DNMT1 and 3a methyltransferases, no methylation was detected in IUGR neonates—indicating that methylation was unlikely to explain PDX1 repression early in life. Furthermore, DNA methyltransferase inhibition did not normalize PDX expression ex vivo, while patterns of histone modification, USF binding to the PDX promoter, and PDX expression were largely normalized by HDAC inhibition. Similar epigenetic patterns, with repressive histone modifications without altered DNA methylation, have also been recently associated with reduced expression of the GLUT4 glucose transporter in skeletal muscle in rats with both intrauterine and early postnatal caloric restriction (Raychaudhuri et al., 2008). Together, these data indicate that progressive silencing of gene expression is largely linked to abnormal patterns of histone modification, which can be observed within days following the onset of intrauterine stress. More importantly, these early epigenetic changes initiate a disturbing pattern of progressive transcriptional repression— even in the absence of further experimental insults during postnatal life. Together, these elegant studies provide molecular evidence to support epigenetic mechanisms linking the fetal environment to progressive transcriptional dysregulation and adult disease risk (Figure 1). Many questions remain unanswered. Which components of the intrauterine metabolic environment initiate the developmental cascade of epigenetic modification? Which mechanisms contribute to progressive methylation with aging? Are similar patterns observed for additional key regulatory genes, in other models of IUGR, in other tissues, or in humans? These data on the surface may initially provoke pessimism—that diabetes risk is ‘‘programmed’’ during prenatal life and therefore less modifiable. However, animal studies indicate that there are critical periods of developmental plasticity during which nutritional and pharmacologic interventions can reverse abnormal metabolic function and reduce the risk of adult disease (Jimenez-Chillaron et al., 2006; Stoffers et al., 2003). Thus, optimism should arise from the implication that there may be a window for potential postnatal therapeutic interventions, particularly for LBW children, via prevention of accelerated postnatal growth and obesity onset.
Previews Barker, D.J., Osmond, C., Golding, J., Kuh, D., and Wadsworth, M.E. (1989). BMJ 298, 564– 567. Drake, A.J., and Walker, B.R. (2004). J. Endocrinol. 180, 1–16. Fu, Q., McKnight, R.A., Yu, X., Wang, L., Callaway, C.W., and Lane, R.H. (2004). Physiol. Genomics 20, 108–116. Jensen, C.B., Storgaard, H., Madsbad, S., Richter, E.A., and Vaag, A.A. (2007). J. Clin. Endocrinol. Metab. 92, 1530–1534. Jimenez-Chillaron, J.C., Hernandez-Valencia, M., Lightner, A., Faucette, R.R., Reamer, C., Przybyla, R., Ruest, S., Barry, K., Otis, J.P., and Patti, M.E. (2006). Diabetologia 49, 1974–1984. Jimenez-Chillaron, J.C., Hernandez-Valencia, M., Reamer, C., Fisher, S., Joszi, A., Hirshman, M., Oge, A., Walrond, S., Przybyla, R., Boozer, C., et al. (2005). Diabetes 54, 702–711.
Figure 1. Diabetes Risk Can Begin during Prenatal Life Intrauterine stressors, including maternal undernutrition or placental dysfunction (leading to impaired blood flow, nutrient transport, or hypoxia) can initiate abnormal patterns of development and histone modification. Additional postnatal environmental factors, including accelerated postnatal growth, obesity, inactivity, and aging can further contribute to DM risk, potentially via further histone modifications and DNA methylation in critical tissues.
In the obesogenic environment of the twenty-first century, we need to focus further scientific attention to design and implement novel nutritional and pharmacologic strategies aimed at our youngest at-risk population in order to interrupt the vicious cycle of obesity and diabetes risk.
Park, J.H., Stoffers, D.A., Nicholls, R.D., and Simmons, R.A. (2008). J. Clin. Invest. 118, 2316– 2324. Raychaudhuri, N., Raychaudhuri, S., Thamotharan, M., and Devaskar, S.U. (2008). J. Biol. Chem. 283, 13611–13626.
REFERENCES Barker, D.J., Hales, C.N., Fall, C.H., Osmond, C., Phipps, K., and Clark, P.M. (1993). Diabetologia 36, 62–67.
Stoffers, D.A., Desai, B.M., DeLeon, D.D., and Simmons, R.A. (2003). Diabetes 52, 734–740.
Barker, D.J., Osmond, C., Forsen, T.J., Kajantie, E., and Eriksson, J.G. (2005). N. Engl. J. Med. 353, 1802–1809.
Waterland, R.A., and Jirtle, R.L. (2003). Mol. Cell. Biol. 23, 5293–5300.
The Double Life of Irs Rebecca A. Haeusler1 and Domenico Accili1,* 1Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10027, USA *Correspondence: [email protected]
The liver plays a central role in lipid and glucose metabolism. Two studies in this issue (Kubota et al., 2008; Dong et al., 2008) on the insulin-signaling adaptors Irs1 and Irs2 prompt a critical reappraisal of the physiology of fasting and of the integrated control of hepatic insulin action. Unlike other receptor tyrosine kinases, insulin receptors grace the surface of target cells as preassembled heterodimers and use adaptor proteins to activate PI3K. The molecular cloning of these adaptors, named insulin receptor substrates (Irs), provided a cogent mechanis-
tic and evolutionary explanation for the divergence of insulin signaling from oncogene and growth-factor signaling. Irs proteins carry out various functions downstream of insulin (and IGF) receptors by (1) providing a juxtamembrane localization signal for PIP3 generation, (2) amplify-
ing the signal engendered by receptor autophosphorylation, and (3) engaging a panoply of substrates that account for the diverse actions of insulin (White, 2003). Phenotypic differences between different Irs knockout mice ushered in the idea that Irs play distinct roles in different
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