JAX Notes April 01, 2009

JAX® Mice help reveal potential health benefits of resveratrol

What do red wine, soybeans, pomegranates, mulberries, red grapes and peanuts have in common? They all contain resveratrol (RSV or trans-3,5,4-trihydroxystilbene), a polyphenolic phytoalexin produced naturally by certain plants and synthesized commercially by GlaxoSmithKline and Sigma. Resveratrol has made quite a splash in biomedical research, where it has been shown to provide various health benefits, including longer lifespan in mice, yeast, worms and flies. Its potential benefits to humans were also the subject of an episode of CBS' "60 Minutes." RSV may even explain the "French Paradox"—why, in spite of their rich, high-fat cuisine, the people of Southern France have such a low incidence of cardiovascular disease. Could it be because they consume large amounts of red wine? The jury on this potential "fountain of youth" is still out, but with the help of JAX® Mice, RSV's modus operandi and potential to improve human life are being exposed.

Resveratrol thwarts alcohol-induced fatty liver disease in C57BL/6J mice

In a study funded by the National Institute on Alcoholism and Alcohol Abuse, scientists at the University of South Florida Health Sciences Center found that resveratrol helps C57BL/6J (000664) mice (known for their predilection for alcohol) fight alcohol-induced fatty liver disease (Ajmo et al. 2008). They confirmed previous research suggesting that alcohol inhibits AMPK (a/k/a PRKA, protein kinase, AMP-activated, alpha) and sirtuin 1 (SIRT1), two critical signaling molecules that regulate fat breakdown in the liver, and that, in contrast, RSV helps clear out fat by activating AMPK and SIRT1.

Additionally, the increased expression of SIRT1 and AMPK mediated by RSV

  • lowered the levels of SREBP-1c protein (SREBF1, sterol regulatory element binding transcription factor 1);
  • activated transcription of PGC-1alpha (Ppargc1a, peroxisome proliferative activated receptor, gamma, coactivator 1 alpha);
  • raised the levels of circulating adiponectin, an obesity-controlling hormone produced by fat cells;
  • up-regulated adiponectin receptors in the liver, increasing the effectiveness of the circulating adiponectin.

Curiously, alcohol seemed to enhance many of these effects. Resveratrol appears to coordinate the activities of fat metabolism through reducing lipid synthesis and increasing fatty acid oxidation.

Resveratrol improves quality of life in C57BL/6N mice

In 2008, an interdisciplinary team of researchers at Harvard revealed that resveratrol may reverse or slow age-related diseases and deterioration in C57BL/6N mice (Pearson et al. 2008). RSV-treated mice (compared to controls) had greater bone mineral density and strength, better vascular function and reduced cardiovascular risk, oxidative stress and apoptosis.  They expressed fewer inflammation-related molecules and lived 25-26% longer. RSV seemed to reduce the internal signs of aging even when treatment was not started until midlife. Many of its effects mimicked those of calorie-restricted mice.

Resveratrol protects C57BL/6J mice from metabolic disease

A team of American, Finnish and French researchers reported that resveratrol protects C57BL/6J mice against diet-induced-obesity and insulin resistance (Lagouge et al. 2006). RSV-treated mice were leaner, consumed more oxygen and could run twice as far as untreated mice, suggesting that resveratrol reduces muscle fatigue. Researchers concluded that RSV mediates lifespan-increasing effects by activating SIRT1, a deacetylase that increases PGC-1alpha (PPARGC1A) activity. Low PGC-1alpha expression has been associated with low aerobic capacity and reduced expression of oxidative phosphorylation and mitochondrial biogenesis genes, all potential risk factors for cardiovascular and metabolic diseases. The authors also found three single-nucleotide polymorphisms in the human SIRT1 gene that are significantly associated with energy homeostasis. These results substantiated SIRT1's key role in energy homeostasis and implied that resveratrol could be used to modulate energy expenditure to improve human health.

Resveratrol decreases plaque formation in Alzheimer's mouse model

Researchers from New York Medical College and Cornell University reported that resveratrol decreases plaque formation in a transgenic mouse model of Alzheimer's Disease (AD), Tg19959 (Karuppagounder et al. 2008). Tg19959 contains multiple human Alzheimer's mutations, APP695 and two familial AD mutations (KM670/671NL and V717F), under the control of the hamster prion protein promoter, and on the B6SJLF1/J (100012) background. RSV diminished plaque formation in AD mice in a region-specific manner, particularly in the medial cortex (48% reduction), the striatum (by 89%) and the hypothalamus (90%). The authors suggested that resveratrol may protect against plaque formation.

Resveratrol decreases severity of experimentally-induced multiple sclerosis in SJL/J mice

University of Nebraska researchers reported that resveratrol significantly reduces the symptoms of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, in SJL/J mice (000686) (Imler and Petro 2009). Typically, during EAE, T cells and macrophages infiltrate the brain, produce cytokines IL17, IFNγ, TNFa;, or IL6, resulting in autoimmune neuroinflammation. However, if infiltrating T cells simultaneously produce IL17 and IL10 or if infiltrating CD4-NKT cells produce IFNγ, mice are protected against EAE. Consistent with this mechanism, the authors found that RSV protected SJL/J mice against EAE by mediating the levels of IL17 and IL10 and IFNγ-secreting CD4- T cells and by repressing macrophage expression of IL6 and IL12/23 p40, indicating that resveratrol has anti-inflammatory capabilities.

Is resveratrol a new wonder drug? It's too early to tell, but if its effects in humans are similar to those in mice, it will have a wide range of applications for treating or even preventing a host of cardiovascular, metabolic, autoimmune and neurodegenerative diseases.

References

Ajmo, J. M., Liang, X., Rogers, C. Q., Pennock, B., & You, M. 2008. Resveratrol alleviates alcoholic fatty liver in mice.Am J Phys Gastroint Liver Phys 295:G833-42.

Imler TJ, Jr, Petro TM. 2009. Decreased severity of experimental autoimmune encephalomyelitis during resveratrol administration is associated with increased IL-17+ IL-10+ T cells, CD4 IFN-γ+ cells, and decreased macrophage IL-6 expression. Int Immunopharmacol 9:134-43.

Karuppagounder SS, Pinto JT, Xu H,Chen HL, Beal MF, Gibson GE. 2008. Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's disease.  Neurochem Int. 54(2): 111–118.

Lagouge M et al. 2006. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109-22.

Pearson KJ et al. 2008. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 8:157-68.