Baur Lab Research
We are interested in understanding the basic mechanisms that lead to aging, and how interventions such as caloric restriction (CR) are able to slow the process. Sirtuins, a conserved family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases and ADP-ribosyltransferases, have been proposed to mediate critical effects of CR in mammals and small molecule activators of the sirtuin SIRT1, such as resveratrol, improve health and produce some effects reminiscent of CR in mice. We are continuing to test the hypothesis that sirtuins play a critical role in mammalian CR, exploring potential upstream mechanisms that could regulate their activity, and downstream effects that could account for changes in health and longevity. Elucidating the mechanism(s) by which CR extends lifespan is expected to yield insights into the causes of aging and to highlight new therapeutic approaches to the prevention and treatment of age-related disease.
Current Research Projects
The Role of Nicotinamide Phosphoribosyltransferase (Nampt) in Caloric Restriction
Increased NAD levels are observed in several tissues during CR, and may contribute to sirtuin activation. Nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme in the generation of NAD from nicotinamide (Figure 1), is induced by fasting, suggesting it may mediate the increase in NAD during CR. Overexpression of Nampt in cultured cells is sufficient to enhance the activity of SIRT1 and other sirtuins, and mice lacking one copy of the gene for Nampt have impaired glucose tolerance and defects in insulin secretion. Surprisingly, Nampt is secreted from adipose tissue and is identical to the adipokine visfatin, whose circulating concentration correlates positively with obesity and inflammation. To resolve these seemingly conflicting roles for Nampt, and test its ability to mediate salient effects of CR, we have created a line of Nampt transgenic mice, which are currently being characterized.
Molecular Mechanisms of Rapamycin's Effects on Health and Longevity
Recently, we have been investigating the mechanisms by which rapamycin affects metabolism in mice. Rapamycin is the only compound that has been unambiguously shown to extend the maximum lifespan of a mammalian species. However, the underlying mechanisms remain unknown, and side effects including immunosuppression and the elevation of cardiovascular risk factors are likely to limit the utility of the drug in humans. Together with our collaborators in the Sabatini lab (Whitehead Institute), we have shown that in addition to inhibiting its canonical target, mTOR complex 1, chronic rapamycin treatment disrupts mTORC2, resulting in insulin resistance. Several current lines of investigation will test whether mTORC2 disruption is responsible for other detrimental or beneficial effects of rapamycin, and whether the effects of the drug on longevity are separable from its undesirable side effects.
Mitochondrial Mass as a Determinant of Free Radical Production and Insulin Sensitivity in Cells
Another area of interest in the lab is the role of mitochondrial biogenesis in CR. Although it has been studied since the 1930s, CR was shown only recently to paradoxically increase the number of mitochondria in many tissues. The consequences of this increase on reactive oxygen species generation, stress resistance, and insulin sensitivity are not known and cannot easily be distinguished from other effects of CR in vivo. To get around this problem, we are employing various strategies to recapitulate the increase in mitochondrial biogenesis in cell culture. We plan to use this system to functionally characterize cells with increased mitochondrial content and to understand how mitochondrial mass is regulated. Currently, we are testing the effects of “extra” mitochondrial on free radical production, insulin sensitivity, and stress resistance in a variety of cell lines.
Testing the SIRT1-Dependence of Resveratrol’s Effects In Vivo
Resveratrol is a naturally occurring polyphenol that interacts with a number of mammalian enzymes, and was the top hit in a screen for activators of SIRT1, an enzyme potentially involved in the beneficial effects of CR. Resveratrol has since been shown to extend lifespan in lower organisms, and to provide numerous health benefits in rodents, including increased insulin sensitivity, endurance, and even survival in obese mice. It is generally presumed that these benefits result directly from activation of SIRT1, however, there is little experimental evidence to support this assertion. Although SIRT1 activity appears to be higher in treated animals, resveratrol has other targets and does not appear to achieve the concentrations in vivo that are required to activate SIRT1 in vitro. Moreover, it has not been possible to demonstrate the effectiveness of resveratrol in vitro unless fluorescent substrates are used. Testing the effect of resveratrol in mice that lack the SIRT1 gene has not been possible because these mice have a severe phenotype including developmental defects and metabolic abnormalities. We are using an inducible system to delete the SIRT1 gene in healthy adult animals, allowing a definitive test of whether resveratrol works through this enzyme. In addition, this line of mice will be useful for testing the role of SIRT1 in the lifespan-extending effects of CR, and other aspects of metabolism.