The Role of SIRT1 in Preventing Mitochondrial Dysfunction with Obesity and Aging

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The Role of SIRT1 in Preventing Mitochondrial Dysfunction with Obesity and Aging

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Title: The Role of SIRT1 in Preventing Mitochondrial Dysfunction with Obesity and Aging
Author: Price, Nathan Loftus
Citation: Price, Nathan Loftus. 2012. The Role of SIRT1 in Preventing Mitochondrial Dysfunction with Obesity and Aging. Doctoral dissertation, Harvard University.
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Abstract: Mitochondrial function declines with aging and obesity, and has been implicated in the development of many age-related diseases. Caloric restriction (CR) prevents aging and has been shown to induce mitochondrial biogenesis and improve mitochondrial function. These effects may involve increased activity of the \(NAD^+\)-dependent deacetylase SIRT1. Indeed, overexpression of SIRT1 reproduces many of the health benefits of CR including induction of mitochondrial biogenesis by deacetylation and activation of the transcriptional co-activator \(PGC-1\alpha\). Because mitochondria regulate cellular functions important for aging, including, cellular energy production, ROS generation, and apoptosis, determining why mitochondrial function declines with age will improve our understanding of the underlying forces that drive organismal aging. Resveratrol and other SIRT1 activators induce mitochondrial biogenesis and protect against metabolic decline, but whether SIRT1 mediates these benefits is still a matter of debate. To circumvent the developmental defects of germ-line SIRT1 knockouts, we have developed the first inducible system that permits whole-body deletion of SIRT1 in adult mice. Obese mice treated with a moderate dose of resveratrol showed increased mitochondrial biogenesis and function, AMPK activation, and increased \(NAD^+\) levels in skeletal muscle, whereas SIRT1 knockouts displayed none of these benefits. Overexpression of SIRT1 in mice mimicked these effects, demonstrating that SIRT1 is sufficient and necessary for resveratrol to increase mitochondrial function in obese animals, and indicating a central role for SIRT1 in mediating the benefits of this molecule on muscle. Loss of SIRT1 or aging causes mitochondrial dysfunction and decreased expression of mitochondrial-encoded electron transport chain (ETC) components. This decrease in mitochondrial-encoded, but not nuclear-encoded ETC components in SIRT1 knockouts, which we have termed “genome asynchrony”, is independent of \(PGC-1\alpha\). Elevating \(NAD^+\) levels by treatment with the \(NAD^+\) precursor NMN prevented genome asynchrony and mitochondrial dysfunction in aged animals, similar to effects seen with CR. Together these data demonstrate that SIRT1 plays an essential role in preventing genome asynchrony, and that maintaining \(NAD^+\) levels and SIRT1 activity with age may prevent mitochondrial dysfunction. Since SIRT1 is required for NMN or resveratrol to improve mitochondrial function, compounds that activate SIRT1 or elevate \(NAD^+\) may help treat or prevent age-related diseases caused by mitochondrial dysfunction.
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