Sirtuins from Bench to Bedside: How Far Are We?

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Background

The silent information regulator 2 protein (Sir2), also called sirtuins are a family of NAD+ dependent class III protein deacetylases involved in the transcriptional and post-translational regulation of proteins involved in regulating the health and lifespan of an organism. After its first discovery in yeast in 1979 by Klar and Fogel, sirtuin expression was found in diverse organisms ranging from bacteria to humans. Sirtuins gained considerable attention when Kaeberlein (1999) found that an extra copy of the Sir2 gene increases the yeast replicative lifespan by 30%. Later studies found that sirtuins or sirtuin analogs can extend the health span and life span of yeast, flies, worms, and rodents, suggesting that sirtuins are evolutionarily conserved regulators of health span and life span.

There are seven sirtuins isoforms (SIRT1-7) in mammals. These isoforms of sirtuins are localized to the nucleus, cytoplasm, and mitochondria, where they catalyze the deacetylation of the lysine residues of a variety of proteins. But, not all sirtuins are dedicated to deacetylase/deacylase activity. They perform multiple enzymatic functions, including (ADP)-ribosylase, demalonylase, desuccinylase, or glutarylase activity. By doing so, sirtuins regulate a broad range of cellular processes, including control of gene expression, metabolism, DNA repair, telomere maintenance, cell growth, and apoptosis, thus directly regulating the health and life span of an organism. Sirtuin homologues have been implicated in almost all diseases, including diabetics, inflammation, neurodegenerative disease, cancer, cardiac and endothelial disease, and sepsis. Most importantly, sirtuins mediate the beneficial effect of calorie restriction, the most robust intervention to prolong the health and life span in vertebrates and invertebrates.

Seventeen years have passed since Howitz's discovery that Resveratrol, a small molecule activator of sirtuin, can extend the yeast life span. Several potent small molecule activators and inhibitors of sirtuins have been discovered ever since. As per clinicaltrials.org, 54 clinical trials have been completed or going on as of now. Despite this rapid progress, several questions need to be addressed. Some of the questions that is important in the context of this Research Topic will be the following.

What are the challenges in taking sirtuins from bench side to bedside? How different are the roles of sirtuins in various organs? Do all the organs benefit equally by activating sirtuins, or do we need to design organ-specific modulation of sirtuin activity? The general trend is to activate sirtuins to better the health span, but it is critical to know if sirtuin activation has a deleterious effect in certain disease conditions. In other words, what are the adverse effects of sirtuin activation, and who will benefit the most by it? It is also essential to know how long and how much we need to modulate sirtuin activity for various diseases or health maintenance? Does the activation of more than one sirtuin have negative or positive consequences in the management of diseases?

We welcome Original Research, Method, Review, Clinical Trials, and Perspective articles addressing the above mentioned subtopics. Further, we encourage contributors to discuss recent advances, methodologies, and their perspective in taking sirtuins from bench to bedside.

Keywords: Sirtuins, aging, mitochondria, diseases, drugs

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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