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Deregulated Nutrient Sensing

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Metabolic activities can put stress on our cells. Too much activity, and changes in nutrient availability and composition cause cells to age faster.

Metabolism and its byproducts, over time, damage cells via oxidative stress, ER stress, calcium signaling, and mitochondrial dysfunction. Therefore, organisms depend on multiple nutrient sensing pathways to make sure that the body takes in just the right amount of nutrition – not too much, not too little. However, these damaging events also deregulate the nutrient-sensing molecules and downstream pathways. A misguided hypothalamus may signal for greater food intake, then, when the body doesn’t really require it. Age-related obesity, diabetes and other metabolic syndromes result. To make things even worse, obesity- and diabetes-related chronic inflammation, operating via JNK and IKK crosstalk, can deregulate nutrient sensing further.

Probably because so many interdependent pathways link metabolism to aging, these are the pathways that have received the most intense focus in the search for anti-aging therapeutics. There was much excitement in the last decade around resveratrol and caloric restriction, the effects of which have now been shown to be limited to mice and other model organisms. Today, intermittent caloric restriction (i.e., fasting) is the only intervention that has been shown to extend human lifespan.


Deregulated Nutrient Sensing
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Metabolic activities can put stress on our cells. Too much activity, and changes in nutrient availability and composition cause cells to age faster.
Did you know?
Blueberries are a wonderful source of healthy nutrients, and is one of the world’s healthiest foods. They provide a long list of bioactive compounds that serve as antioxidants, vitamins, and minerals. Blueberries are known to help with maintaining healthy bones, lowering blood pressure, managing diabetes, preventing cancer, improving mental health, and healthy digestion.

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Featured Solution: SIRTainty® Class III HDAC Assay
SIRTainty® assay principle
Sirtuin-mediated deacetylation of unlabeled peptide substrate generates nicotinamide as a product. The SIRTainty® assay couples sirtuin enzyme activity to nicotinamidase, which cleaves nicotinamide into nicotinic acid and free ammonia. A developer reagent is added, which reacts with the free ammonia to generate a fluorophore. The resulting fluorescent signal is quantified with a conventional fluorometric plate reader.
Sirtuin HDAC Assays Class III histone deacetylases (HDACs), also known as sirtuins, are mechanistically distinct from class I and class II HDACs in that they couple deacetylation of the peptide/protein substrate to cleavage of NAD+ to form nicotinamide and O-acetyl-ADP-ribose. Sirtuins have been intensely researched since it was discovered that their activation led to reduced incidence of aging and age-related diseases such as diabetes. To better understand the biological roles of sirtuins in nutrient sensing, researchers would benefit from an alternative assay that uses untagged, native peptide substrates, enabling the study of sirtuins without the complication of fluorophore-mediated activation. To measure sirtuin activity in a more physiologically relevant manner and address the diversity of sirtuin isoforms and potential substrates, the SIRTainty® assay platform enables the analysis of sirtuin activity using virtually any appropriate substrate.

This new SIRTainty® class III HDAC assay is a flexible, reliable, homogeneous, no-wash assay for quantifying sirtuin activity. Based upon novel, patent-pending technology, this easy-to-perform assay is coupled to nicotinamidase, which catalyzes breakdown of nicotinamide generated upon cleavage of NAD+ during sirtuin-mediated deacetylation of a substrate. Thus, the SIRTainty® assay provides a direct assessment of the activity of class III HDAC enzymes.

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Sirtuin Fluorescence Intensity Siruin substrate preference
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Sirtuin isoform activity. The SIRTainty® assay was effective in measuring activity of all three sirtuin isoforms tested. SIRT2 displayed the highest affinity (Km = 0.14 units) for the acetylated H3K9 substrate used. 
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Siruin substrate preference. Sirt1, Sirt2, and Sirt3 exhibit preference for acetylated (H3K9, H3K9/14, H4K8, and H4K5/8/12/16) versus nonacetylated peptides. Sirt1 and 2, but not Sirt3, demonstrated higher deacetylation activity with a human p53 peptide acetylated at K382 compared to the non-acetylated peptide. 

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