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Sirtuin3 Reprograms Mitochondrial Epigenetic Pathways: How Diet Affects Age

When it comes to acetylation and epigenetics your mind probably goes right to histones. Acetylated histones are associated with relaxed, transcriptionally active DNA. However, acetylation is an important post-translational modification of lysine in many cellular proteins. It is as widespread as phosphorylation. It is reversable. Functionally, acetylation is known to be involved in the effects of calorie restriction on metabolism and aging. Now the first direct evidence of a mechanism underlying this process has been reported.

The journal Molecular Cell has recently published Calorie Restriction and SIRT3 Trigger Global Reprogramming of the Mitochondrial Protein Acetylome, authored by scientists from the University of Wisconsin-Madison and the University of Tokyo. They used model mice with age-related hearing loss for this study. This hearing loss is prevented by calorie restriction (CR). They explored the liver mitochondrial protein acetylome by developing a new quantitative, acetyl-proteomic method. The Sirtuin family of deacetylases were already linked to CR. And  Sirtuin3 was recently shown to be induced during CR. So the researchers explored the regulatory role of tSIRT3 during CR. They identified multiple pathways where SIRT3 is involved in reprogramming mitochondria during CR via acetylation. Interestingly for “Epiexperts”, among those ID’d were mitochondria DNA expression and maintenance pathways.  Part of that SIRT3 led CR reprogramming, is through regulation of mtDNA transcription factors, mtRNA polymerases and mitochondrial ribosome proteins. Please see Table 1. in the pub for the list of SIRT3 targets in this functional group.  The reprogramming during CR of these targets leads to enhanced mtDNA transciption, mtDNA translation and protein quality control.

Recall, mitochondria function to produce ATP from sugar and oxygen, powering the cell. This process also creates oxidative free radicals that contribute to aging. Mitochondria have their own DNA and can make their own proteins. During calorie restriction, mitochondria performance is actually enhanced. They use less oxygen and produce less damaging free radicals. Again, in the model mice this results in prevention of hearing loss.

This is a great paper worth reading. Mainly because it establishes that SIRT3, (of the sirtuins deacetylases family) is directly linked to anti-aging effects. But also because it shows SIRT3 is potentially a significant regulator of mitochondrial epigenetics.  It’s like by eating less, SIRT3 directs mitochondria to become environmentally friendly power stations with high energy efficiency ratings.

Hebert AS, Dittenhafer-Reed KE, Yu W, Bailey DJ, Selen ES, Boersma MD, Carson JJ, Tonelli M, Balloon AJ, Higbee AJ, Westphall MS, Pagliarini DJ, Prolla TA, Assadi-Porter F, Roy S, Denu JM, & Coon JJ (2012). Calorie Restriction and SIRT3 Trigger Global Reprogramming of the Mitochondrial Protein Acetylome. Molecular cell PMID: 23201123

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One Response to Sirtuin3 Reprograms Mitochondrial Epigenetic Pathways: How Diet Affects Age

  1. Bill Graham says:

    Drs. Weinbruch and Prolla, who led the initial caloric restriction studies at Univ of Wisconsin-Madison founded a company, Lifegen Technologies to bring some of their research and techniques to market.

    In late November LifeGen was acquired by NSE, and they in fact have the first line of epigenetic nutriceuticals on the market.

    ‘Vitality’ is a product that largely re-sets a cluster of 52 genes that help regulate mitochondria function to a more youthful expression. Gene chip studies show a remarkable 90%+ revision back to youthful control.

    They now have their sights set on epigenetic weight-loss and weight management, with a product scheduled for widespread release October 2013.

    The implications of this product are staggering, considering the impact that obesity is having on a global basis. There is a business opportunity here as well, please feel free to contact me for more information: wmbgraham (at) gmail

    Anyway I thought it would be interesting to update the E3 community on one of the first commercial applications of this new science! Thank you all for your contributions.

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