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  • What Happens When A Sirtuin1 Gene Activator Is Used Concurrently With A Sirtuin1 Gene Inhibitor?

    September 8, 2016: by Bill Sardi

    Activation of the Sirtuin1 survival gene has been extolled for its epigenetic mimicry of a lifespan-doubling calorie-restricted diet.  In 2003 Harvard-based geneticist David Sinclair reported that the red wine molecule resveratrol profoundly activated the Sirtuin1 gene better than other small molecules.  The opposite signal, Sirtuin1 gene inhibition, was said to emanate from niacin (aka nicotinic acid), a ubiquitous nutrient in food.  So the food/no-food signal inhibits/activates Sirtuin1.

    Then over a decade later niacin-like derivatives such as a commercialized nicotinamide riboside (trade name: Niagen), which are precursors for nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP) began to be extolled for their life extending properties as Sirtuin1 gene inhibitors.  [Annual Review Nutrition 2008]  Nicotinamide adenine dinucleotide (NAD) itself is also marketed as a dietary supplement.

    Niacinamide (aka nicotinamide), the no-flush form of niacin has also been widely sold and consumed in multivitamins for decades.  Niacinamide (nicotinamide) is considered a very efficient precursor for NAD. [Clinical Science Feb 1990] One study showed niacinamide doubles the production of NAD compared to niacin.  [Archives Biochemistry Biophysics Nov 1990] The history of niacinamide as an anti-aging agent dates back to the 1950s. [Connecticut State Medical Journal 1953]

    This reporter has yet to see a comparison of the new designer NAD dietary supplements next to niacinamide.   Maybe multivitamin users have been receiving anti-aging benefits from their habitual use of pills that contain niacinamide without knowing it.

    A puzzlement is that both resveratrol and niacinamide or nicotinamide riboside activate NAD even though their effect on the Sirtuin1 gene oppose each other.  Niacinamide is a Sirtuin1 gene inhibitor [Molecular CellMarch 2005] Resveratrol a Sirtuin1 gene activator.

    Of course the poor man’s way to activate NAD is to practice calorie restriction that makes NAD more bioavailable.

    A fundamental way that calorie restriction extends lifespan is to decrease NAD(H) levels (NAD + hydrogen). [Genes & Development Jan 2004]

    Resveratrol as a molecular mimic of calorie restriction stimulates NAD and the ratio of NAD over NADH without having to practice food deprivation.  [Journal Biological Chemistry Dec 2013]

    Simultaneous Sirtuin1 activation/inhibition

    But what happens when both a Sirtuin1 activator and inhibitor are used simultaneously?  The first demonstration of the concurrent use of resveratrol and niacin (nicotinamide), a Sirtuin1 activator and inhibitor, has now been reported in a model of Huntington’s Disease, known as a mitochondrial disorder of brain cells.

    Researchers said they set out to “demystify” the paradox of Sirtuin1 activation/inhibition in the context of Huntington’s disease.  The first experiment was conducted in a lab dish with brain cells from animals genetically bred for Huntington’s disease.  The mitochondria in these brain cells exhibited dysfunctional mitochondria.  Mitochondria are cellular bodies that produce cell energy in the form of adenosine triphosphate (ATP).

    Remarkably, resveratrol “completely restored healthy protein levels” (PGC-1a gene proteins which is the master regulator of mitochondrial renewal).  Nicotinamide (niacinamide) also increased NAD levels and increased PGC-1a as a positive add on.

    Researchers measured a 37% decline in PGC-1a levels in brain cells from animals with Huntington’s disease and resveratrol recovered PGC-1a protein levels.  Nicotinamide worked indirectly, raising NAD levels, which then by virtue of NAD’s ability to transport electrons in the mitochondria, improved mitochondrial function.

    Resveratrol resulted in lab animals maintaining their balance on a spinning rod (rotarod) for a longer period of time, which suggests their motor coordination had obviously been restored.  In fact, resveratrol completely restored the ability of these lab animals to balance themselves on a spinning rod.  This improved physical performance was accompanied by an increase in the number of mitochondria in their brain cells.  [Molecular Neurobiology Sept 2, 2016]

    Researchers wrote: “the most intriguing aspect is how these compounds exert opposite actions on Sirtuin1 activation yet trigger similar survival pathways.”  The positive effect of resveratrol was sustained over time while nicotinamide initially raised NAD levels but prolonged treatment was ineffective.

    Mitochondrial renewal

    Readers here may ask, how does resveratrol increase the number of mitochondria in aged or diseased cells?  Resveratrol does this via a biological phenomenon called biogenesis.  Parts of used-up mitochondria swirl in a process called fusion and then break up into renewed mitochondria in a process called fission.  [Essays Biochemistry 2010; Annual Review Genetics 2012]

    The mitochondria, those atomic power plants that produce adenosine triphosphate (ATP), the energy currency of living cells, begin to malfunction with advancing age.  By age 80 it is said that only 4% of mitochondria are functional. [Cell 2005]

    High-energy demand tissues like the brain and heart are certainly in need of mitochondrial regeneration in old age and in certain mitochondrial disorders, like Huntington’s disease.  Other notable inherited mitochondrial disorders include Leber’s hereditary optic neuropathy, diabetes + deafness and retinitis pigmentosa (night blindness).  But basically everyone ends up with mitochondrial problems if they live long enough.  [Advances Experimental Biology & Medicine 2012]

    There are hundreds of mitochondria in a single living cell.  At any one instance in time there are about one billion ATP molecules in the human body.  []

    Mitochondria are also the locus for over 90% of the free radicals generated in the body.  These free radicals are generated from unpaired electrons in the mitochondria that emanate primarily from oxygen (superoxide, hydroxyl radicals and hydrogen peroxide) and to a lesser extent by nitrogen (nitric oxide, nitrogen dioxide and peroxynitrite).

    On first glance, it would appear that supplemental antioxidants that quell tissue destructive free radicals in the mitochondria would be of importance.  [Journal Reproductive Infertility Oct 2013; Knowledge of Health]  But only certain small molecules are effective mitochondrial antioxidants. [Current Pharmaceutical Design 2014]

    In particular, resveratrol has been identified as a potent agent that renews mitochondrial activity and volume.  [Oxidative Medicine Cellular Longevity 2016]

    While the Sirtuin1 gene is extolled for its ability to renew mitochondria, Sirtuin3 is known as the primary mitochondrial antioxidant in the family of seven Sirtuin genes.  Mitochondrial biogenesis (renewal) is controlled by activation of PARKIN and PINK1 genes via Sirtuin3, and facilitated by resveratrol.

    Longevinex® is the only branded resveratrol product to exhibit proven mitochondrial renewal via the Sirtuin3.  [Oxidative Medicine Cellular Longevity 2014]  Longevinex® is superior (295% better) to plain resveratrol in activation of Sirtuin3. [Canadian Journal Physiology Pharmacology 2010]

    An estimated 30,000 Americans suffer from Huntington’s disease.  The problem is in translating resveratrol from the laboratory to the clinic.  Modern medicine typically sets out to produce analogs (look-alike molecules) it can patent and market as a drug.  Dietary supplements like resveratrol are caught in a quandary as they can’t claim their treat or prevent any disease.

    There is an ongoing human clinical trial using 80 mg of resveratrol that will reach completion in 2018. [Clinical Trials]  However, will modern medicine put resveratrol into practice if it isn’t a drug?

    As promising as it may be, unless Huntington’s disease patients venture on their own without doctor’s confirmation to take resveratrol pills, resveratrol is not likely to ever come into common use for mitochondrial disorders.  – ©2016 Bill Sardi,

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