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  • Resveratrol Rescues Worn Out Cells From A Senescent State by Altering RNA Splicing, Surprisingly Not By Activation Of The Sirtuin1 Survival Gene

    June 15, 2020: by Bill Sardi

    Many longevity seekers have heard all about the Sirtuin1 survival gene, that gene that is activated when humans are under physical or mental stress, such as during starvation or intentional calorie restriction.  The seminal work on this was done by David Sinclair PhD, of Harvard Medical School, in 2003.  An anti-aging pill was at hand.

    As it so happened, the wine-drinking French had high cholesterol numbers but a far lower rate of death from coronary artery disease than North Americans, a healthy practice attributed to resveratrol and other similar molecules in aged French wine.  In the 1990s this became known as the French Paradox.  Given that resveratrol molecularly mimics a limited calorie diet, a link was made between wine and longevity.

    This may have been one of the greatest discoveries ever in the history of modern medicine, except governments couldn’t fathom how to provide a pension for a growing population of 120-year-olds, so red wine pills were summarily dismissed.  No government was going to put its seal of approval on financial obligations it couldn’t possibly make.  No, Medicare was not going to pay for an anti-aging pill, regardless of a longevity dividend where 7 added years of independent disease-free living would spare Medicare from insolvency, a goal espoused by S. Jay Olshansky of the University of Illinois.

    Today, only a couple hundred thousand Americans take resveratrol pills while a growing number practice intermittent calorie restriction, mostly to slim down, not live longer.  Statin drugs and aspirin have been scientifically dismissed.  If only resveratrol had taken their place.

    Cellular senescence

    It took another 15 years or so from when Harvard Professor David Sinclair announced resveratrol as a mimic of calorie restriction for the idea of cell senescence to be widely disseminated to the public.

    As cells grow old they no longer replicate (renew themselves) and become senescent.  These zombie senescent cells result in frailty and a shortened lifespan.

    Suddenly another resveratrol-like small molecule abundant in strawberries, fisetin, was reported to abolish senescent cells in the bodyResveratrol inhibits cell senescence too, though not as demonstrably as fisetin.

    Enter RNA splicing

    Only recently have researchers uncovered another pathway to reverse cell senescence – RNA splicing.  What in the world is that?

    DNA is double-stranded.  RNA is single stranded.

    When cells renew themselves a section of DNA that comprises a single gene is copied and then spliced into a single RNA strand that has extraneous material.

    RNA must be processed before it become messenger RNA that can initiate the synthesis of proteins, which is what genes do – produce proteins in response to our environment, what is called epigenetics (should be called adaptive genetics versus inherited genetics).

    In RNA processing, certain inconsequential sequences within RNA called introns must be removed, what is called RNA splicing.  What remains are exons.

    Within the 3 billion sequenced nucleotides (steps on the DNA ladder) that comprise DNA (Adenine, Cytosine, Guanine, Thymine), are ~21,000 genes that produce 250,000 to 1,000,000 proteins, what is called gene expression.  This process relies upon RNA splicing.

    Puzzlingly, resveratrol is now shown for the first time to “youthify” without activation of the Sirtuin1 survival gene.

    From inherited to controlled longevity

    In the era prior to Harvard’s David Sinclair and MIT’s Leonard Guarente research, biologists only understood genes to be stagnant and longevity to be inherited.   Now genes could be molecularly modified and longevity reliably achieved via mimicry of calorie restriction, a dietary practice that was shown to double the lifespan and healthspan of various forms of life by Clive MacCay at Cornell University in 1935.

    RNA splicing is one of nature’s miraculous phenomena.  Courtesy of the Cold Spring Harbor Laboratory, you can view a video that visually explains RNA splicing.

    But let’s get back to the most recent discovery, that resveratrol plays a prominent role in RNA splicing.

    Remarkably, resveratrol, in a fashion superior to synthetic versions of resveratrol, has now been found to reverse cell senescence.  Said in another way, resveratrol can reverse the biological clock hands of time – – –  biologically younger while chronologically older on the calendar.  Hey, you mean I don’t have to grow old?  Yes, that is what this means.  And you are never too old to benefit.

    Lifespan with healthspan

    This means healthspan will accompany lifespan.  Now that is a sore point with most people who contemplate whether they want to live longer or not.

    Recognize how important RNA splicing is in cell renewal.  If RNA splicing gets foiled, genes don’t make proteins, cells grow old, and humans become frail and old.

    This resveratrol-activated cell renewal process as evidenced by turning old cells young again was recently demonstrated and published in a recent issue of  GerontologyA prior report by the same researchers also described this phenomenon.

    Resveratrol was shown to be about 25% more powerful at reversal of cellular aging via RNA splicing than man-made versions of resveratrol with molecular tails added.

    Wait, there’s more!  With advancing age the supply of stem cells becomes exhausted.  Pools of stem cells throughout the body facilitate cellular repair.  Resveratrol preserves these stem cell pools via RNA splicing.

    RNA splicing was also found to lengthen the end-caps on chromosomes called telomeres. Resveratrol activates a transient increase in telomerase, an enzyme required for telomere repair.

    Whereas fisetin kills off senescent cells (apoptosis), resveratrol simply converts them back to a youthful state.

    Sometimes there are fascinating moments in biology, and this is one of them.  Of course, resveratrol has produced a number of these fascinating moments, too numerous to mention here.

    Convincing demanding longevity seekers

    This discovery is also important to sophisticated and demanding longevity seekers who have become savvy enough to know lifespan without healthspan is no way to live.  The idea of living the last 30-40 years of life in an incapacitated state is abhorrent to most people.  Surveys show more people buy into the idea of living longer when they hear they can remain independent, active, even without cataracts, wrinkles and greying hair.

    Modern medicine has left the indelible impression that super-longevity is accompanied by a debilitated state exemplified by loss of bowel control, incontinence, drooling at the mouth, shortened stature, and loss of memory.  At that point, people say they would rather be dead.

    Now the prospect of an unlimited lifespan and healthspan is real.  The goal is to flicker once like a lightbulb and go out instead of suffer through years of chronic disease.

    Now, just how do you prove this to a skeptical public? And how do you overcome the doctoring barrier?  To prescribe resveratrol is to order up less disease to treat.  That is anathema to modern medicine.

    Given no promises can be made, to the faithful who have been taking resveratrol pills since their inception in 2004, they can only prove resveratrol’s value one year at a time.  The last man standing in the class of 2004 forward may be the man who habitually took a resveratrol pill.

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