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  • Sorting Out The Science Behind Modern Medicine’s Newest Anti-Aging Pills

    February 23, 2015: by Bill Sardi

    A decade after the red wine molecule resveratrol (rez-vair-ah-trol) was introduced as an anti-aging pill, molecular biologists, as they are called, have introduced a whole new strategy that promises to produce nearly ageless humans who will live an indefinitely long and healthy lifespan.

    These new “high-brow” youth pills come sans all the hype and hyperbole that accompanied resveratrol dietary supplements when they were first introduced and marketed by online hucksters who offered a free bottle of red wine pills to consumers who suddenly found their credit cards being billed each month without their knowledge.

    The latest anti-aging science is very complex and difficult to follow let alone explain and rouse up questions about whether a common variety of a B vitamin might perform as well as this new generation of youth pills just now introduced.  But if the science is confusing enough, maybe nobody will notice.

    Difficulty translating the science

    Before I lose you in all the scientific mumbo-jumbo, let me tell you it is quite a challenge to translate this science into practical advice.

    See if you can comprehend this sentence about how the new longevity pills work: “The roles played by the NAD+: NAD(H) ratio are complex. It controls the activity of key enzymes in cellular respiration — glyceraldehyde 3-phosphate dehydrogenase, which catalyzes the sixth step in glycolysis, and pyruvate dehydrogenase, which decarboxylates acetyl-CoA for use in the Krebs cycle — thus linking glycolysis to oxidative phosphorylation.” [Longevity Medicine Review]

    If you think that is complicated, try to comprehend this metabolism map that explains the science behind all this (below).

    Metabolism map

    Hope you followed all that.  And here I am a non-biology-trained journalist trying to interpret all this for a band of longevity seekers who want to follow every step of anti-aging science as it occurs.

    Point of fact: the two molecules now being promoted as anti-aging elixirs, nicotinamide mononucleotide and nicotinamide riboside, are both made naturally in the body from nicotinamide (aka niacinamide), the latter being widely available in multivitamins as a non-flushing form of niacin.  The objective is to use either of the above molecules to produce NAD (nicotinamide adenine dinucleotide) that is a metabolic switch.  NAD levels decline with advancing age for unexplained reasons, hence the need for NAD booster shots.

    Bottom line: NAD is a business opportunity for the scientific elites.

    Why were niacin-based NAD boosters passed over a decade ago?

    A decade ago resveratrol was first reported to switch on a survival gene called Sirtuin1 which is also activated by a calorie restricted diet that doubles the lifespan and healthspan of laboratory animals.

    Sirtuin1 is one of a family of seven sirtuin genes that produce what are called NAD (nicotinamide adenine dinucleotide) enzymes, known as the master switches of metabolism.  What these NAD regulators do is help hand off electrons in a game of “hot potato.”  If electrons aren’t handled properly toxic free radicals can be produced that damage DNA, the genetic material inside living cells.  NAD also facilitates communication between the DNA center (nucleus of cells) and the energy-making cellular compartments called mitochondria.

    Resveratrol actually raises NAD to normal levels but anti-aging researchers want a more sophisticated molecule they can build new patentable drugs around rather than off-the-shelf vitamins or herbal extracts that may do the same thing.  [Cell May 2, 2012]

    Wait a minute.  If resveratrol raises NAD levels what do I need to take one of these new NAD boosters for?

    Do you need to boost NAD if you take resveratrol pills?

    Resveratrol molecularly mimics a calorie-restricted diet.  A decade ago I learned that niacin is ubiquitous in food and switches off benefits of a calorie-restricted diet while resveratrol switches them back on. So why do we want to take niacin-like molecules to live longer, which appears to be like a football player who got confused and ran the wrong way into the opposing team’s end zone.

    Here is the reason why.  In the cell renewal cycle about 5000 DNA breaks occur as a result of free radical destruction.  About 1% of these DNA breaks occur at both ends of DNA strands that attach to the DNA ladder (called double-stranded DNA breaks).  Repair of these DNA breaks is facilitated by NAD (via something called PARP).  However, over-activation of the DNA-repair agent PARP can reduce cell survival.  NAD keeps PARP in check.  Without NAD cell energy declines and cell death may result.  [PLoS One April 26, 2011]

    The following chart shows how much NAD is being used up via PARP per hour in young, middle aged and old rodents.


    Chart: NAD

    NAD depletion impairs Sirtuin1 gene activity.  Adequate NAD levels are critical to maintain Sirtuin1 gene activity.  Without adequate levels of NAD cells become lethargic, DNA repair is compromised and free radicals run wild.  The bottom line lesson is that our cells run out of NAD and can’t control DNA damage or maintain cell energy with advancing age.

    Nicotinamide riboside is demonstrated to produce unprecedented youthful effects

    In December of 2013 David Sinclair, the Harvard-based “pied piper” of anti-aging pills, reported that a decline in NAD with advancing age is what disrupts communications between the nucleus or genetic center of cells and the mitochondria, small power plants that produce cellular energy.  Sinclair reported that the use of nicotinamide mononucleotide rapidly reversed aging in muscle tissue of laboratory mice equivalent to make a 60-year old biologically young (20-years old) once again. [Cell Dec 2013]

    A decline in NAD results in a “pseudo-hypoxic state” (I told you this was going to be difficult to understand).  Pseudo hypoxia is when living cells are fooled into thinking they are oxygen deprived (hypoxia).  Less and less energy is made in cells as they age and more and more DNA is damaged and this process progressively accelerates aging.

    So scientists now propose, rather than employing the most commonly used precursor of NAD, niacinamide, which is widely available as a dietary supplement, that maybe nicotinamide mononucleotide or nicotinamide riboside should be employed.  NAD is recycled (salvaged) by these two molecules.  Niacinamide (aka nicotinamide) is the major material upon which NAD enzymes work. [Advances Enzymology Related Areas Molecular Biology 1999]

    Decreases in NAD levels that normally accompany aging impair sirtuin gene activity. [PLos One Sept 2014]  So NAD regulates Sirtuin1 gene activity and therefore, maybe the provision of something that raises NAD levels (i.e. one of those new NAD boosters promoted by Harvard or MIT) will help resveratrol work better.  [Journal Biological Chemistry Dec 3, 2004]

    Here is how other researchers explain the rationale behind NAD boosters:

    Deficiency of NAD… abolishes sirtuin gene action whereas increased NAD induces Sirtuin gene function; therefore, consumption of NAD helps sirtuin genes to exert their effects and regulate aging (paraphrased).  [Journal Biomedicine Biotechnology 2011]

    A lot of longevity seekers who are eager to make guinea pigs out of themselves simply ask where they can get these molecules.  Ah hem, there isn’t a single published human study on either of these more sophisticated NAD precursors yet.  The science presently consists of a small number of anecdotal reports.  That is what skeptics have long criticized dietary supplements for.

    Regardless of the lack of human studies, nicotinamide riboside is just now entering the market as a dietary supplement and MIT researchers have recently introduced their own combo anti-aging pill with resveratrol and nicotinamide riboside, one of the niacin-like molecules.  The science behind nicotinamide riboside is said to be promising. [Cell Metabolism June 6, 2012]

    Behind the curtains

    To help you see the behind the curtains, from the business side of things, efforts to introduce anti-aging pills as drugs have failed, so the science community has capitulated and introduced is anti-aging elixirs as nutraceuticals, not drugs.  MIT has its molecule – nicotinamide riboside, while Harvard has its molecule – nicotinamide mononucleotide.  Just wait till Caltech comes up with its own anti-aging pill.

    NAD/NADH Ratio

    Now NAD is a positively charged molecule that accepts electrons from other molecules and converts into NADH (or NADPH), which is also available as a dietary supplement.  (NADH or NADPH stands for nicotinamide adenine dinucleotide phosphate). []

    NADH is the stable (reduced) form of NAD and it is oxidized back to NAD in a constant circuitous reaction.  NADH lowers cholesterol and blood pressure, enhances immunity and improves memory and protects the liver from alcohol damage.

    With advancing age NAD levels decline and NADH levels rise.  The NAD/NADH ratio is out of balance (see charts below).


    Chart: NAD, NADH

    With advancing age, NAD declines, NADH rises.  [PLoS One April 26, 2011]

    No explanation is offered as to why NAD declines and NADH rises with advancing age but there is evidence that NADH releases iron that then generates the “rusting” of aging.  Archives Biochemistry & Biophysics Dec 1989] Possibly the progressive accumulation of iron with advancing age results in reduced NAD.

    Researchers say:

    Overall, our results show that oxidative stress increases with age, (appearing to accelerate more rapidly after mid life), in association with reduced antioxidant defense mechanisms, and mitochondrial dysfunction; data consistent with the predictions of the free-radical theory of aging. [PLoS One April 26, 2011]

    By now I’m sure you are saying you didn’t ask for all this science.

    Well, you don’t just want to jump into the sea of longevity without understanding why, do you?

    Are these designer NAD booster pills needed or will niacinamide, an economical form of niacin that is a precursor to NAD, work as well?  We don’t know.  There are no studies comparing niacinamide, nicotinamide mononucleotide and nicotamide riboside in humans.

    This author believes a better NAD booster has already been produced and is available (Longevinex®).  It boosts NAD by demonstrably inhibiting the hypoxia gene (hypoxia inducing factor 1 or HIF1).  You can read about it here. [ Dec 24, 2013]

    I have also reviewed the historical science behind niacinamide.  I traced back to 1953 when a report in the Connecticut State Medical Journal said: “niacinamide therapy for joint mobility produces therapeutic reversal of a common clinical manifestation of the normal aging process.”  [ Jan 3, 2014]

    That sounds like the most recent discovery where aging was reversed in the muscle of laboratory mice, resulting in 60-year old animals 20-years old again in biological terms.  Has niacin therapy been passed over for over sixty years?

    Studies show that requirements for NAD can be met with less than 20 milligrams of daily niacin or niacinamide but even larger amounts of this vitamin may offer health benefits with advancing age. [Annual Review Nutritrion 2008]

    You’ll have to sort it out for yourself from here until more conclusive studies are forthcoming.  ©2015 Bill Sardi,

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