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  • Re-Thinking The Anti-Aging Pill

    August 5, 2019: by Bill Sardi

    Longevity seekers have heard all this before, but we hear more today:

    “Anti-Ageing drugs are coming” – New Scientist April 2019; Medical Xpress Sept. 2018

    “Longevity and anti-aging research: prime time for an impact on the globe” – Harvard Gazette March 2019

    “Healthy To 100?”  — San Diego Union Tribune July 2019

    You may be alive when the first anti-aging pill is granted approval by health authorities. Or hve one or two already materialized but just dismissed by those who seek to control the anti-aging marketplace?  Or will public health authorities ever let an anti-aging pill gain traction?

    Anti-aging investigator Josh Mitteldorf says “it may soon be possible to measure changes in the rate of human aging over periods as short as a year or two” instead of the impractical challenge of a lifetime study in humans to produce conclusive evidence.

    Don’t hold your breath for the first human trial of an purported anti-aging pill (anti-diabetic drug metformin/Glucophage) is about to begin, and will take 5-7 years to complete.  But metformin only increased lifespan in lab animals by 4-6%.

    Is the public being set up for disappointment that will dash or delay the approval of more promising anti-aging agents?  And given that metformin may induce vitamin deficiencies and other side effects such as chronic diarrhea, I wouldn’t be surprised if the study were sponsored by the makers of Depend® adult diapers.

    Historical anti-aging pills

    In modern times we’ve lived through various eras of anti-aging pills, starting with deprenyl (Selegiline) in the 1960s, human growth hormone in the 1990s, resveratrol in 2003, and more recently niacin-like molecules  in 2003, aspirin in 2005.

    More recently the introduction of molecules that inhibit living cells from becoming old (senescent) has biologists saying an anti-aging pill is just around the corner, centered around a molecule found in strawberries: fisetin.

    But wait, there is yet another upcoming development in the race to introduce a proven anti-aging technology.  Harvard Professor David Sinclair, the “Johnny Appleseed” who spearheads the molecular anti-aging movement, now talks of injecting genes to produce youthful animals.  These are so-called Yamanaka factors, highly expressed embryonic stem cells that can propagate indefinitely and exchange old cells for new throughout the body – heart, brain, liver, etc.  Sinclair says he has a scientific paper under review for publication that explains this cell reprogramming technology.  This latest development is reported to have biotech companies ramping up their R&D.

    The longevity pill committee

    To face the challenges of gaining government approval for anti-aging technologies and hurdling anticipated foot dragging by pharmaceutical companies and physician groups, a group of leading anti-aging investigators from Harvard, MIT and other institutions have formed the Academy for Health & Lifespan Research.  These researchers say they want to speak with one voice to be able to help corporations and governments develop realistic projections of what human life is going to be like 10, 20, 50 years from now.  They intend to upset the current pharmacological model of one drug for each disease.  A drug that slows or reverses aging would make many drugs unnecessary, or at least delay their use.

    Any technology proven to slow or reverse aging would be expected to save trillions of healthcare dollars now directed towards treating the many maladies of aging — cataracts, cancer, hypertension, heart disease and diabetes.

    But obviously, government approval is sought to gain insurance reimbursement for the “disease” of aging.  Such a pill would only be reimbursed by pools of money in public or private insurance funds beyond a certain age so the young would be paying for the old.

    The Academy of Health & Lifespan Research intends to control what gets to market and obtain Medicare funding.  A seal of approval is under discussion.

    Assessment of anti-aging practices and molecules

    I’m going to assess the leading candidates for the prize as the world’s first bona fide anti-aging pill.  After some scientific scrutiny, a real anti-aging pill will materialize, and it hopefully won’t be a dud.

    Calorie restriction is dubbed “the most powerful intervention known to retard biological aging in mammals.”  In 1935 Clive McCay at Cornell University demonstrated that life-long calorie restriction doubled the lifespan and healthspan of mammals.

    Then later Richard Weindruch and Roy Walford demonstrated that late-in-life calorie restriction could exert the same robust anti-aging effects as life-long CR.  Later, researcher Steven Spindler showed it is possible to achieve extensions of lifespan in lab animals when intervention is initiated late in life.

    Calorie restriction (fasting), exercise and blood-letting are three known practices that unarguably extend the human lifespan.

    The most talked about anti-aging molecules are:

    Resveratrol, Rapamycin (mTOR inhibitor), aspirin, Klotho gene protein, fisetin, niacin derivatives, vitamin C.

    The financial reward

    The quest to develop and introduce a proven anti-aging pill is following the route of pharmaceuticals.  The most expensive and financially rewarding technologies rise to the top.  While the most lucrative anti-aging technologies are required for biotech companies to be compensated for their multi-million-dollar investments and for physicians to prescribe them, these ventures appear to give no consideration for cost.  Greatest return on investment comes at the cost of affordability.  Hence, anti-aging pill companies would seek government approval in hopes of attaining insurance reimbursement.  To do that, aging has to be declared a disease.  But just how does a physician diagnose aging when it affects everyone?

    A landmark report published at states:

    “A high-priced drug taken by everyone could place a burden on already strained health care system, including Medicare, which presumably would have to pay for everyone to take the drug for many decades.”

    There have to be offsetting savings weighed against more years of Social Security payments.  Keeping aging adults healthy and functional and employed so they can retire at a later date is one such off-setting objective.

    What is the primary cause of aging?

    There may be anti-aging pills that favorably switch genes, but do they address the real cause of aging or just some downstream associated but not causal mechanism?  There may be many secondary “causes” or instigators of aging involving cell metabolism, mitochondrial cell energy, etc.  But as this paper unequivocally presents the accumulation of minerals after childhood growth is the “malignant spirit” and primary driver of aging.  You may wish to read my 3-part report entitled THE OVERMINERALIZATION THEORY OF AGING.

    To summarize, biological aging doesn’t begin till full childhood growth is achieved (~ age 18).  Up to that point individuals are having birthdays but not aging.  There are three speeds of aging: 1) childhood growth, no biological aging; 2) accelerated progressive aging in middle age correlated with increasing iron/calcium stores in the body; 3) as minerals level off, the rate of aging in the latter years of life slows down.  There is no explanation for these three life stages of aging other than accumulation of minerals

    My investigation reveals the accumulation of minerals, namely iron, copper and calcium after full childhood growth is completed ~age 18, is the root cause of aging.  During the growth years demand for iron, copper and calcium are great.  But thereafter these minerals accumulate, generating iron/copper induced free radicals and calcification of tissues.

    Full-grown males (age 18) accumulate iron at the rate of 1 milligram per day of life.  By age 40 males may have accumulated thousands of milligrams of excess iron, most of it carried on hemoglobin in red blood cells.  At age 40 a man will have double the amount of iron and four times as much calcium as a 40-year old female and will incur double the rate of diabetes, cancer and heart disease.  An early hysterectomy and cessation of menstruation will result in the same rate of disease for women as men.

    Measure the rate of aging by cellular debris (lipofuscin)

    The accumulation of cellular debris known as lipofuscin is accelerated with the completion of childhood growth.  That is when human aging begins.  Up till then, humans are only having birthdays (calendar aging, nor biological aging).  Lipofuscin accumulation serves as a biological marker of human aging.  Internal lipofuscin accumulation can be determined without tissue biopsy by direct visual examination of the human eye aided by magnification.  Therefore, premature aging can be determined.  Females, by virtue of menstrual blood loss, avert iron overload, given that 80+% of iron is located in red blood cells.  Women also donate iron, copper and calcium to their offspring.

    Minerals control aging genes, not calendar aging per se

    Accumulation of minerals, particularly when they are unbound (free iron, copper, calcium), triggers the protein making (epigenetic expression) of aging genes such as a master gene transcription factor known as nuclear factor NF-kappa B.  This is an inflammatory trigger.  Biologists have coined aging as “inflammaging, chronic low-grade “fire and smoke” in the human body.  NF-kappa B is linked with many genes involved in aging and anti-aging, namely Sirtuins, FOXO, mTOR (target of rapamycin).

    All of the anti-aging molecules identified in modern times in some way control metals, particularly iron, as shown in the graphic below.

    For example, aspirin is posed as an anti-aging pill.  Aspirin induces a small blood loss and therefore reduction in iron load.  Polyphenols such as resveratrol (copper), quercetin (iron) and IP6 rice bran (all metals and calcium) work synergistically to mop up (chelate) loose (unbound) minerals.  Fisetin works by reduction of loss of ferritin, an iron binding molecule.

    Mineral control serves to slow or reverse human aging by reduction in mineral intake (calorie restriction, avoidance of iron-rich red meat or calcium-rich dairy) or direct elimination of iron (bloodletting).

    Too much is made of gene-controlling molecules.  The genes are only the facilitators of aging.  Genes can be switch on or off (make proteins = gene expression; cease making gene proteins = gene silencing).  Molecules can switch genes and mimic a lifespan-prolonging limited calorie diet.

    Calcium is also a driver of aging.  Higher calcium arterial scores (greater than 1000 Agatston score) are associated with a decrease in survival.  Death rates increase by 20-30% individuals with higher calcium arterial scores.

    The following chart graphically summarizes and compares the properties of each of these anti-aging agents.

    Comparison: Anti-aging strategies

    Approach / Intevention Calorie restricted diet (fasting) Blood Letting Calorie restriction Mimics (Sirt1 survival Gene) mTOR Inhibitors Metformin Vitamin D receptor Anti-Senolytic Agents Aspirin NAD Boosters Niacin and Niacin like Molecules Restoration Vitamin C synthesis
    Gene Target Sirtuin 1 Ferritin Sirtuin 1 mTOR mTOR
    Sirtuin 1
    Klotho BCL, p15, p53-FOX4 COX1, COX2 Sirtuin 1 GULO
    Advocates Clive McCay 1935 Eugene Weinberg 2009 David Sinclair 2004 Mikhail Barocliny 2010 Nir Barzalai 2016 Y Nabeshima 1997 James L Kirkland Mayo Clinic 2017 David Sinclair Len Guarente 2014 Irwin Stone 1972
    Molecules Unnecessary Unnecessary Resveratrol Rapamycin (Sirolimus) Metformin (Glucophage) Klotho Protein Fisetin Quercetin Acetyl- salicylic acid NAD Nicotinamide riboside, NMN Olive Extract
    Longevity Effect Doubles health span/ lifespan Should mimic calorie restricition +31% (animals) +60% Lifespan (animals) +23% Phenformin (animals) + 8% metformin (animals) +20-30% (animals) +36% (animals) -7% reduction in all-cause mortality (humans) +5% (animals) +270% Health Span & Lifespan (animals)
    Reference J Nutrition 2010 Knowledge of Health 2014 Biochimica Biophysica Acta 2015 eLife 2016 Gerontology 1980 Bulletin Exp. Biology & Med 2005 Science 2008 J Am Geriatric Society 2018, Nature Medicine 2018 Am j Cardiology 2006 Science 2016 Whole Foods 2018, Aging 2016
    Mineral control / chelation
    Drawbacks Anemia Not reported Uncommon Non-mortal Low-dose is safe B1 & B12 depletion Not reported Not reported Bleeding ulcers, Brain hemorrhage, Death No serious side effects Diarrhea (mega doses)


    Sorting out anti-aging strategies

    There are other strategies to conquer aging that have become favorites among anti-aging researchers and the public, namely mTOR inhibitors such as rapamycin and telomere-lengthening agents.  These are briefly discussed below.

    mTOR, iron and aging

    mTOR (target of rapamycin) is a gene target for longevity.  Rapamycin is an approved drug used to prevent organ transplant rejection.  Rapamycin (Sirolimus) is fraught with side effects but is utilized at very low doses.  Given this anti-aging molecule is already approved by the FDA, it can be prescribed for off-label uses.  This author is unaware of any doctor prescribing it for the purpose of achieving longevity.

    Biology commentator Dennis Mangan writes that iron, not mTOR, is the primary driver of aging.  Iron chelators inhibit the mTOR gene and slow aging.  Life-long accumulation of iron activates mTOR and accelerates aging.  Calorie restriction limits iron intake and inhibition of iron absorption from food extends lifespan.


    Longevity seekers have become fascinated over telomeres, end caps of our chromosomes.  An over simplification is that longer telomeres are associated but do not directly induce longer lifespans.

    The activation of telomerase, the enzyme that repairs broken telomeres, is associated with a favorable metabolism that controls aging over chronological (calendar) ageTelomerase- deficient mice experience a shortened lifespanTelomerase is a magnesium dependent enzyme, which suggests a molecular approach to longevity.

    Accelerated shortening of telomeres is associated accelerated aging.  Dogs, with long incisors to chew iron-rich meat, lose telomere DNA 10 times faster than humans. Telomeres are longer in females who generally live longer than males.

    Public fascination over lengthening or reduction in the length of telomeres, end caps of our chromosomes, is a misdirection.  Telomere shortening is a consequence, not a cause of human aging.  Telomere shortening is an indicator of oxidationHigh body iron stores are associated with shorter telomeres.  Similarly, increased transport of iron in the body as measured by transferrin is associated with telomere aging (shortening).  Again, taking iron supplements shortens telomeres.   Inherited iron overload (hemochromatosis) is associated with shorter telomeres.  Telomere shortening is more pronounced among omnivores who consume highly absorbable heme iron from meat compared to vegetarians who consume non-heme iron from plant foods.  So, iron supersedes control of telomeres and aging.  Telomere shortening due to iron-induced oxidation confirms the overmineralization theory of aging.

    Iron as the malignant agent of aging

    Ferritin is a protein that stores iron.  Normal ferritin levels range from 20-250 in adult males and 10-120 in adult females.

    Centenarians have lower iron storage levels (ferritin) than younger (60s) adults. Adults in their 60s averaged 1314 nanograms iron per milliliter of blood versus 713 nanograms per milliliter in centenarians).

    Women who give birth to offspring late in life (beyond age 33) are more likely to live longer than women who give birth earlier in life.  Women who gave birth to a child after age 40 have four times greater odds of being a centenariancompared to women who had their last child at a younger age.  The average blood loss after a vaginal delivery of a single baby is around half a quart (500 milliliters).  Caesarian deliveries result in loss of a quart of blood (1000 milliliters).  Birthing is a blood-letting event.

    It’s not calories

    There is misdirection when it is said that calorie restriction induces longevity.  By virtue of eating less food (calorie restriction), less iron, copper and calcium are consumed.  Researchers show that as iron accumulates in the brain with advancing age of monkeys, their balance and coordination decline.  This decline is caused by iron.  In a telling lab experiment published in the journal Biogerontology, animals were given 1) rat chow; 2) 40% less calorie diet (less minerals); 3) calorie restricted diet with added minerals.  Dietary restriction did NOT reduce aging deposits in the brain compared to animals fed a normal diet while animals given extra minerals experienced accelerated brain aging.

    The multi-ingredient anti-aging pill

    One anti-aging researcher proposes an anti-aging polypill that combines an mTOR inhibitor like rapamycin with aspirin, metformin, a cholesterol-lowering statin drug and blood pressure-lowering drugs.  Such a combination would induce a number of nutrient deficiencies (vitamin B12, B1, coenzyme Q10, zinc, vitamin C).

    Numerous anti-aging molecules target various genes to produce anti-aging effects.

    Whatever molecules are utilized as anti-aging agents, to exert biological effects on the human brain, molecules need to be small (less than 900 Daltons molecular weight) so they can pass through the blood-brain barrier.  Here is the molecular weight for molecules found in one commercially available multi-ingredient anti-aging pill (Longevinex®).

    • Resveratrol 228 Daltons
    • Quercetin 302 Daltons
    • Rice bran IP6 660 Daltons
    • Fisetin 286 Daltons
    • Vitamin D 384 Daltons

    Combined use of anti-aging molecules is being discussed.  Combinations of anti-aging molecules are documented to enhance the activation of the Sirtuin1 survival gene as well as inhibit mTOR.

    Resveratrol combined with vitamin D exhibits superior ability to counter memory impairment in laboratory mice.

    A multi-ingredient anti-aging pill would produce more demonstrable anti-aging effects, both slowing aging and reversal of aging by mineral chelation.  The mineral-chelating/controlling properties of a commercially available multi-ingredient anti-aging pill (Longevinex®) are as follows:

    Lipofuscin (cellular debris)

    Lipofuscin (cellular debris) accumulation correlates with chronological (calendar) aging.  Lipofuscin is not a bystander in the aging process.  Iron accumulates within lipofuscin and generates free radicals and inflammation. Once formed within cells, it is said there is no way to reverse lipofuscin accumulation.   An overlooked research study showed bran that contains IP6 was equal to calorie restriction in slowing the accumulation of lipofuscin.

    Chart: Lipofuscin Increase

    Progressive increase of cellular debris (lipofuscin) in the human eye with advancing age, beginning from age 20 years.

    The superiority of resveratrol

    Chart: Resveratrol Actions

    One of the startling findings is when the mechanisms behind all of the proposed anti-aging pills are studied, resveratrol replicates the biological action of aspirin, mTOR inhibitor rapamycin, niacin-like NAD boosters, increases sensitivity of the vitamin D receptor as well as controls minerals and inhibits NF-kappa B and tickles known anti-aging genes like Sirtuins.

    All of the anti-aging properties of other candidate molecules are performed by resveratrol.

    Resveratrol and a calorie restricted diet exhibit a comparable effect on the Sirtuin1 survival gene, making it a true molecular mimic of calorie restriction.

    Resveratrol both kills off senescent cells as well as reduces the number of cells that become senescent.

    Fisetin is a newly identified anti-aging molecule.  Abundant in strawberries (~2 mg per berry), its molecular structure is resembles resveratrol.  Fisetin inhibits inflammation like aspirin, molecularly mimics calorie restriction, inhibits mTOR like rapamycin, and activates the Sirtuin1 survival gene.

    Resveratrol, the most researched anti-aging molecule, failed to mimic lifespan doubling calorie restricted diets in laboratory mice by a wide margin, which suggests multiple molecules may be more efficacious.  In nature, such as in grape wine, resveratrol exists with other powerful antioxidants to produce a synergistic effect.   When a multi-ingredient anti-aging pill (Longevinex®) was put to the test in lab animals, it exerted 9-fold greater epigenetic activity (1711 genes activated) than a calorie restricted diet (198 genes activated) or plain resveratrol (225 genes activated).

    Chart: Longevinex actions

    Calorie restriction + adequate nutrition

    What goes unmentioned is that all these longevity experiments in the animal lab were proven with a “generous provision of essential nutrients.”  All calorie restriction laboratory studies have involved the provision of “adequate nutrition” to lab animals as a prerequisite.  It cannot be assumed that the provision of nutrients from the modern calorie-rich/nutrient poor western diet is adequate when anti-aging pills are utilized.  What we have today is “high calorie malnutrition.”

    Opposition to an anti-aging pill

    Which biotech company will persuade the FDA their elixir is the real anti-aging pill, the antidote to the scourge of aging?  Major pharmaceutical companies and modern medicine itself loathes of such a day when the many drugs that address all of the mental and physical manifestations of aging are replaced by just one pill.  Such a pill would save trillions of dollars in health care costs.

    To clear the field for biotech firms, oligarchs who fund most startup biotech companies were able to persuade federal authorities to consider any dietary supplement company that makes claims its products prolong human life as engaging in criminal activity, even if there is evidence for same.  Bankers enforce this measure by reviewing websites and yanking merchant accounts from any online supplement companies that

    Will we find longevity at the doctor’s office?

    Modern medicine is pricing itself out of business.  Anti-aging doctors pursue the most financially rewarding technologies, most which are excessively expensive and beyond the means of most Americans.  Physicians are unlikely to embrace any anti-aging technology that puts them out of business.  Right now physicians make more money treating, but not curing, each and every disease that emanates from the aging process.

    The American Academy of Anti-Aging Medicine boasts 26,000 physician members.  A prescriptive anti-aging program offered by one of the Academy members is said to involve a $2500 initial evaluation fee and subsequent annual check-up for $1995 and a monthly program fee of $350.

    For physicians to embrace an anti-aging pill, they would have to be lured by a financial reward equal to or greater than the income they now generate.

    While a percentage of the population would likely be swayed to take an anti-aging pill once the Food & Drug Administration grants approval of such an elixir, aging must first be declared a disease in order for the FDA to regulate it.  FDA approval will predictably be political with all kinds of forces hindering or blocking approval of such a pill.  Forces behind population control, concerns over bankruptcy of Medicare and Social Security, and elimination of need for many prescription drugs as well less demand for doctoring would gather covert and overt opposition to such a pill.  Waiting for FDA approval may be a misdirection because of the many camps in modern medicine that pull in different directions.

    Vitamin C overlooked

    An overlooked anti-aging agent is vitamin C.  A landmark study conducted by Canadian researchers shows, if animal lab data can be applied to humans, that maintaining levels of vitamin C would theoretically produce a 270% increase in health span and lifespan (from 8.5 to 24.0 months lifespan increase in rodents).   That would be far greater than any other proposed anti-aging strategy or molecule.

    An effort to restore internal vitamin C synthesis in humans is underway.


    • Individuals will have to make up their own mind about anti-aging pills and forego waiting for approval by any self-appointed committee or government agency that will only shigt the real consumer cost of an anti-aging pill onto insurers who raise premiums, which drives up the cost.  If consumers are left to purchase high-tech anti-aging pills on their own, the cost would likely be prohibitive.   There are affordable anti-aging pills that are currently available.
    • A bona fide anti-aging pill needs to address over-mineralization as the primary driver of aging by inclusion of mineral-controlling molecules.  Dietary reduction of dietary iron/copper/calcium intake would serve to slow aging.  Blood-letting is an economical approach to longevity but probably should only be practiced by middle-aged adults.
    • A multi-ingredient anti-aging pill would produce superior biological activity over any single nutrient or synthetic molecule.
    • In the animal lab, to produce consistent longevity effects animals are given “adequate nutrition” in fortified lab chow.  This suggests for those few who actually practice calorie restriction or intermittent fasting, or even take a calorie restriction mimic, a comprehensive iron/copper-free multivitamin is in order.  Today’s American diet cannot be considered “adequate nutrition” but rather “high calorie malnutrition.”
    • When anti-aging strategies are compared, the re-establishment of continual internal synthesis of vitamin C in humans would theoretically produce a longer healthy lifespan than even calorie restriction.  Based upon studies of lifespan extension in the animal lab, maintaining vitamin C levels to the level once achieved before a gene mutation halted endogenous synthesis of vitamin C in humans would theoretically add 270% to the human lifespan.  An effort to epigenetically restore endogenous vitamin C synthesis in humans is underway and reports early success.

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