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How the world got lost on
the road to an anti-aging pill
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December 21, 2015: by Bill Sardi
What a year in anti-aging research and anti-aging pill offerings. An article in The Daily Beast called it “The Year We Decided To Live Forever,” referring to the billionaires (Peter Thiel, Breakout Labs; Larry Ellison, Oracle CEO; Paul Glenn, anti-aging philanthropist; Larry Page, Google co-founder, Calico; Craig Venter, Human Longevity) who have dedicated hundreds of millions of dollars in the pursuit of biological immortality. [Daily Beast Dec 4, 2015]
Researchers say the world may finally get an anti-aging pill, but it will be on their terms. Somebody has to pay back the millions of dollars being invested in developmental drugs for what has been called “the greatest problem of our time” – aging.
One researcher says such a drug “would be the most profitable drug ever made.” Well, maybe not the first one recently given a
go-ahead by the FDA. A human clinical study of metformin (aka Glucophage), an existing anti-diabetic drug that can be purchased online for ~$4 for a 1-month supply, will be launched in 2016 with news headlines that say this pill could “help humans live 120 years.” [Daily Mail UK Nov 30, 2015]
But based upon prior metformin studies, let’s try adding another 5-6 years to the American lifespan. At least we will save money on birthday candles if metformin doesn’t live up to its hype.
And don’t anticipate metformin to be without side effects as it induces vitamin B1, B12 and magnesium deficiencies. [Molecular Pharmacology 2015; Internal Emergency Medicine 2015; PLoS One 2013] Because of its interference with B vitamins, metformin raises homycysteine, an undesirable blood protein implicated in nervous system disorders. [Human Reproduction 2005]
With the FDA go-ahead, scientists and other organizations will attempt to raise funds ($50 million) and recruit 3000 patients, 70-80 years of age, for the study. (Gee, if they would only do that for resveratrol L).
Another piece of good news that has escaped notice is that researchers, by recruiting senior adults, obviously believe a person is never too old to benefit from anti-aging strategies. The study will measure reversal of aging in octogenarians rather than just slowing the rate of aging in middle agers.
The Targeting Aging With Metformin (TAME) study will be getting all the attention from the news media in 2016 but will take 5-7 years to complete. [Nature June 2015]
Of interest, metformin and resveratrol are frequently mentioned together as anti-aging pills. [Nutrition Research Reviews 2015; Annals New York Academy Science 2015] Metformin largely works by raising a cell energy-sensing molecule called AMPK. For what it’s worth, resveratrol is 50-200 times better at raising AMPK levels than metformin. [Diabetes 2006]
Researchers note that metformin can restore elevated oxygen consumption levels in sugar-laden tissues via AMPK. [Experimental Gerontology Oct 2015] By the 4th decade of life our ability to process oxygen is decreased by 10%; by the 5th decade by another 20%; by the 7th decade we lose yet another 30%. So this energy/oxygen-sensing ability of metformin, and more so of resveratrol, becomes a dominant factor in the control of the rate of aging.
Another important taboo was crossed this past year that may have been overlooked. A major university, Massachusetts Institute of Technology (MIT) no less, dared to offer its version of an anti-aging pill as a dietary supplement rather than a drug. [MIT Technology Review Feb 3, 2015] After all, it is a version of niacin-vitamin B3. The last anti-aging drug company that tried that, Sirtris Pharmaceuticals, faced admonishment from its parent company in Europe. [Xconomy.com 2010]
MIT’s anti-aging pill provides an active form of niacin – nicotinamide riboside along with a form of resveratrol called pterostilbene. While there are no human studies to back their use, individually or combined, the science is valid. Noted anti-aging researcher Leonard Guarente heads up the MIT team.
The problem for MIT’s new anti-aging pill, trade name Basis by Elysium Health, is that there is no frenzy to buy it. [Elysium Health] Public demand for anti-aging pills is measured in yawns. For example, a 2011 survey in Australia found only 35% would use a life-extension technology and nearly half believed an anti-aging pill would do more harm than good to society overall. [Sydney Morning Herald Oct 3, 2015]
Harvard’s David Sinclair is still in the anti-aging pill race. Sinclair jump-started a temporary demand for anti-aging pills in 2003 when he first reported that a red wine molecule, resveratrol (rez-vair-ah-trol), known to reduce mortal heart attacks, was linked to a calorie restricted diet that doubles lifespan in animal experiments. [Nature 2003]
In 2015 Sinclair reported on the use of another niacin derivative, nicotinamide mononucleotide as an anti-aging pill. [Scientific American March 11, 2015] Sinclair, in a recently published report in the European Heart Journal, says with this form of niacin plus specific sirtuin-1 survival gene activators (resveratrol) “we anticipate that this field will move quickly from bench to bedside.” [European Heart Journal 2015] That remains to be proven. Surprisingly, nicotinamide mononucleotide has been available for some time as an economical dietary supplement. [Source Naturals]
Another landmark report entitled “Does A Real Anti-Aging Pill Already Exist?” by health writer Bill Gifford explored the third most commonly mentioned anti-aging molecule behind metformin and resveratrol, rapamycin (aka Sirolimus). [Bloomberg News Feb 12, 2015]
Rapamycin is an FDA approved drug used for organ transplant patients. It inhibits a gene called mTOR (target of rapamycin), activating a cell cleansing process called autophagy. Doctors could begin prescribing rapamycin today for off-label use.
Mikhail Blagoklonny of Cell Stress Biology in Roswell, New York, is the chief advocate for rapamycin as an anti-aging drug. In 2010 Blagosklonny said “rapamycin will become the cornerstone of anti-aging therapy in our lifetime.” [Cell Cycle 2010] He says low-dose rapamycin is safe and there is no need to further study rapamycin as it has “already entered the clinic.” [Oncotarget Aug 2015]
A setback in the science of rapamycin was reported when it would found that rapamycin reduced the lifespan of diabetic mice. Mortality was increased 1.7-fold. [Journal Gerontology A Biological Science Medical Science Oct 2015]
Noted researcher Matt Kaeberlein intends to study rapamycin with aging dogs in the coming months ahead. [Veterinary Pathology June 2015]
Matt Kaeberlein has been pleading for dosage studies to clarify prescribing instructions for physicians. Kaeberlein says initiation of rapamycin treatment late in life may be sufficient to extend lifespan. He says rapamycin is “the only pharmaceutical agent thus far shown to reproducibly extend lifespan and delay a subset of age-associated pathologies in multiple strains of mice.” [Journal Genetic Genomics 2014]
Another interesting finding this year was that the addition of vitamin A to rapamycin produces dramatically improved inhibition of aging in a lab dish study of cells involved in a premature aging disorder called progeria. [Oncotarget Oct 2015]
Another anti-aging strategy that came into view in 2015 is parabiosis, the mixing of young blood with old to rejuvenate living tissues. About a decade ago researchers sewed an old mouse with a young one so they had a shared circulatory system and strikingly, the old mouse became young again. Now researchers searched for a blood factor responsible for this age-reversing effect and identified GDF-11 (growth differentiation factor 11) as the active agent. Injection of GDF-11 enhanced stem cell function. [Cell Metabolism 2014] Even though GDF-11 has been called into question [Nature 2015] researchers are sticking to their guns and persist in their findings.
The first results of older humans with mild Alzheimer’s disease given blood transfusions from healthy young adults are due to be reported in 2016. That ought to be an exciting moment in anti-aging research. [New Scientist 2015]
Yet another anti-aging strategy emerged from late-breaking science this past year. Dietary molecules called polyamines, provided abundantly in wheat germ, reset the body’s 24-hour circadian clock and prolong the healthspan and lifespan of humans. [Cell Metabolism 2015] Centenarians exhibit healthy levels of polyamines. [Rejuventation Research 2012] A more complete report on polyamines as an anti-aging strategy can be found at ResveratrolNews.com. [ResveratrolNews.com Oct 14, 2015]
Folic acid (vitamin B9) has been shown for the first time to extend the life of a living organism (roundworms) and delay aging. It does so by targeting the mTOR gene much like resveratrol and metformin. [Age Dec 2015] This is quite a discovery.
Another startling discovery is that the amino acid citrulline, found naturally in watermelons, reduced mortality at 12 weeks from 20% to 0% in laboratory mice and improved muscle mass. [Journal Nutrition July 2015]
A study published in 2010 is instructive. In both lab dish and laboratory animals, resveratrol was shown to exert health benefits via activation of a gene transcription factor called Nrf2. Nrf2 controls internal antioxidants (SOD, catalase, glutathione, heme oxygenase) which produces an anti-aging effect. Genetic depletion of Nrf2 abrogates the ability of resveratrol to improve arterial health.
Researchers note that the dose concentration of resveratrol which activates Nrf2 is physiologically relevant, that is, it is achievable. However, they note that “such levels of resveratrol are not generally achieved through the consumption of Mediterranean diets or red wine, when resveratrol is used as a dietary supplement, it can achieve measurable levels in blood plasma to activate Nrf2 and attenuate oxidative stress. Surprisingly, this can be achieved with lower concentrations of resveratrol than needed to activate the Sirtuin-1 survival gene! [American Journal Physiology Heart & Circulatory Physiology July 2010]
Low-dose toxins, like resveratrol, induce a counter-adaptive response in living tissues, activating endogenous antioxidant defenses (enzymatic antioxidants SOD, catalase, glutathione, heme oxygenase). Mega-doses negate this effect. [Trends Neuroscience 2008; Neurochemical Research 2008] It is this low-dose protective response that is associated with longevity. [Biogerontology 2015; Journal Cellular Communication Signaling 2014]
Low-dose resveratrol is considered a molecule that activates Nrf2 as a hormesis agent. [Human Experimental Toxicology Dec 2010; Human Experimental Toxicology 2010] Researchers recommend human clinical trials be based on a clear understanding that lower doses of resveratrol deliver health benefits and higher doses detrimental effects. [Human Experimental Toxicology 2010]
Resveratrol has been roundly criticized for a lack of human studies a decade after it became widely known as a longevity factor. Two positive human studies have been published this year involving resveratrol. Both employed mega-doses of resveratrol.
The first study was a year-long controlled study that successfully employed 1000-2000 milligrams/day for 1 year of oral resveratrol which resulted in a decline in undesirable beta amyloid in blood plasma. [Neurology Oct 2015]
Beta amyloid is a component of brain plaque in Alzheimer’s disease. The problem with blood plasma measurements is that this assumes lower circulating levels of amyloid are desirable. Actually, a problem in the brain is the oxidation and accumulation of amyloid and its faulty disposal, something researchers call efflux. [Neurotoxicity Research 2001]
If efflux of amyloid from the brain is increased, then blood serum levels would be higher, not lower. I’m not sure of the validity of this report given the questionable design of the study. I quote from a published study: “Resveratrol does not inhibit beta amyloid production because it has no effect on beta amyloid-producing enzymes, but promotes instead intracellular degradation of beta amyloid.” [Journal Biological Chemistry 2005]
The second published study involving mega-dose resveratrol involved middle-aged males with metabolic syndrome (overweight, blood sugar problems) in a short-term study (16 weeks) to measure bone density. A 1000 mg daily dose of resveratrol was effective at improving measures of bone density as measured by bone alkaline phosphatase; the 150 mg/day dose was ineffective. [Journal Clinical Endocrinology Metabolism 2014]
It is also possible mega-dose resveratrol was needed to provoke a biological effect in the short-term. It’s also possible mega-dose resveratrol prevents bone loss but does not prolong life.
Another caveat in interpretation of these mega-dose studies where it is said that wine does not provide sufficient resveratrol when compared to studies where pure resveratrol was used. Yes, but wine is not just resveratrol, it provides an array of antioxidant polyphenols (resveratrol, quercetin, catechin, gallic acid, ferulic acid, kaempferol, and others) that in total produce a synergistic effect that are more powerful than mega-dose resveratrol alone. [Planta Medica 2012; Translational Oncology 2008]
When laboratory mice were given three doses of resveratrol, the human equivalent of 2100 mg, 4200 mg and 6300 mg/day, the highest dose was the most effective at preventing bone loss in these mice. But it must be said that this was under experimental conditions where the mice were given the human equivalent of 7000 milligrams of iron (equivalent to ~400 iron pills in humans) to induce oxidation and decay of bone. This is an abnormal experience outside of the physiological conditions facing humans. [Journal Nutritional Biochemistry Nov 2015] Mega-dose resveratrol would not likely be needed under more normal circumstances.
John Pezzuto PhD, of the University of Hawaii College of Pharmacy, who first reported on resveratrol’s uncommon ability to quell cancer at all three stages of development (initiation, growth and spread) in 1997 [Science 1997], eighteen years later says the added advantage of resveratrol as a dietary supplement is its “pristine safety profile.” [Biochemica Biophysica Acta June 2015]
Who will be the change-agent to coax American medicine out of its treat-age-related-diseases-as-they-occur mode to a new paradigm of delay-aging/delay chronic disease altogether?
There have to be financial incentives for drug or supplement companies, but in this case, public adoption of such a pill might rely upon physician recommendation and insurance coverage. But just when would physicians diagnose “premature aging” and prescribe such a pill? At age 40, 50, 60?
A report published in the journal Aging Cell says: “there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. “ However, that statement was made at the “Interventions To Slow Aging In Humans: Are We Ready?” workshop in October of 2013. [Aging Cell Aug 2015]
One lone researcher says “there is sufficient evidence available to argue for interventions that can target fundamental aging processes, yet this scenario has barely entered public consciousness, and far from being a point of vigorous debate seems to be ignored by policy makers.” [Frontiers Genetics July 2015]
However, this author believes the upheaval of the health care system towards use of a single pill that will address all chronic age-related disease is something that must be covertly resisted, as it would dramatically reduce revenues to pharmaceutical companies and doctors. Wall Street health sector stocks would tumble at even the thought of an anti-aging pill. Trillions of dollars would be taken out of health care budgets. Aging is the funnel for all chronic disease. It is the fundamental pipeline to create drugs and treatments that only temporarily address symptoms of aging.
The major disappointment is that while metformin may indeed prolong human life and delay morbidity as a molecular mimic of a calorie-restricted diet, it won’t come close to what calorie restriction accomplishes in laboratory animals – a doubling of healthspan and lifespan. Modern medicine, out to protect its turf, would select a drug that will only have a modest effect on aging so as to head off any growing demand for an anti-aging pill. When the TAME/metformin study is completed in 2020-2022 it will be said that resveratrol pills are still unproven (but not disproven).
Placing all 55 million Americans with Medicare on metformin would cost ~$2.64 billion. For comparison, resveratrol is 50-200 times more effective, is far safer than aspirin or metformin, and would produce more profound biological effects.
Anti-aging pills might be easier to sell if marketers emphasized they not only address the length of life but also the quality of life. Most people loathe the idea of living longer with chronic disease. As some researchers now emphasize, you cannot lower mortality without reducing morbidity. That is the real promise of an anti-aging pill, to deliver quality with quantity, to add more healthy years.
For reference, only about 18% of senior adults describe themselves as “successfully aging.” As one researcher put it, unless vast improvements are made in health care, “we may end up with a world in which we spend more money than ever before to keep more people than ever before more miserable than ever before.” [Frontiers in Genetics 2015]
Utilizing gene chip technology, researchers have announced the development of a blood test that measures the healthy aging via analysis of 150 genes. The test provides a measure of the difference between chronological (calendar) age and biological age. The test measures modifiable gene proteins rather than inherited gene structure (gene mutations). This suggests an adult who is aging prematurely may be able to intervene and turns back the biological clock hands of time, even in old age. [Genome Biology 2015] The blood test is expected to be commercially available within a year. Just think, you can put your own anti-aging pill to the test.
There may be a day when modern medicine blesses an anti-aging pill as long as it doesn’t upset present income streams. But even if a longevity pill emerges, it may have to be forced down the throat of some people. Read the story of a 50-year old woman who couldn’t stand the idea of growing old and was allowed to die because she didn’t want to be “poor or ugly.” [Daily Mail UK] A journalist recently wrote that he would pass on any anti-aging pill. He said: “Forget it, God gave us a ‘best-before’ date.” [Toronto Sun Nov 30, 2015]
Now if there were only a pill that would eradicate wrinkles and people would be paid to take it, or at least a mirror that reflects a more youthful image. — ©2015 Bill Sardi, ResveratrolNews.com
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