Re: [GRG] FW: Quantifying the Effectiveness of Anti-Aging Interventions

Mike,Great email, you should write an article and post it publicly so that I can share it. Now I don’t agree with it fully with it, but it does somewhat describe what I have seen in research. 1- A University study comes out with spectacular news on a “natural” and “non-patentable” molecule (or complex).2- Other Universities study it, and if it’s amazing… a Pharmaceutical will pick it up to study it as well.3- Universities go on to produce a wide variety of studies on the molecule, and gets noticed by supplement manufacturers. Some manufacturers take a leap of faith and invest in producing and marketing a product.4- Pharmas keep on studying it, and keep all research a secret.5- Universities, that use donated funds… don’t typically publish negative information, but instead dig through the data for a juicy correlation to publish instead… and more studies are published.6- Pharmas upon realizing that the molecule has possibilities, will then try to modify it and patent it. Again, no research is provided to the public on the reasons they believe it has “possibilities”. Some Pharmas may even purchase the research, methods and IP of a natural molecule from another company for … 700 million dollars. (ie. Sirtris) 7- Universities continue to do research and help students earn their Ph.D. while providing information to other scientists when the research is published. Students rotate out of research and into the real world, some going to work for Pharmas.
8- Supplement manufacturers limited by the FDA and FTC, market and sell the product and depending on the customers feedback… increase or decrease the marketing of the product. (Supply and demand forces products in and out of the market).9- Pharmas provide a finished product, that hasn’t killed most of the people taking it… and may work for some. They push it to Doctors for a very specific illness or issue… and then provide other studies to doctors to help with “Off Label Use”, to help increase profit margins.Of course, we have seen that Pharmas provide only those studies that typically favor their “product” over that of a natural substance. I don’t think I have ever seen a Pharma shoot itself in the foot and do otherwise.While Universities are the best (IMHO) at producing un-biased data, I notice that they really don’t publish there failures. This is partially done because of the scientist who is researching the data and because of the University that wants positive results to garner donations and stature. Folks on Longecity are educated. I believe they know that a study maybe faulty, a molecule may not increase lifespan, and there are issues with how research is presently done, everywhere. But they make the best decision they can with the information they are given. I agree when you state the following:”Thus, any application of drugs based on animal testing in aging humans demands “as soon as possible” validation, which, in this case, means that meaningful feedback can be obtained in the space of a few years.”But in this world of capitalism there exists business decisions that trump the spending of money on research, specially when it is expensive and can generally only be done by an already large and extremely successful Pharma or maybe a Supplement company… given the expense, the type exclusivity and patent options available, the decision is a difficult one.While you may consider me a “Supplement Peddler” like Bill Faloon of LEF, the folks at IHerb or VitaCost… I assure you I don’t live in a mansion, I don’t have a Yacht and don’t care for those assumptions. The fact of the matter, is that supplement makers are not “richer than Croesus” otherwise some of us would spend the money on these non-patentable molecules. I have spent money on providing non-patentable materials to Universities along with equipment because I want them to research natural materials. Does that make me an evil supplement peddler or one that helps Universities with their research on these materials that Pharmas wouldn’t touch because of the low profit margin they could produce?Do supplement makers provide data on their failures in new product development? Well many don’t, and if they do it is in a way that will help them expose a better product that they are selling. We did it ourselves. Yes we initially believed we had a great product to compete against the staple in the “industry” and a molecule discovered by Geron. Our product failed compared to TA-65 and we published it: http://ift.tt/1EfWs0Q the climate in a capitalist society limits the type of information we all have access too. I believe science would be greatly advanced by the publication of the failures… specially from Pharmas. 

Of course that will never happen because of greed, but who here doesn’t think the publication of failures and open access from the Pharmas for their patented products, would help us all not reinvent the wheel and move on to new discoveries?

Anthony Loera

President

RevGenetics

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(F) 866-430-3953www.RevGenetics.com

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On Thu, Feb 26, 2015 at 9:52 AM, John M. “Johnny” Adams, GRG Exec Director wrote:

Dear GRG Member,

 

Forwarded from member Mike Darwin

 

This information is important and relevant to GRG mission.  

 

Images didn’t come through in original – Mike, could you resend images?

 

Johnny

 

From: Mike Darwin [mailto:m2darwin@aol.com] Sent: Tuesday, February 24, 2015 1:22 AMSubject: Quantifying the Effectiveness of Anti-Aging Interventions

 

 

I believe that a point I’ve been trying to make, for years now, simply isn’t registering. There is a vast difference between research scientists of any stripe, and people who are actually trying to extend their own life and healthspans NOW. Individuals who want to try various interventions on an ad hoc basis are, of course, not required to follow the scientific method, or to use any kind of objective measurement of their rate or extent of aging. Or are they?

 

I would argue that the answer to that question depends upon what they want to achieve and what their position of public advocacy is. If you publicly advocate or make claims for any anti- aging intervention, and especially if you market products to slow, halt or reverse aging, or any aging related degenerative disease, then I believe you should be held accountable to provide evidence that any such interventions actually show reasonable, meaningful, outcome data in humans. The government may not require this, but those of us in the life extension should!

 

It is well established that pharmacological research data from rodent studies, and even from larger animal studies, rarely translates to humans. As an example, if you are a rodent with cancer the chances are very good that your cancer is curable, or highly treatable. What then is the translation rate from success in treating cancer in rodents to success in humans? The answer is about 8%! 

http://ift.tt/1iPjfn7

 

What’s the success rate for drugs to treat stroke (regional brain ischemia), cardiac arrest (global brain ischemia) or heart attack (primary cardiac ischemia)? The answer is 0%. That’s right, after two decades and billions of dollars the translation rate is zero. These appallingly low numbers hold true across most of the spectrum of chronic and degenerative diseases, and this harsh reality is reflected in money spent on drug development versus drugs emerging from the pipeline:

 

 

This failure of translational research is referred to as “the valley of death”. The relevance of this to anti-aging research is that pharmaceutical companies base their commitment to drug development not on small, one-off, or even multiple animal studies showing promising results, such as those routinely used by supplement marketers, but rather on extensive further studies. The results of this additional study by drug companies is that most of the positive data from preliminary studies reported in the literature are invalidated. Thus, if animal research shows that a molecule induces mitochondriogenesis and that this improves some aspect of age-related degeneration, that’s merely a starting point that will launch much more intensive study. And more than 90% of the time, these subsequent studies uncover problems with potential application of the molecule and not infrequently prove to be irreproducible, injurious, or irrelevant in terms of therapeutic effect.  

 

rHGH yields fantastic improvements in acute function and in improved well being in humans (and it works in animals, too). But the adverse effects are so severe that it’s clinical utility for rejuvenation is essentially nil. In the frail elderly it doesn’t reverse sarcopenia and in the healthy elderly it has life threatening and life shortening adverse effects. Roughly 25% of all new drugs are either withdrawn, or get Black Box warnings within 15 years of introduction. These are drugs that pharmaceutical companies have vetted for safety and efficacy by fairly rigorous means. By contrast, supplements, which can be and often are as bioactive as ethical drugs, receive exactly zero vetting, and exactly zero long-term follow up, or indeed any follow up at all! 

 

The incidence of adverse effects that results in most new drug withdrawals, or Black Box warnings is, in terms of absolute numbers, very small. It’s so small that these adverse effects are not detectable in either Phase III clinical trials, nor in the first few years of after-market surveys wherein many thousands of people are taking the drugs. If vitamin E in doses of 400 IU QD or greater, selenium in doses 200 mcg QD or greater, stinging nettle, or many other “supplements” were subjected to the same kind of surveillance for an unacceptable adverse effect to benefit ratio they would be pulled from the market in a heartbeat. And that begs the question of the safety and efficacy of the plethora of other supplements and highly bioactive molecules being hawked for life extension. In reality, this isn’t much of a question, because, barring a miracle, there is every reason to believe that these agents will perform just as well, or more accurately, just as poorly as do ethical pharmaceuticals – or worse. 

 

But where this gets really interesting in terms of anti-aging interventions, is that when the many positive rodent studies with various supplements commonly taken by life extensionists are carefully replicated by an scientist expert in doing lifespan studies, such Steven Spindler of UCR, the positive benefits shown in earlier studies disappear:

 

Influence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice.

Spindler SR, Mote PL, Flegal JM, Teter B.

Rejuvenation Res. 2013 Apr;16(2):143-51. doi: 10.1089/rej.2012.1386.

PMID:

 

23432089

 

[PubMed – indexed for MEDLINE] 

Related citations Remove from clipboard

Select item 24370781[ ]2.

Lifespan effects of simple and complex nutraceutical combinations fed isocalorically to mice.

Spindler SR, Mote PL, Flegal JM.

Age (Dordr). 2014 Apr;36(2):705-18. doi: 10.1007/s11357-013-9609-9. Epub 2013 Dec 28.

PMID:

 

24370781

 

[PubMed – indexed for MEDLINE] 

Related citations Remove from clipboard

Select item 22451473[ ]3.

Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous mice.

Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DE.

J Gerontol A Biol Sci Med Sci. 2013 Jan;68(1):6-16. doi: 10.1093/gerona/gls070. Epub 2012 Mar 26.

PMID:

 

22451473

 

[PubMed – indexed for MEDLINE] 

Free PMC Article

 

What this means is that the many thousands of hard core life extensionists who are taking “anti-aging” supplements at considerable financial cost are doing so with the overwhelming probability that at best they won’t work, and at worst they may cause serious morbidity, a shortening of lifespan, or death. Age associated morbidity and mortality (and thus aging itself) is a logarithmic prices starting around age 30. This suggests that the effectiveness of almost all currently available “nutraceutical” products will be negligible, or nonexistent, when administered to people younger than age 30. Thus, when people in their 20s or 30s engage in such unproven (and statistically very unlikely to work) interventions, the risk to benefit ratio can only be adverse. However, because there is no monitoring or surveillance of any kind, it’s impossible to know. 

 

If you’ve been in the life extension community for very long, you’ll find no shortage of people who have experienced serious adverse effects from taking the “suggested” amounts of any number of  so called anti-aging supplements – and I’m one of them.  I began taking a product called Mitochondrial Energy Optimizer since shortly after it was first marked by the Life Extension Foundation. I took the product for several years with no discernible adverse effects. Over a period of several weeks I began having episodes of dyspepsia and stomach pain. These symptoms grew steadily worse until they were almost unbearable. I saw my physician who examined me, did blood work (which was normal), and suggested I try a short course of an OTC proton pump inhibitor to see if there was any improvement. There was, but the improvement didn’t last long and the stomach pain slowly returned and increased in severity. At this point not only was my discomfort severe, I was also finding it difficult to eat due to both a lack of appetite from the nausea and severe exacerbation of the pain which occurred when I ate a “large” meal, such as lunch or dinner. 

 

When I returned to my doctor he decided to order an endoscopic examination of my stomach and esophagus. This required conscious sedation with propofol (a material risk), was very inconvenient and cost a small fortune. The results of the exam suggested a chronic inflammatory gastritis which the gastroenterologist who performed the procedure said was possibly a “chemical gastritis”. He remarked that it reminded him of what he had seen in cases of chronic ipecac ingestion by patients with anorexia nevosa. My physician began carefully inquiring into the details of all medications and supplements I was taking. His suggestion was that I begin discontinuing the supplements I was taking one at a time while waiting a few days before discontinuing the next one. The third supplement I discontinued was LEF’s Mitochondrial Energy Optimizer. The results were immediate and positive – almost instant relief from the acute gastric and epigastric pain with the nausea and accompanying anorexia subsiding within a few days. 

 

I placed a call to Bill Faloon of LEF and told him of my experience. His response was, “Yeah, we’ve been getting a lot of complaints like this and the problem seems to be the stinging nettle root extract we recently added to the product. We’re re formulating, so you shouldn’t have any further problems with new new formula. I’ll have someone send you a complimentary bottle of  the reformulated product.” When I subsequently visited a friend in London, I discovered that he had had the same problems with this product and that he ended up discarding ~ $300 worth of this product! 

 

LEF consistently reformulates its proprietary products and it there is no history of these reformulations on their website. As should be apparent, this makes any effort to determine the long term effects, good or bad, of these “cocktail products” impossible to determine. It also makes it difficult for the consumer to know whether a product he has taken for years with no apparent ill effects is now causing a serious medical problem! These kinds of shenanigans were a  staple of the patent medicine era which was a major factor in the creation of the U.S. FDA. “Natural” doesn’t mean safe and it doesn’t even mean more safe than ethical pharmaceuticals – most of which, BTW, are derived from naturally occurring molecules. [The bulk of our pharmacopeia is derived from plants and animals with most chemical modifications being made to enhance efficacy, bioavailability and product stability – as well as patentability.]

 

With the advent of noninvasive and completely safe medical imaging, such MRI, it is now possible to monitor both gross and regional brain volume with a high degree of precision. Longitudinal evaluation of cerebral atrophy should be a definitive indicator of any truly effective anti-aging regimen in humans who are 50 and older. There has been considerable debate over whether cerebral atrophy actually occurs in normal, healthy aging, absent discrete neurodegenerative diseases, such as AD, multi-infarct disease, MCI and so on. This recent study by Fjell, et al.,  http://ift.tt/1FSJvsL indicates that cerebral atrophy proceeds in all aging humans, including those free from any evidence of discrete neurological disease, albeit to different degrees and at different rates in different individuals. As the authors conclude: 

 

“Thus, even in a group of superstable elderly, significant longitudinal atrophy was observed over as short a time interval as 1 year. The magnitude of atrophy may seem small, but over a decade, the median ROI would show more than 5.4% decline, and hippocampus would shrink about 10.8%. If such changes are happening throughout large parts of the adult life span, the percentage reduction will be substantial.”

Clearly, if this is the case, then any putative anti-aging regime which fails to greatly slow or halt this loss of brain mass in an individual practicing it is doomed to end either in failure to extend lifespan, or arguably worse, dementia in old age. And it’s not like you have to wait very long to find out how you are doing! As the data from Fjell, et al., show, progressive cerebral atrophy was detectable in all participants over a period of just one year! I for one am beyond weary from listening to claims that this or that modality is going to, or is even likely to extend lifespan and/or preserve cognitive function into very old age. Other recent advances in medical imagining, such as coronary calcium scoring (in men), also offer the prospect of providing valuable, if not definitive information on the effectiveness of anti-aging interventions. The presence and/or progression of coronary calcium burden is highly prognostic of cardiovascular disease and death: http://ift.tt/1FSJy7O

 

Gender-Specific Survival as a Function of Coronary Calcium Score (above).

While radiation exposure from the spiral CT scanning required to determine the coronary calcium score is not free of risk, that risk is modest in men 50 or older and may possibly be reduced by pre-scan treatment with (ironically) appropriate OTC antioxidant molecules in supra-physiologic doses: 

 

http://ift.tt/1EfWs10

 

http://ift.tt/1FSJvIZ

 

http://ift.tt/1FSJy7S

 

http://ift.tt/1FSJy7U

 

http://ift.tt/1FSJyo8

 

http://ift.tt/1EfWpCj

 

http://ift.tt/1FSJvJ5

 

http://ift.tt/1EfWpCj

 

http://ift.tt/1FSJvJ7

 

The advantage here bring that only one or two doses are likely to be required, as opposed to chronic treatment as is used in life extension regimes.

Gay men dying of AIDS before the advent of effective drugs acted far more sensibly than life extensionists engaging in DIY interventive gerontology research on themselves, since they at least looked at every prognostic biomarker available, such as T-cell counts, skin anergy and the like. If what they were trying didn’t work, they reported on it via AIDS Treatment News, or other similar venues, and then promptly tried something else. My impression is that almost all of the people trying interventive approaches to slowing, halting or reversing aging on themselves have failed to realize that they have a disease which is every bit as terminal, and far more urgent to treat effectively, than was AIDS. After all, AIDS is an infection with a single etiologic agent, and while the virus’s high mutation rate presented many complex problems, it was and is a trivial problem compared to aging. Some people infected with HIV didn’t progress to AIDS, and some few who did got better without treatment. By contrast, aging has an incidence of 100% and a mortality rate of 100%. Of the roughly 108 billion people who have lived and died before us, exactly none have been immune to aging and just gone on living indefinitely. That makes aging the most lethal disease in the world with a prognosis for everyone that is catastrophic everyone. Thus, any adult alive today is arguably in a much more dire situation than any patient with full blown AIDS was in 1981, or with just about any other lethal disease, for that matter. They may have a greater absolute number of years of life remaining, but the magnitude of the problem is so much greater that any increase in time remaining likely presents little or no advantage whatsoever. 

The urgency of the problem appears lost on them, and that implies that they are delusional about the effectiveness of existing and proposed immediate interventions, or believe that those academics, or the researchers working in commercial pharmaceutical labs, are going to come to their rescue at some ill defined and nebulous point in the future. Even if this possibility could be meaningfully quantified, it would in no way justify the mind-blowing hubris of simply swallowing this or that, without even bothering to spend $300 a year for an MRI of the brain to see if their brain is continuing to disappear! That’s madness, foolishness, or both.

The rational response to careless self experimenters like those on Longecity, and to those here as well, is to say, “Give me a break! We don’t want to hear about any molecule(s) you are gobbling to treat aging absent hard, objective and inexpensive to obtain longitudinal data that shows that they are working.” Data obtained from pharmacological research in rodents has a near zero statistical correlation with successful translation to humans in the clinical setting in degenerative diseases. Such research has been almost a total bust in this respect, and has proved, almost exclusively, useful only for the most basic mechanistic insights into the pathophysiology of degenerative diseases in humans. Thus, any application of drugs based on animal testing in aging humans demands “as soon as possible” validation, which, in this case, means that meaningful feedback can be obtained in the space of a few years. To fail to undertake such validation is reckless folly given the high cost of the interventions, the significant potential for inflicting more harm than good and the catastrophic effect if the intervention fails to work as anticipated: namely that you die of aging or an adverse effect of the experimental  treatment. 

Supplement peddlers have grown richer than Croesus, live in mansions and own yachts without producing a single credible shred of scientific evidence that anything they hawk has, or ever will extend the mean or maximum human lifespan by one day. It seems like what is needed here is the “Queer Eye for the Anti-Aging Guy.” And now you have it.

Mike Darwin

 

 

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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