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

On Mar 9, 2015, at 1:59 AM, Michael Price wrote:

Hi Mike,

Whether we think P&S’s science is still valid is not the point.  They were arguing from within the scientific paradigm, which is why they kicked LE to a new and enduring height of popularity.  Despite this much of their science is now outdated, since they were adherents back then of the free radical theory of aging, which has not stood the test of time.  (Interestingly P&S have moved on to a more holistic view of metabolism, unlike much of the literature, which still rabbits on about antioxidants.)

I guess we’ll just have to agree to disagree on this point. I think it was the other way around, that it was advances in gerontology that were underway because of global advances in the life sciences, in particular in biochemistry and molecular biology, that made the work possible that P&S subsequently capitalized on. I say this because I was foolishly taking BHT circa 1975, and the only reason I didn’t take ethoxyquin, was that the the 250 ml bottle of Santoquin that Monsanto sent me gratis, as a sample (oh, those were the days!), contained stuff that made used crank case oil look and smell appetizing, by comparison. It was just so vile tasting and smelling, as well as being completely hydrophobic, that I couldn’t figure out how to take it. 

And I wasn’t alone: lots of other people were taking industrial antioxidants at that time in order to try and extend lifespsn. I had never heard of P&S at that time, and didn’t hear of them till their first book was published in 1983.  If I recall correctly, John Mann’s book, with a similar title, had been out for some years prior to P&S’s. Thus, from my perspective, the fundamental change was the birth of the free radical theory of aging, which had already caused a renaissance of gerontological science, and increasing evidence for Bjorksten’s cross linkage theory of aging. 

True scientific advance (and sustained work in the area) rises or falls on the basis of the science itself. The rejuvenation of gerontology happened independent of popular books about it and was sustained by solid, scientific advances attracting grad students and funding into the area. If the science goes away, stops progressing, etc., then the popular books also wither away and disappear. Interestingly, almost of all of the soft money funding for gerontology has come from sources that were convinced of the value, or even the demographic necessity, of gerontology research long before P&S, independently of them, or even in spite of them. Convincing Ma & Pa Kettle that life extension, a la P&S, is workable has little to do with creating sustainable science. I say this because this kind of thing has happened repeatedly in the past: Brown-Sequard, Metchinkoff, Carrell and Lindbergh… 

There’s this idea that people today are statistically uniquely more positive in their attitude towards life extension and in their belief in its credibility. I don’t think history bears this out. In fact, gerontology has had a heavy burden of discredit-ability to overcome, based on past hyperbole, bad science and outright fraud. 

To me, the real heroes were people like Mc Kay, Bjorksten and Harmon who provided scientific evidence and a theoretical framework for understanding and intervening in aging. Ditto the half dozen or so molecular and evolutionary biologists who showed that you could radically extend lifespan and youth-span by relatively straightforward alterations in a single gene, or a few genes. The National Institute of Aging (NIA) was created long before, and completely independent of, P&S. Below is a picture of my teenage cryobiology lab in Indianapolis. If you look closely at the poster on the closet door, you’ll see on it an advocacy poster for the creation of the NIA.

Complete nerd that I was, I was active in writing letters and gathering signatures for Congress to pass the bill creating the NIA. Thats me, at exactly that tim, in the photo below: 

Despite enormous resistance, Ted Kennedy was able to get the NIA passed, and the reason for that was that, even in the early 1970s, the powers that be understood that the demographics of aging in the U.S. threatened the solvency of Social Security and even had the potential of bankrupting the U.S. government as a whole. The NIA was created in 1974 and the pictures above are from circa 1972-3. 

I don’t show these pictures to paint myself as somehow significant in the formation of the NIA, LOL, but rather to point out that how and when you become convinced of, and a participant in life extension, cryonics, or any area of thought or endeavor, likely profoundly colors your perception of it.

A few years back, when I was reading Aubrey devGray’s popular books on SENS, I was both saddened and amused to read about his “epiphany” regarding lipofuscin. In particular, I was amused to see him sending other researchers scurrying about graveyards in the Cambridge area to find microorganisms capable of decomposing lipofuscin, which Aubrey incorrectly asserts is composed exclusively of cross linked lipids and carbohydrates (it is, in fact, mostly cross linked proteins and lipids and the proteins are what hold, and make refractory to degradation, the lipids). I felt this way because when I got involved in cryonics and gerontology in 1968, the gerontologist making the the covers of national magazines, like PARADE, was Johann Bjorksten with articles titled “Will We Live to Be 200?” 

Johann Bjorksten, 1972

Bjorksten had taken note of lipofuscin, then called ceroid, or age pigment, in the 1930s, and had proposed the cross linkage theory of aging in 1942. Over 20 years before Aubrey was born, Bjorksten asked a critically important question: “If eukaryotic cells cannot digest the ceroid pigment that accumulates in them, and ceroid pigment comprises a significant fraction of the non-dividing cell mass at the time eukaryotic organisms die, then why is the earth not covered in a layer of ceroid pigment?” The stuff is incredibly stable, and is even resistant to hydrolysis, oxidation and UV degradation, so how is it recycled in the biosphere? 

Bjorksten believed that there must be microorganisms capable of decomposing ceroid, aka, lipofuscin, and he set out to find them. And he did! He found that a strain of the common soil microorganism, Bacillus cereus,which can be pathogenic in people and is, in fact, responsible for fried rice syndrome, produced a variety of enzymes that could digest lipofuscin. What’s more, these were structurally unique enzymes which consisted of barely more than the active catalytic site, which he christened “micro-enzymes”. They pretty much had to be “micro-enzymes” in order to get inside the densely cross linked molecular structure of lipofuscin. He isolated and characterized 7 of the most promising of these enzymes and assigned rights to a number of small U.S. and European pharmaceutical companies. He also published this work:

1. Bjorksten, Johan, Weyer, Elliott, and Ashman, Stephen M. Study of low molecular weight proteolytic enzymes, 1971, Finska Kemists Medd, 80: 70-87.

2. Schenk, Roy U., Bjorksten, Johan, Ashman, Stephen M., and Burrowbridge, George T. The search for microenzymes. Anomalous behavior of pronase. Suomen Kemistilehti B, 1972,45: 343-348.

3. Schenk, Roy U., and Bjorksten, Johan. The search for microenzymes: The enzyme of bacillus cereus, Finska Kemists Medd, 1973, 82: 26-46.

4. Bjorksten, Johan. Longevity 2-Past, Present, Future, 1987, JAB Publishing, Charleston, SC.

Now, jump forward 30 years to 2002:

“Several major diseases of old age, including atherosclerosis, macular degeneration and neurodegenerative diseases are associated with the intracellular accumulation of substances that impair cellular function and viability. Moreover, the accumulation of lipofuscin, a substance that may have similarly deleterious effects, is one of the most universal markers of aging in postmitotic cells. Reversing this accumulation may thus be valuable, but has proven challenging, doubtless because substances resistant to cellular catabolism are inherently hard to degrade. We suggest a radically new approach: augmenting humans’ natural catabolic machinery with microbial enzymes. Many recalcitrant organic molecules are naturally degraded in the soil. Since the soil in certain environments – graveyards, for example – is enriched in human remains but does not accumulate these substances, it presumably harbours microbes that degrade them. The enzymes responsible could be identified and engineered to metabolise these substances in vivo. Here, we survey a range of such substances, their putative roles in age-related diseases and the possible benefits of their removal. We discuss how microbes capable of degrading them can be isolated, characterised and their relevant enzymes engineered for this purpose and ways to avoid potential side-effects.”

This quote isn’t from one of Bjotksten’s papers, nor is it from one of his intellectual heirs. Rather, it’s from Aubrey de Grey, who has the likes of Dr. John Archer, of Cambridge, one of the fathers of bioremediation, sending grad students out to graveyards to look for lipofuscin lysing bacteria! More astonishingly, Aubrey publishes these three papers in highly respected journals without every so much as mentioning Johann Bjorksten’s name, let alone citing him the references:

Appropriating microbial catabolism: a proposal to treat and prevent neurodegeneration. de Grey AD. Neurobiol Aging. 2006 Apr;27(4):589-95. Epub 2005 Oct 3. Review. PMID:16207503

Select item 12413818Bioremediation meets biomedicine: therapeutic translation of microbial catabolism to the lysosome. de Grey AD. Trends Biotechnol. 2002 Nov;20(11):452-5. 
PMID:
 
12413818

Select item 16040282Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases. de Grey AD, Alvarez PJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR. Ageing Res Rev. 2005 Aug;4(3):315-38. Review. 
PMID:
 
16040282
 

Sadly, these three papers are all speculative and hypothetical and thus they not only fail to mention the previous ideas and the previous work, they fail to disclose the most critical fact of all, namely, that the work was successful! In fact, Bjotksten had demonstrated preliminary safety and efficacy of his microproteases before his licensed their further development to outside firms!

The charitable interpretation of this story is that Aubrey simply didn’t know about Bjorksten, and presumably never found out. Personally, I find this a little hard to believe, especially given Ward Dean’s excellent 3-part article on Bjorksten, which has been online since 2003:

http://ift.tt/1NOFU4w

http://ift.tt/1FRNndE

http://ift.tt/1NOFXgO

Nevertheless, if the charitable interpretation is indeed the correct one, then this serves as an example of how our perception of a scientific discipline, or arena of social or political action, are shaped by how and when we enter it.

From my perspective of having come into life extension in 1968, P&S were a fad that was a side effect of a deep, ongoing process of scientific advance and increasing overall credibility of gerontology and life extension work – both in the research and popular arenas. Saul Kent’s book, The Life Extension Revolution: The definitive guide to better health, longer life, and physical immortality, had come out three years before, as had John Mann’s The Secrets of Life Extension. Pearson and Shaw created a lot of public interest in supplements, but I honestly don’t believe they had any meaningful influence on the advance of gerontology, and certainly not on improving its scientific credibility. I’m more than happy to be proven wrong on this. If it can be shown that any significant fraction of researchers in aging, or of funding for work in aging, resulted from their books, that would be fascinating and important evidence to the contrary. Perhaps the best case for an influence on funding might be LEF, which certainly came about by exploiting the interest in P&S. However, I suspect that funding from LEF represents a tiny fraction of the amount of money spent on relevant basic and applied gerontological and anti-aging research. Ironically, a far better case could be made for the impact of P&S on cryonics!

Again, my point here is that of perspective and context. From my perspective, P&S were a fad that came and went and that will repeat itself at regular intervals. Since you are not in the U.S., you may not know of, or be fully able to appreciate the magnitude of the Dr. Oz phenomenon, which is almost identical to the P&S Life Extension phenomenon of 20 years before. You may not agree with me, but this is my explanation and justification for both my remarks and my perspective.

Mike Darwin

Based on conversations with out mutual acquaintance, I think you’ll find it was B-vitamins that caused the kidney pain, not vitamin C.

Finally, Pauling = Newton?  Hah.  The only equal of Newton was perhaps Archimedes.  But I know you’re only joking on this….

regards
Michael

Mike, the fact that Pearson and Shaw (P&S) provided some factually accurate content in their books, and some good and correct practical and philosophical arguments about the undesirability of aging and death, are irrelevant to the nature and purpose of my comments about them, and of of my overall characterization of them. Linus Pauling was one of the few minds I’d class near Newton’s, and had he seen Rosie Franklin’s X-ray crystallographs of DNA and intuited its structure correctly, I’d have ranked him with Newton. He was the antithesis of P&S: respectable, erudite, and for most of his life, a careful scientist. But his work on vitamin C was bunk and his wild claims for it ludicrous. This does not mean that there was not factual material present in his books and papers about vitamin C, just that the overall message was WRONG and that, on balance, it almost certainly did more harm than good. 

I just sanded the pyrolysis products off the text blocks of P&S’s two books and “restored” the covers and dust jackets with a wipe down with drain cleaner. Ironically, their two books survived the fire, when so many, many more valuable ones were lost. It’s hard not to peruse the books I’m cleaning and I had looked through Life Extension just a few days ago. If you turn to page 468-469 of the first edition you will see a list of supplements they take:

Based on the clinical literature of the last two decades, the protocol listed above would  be expected to cause significant statistical morbidity and mortality. The doses of niacin used are associated with increased Type II diabetes, increased overall mortality, and no show benefit in decreasing CVD. The doses of vitamin E, from the lowest to the highest, are associated with a large increase in intracranial bleeding. Chronic use of vasopressin is not innocuous and is associated with increased risk of stroke and heart attack. Vitamin C in doses of 3 grams QD is associated with accelerated atherosclerosis and systemic injury due to its up-regulation of the Fenton reaction – even in the presence of other antioxidant vitamins. 

Their suggestion of sex hormone replacement therapy (HRT) for post-menopausal women nothing short of disastrous. Today, this treatment is used only in the most intractable cases of post menopausal syndrome for shortest possible period of time, and then only with the clear understanding that it is likely to significantly raise the risk of reproductive cancers. So many women that I personally knew in the life extension community used HRT, that it ended up being more common for them to have a reproductive cancer, than not – especially breast cancer. I think the very high incidence I’ve observed was due to far earlier and far more aggressive use of HRT than was the case for women given this treatment in the general population. 

The majority of the molecules they recommended for specific diseases, such as BHT for Herpes, and later for HIV, simply didn’t work, or were far more toxic and vastly less effective than ethical pharmaceutical drugs available at that time. On a broader level, their message about the effective application of the scientific method, and about the validity of conclusions that should be drawn from animal studies was wrong, and anyone following their recommendations would be at much increased likelihood of suffering injury or death. I know of people who suffered from following these recommendations – some in ways that they and I still don’t understand. For instance, there is a medical physicist whom we both know who developed serious back pain while taking high dose vitamin C. This resolved after it was discontinued, however, even now, decades later, this individual cannot take supraphysiologic doses of vitamin C with a return of the back pain – which turned out to be renal in origin. 

Both Scientology and the Catholic Church have true and valid things in their teachings, and both do charitable works that most would agree have merit. Similarly, both institutions have decent and caring people in them. Nevertheless, this doesn’t absolve them from the characterization of being purveyors of irrational nonsense, and not infrequently of verifiable, outright falsehoods. They are thus under the same umbrella as Tele-evangelists and itinerant tent preachers and at their core, they are profoundly anti-intellectual, anti-science and anti-reason, no matter how much they may cloak themselves in any of these things. 

It’s entirely reasonable to classify individuals and institutions in this way, just as it is entirely reasonable to classify Hitler as an evil, ruthless, dictator, even though he loved animals, was kind to (some) children and was beloved as a boss by virtually all of his employees.

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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