AGINGSCIENCES™ – Anti-Aging Firewalls™

It is now approximately 11 months since I posted the first version of the Anti-Aging Firewalls treatise and it is interesting to identify how the current version of the treatise (which might  be considered to be Version 1.9) is different from the original one.  I have been updating the treatise frequently, sometimes weekly, sometimes daily.  There have been at least a dozen major upgrades and additions over the period including one made today which includes a new section on the Relationships among the theories of aging. Compared to the original, the treatise now:

·        Embodies three additional theories of aging beyond the original 11 ones, Telomere Shortening and Damage, Programmed Epigenomic Changes, and Decline in Adult Stem Cell Differentiation,

·        Embodies significant discussions throughout on the relationships among the theories of aging including the new section on that topic,

·        Has a summary section describing the Combined Lifestyle Regimen,

·        Has a revised  Combined Dietary Supplement regimen with a few substances added to the original list, a deletion or two and revised dosages for a few supplements,

·        Embodies considerable discussion on selected topics including stem cell differentiation, neurogenesis, telomerase-related developments and the role of NF-kappaB,

·        Provides a much larger number of research literature research links backing up key points,

·        Provides considerable more discussion on the roles of certain of the dietary supplements, and

·         Embodies a series of technical notes on subjects like protein folding, telomerase binding proteins, and the firewall against osteoarthritis

These changes reflect two factors: first, developments reported in the research literature during the 11-month period that came to my attention, and second, continuing increase in my own awareness and comprehension.  I believe the net result is improvement in the scientific integrity and comprehensiveness of the treatise.  This Blog, started in January 2009, now includes some 55 major postings and is an important complement to the treatise.  Specifically, I have explored certain topics here that are peripheral to the main treatise, topics like epigenomics, population longevity studies, the economics of longevity and the prospects for living very long. A complete list of postings can be found by clicking on the left on Site Admin and then on the Manage tab.  You might have to be a registered user and login in order to access the entire list.

A step of progress was reported this week in developing better understanding of the molecular processes underlying Alzheimer’s Disease.  For some time it has been known that beta-amyloid protein shows up in excessive quantities in the brains of Alzheimer’s Disease patients and that this protein causes synaptic damage to neurons.  But the mechanism by which damage was inflicted was unknown.  In the new research it was observed that beta-amyloid protein multimers create excessive production of nitric oxide.  This free-radical substance was shown to attack a mitochondrial protein Drp1 in cultured nerve cells through a process known as S-nitrosylation.  This in turn led to activation of enzymatic activity that induces mitochondrial fragmentation. The reaction damages neuron synapses leading to nerve cell death and eventually to loss of brain function.  It is thought that one avenue of therapy for Alzheimer’s Disease that could come out of this understanding could be blockage of S-nitrosylation.  Or better yet, figure out how to prevent the buildup of beta-amyloid protein in the first place,

Here are a few recent longevity news tidbits derived from studies published in geriatrics journals.  Two of the news reports confuse cause and effect and project a probably-incorrect message. 

·        Seniors can use computerized brain exercises to improve their memory and ability to think faster(ref). My comment is sure, and the best computer brain exercise for me is researching how to live a lot longer.

·        The news article in the Tehran Times is entitled Daily naps may raise older women’s death risk. ‘White women who took a daily siesta were 44 percent more likely to die from any cause, 58 percent more prone to dying from heart problems, and nearly 60 percent more likely to die from non-cardiovascular or non-cancer causes.(ref)’  However, I point out that people who are quite sick may take more naps than those who are healthy.  So, napping itself may not cause increased mortality but may be the result of mortality-inducing illnesses.

·        Specific personality traits are associated with children of centenarians and their longevity including low neuroticism, high extraversion and high agreeableness.  Apparently these traits enable much better management of stress(ref).  My comment is yes and that these characteristics are not only inherited but to some extent can be learned even by us old folks.

·        The news item is entitled Keep Hold of Those Car Keys: Driving May Be Good for Your Health.  A study in Florida of 660 older people, aged aged 63 to 97, showed that people who kept driving were four to six times more likely to still be alive after a three-year period than their counterparts who stopped driving(ref).  I comment again that it is important not to confuse cause with effect.  Most of the people who stopped driving were probably a lot sicker to start with than those who kept driving.  Stopping driving itself was probably the effect of sicknesses and not the cause of the increased mortality.

When lifespans of 160+ years become routinely available it will most likely be due to research results coming out of the “omics:”  genomics, epigenomics, proteomics, etc.  This is a short introduction to some of the most important omics and how they fit in the universe of longevity-related research.

Genomics  This is the granddaddy omics, the study of the genomes of organisms, eg. the chromosomes, genes and so-called non-coding DNA on chromosomes.  Back a dozen years ago when we were starting to decode the human genome some scientists thought that once we got the genes in the human genome down the rest would be easy.  Now we understand that that was just the start of the omics revolution. Clearly, longevity has a lot to do with genes.  Here is a list of genes that have been analyzed for their possible association with human longevity.  As you can see from looking at that long list, the pieces of research evidence gathered so far tend to be scattered fragments.

Epigenomics This is the study of encoded possibly inheritable DNA information acquired in the processes of living that is not in the sequences of genes themselves.  The encoding is via DNA methylation and histone acytelation. (See the Feb 28, 2009 post on this Blog Epigenetics, Epigenomics and Aging.  Also the March 20 2009 post on this Blog DNA methylation, personalized medicine and longevity. Very likely, major gains in longevity will result from epigenetic reprogramming, possibly via nutrigenomic interventions.  The regimen of supplements suggested in Anti-Aging Firewalls is a start.

Proteomics  This is the study of proteins, particularly their structures and functions in relationship to gene activation.  (See the February 26 2009 post on this Blog on Protein origami and aging and the March 6 post Do your proteins get tied up in knots?) Clearly, proteomics is of central relevance to Epigenomics and also to Genomics since genes make proteins and proteins condition the activation of genes.

Transcriptomics This is the global study of gene expression at the RNA level(ref).  It is the study of all messenger RNA (mRNA) molecules, or “transcripts,” produced in a cell, a population of cells or an entire organism.  Since messenger RNA is produced by genes and encodes instructions for making proteins, transcriptomics stands in the middle between Genomics and Proteomics.  As such, it is also central to longevity research.  By now it should becoming clear that all the omics up to this point address different but highly related aspects of fundamental processes that occur in cells.  They share two other very important properties, which are 1. that very large data bases are being built in each of these omics areas and 2. ever-superior tools are being built for creating such databases such as improved microarray and digital gene-expression profiling technology and qualitative real-time polymerase chain reaction systems (ones that can measure the abundance of specific sequences of DNA or RNA in a sample).  These databases and tools increasingly play central roles in basic discoveries related to human longevity.

Pharmacogenomics This is the study which looks at the influence of genetic variation on drug response in patients by correlating gene expression or gene variations (e.g. single-nucleotide polymorphisms) with a drug’s efficacy, toxicity or unintended effects.  Pharmacogenomics is a branch of pharmacology that looks forward to the day when drugs might be tailor-made for individuals in a way that is adapted to each person’s own genetic makeup(ref). No doubt, by combating age-related diseases those drugs will allow many people to live longer.

Nutrigenomics This is the study of how the bioactive constituents of foods and dietary supplements affect gene expression, again in the light of individual epigenomic history. A practical goal of nutrigenomics is – “to devise genome-based nutritional interventions to prevent, delay, and treat diseases such asthma, obesity, Type 2 diabetes, cardiovascular disease, and prostate cancer(ref).” A more-detailed discussion of this topic was posted on this Blog on March 4.  And I expect to be writing more about it in coming months.

Ecogenomics This is the study of genetic materials as they occur in an environment where there is an ecological system in operation.  It also involves application of such knowledge to ecological and evolutionary processes.  Ecogenomics defines biodiversity at the DNA level and uses molecular techniques to quantify the functions and interactions of organisms at an ecosystem level(ref). Future public health ecosystem interventions are likely to have major impacts on overall longevity as they have historically (e.g., installing sanitation systems, cleaning up rivers).

Agrigenomics This is the study of the genetic makeup of agricultural plants and how all the genes work together to produce a crop(ref).  Possibilities for longevity include the development of much healthier foods.

All together, these omics fields define a new era of both theoretical and applied systems biology.  As we more understand life we will more understand what it takes to live longer and more healthily.  So each of these fields is in fact an area of longevity research.

Nutrigenomics is one of the many latest “omics,” a hybrid of research focused on study of the relationships among nutrition and genomics.  A podcast discussing this emerging field can be found here.  The field is concerned with identifying how the bioactive constituents of foods and dietary supplements affect gene expression.  One of the objectives of nutrigenomics is identifying personalized nutritional interventions for improving health and wellness and interventions for addressing specific disease susceptibilities and conditions like diabetes and arthrosclerosis. The intent is to develop individualized nutrigenomic profiles – profiles that cross-correlate genomic, epigenomic and proteomic markers for an individual to the biomolecular actions to specific nutrients.  Realizing this intent will first require much further research to identify important omics markers to identify key constitutional parameters and specific disease susceptibilities.  Second, it will require much further research in ways in which nutrition can be utilized to affect individual epigenomic profiles and specific gene expression sequences.  Research in both of these domains is already proceeding at an accelerating pace.  The dietary suggestions and regimen of dietary supplements in the Anti-Aging Firewalls treatise can be considered to be a zeroth-order approach to nutrigenomics – one that is to some extent based on known omics interactions but that does not take personal omics differences into account. Nutrigenomics based on individual profiles should provide a much higher-resolution approach to looking at the relevance of foods and dietary supplements than is possible on the basis of overall population studies.  In time, nutrigenomics will see the development of diagnostic tests and dietary and other intervention strategies for specific diseases. It will also allow the development of highly personalized diets and supplement regimens for disease prevention and longevity.  I intend to continue tracking and reporting here on those developments.

Nanotechnology is a wild and unregulated frontier.  It could offer great health benefits.  For example,   Japanese researchers have developed a nanoparticle that fuses with cancer but not normal cells and induces apoptosis in those cancer cells(ref).  On another front, there is concern that nanoparticles in cosmetics and personal care products will end up in the environment where they may have serious adverse effects(ref).

Increasing numbers of consumer products are being based on nanoscale ingredients and among them are over 44 dietary supplements, sometimes called nanoceuticals.  Claims are made by the manufacturers of many of these substances that they offer greatly enhanced bioavailability or offer other unique health benefits.  These nanoceuticals like other dietary supplements are not evaluated by the FDA or any other regulatory organization for either efficacy or safety.  However, nanoparticulate forms of familiar substances like silver have different properties than the conventional forms and the long-term consequences of ingesting them are unknown.  For example are nanoscale silver particles eventually excreted from the body or do they lodge in or next to cells and stay there? What do these nanoparticles do to cell membranes and how do they affect cell signaling?  There could be important benefits to using some nanoceuticals and there could also be serious dangers involved with taking others.  An editorial in the Feb 9 online edition of Chemical and Engineering News points out this situation and the weakness of the FDA regulations in not defining whether a nanoparticulate form of a familiar dietary substance should be treated as a new substance.  Much stronger government oversite of nanoceuticals and other nanoscale consumer products is needed soon, for the numbers of companies producing such products is swelling rapidly(ref).  In the interim I personally would not want to consume or suggest consuming a nanoceutical without seeing ample published research that establishes both its efficacy and long-term safety.  And the same is true for breathing one.

On the surface it appears that the 14^th theory of aging in my Anti-Aging Firewalls treatise Decline in Adult Stem Cell Differentiation is very different than the  12^th theory Telomere Shortening. And these two theories seem to be different than the 2^nd  theory Cell DNA Mutation.  However, a number of recent studies show a growing web of relationships among these theories.  For example,  telomeric dysfunction may be at the heart of the decreasing capability of stem and progenitor cells to replicate and renew tissues with increasing age (ref,ref,ref,ref).  These and similar studies have looked at telomere shortening in hematopoietic stem cells (HSC), mesenchymal progenitor cells, osteoblasts and neural progenitor cells.   One study suggests that proteins secreted from telomere-dysfunctional bone-marrow cells may provide accurate biomarkers of aging. As usual when it comes to aging, there are wheels within wheels.  Among the many cellular proteins that influence telomere structure, function and enlongation are the telomerase binding factors TRF1 and TRF2 and less-directly shelterin-complex, PinX, Apollo and tankyrase(ref).  TRF2seems to play a key role in the differentiation of neural stem cells(ref) as well as in cancer proliferation.  In a closely related front, telomerase expression and TRF2 seem to play key roles in maintenance of DNA repair mechanisms in neural cells and stem cells(ref).  While we are not there yet we are getting closer to a unified theory of aging.  Also it is already clear how an anti-aging firewall intervention intended to address aging according to one theory, taking astragaloside IV as a supplement to activate telomerase expression, addresses aging according to several other of the theories as well.

There has been a lot of press this week about a study conducted in India using the “Polypill,”  a combination of a beta-blocker, a diuretic, an ace inhibitor, folic acid, a statin and aspirin rolled into a single pill.  The intent of the pill is to reduce four risk factors for cardiovascular disease: LDL cholesterol, blood pressure, platelet function, and serum homocysteine.  The new study involved testing the Polypill on 2,053 subjects aged between 45 and 80 for 12 week, people without cardiovascular disease (CVD) but having one major risk factor for CVD such as high cholesterol, diabetes,  smoking, or high blood pressure.  The pill was found to reduce high blood pressure and LDL cholesterol without major side-effects – not surprising given the pill’s ingredients.  Of course, the study was far too short to show any final outcomes.  The Polypill has received somewhat of a mixed reception.  One thoughtful analysis argues that the same benefits can be achieved by taking Essential Fatty Acids, such as in fish oils. “Thus, EFAs and their metabolites show all the classic actions expected of the ‘polypill’. Unlike the proposed ‘polypill’, EFAs are endogenous molecules present in almost all tissues, have no significant or few side effects, can be taken orally for long periods of time even by pregnant women, lactating mothers, and infants, children, and adults; and have been known to reduce the incidence cardiovascular diseases including stroke.“  Others are also skeptical that the Polypill should be taken by everyone in lieu of good lifestyle preventative measures.  Medpagetoday quotes Robert Bonow, M.D., professor of medicine at Chicago’s Feinberg School of Medicine at Northwestern University: “We already have a polypill — it’s called exercise,”

You probably never heard of DHMEQ but probably will he hearing a lot about it in the future.  The initials stand for dehydroxymethylepoxyquinomicin, a powerful recently-discovered inhibitor of NF-kappaB.  You might recall that the nuclear activation factor NF-kappaB plays a central role in the 13^th theory of aging, Programmed Genetic Changes.  Runaway overexpression of NF-kappaB is thought to be a key factor in many maladies of old age, particularly inflammatory diseases like arthritis and cancers.  NF-kappaB is constitutively activated in the majority of cancers and is responsible, in large part, for tumor cell survival, growth and direct activation of anti-apoptotic gene factors.  DHMEQ powerfully blocks expression of NF-kappaB and a host of recent publications suggests that it might be useful as a therapeutic agent for several inflammatory diseases and cancers.  You can find some of these publications using a Google search  here.  DHMEQ is unlike some other inhibitors of NF-kappaB in that it selectively blocks translocation into the cell nucleus rather than blocking its action on specific genes.   Although all experiments to date with rodents suggest that DHMEQ is safe, to my knowledge it is not generally available today either as a supplement or as a proprietary drug.  I would not be surprised to see it becoming available in one or both of those formats soon after human safety is established.  In the interim I remind my readers that no less than 33 dietary substances in my anti-aging firewall related to programmed genetic changes are inhibitors of NF-kappaB.  Selective research studies like this one suggest that certain of the firewall NF-kappaB inhibitor substances like curcumin and resveratrol may be comparably powerful in their anti-cancer activities as DHMEQ.

The last two posts on this blog identified Giuliano’s Law of Anti-Aging and discussed how I see it applying to my personal aging.  This post discusses why I think the law or a close variant of it is valid.  Again, the Law is:

·        Starting now, every seven years will see the emergence of practical age-extension interventions (ones that have a potential of leading to extraordinary longevity) that double the power of the interventions available at the start of the 7 year period.  That is, on an average basis, the practical anti-aging interventions available at the end of a seven-year period will enable twice the number of years of life extension than did the interventions available at the start of the period.  Life extension is measured in years of life expectancy beyond those actuarially predicted for a given population. 

This law is valid for the same reason Moore’s Law for integrated electronics is valid – the law that the number of transistor elements on a chip at a given price point doubles roughly every two years.  This law has held for 40 years and is responsible for the corresponding increase in cost-effectiveness of computers, cell phones and all other electronics.  This law was the result of a strong positive feedback relationship between societal need, market, economic contribution, market vehicles, user applications, marketing channels, changes in user expectations advancement in the relevant basic science, advancement of technology, advancement of manufacturing capability and an entrepreneurial environment.  Each has promoted each other and continues to do so today.  The same factors apply to the technology of life extension.  I touch on each of these here.

Societal need, market, marketing channels and economics:  “Baby Boomers,” those born during the 15-20 years of very high birthrates after the end of World War II, are in their 50s and 60s now with many retiring.  Increasingly being beset with the diseases of age like cancers and cardiovascular problems, many are becoming painfully aware of their mortality and desirous of being in good health.  Keeping elderly people healthy and productive could yield unbelievable economic benefits, not only in reduction of runaway health care costs but in gained productivity. Extending longevity is essentially the preservation of human capital(ref).  Life extension in good health of just 10 years would extend the productive working years from about 40 years to 50 years , an increase of 25%.   That shift alone would be worth trillions of dollars of benefit to our society(see references).

Changes in user expectations:  Older people increasingly want to remain healthier longer.  Right now that pressure is felt by the health care industry but that industry is mainly devoted to trying to fix problems that come with aging after they have occurred and often when it is too late to do much good.  Today there is much discussion of “preventive medicine,” mainly focused on educating people to avoid habits which create disease and early mortality like smoking, obesity and living on saturated fats.  Anti-aging programs go the next step and are more proactive in protecting against diseases and causes of mortality,  As older people become more educated about the longevity options available to them they can be expected to tke advantage of them.

Market vehicles, user applications, marketing channels: Wellness, closely associated with longevity, is a collection of industries including dietary supplements, health clubs and resorts, fitness and exercise machinery, etc.  Dietary supplements alone represents a $22.5 billion industry.  And that does not include the institutionalized  health care industry, the largest industry in the US and among the fastest growing  and accounting for about 15 million jobs and about 600,000 establishments.  The Federal Government, State Governments, communities, and HMOs all have a vested interest in the longevity of their memberships assuming that longevity translates into longer healthy lives and postponement of the diseases of old age.  It is in the interest of these groups to promote longevity.  Increasing longevity may be the single best available way of enhancing the productivity and economic well being of our society.

Advancement in the relevant basic science:  How an organism ages is intrinsic to its essential design on a molecular biology, genetics, proteomics, transcriptomics and epigenomic basis.  Each species be it Galapagos giant tortoises, humans or fruit flies has its own design and typical life span.  Understanding the basic mechanisms of living organisms is therefore essential to understanding aging; there are no short-cuts.  So the good news is that there is a vast amount of research in the basic life sciences that is highly relevant to aging although it may be motivated by other goals such as finding cures for cancers or AIDS. I think the most basic discoveries related to life extension in the coming will be by-products of such other life sciences research.  The budget of the National Institutes of Health has been $28 billion and is going up and that is a fraction of the world-wide total. Researchers working directly in the field of aging will play important integrative roles but their contributions will be relatively minor. 

We know that living organisms consist of extremely complex interacting systems and subsystems based on molecular messaging and we are slowly developing understanding of some of those signaling systems, one at a time.  Many of these systems are already known to offer intervention points that might potentially allow extension of longevity, but the issue is how to do this without messing up other related systems.  For example, somatic stem cell proliferation can be promoted by inhibiting expression of the P16 protein; however P16 is an important restrainer of cancers.  The trick is to find interventions that provide some life extension without compromising something else, a problem akin to applying a patch that does not create its own bugs to a very complex computer program written in an unknown language.   I therefore see discoveries that enhance longevity as likely to be incremental over decades rather than a mega-breakthrough that finds The Fountain of Youth.

Advancement in technology:  Advances in life sciences research and development technology are proceeding at an exponential rate and these are empowering the rising rate of discovery.  What do we have today that we did not have 7 years ago?  Here is a starter list: * immense highly accessible data bases in the areas of genomics, epigenetic, proteomics including protein interactions and folding * vastly improved data mining and system modeling software,, * computers 20 times faster and more powerful, greatly improved Internet networking among researchers, * gene and protein chips with at least 10-100 times the capacity (Moore’s Law works for those chips too), sequencers and bio-chip scanners of all kinds with at least 10 times the power.  What will be have 7 years from now?  Probably an additional order-of-magnitude improvement in each of these areas plus new additional research facilities.  Genetic profiling of individual humans is likely to become commonplace, for example.

Advancement in manufacturing:  The biotechnology and pharmaceutical industries have developed sophisticated bio-manufacturing capabilities and stand ready to manufacture and sell any products that show promise of having a market and potential for profits.  The biotechnology industry has revenues of about $100 billion a year, can raise capital as needed, and is on the lookout for new products.

Entreprenurial environment: Universities and venture people appear to be ready to invest in startup ventures that show promise for longevity. Among the small companies engaged in longevity-related R&D are Geron, Sierra Pharmaceuticals, Elixir Pharmaceuticals, Centagentix, Sirtuis, DeCode Genetics, 23andMe, Juvenon, Rejuvenon, Roche Diagnostics, and Alteon. The list is likely to grow much longer.

I have covered the factors that drive the operation of Giuliano’s Law.  I am fairly certain the growth will be exponential.  The one factor in the law that I am least certain of is the 7 year period for doubling.  Why not 2 years as for Moore’s Law or 5 years?  I picked 7 years for two reasons: First, to be conservative.  The doubling time could be less especially given the large new emphasis on health sciences research and preventive medicine in President Obama’s stimulus package.  Second, I estimate that the power of my anti-aging firewall roughly doubled in the last 7 years.  In 2002 my list of anti-aging supplements did not include alpha-lipoic acid, acytl-l-carnitine, resverarol, concentrated curcumin, large doses of vitamin D3, or astragaloside IV.  Either the objective research supporting the uses of these substances did not exist or they were not available.  Also the knowledge relating inhibition of NF-kappaB to longevity and to 33 dietary supplements in the firewall didn’t exist then.  And also, during those years I have honed my lifestyle eating and exercise patterns to be more healthy as relevant large-population studies have been published.

So, I want to reserve the right to reduce the doubling period in Giuliano’s Law as time plays out.