30. March 2009 by admin.

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.

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29. March 2009 by admin.

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. 

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28. March 2009 by admin.

In yesterday’s post I proposed Giuliano’s Law of Anti Aging:

·        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. 

I then went on to calculate my longevity prospects in a quick-and-dirty manner to establish a point: Assuming the law is valid, with each additional year I manage to keep living in good health, if I keep up my anti-aging firewalls program and keep improving that program to reflect ongoing research, my probability of living another year in good health goes up instead of down despite my advancing chronological age.  My purpose here is to do the calculations a bit more carefully to establish the same point.  I consider three cases:

Case 1:  I discontinue my anti-aging firewalls program and go about living a normal life.

Although I am chronologically 79 I estimate that my physiological age is 72, reflecting the fact that I have been pursuing an anti-aging program for over a dozen years now and reflecting other factors such as appearance, relative health, energy, activity levels, etc.  Looking at the actuarial tables for age 72 this means my current life expectancy looking forward is 12 more years which would bring me to a chronological age of 91.  Of course this does not necessarily mean that I would live that long.  In the coming year I would face the probability of death from all causes that a 72 year-old would face.  I could actually live more or less than that.  If I managed to live 7 more years to chronological age of 86, at that time my life expectancy would be that of a 79 year-old, or 8 years looking forward.

Case 2: I continue pursuing my existing anti-aging firewall program keeping it exactly as it is now.

In this case my current life expectancy is the same 12 years as above from the actuarial table, plus another 7 years from pursuing the firewall program or a total of 19 years, which would bring me to a chronological age of 98.  If I managed to live to a chronological age of 86, I would not perceptively age from my current physiological age according to my estimation.  Every year I would face some probability of death from all causes, but a smaller probability than that an average 72 year-old faces because of the protective effects of the firewalls against many common diseases of aging.  The situation would be the same for the next 7-year period, etc.  Not so bad, and likely to get me to or beyond 100.  The same point I made in yesterday’s blog entry.

Case 3: I continue to follow all the relevant threads of anti-aging research, to update the Anti-Aging Firewalls Treatise weekly or more as I have been doing, and periodically update the firewalls and firewall program to reflect this emerging new knowledge.  Further, I incorporate new science-based anti-aging substances and procedures into the firewall program as they become available.

This is the most interesting case, the one where Giuliano’s law becomes relevant.  Right now my life expectancy would be the same as in Case 2.  But consider the situation 7 years from now assuming I am still alive then.  By then assuming Giuliano’s law, the anti-aging firewall program will have twice the efficacy of the program I am pursuing today.  Assuming the efficacy has increased somewhat uniformly over the 7 year period, my physiological age will have retreated somewhat, say 3 years to age 69.  My life expectancy then would be 14 years from the actuarial table plus another 14 years due to the firewall program or a total of 28 years.  So, from a chronological perspective at age 86 my life expectancy would be to live to age 114.  And at chronological age 86 I would still face a probability of death from all causes, but a far smaller probability than an average 69 year-old faces, again because of the protective effects of the firewalls.  Let’s jump out one more 7-year increment to chronological age 93.  By then the firewall program should have 4 times the efficacy of today’s program.  My physiological age should have retreated at least 15 more years back to 54 years of age.  My life expectancy would be 26 years from the actuarial table plus 28 years from the firewall program or a total of 53 years bringing me to chronological age 146. At chronological age 93 I would still face some probability of death from all causes, but a much smaller probability than an average 54 year-old would face. The projection will be that I will break the 122 year human age barrier.  Assuming of course I am not hit by lightening, run over by a taxi or hit by a speedboat  on one of my long swims out in Lake Winnipausakee.

The core assumptions of these scenarios are: 1. My physiological age is 7 years less than my chronological or actuarial age today because of my past anti-aging program participation, 2.  Today’s anti-aging firewalls program will add an average of 7 years to the life of a 79 year-old average male, and 3. Incorporating new knowledge as it is discovered, the life-extending efficacy of the firewalls program can be expected to approximately double every 7 year period (Giuliano’s Law).  Assumptions 1 and 2 are based both on theory and on my subjective sense of looking, acting, feeling and having health patterns of a considerably younger person, conservatively one 7 years younger.  I assume that the retardation of physiological aging due to having been on the anti-aging firewalls program is permanent, in my epigenome.  That is, if I stop the program I won’t lose those 7 years of youth in a few days.   I will provide an argument justifying Assumption 3, Giuliano’s Law, in a later blog post. The ultimate validity of these assumptions will be proven only over a long period of time.   I think I can wait.

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26. March 2009 by admin.

What is the prospect of a healthy disease-free adult breaking through the existing 122 year human age limit and going on to live to 150, 200 or 300 years by constantly follows the latest and best anti-aging program?  This is a matter of speculation and speculation on this topic is what I share here. I, for one, expect to break through the limit.

First of all, let me state my opinion on the current stage of anti-aging knowledge and interventions.  These are laid out in detail in my Anti-Aging Firewalls Treatise.  My best guess (and it is only a guess) is, that if you are less than 80 years old, in excellent health, physical and mental condition, and seriously following the lifestyle and supplement firewalls as they are now laid out now, March 26, 2009, you will have a good shot at living to 100 years, perhaps even beyond that point.  Of course time of death will be a stochastic variable depending on numerous personal and environmental factors.  The effects of taking some of the supplements like resveratrol, the alpha lipoic acid–acytl-l-carnitine combination and astragaloside IV will not be known for decades and could possibly buy you a number of additional years. 

Second, I believe that if you carefully follow research related to aging over the coming years and simultaneously evolve your personal anti-aging firewalls to reflect new research findings as they emerge, you will have a real possibility to go on living and transcend the 122-year age limit and keep living healthily.  And, after that, you can continue to keep living healthily for perhaps hundreds of years.  This assumes, of course, a context of a healthy and safe society.

Let me put this in very personal terms. My anti-aging supplement regimen is considerably more sophisticated now at age 79 than it was three years ago and I am observing anti-aging lifestyle protocols like regular exercise more rigorously.  I look the same in photos taken then and now.  I feel as good and have comparable physical, mental and sexual energy.  I might even have a bit more hair on the top of my head, energy and mental acuity.  In other words, I don’t think I have aged much during that time.  But I have evolved and focused my anti-aging defenses significantly.  What I know about aging, its causes and possible anti-aging interventions has grown enormously during those 3 years.   How about the coming three years?  I seem to be able to keep going without slowing doing what I am doing now, assuming I am not hit by a bus or killed in a car accident.  But according to all indications the progress in anti-aging research in the coming 3 years should be much greater than that in the last 3 years. And it will continue to accelerate thereafter.   I am talking about all the kinds of research that shed light on aging, whether that research is motivated by a desire to find a cure for cancer, AIDS or other diseases or by a desire to comprehend cell-cycle topics like apoptosis or cell-cycle arrest better or by a desire to characterize DNA methylation patterns in the human epigenome.  And along with that progress I expect will be identification of ever-more sophisticated practical science-based anti-aging interventions which I will adopt as soon as they are available.  That is the way it has been.  That is the way it will be even more.

In fact I suggest Giuliano’s Law of Anti-Aging, a counterpart to Moore’s law that has characterized the growth in cost-effectiveness of microprocessors since the 1960s:

·        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.. 

Of course, validation of this law will take many decades.  Objective measurements relating anti-aging interventions to extraordinary longevity are yet to be established.

So, for example, if I  assume that today’s anti-aging firewalls confer an average of only 7 years of life expectancy beyond the normal actuarial projection for me, a 79 year-old, then in 2016 I will have 14 years of additional life expectancy beyond the actuarial projection for my age at that time, 86.  The 2004  actuarial table for adult males gives me 8.11 additional years now.  So if I assume 7 additional years due to my anti-aging regimen I now have 15 years of life expectancy to play with, e.g I can expect to live till 94 (which I think is far too low given that my mother lived to 93 without anti-aging interventions).  According to Giuliano’s law, in 2016 I will have the actuarial expectancy for that age, 5.1 years, plus a number of years due to the anti-aging interventions available then.  That number will be twice the 2009 number for 79 year old or 14 years.  Why still 79 instead of 86?  Because I have adjusted my 2016 chronicle age downward to reflect my firewall-adjusted age which remains at 79.   So my adjusted life expectancy will have gone up from 15 years to 19 years by the end of the 7 year period.  By 2023 my life expectancy will have gone up to 31 years. I therefore suspect that with each additional year I manage to keep living in good health, if I keep up my anti-aging research program my probability of living another year in good health goes up instead of down despite my advancing chronicle age.  If you are significantly younger than me, your odds of breaking the 122 age limit barrier are much better.

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25. March 2009 by admin.

The first fantasy:  In the Hollywood movie, late at night in her lab the young attractive researcher discovers how to activate “The Longevity Gene,” making human life spans of 200 years possible.  Then her “secret” gets stolen by bad guys and she sets out to get it back.  And the story goes on from there.  In real life the scientific situation is nowhere so simple.  There are hundreds of genes that have something or the other to do with longevity and dozens of complex proteomic signaling pathways that weave them and other genes together. There is no single known master longevity gene, and in fact such a gene might not exist.  So, what is known about “longevity genes?”  A couple of recent studies provides clues:

For one thing, there appears to be a remarkable similarity of “longevity” genes across a wide spectrum of species ranging from yeast to worms to flies to humans.  That appears to be a conclusion revealed by a proteomics study done by the Buck Institute for Age Research based on a “longevity protein network” developed at Prolexys Pharmaceuticals in Salt Lake City, UT. The longevity network looks at 3,271 interactions among 2,338 proteins that impact on life span in yeast, nematode worms or flies.   It also looks at equivalent human versions of 175 of these proteins  and 2,163 additional human proteins that interact with those proteins. The longevity protein network was derived from the Prolexys human interactome database which contains over 120,000 non-redundant interactions among human proteins - the largest of its kind in the world.

“Researchers found that there is a complex web of interactions among the human equivalents of the many longevity genes found in simple animals. The results revealed a ‘surprisingly close relationship between aging processes in humans and simpler organisms.’”  This is an interesting result given the dramatically different life spans involved and the fact that every species has its own typical life span.  Fruit flies, drosophila melanogaster, normally live 7-8 days.  Humans normally live 3,600 times as long.  It appears that many genes regulating aging have been conserved during the process of evolution over more than a billion years.  That result is confirmed by another study done at the University of Wisconsin that identified 25 longevity genes shared by single-celled budding yeast and the roundworm C. elegans.

I believe the result lends credence to  the Programmed genetic changes theory of aging.  Every species has its own program.  And the program evolves as the species evolves.  But where is the program?  It may not be in the genes themselves but in large part in the epigenome, in inherited patterns of DNA methylation and histone acetylation.  We may not be able to change our human genes so easily, but we can certainly affect the epigenome and do so unwittingly every day.  So here is a more sophisticated fantasy: we figure out ways to modify our epigenome so we can live longer.  For example, suppose we wanted to control P53 apoptotic overactivity leading to cell death or senescence.  Suppose we could find a way for reducing activation of P53, say by activating SIRT1 by resveratrol which in turn deacetylates P53.  Not completely a fantasy(ref), perhaps this is a minor update patch to the epigenomic longevity program, one that might prove to be of practical value. 

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23. March 2009 by admin.

A recent Finish study evaluated the effect of frequency of sexual intercourse on risk of subsequent erectile dysfunction.  The study was based on written interview data.  A sample consisting of 989 men aged 55 to 75 years (mean 59.2 years) was followed over a 5 year period.  All men were free of erectile dysfunction at study baseline.  The major finding was that the risk of erectile dysfunction was inversely related to the frequency of intercourse and that regular intercourse protects against the development of erectile dysfunction in men in this age range.  Men reporting intercourse less than once per week at baseline had more than twice the incidence of erectile dysfunction compared with those reporting intercourse at least once per week, that is 79 versus 33.  This is yet another example of use it or lose it when body capabilities of older people are concerned.

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22. March 2009 by admin.

Graying hair is a sure-fire sign of aging.  But what is going on?  Actually, the hair is being bleached.  Recently-reported research indicates that graying with age is due to a buildup of hydrogen peroxide in human scalp hair shafts – yes the same stuff used to bleach hair.  The peroxide blocks synthesis of our hair’s natural pigment, melanin.  The buildup of hydrogen peroxide is caused by a reduction of an enzyme that converts hydrogen peroxide into water and oxygen, and the graying is compounded by low levels of methionine sulfoxide reducase (MSR) A and B, enzymes that repair hair follicles.  Further, these events disrupt the formation of tyrosinase, a key enzyme involved in the production of melanin.  

What can be done about all this to bring back naturally-colored hair?  That is unclear for now but there are hints.  It appears that a key step in the sequence of hair-bleaching events, oxidation of methionine sulfoxide, can be blocked in-vitro by L-methionine.  Methionine is an amino acid that can be found in sesame seeds, Brazil nuts, fish, meats, and certain plant seeds.  L-methionine is also readily available as a dietary supplement.  Taurine, an amino acid derivative from L-methionine and cysteine metabolism, and also available a dietary supplement, also seems to have a protective effect on human hair follicles in-vitro(ref).  However, so far I have seen no research evidence that dietary L-methionine or taurine can have any impact on human hair color or density.

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20. March 2009 by admin.

We as people are very different from each other.  And a medicine that may work well on one person may not work well on another or even poison him.  The dream of personalized  medicine is that your genetic and epigenetic signature is identified in sufficient detail to indicate your disease susceptibilities and your likely responsiveness to treatment options.  Even further, the signature at any point in time may tell you about diseases you already possess that you do not know about, like silent cancers.  This is where DNA methylation comes in,  a process by means of which sites adjacent to genes on chromosomes (promoter regions) are chemically methylated after a cycle of DNA replication(ref).  The methylation is passed on in the course of cell divisions and through generations of people.  The methylation pattern captures the ancesteral history of the cell that is not in the genes themselves and is unique to every cell.  DNA methylation is thought to be one of the main ways epigenetic information is captured and passed on.  See the Feb 28 post in this blog on Epigenetics, Epigenomics and Aging.  Also, this subject is discussed in yesterday’s post Rebooting cells and longevity.

The DNA methylation profiles of individuals are unique, change with aging, and include valuable clues to disease and treatment progress.  For example, DNA methylation of tumor suppressor genes predicts the relapse risk in acute myeloid leukemia for patients in clinical remission(ref).   So, research groups throughout the world are building databases of DNA methylation epigenomic information, in part to establish methylation markers that are “normal” and other markers that indicate diseases, susceptibility to particular disease conditions and associated information . Epigenomics is a company that is focusing on cancer diagnostics based on looking at DNA methylation.  Its goal is to develop and commercialize easy-to-use diagnostic tests for cancer, tests that can be applied at early stages before symptoms occur.  The tests Epigenomics has under development use readily-available body fluids such as blood or urine and are based on detecting differences in DNA methylation patterns between healthy and sick individuals or between subgroups of patients within disease classifications.  One intent is to identify cancer-specific DNA methylation patterns while a patient’s cancer is in a very early stage and more likely to be curable(ref).  For example, researchers in Epigenomics have identified a region in the Septin9 gene that is methylated in 90% of colorectal cancer tissues.  This methylation is found little or not at all in normal colorectal tissues.  DNA methylation testing is not yet part of regular clinical practice but probably will be starting very soon.  Epigenomics has three products in the development pipeline, one for colorectal cancer screening, one for prostate cancer screening and one for lung cancer screening.

DNA methylation is impacted by aging and impacts on aging(ref).  Methylation in the promoter region of genes is thought generally to be associated with gene silencing.  Longevity-related and health-promoting genes may be turned off in the process of aging due to progressive methylation.  The P66Shc gene for example, associated with longevity in mammals, appears to be silenced through some combination of histone deactylation (resulting in protein folding) and cytosine methylation(ref).  Little is known yet about how to go about DNA demethylation, but demethylation appears to be necessary for epigenetic cell reprogramming(ref).  Also, relatively little is known yet about how DNA methylation plays out in aging, yet alone how to work with DNA methylation in order to stop or reverse aging.  Again, it appears that the more we discover, the more there is that we know we don’t know.

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19. March 2009 by admin.

An amazing discovery is still in the process of being made.  Exposing the DNA of many kinds of body cells to just four transcription-factor proteins causes a cell to lose all memory of what it is and does and become what is called an Induced Pluripotent Stem Cell (iPS cell), a cell very much like an embryonic stem (ES) cell.  It appears that an iPS cell, like an ES cell, is capable of progressively differentiating into any cell type, be it heart, skin, nerve, bone or muscle.  In other words the four proteins reboot the cell into embryonic stem-cell type pluripotency.  The entire history of epigenomic information that cell has inherited from its progenitors over the entire life of the animal is simply wiped out.  This includes not only information about what the cell has become (e.g. a brain neuron or a bone or liver cell) but also the history of experiences inherited from its progenitors going back to the inception of the animal.  This history, expressed via methylated DNA can strongly condition the behavior of the cell.  See the Feb 28 post in this blog on Epigenetics, Epigenomics and Aging.  

The proteins are Oct4, Sox2, Klf4, and c-Myc.  Oct4 and Sox2 are transcription factors known to have to do with ES self-renewal and proliferation.  Klf4, and c-Myc are transcription factors known for their roles in cell proliferation, differentiation and survival and regulating gene expression.  This reprogramming effect was at first reported in 2006 and limited to starting with mouse fibroblast cells carrying engineered selection markers(ref,ref).  Later, the effect was demonstrated using a retrovirus to transport the proteins into the nuclii of mouse cells(ref) without a need for engineered cells.  However, the retrovirus could also inject its own DNA into the chromosomes affected, so the process appeared to be unreliable because it could affect the genome of the cell.  More recently, it has been possible to induce pluripotent stem (iPS) cells from mouse fibroblasts and liver cells by using relatively benign nonintegrating adenoviruses(ref).  It appears in several experiments that the four proteins wipe clean all the lifelong DNA epigenetic modifications that normally occur as a stem cell progressively differentiates into being a very specific kind of body cell, like a hair follicle cell.  “DNA methylation, gene expression and chromatin state of such induced reprogrammed stem cells are similar to those of ES cells.”

This discovery is still in process because most experimental work so far has been with mouse cells and it is still not known for sure how completely  similar the behavior of iPS and ES are.  Nobody has been able so far to make a mouse out of an iPS cell, for example. The possible implications for regenerative medicine are immense.  The idea is to remove some cells from a person, say a small tube of blood cells, restore these in the lab to being iPS cells and then use these in lieu of ES cells for organ regeneration in that person.  Because the cells are from the same person, there would be no problem of immune system rejection.  Several issues require resolution before this kind of therapy can be practical, however.  First, the pluripotency and safety of using human iPS cells must be confirmed.  There is a possibility that they could contain genetic remnants of the andovirus vector that could create mischief for example.  Second, it is important to find effective ways for introducing the iPS cells into human organs so they achieve the desired results of organ regeneration.  If ES or iPS are randomly injected into body tissues they are likely to form teratomas, ugly encapsulated structures of varied body tissues including lung, heart, liver or brain tissue, or bone, teeth or hair.  Careful attention has to be paid to signaling structure to assure the ES or iPS make the kind of tissues desired and only that kind.  This is a fundamental issue of organ regeneration via stem cell therapy whether ES or iPS cells are used.  Also I am unclear about another important matter.  What happens to the telomeres in a cell from a mature person when it is converted to an iPS cell?  Do the telomeres stay short reflecting the age of the donor or are they somehow enlongated as they would be in an ES cell?  Does an iPS cell have sufficient expression of telomerase when it differentiates to carry it through the large number of generations required for effective organ renewal?  As far as I know, these are issues still to be researched.

In terms of aging, the four proteins seem to turn the clock back in a cell to ground zero.  That is, all the epigenetic information (DNA methylation) that cell and its parents, grandparents, great-grandparents, etc.  gathered in the process of many rounds of cell differentiation and division and life experience is completely wiped away in the process of it becoming reprogrammed as an iPS cell.  For halting or even reversing human aging we don’t want that to happen to most of the cells in our body; it would turn us into blobs of undifferentiated stem cells.  What we might like, however, is selectively to erase epigenetic information related to programmed aging while retaining epigenetic information related to cell differentiation.  Or, more simply put, we would like selectively to reset our cells to a younger state while keeping the degree of cell differentiation appropriate to that younger state.  See the discussion of the Programmed genetic changes theory of aging in my Anti-Aging Firewalls treatise.  This is a challenge of a quite different order of magnitude than is simple rebooting. 

We can probably expect important new research results related to iPS cells in the coming year, months or even weeks. 

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17. March 2009 by admin.

A reported large-scale population study by Scottish researchers indicates that longevity is highly correlated with childhood intelligence quotient, especially for people who grow up in poorer neighborhoods.  A thousand people were followed during a 70-year span.  During a 25 year interval  “— 51 percent of the men and 38 percent of the women in the study died. In simple terms, there was a 17 percent greater chance of death for every 15 points of lower childhood IQ. After adjusting for deprivation and social class, this difference was reduced to 12 percent.  These adjustments separated socioeconomic effects from IQ and explained some, but not all, of the differences associated with lower IQ.”  The reasons for this effect are not clear.  One possibility according to the study authors is that poorer people with lower childhood IQ lead more deprived lives and are more vulnerable to diseases and other causes of death.  Another possibility is that low childhood IQ combined with poverty was correlated with low childhood health in the first place leading to increased mortality.  I suggest a third possibility: that members of the higher IQ group had more willingness, commitment and capability to pay attention to their health and longevity and that this effect transcended socioeconomic class.

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