28. February 2009 by admin.

Human traits and gene expression are affected by signals that can result from interaction with our environment, including what a mother eats and the social conditioning received by a young child.  Imagine a control system of biomolecular switches that can turn expression of genes on or off.  And imagine that those switches can be controlled by what we eat, do or experience in any way or even think.  Further imagine that the positions of those switches, genes being turned on or off, can be inherited.  If you can imagine those things you have imagined the science called Epigenetics.  Epigenetics and epigenomics are concerned with the study of changes in the regulation of gene activity and expression that are not dependent on gene sequence in DNA.  The subjects are a bit dense but are of considerable and growing importance for disease and aging research.  Here is a primer:

Epigenetics may be concerned with both heritable and non-heritable changes in gene activity and expression and also stable, long-term alterations in the gene transcriptional potential of a cell.  While epigenetics refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome(ref). 

Events in the early development of an organism can affect the phenotype (observable characteristics and traits) creating biological changes in the epigenome (the overall epigenetic state of a cell or organism).   This is a way of saying that genes by themselves do not determine our destinies or the diseases we get or the way we age.  Simply put, there is a lot more going on in a higher organism than can be explained by genetics.  Humans physical traits are determined not only by what is in our genes but also by factors that affect gene expression and changes in gene regulation such as are evident in the growth of an embryo or in differentiation of stem cells.  For example, what are the factors that allow a single fertilized human egg to continue dividing into all of the specialized cell types and organs – blood cells, neurons, bone cells, muscle cells, etc.?  That information is both genomic and epigenomic information not provided just by the sequence of genes in a strand of DNA.  Aging itself appears to be an epigenomic phenomenon, with the typical pattern of gene expression changing in the course of a lifetime. 

Like protein folding, a subject I discussed recently, epigenomics is a frontier area where little is yet known compared to what is yet to be learned and where there is a lot of excitement.  It is starting to change the ways we look at many things in biology and medicine.  There is increasing agreement that truly understanding diseases and susceptibilities to diseases is a matter of both genetics and epigenetics seen in the context of environment – and that goes for cancers, neurological and cardiovascular disorders, psychiatric disorders as well as virtually all other diseases.

One area where epigenomic effects are evident is the case of monozygotic twins.  Despite being genetically identical they can be very different in their phenotypes and susceptibilities to many diseases, such as diabetes, schizophrenia and Huntington’s disease and can weigh different amounts even when fed the same diet.  Some of these characteristics may be inherited.  In one experiment at Duke University, two genetically identical mother mice were fed different diets, one a normal diet, the other a diet enriched with choline, betaine, folic acid and vitamin B-12.  The offspring mice looked and were very different.  For one thing the offsprings of the normally fed mice had white hair while the offsprings of the supplemented mother had rich brown hair.  The differences were epigenomic.  Despite genetic identity, the physical characteristics of the offsprings depended on the environment and behavior of the mothers. The implications of this little experiment and similar ones are staggering for those of us concerned with dietary supplementation.  Dietary supplementation of parents can result in their offsprings having an altered biochemical makeup and altered physical characteristics.  And a corollary is that dietary supplementation can cause permanent as well as temporary changes in ourselves as well.  I will probably take 50 to 100 years before we will know for sure which dietary supplements create what results in our offsprings, and in the meantime we will have to play it by ear or depend on animal studies which are yet to be conducted.

Genetic imprinting is a process that has been known for some time.  For certain genes, either the mother’s version or the father’s version is selected by an offspring.  This process of selection can profoundly affect disease susceptibility and is now believed to be epigenetically controlled instead of a random one. For example the imprinted KCNK9 potassium channel gene is frequently over-expressed in breast cancers.  Some researchers believe that our ability to diagnose and treat many diseases that have a genetic origin will depend on our identifying the human imprinted genes and determining how they are epigenetically regulated.

One area of epigenomic research is looking for where and how epigenomic information is stored in humans.  The study involves both experimental and computational approaches.  Methylation (the chemical replacement of a hydrogen atom with a methyl group) of  DNA on chromosomes is one of the important encoding mechanisms.  A number of projects have been concerned with mapping the methylation landscape of the human genome, commencing with the Human Epigenome Project that was started in 2000.  The Human Epigenome Pilot Project has “  – recently completed a pilot study of the methylation patterns within the Major Histocompatibility Complex (MHC) - a region of chromosome 6 that is associated with more diseases than any other region in the human genome.”  They believe the project will provide unprecedented insight, particularly applicable to autoimmune diseases. A 5-year initiative involving four research centers was funded recently called the NH Epigenome Roadmap and plans to study 100 cell types, and there are a number of other epigenomic study initiatives. New fast sequencers allow rapid analysis of methylation profiles but the challenge is very complex because diseases may correspond to alterations in both genomic and methylation profiles.  Much is being learned but there is very much more yet to be learned.   

Already, certain DNA methylation changes are known to be associated with aging and others associated with certain diseases like lupus and scleroderma.   It is possible that yet-another theory of aging could be added to my Anti-Aging Firewalls treatise at some point called Changes in DNA methylation profiles.

The impact of epigenetic knowledge is expected to be felt across the board in medicine, including in psychiatry.  Stress and aggression are known to induce epigenetic changes in mice, and addiction does too.  Cocaine exposure, for example, is known to create epigenetic changes in specific areas in the brain. How a mother treats her small daughter may generate epigenomic changes that condition how that girl behaves throughout the rest of her life, and also condition the behavior of her daughter’s daughter.

Epigenomics provides a layer of information applicable to diseases and aging beyond that available in genomics, but there are yet-other layers to consider including proteomics (understanding structures and functions of proteins including factors such as folding) and transcriptomics (understanding the set of all messenger RNA molecules, or “transcripts,” produced in one or a population of cells).  The hope is that by mastering genomics, epigenomics, proteomics and transcriptomics and how they work together in specific instances we will gain mastery over all diseases and the process of aging.  We have a ways to go.

If you have a background in molecular biology and genetics, a more technical discussion of epigenetics can be found here. 

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26. February 2009 by admin.

If I were to add a 15^th theory of aging to this Anti-Aging Firewalls treatise, it would possibly be Misfoldings of proteins.  The basic notion is that stress often leads to the misfolding of proteins, a process that can accelerate with age creating vulnerability to a number of disease and dysfunctional conditions.  Misfolded proteins cannot perform their intended functions, can create active mischief and probably contribute to aging in multiple ways.  This is a relatively new and complex area of molecular biology that is to a large extent still unexplored.  I have posted a long and rather technical note on the subject here in my Antiaging Firewalls Treatise.

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24. February 2009 by admin.

Animals which live extraordinary long lives can provide insight regarding the various theories of aging.  The longevity of the African naked mole rat seems to fly in the face of the the oxidative damage theory of aging, for example(ref).  This little critter is the size of a tiny mouse but lives about eight times longer.  Living up to 28 years,  it is the longest-living rodent.  Its secret to longevity is not known but there are clues.  For example they are very cool, they can all but shut down their metabolism, and they spend a great deal of their life sleeping.  Surprisingly, the markers of oxidative damage in these tiny rats exceed those of mice when they are relatively young.   However the rate of accrual of oxidative damage in these rats does not appear to markedly ramp up with age as it does with mice.  They change very little as they age and females more than 20 years old can give birth.  It seems that the mole rat has a powerful long-lived antioxidant defense system which mice do not have.  I suspect that this observation is just the tip of the iceberg and real insights will come from looking at genes and protein expression and how the rat mitochondria work.  Anyway, if you want a little critter pet that is cool and will not die off on you in a few years, here is your pet.  The only downside is that you won’t see much of your pet since it lives underground..

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23. February 2009 by admin.

A recently reported research study seems to throw the whole the the oxidative damage theory of aging into question, at least for C. elegans, a nematode roundworm.  The researchers created a mutant species by individually knocking out five genes in these worms that confer a natural antioxidative effect, e.g. the production of SOD a detoxifying enzyme.  The worms lived just as long despite the compromise in their ability to handle oxidative damage.  And when one of the genes was knocked out the worms lived actually longer, probably due to alteration of mitochondrial function. Does this kill the venerable Oxidative damage aging theory, the granddaddy of all the aging theories?  Should we stop taking oxidants? Not at all.  There is too much evidence behind that theory and over the years it has provided too useful a model for many aging phenomena.  And the beneficial effects of taking antioxidants are well established.

Longevity is not the only area of science where it is useful to keep multiple theories alive despite the fact that they are sometimes inconsistent with evidence and with each other. The prime example is relativity theory and quantum theory in physics, both of which have enabled enormous strides in physics, engineering, astronomy and technology for over a century now.  These two theories have never been reconciled despite prodigious mathematical efforts to do so.  In an interesting article in The March 2009 Scientific American, A Quantum Threat to Special Relativity, it is argued that the quantum theory and special relativity theory are in fact incompatible and contradictory at the most basic level.  No way either of these theories will be thrown out however – not until a more comprehensive theory comes along that subsumes it.  The theories are just too useful.  I think the same is true with theories of aging – all 14 theories covered in my Anti-Aging Firewalls treatise.  It will be incredible, in fact, if we can manage to get those theories down to two or three more basic ones.

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22. February 2009 by admin.

Since I first drafted the Anti-Aging Firewalls treatise in May of 2008 my perspective on the Telomere shortening theory of aging has become considerably more sophisticated.  Today, in a fairly major update of the treatise I have rewritten much of the section on that theory highlighting a new evolving perspective on that theory and the role of telomerase activation in an anti-aging regimen.

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20. February 2009 by admin.

I often feel like a lucky soldier participating in a long and deadly battle, a soldier whose closest comrades and friends are constantly being wounded or killed.  The battle, of course, is against the ravages of old age and the challenge is to stay alive and healthy.  All my relatives and many of my friends in my age cohort are already dead.  One of my closest college friends is going in for heart bypass surgery Monday; another has diabetes, has experienced unexplained heart stoppages and is having a pacemaker installed Monday; a close friend is having a hip replacement also on Monday; and two more friends are being treated for deadly cancers.  And the problems are increasingly with people 10-25 years younger than I am.  A son in law has already had two knee replacements and is scheduled to have a shoulder replacement.  I, on the other hand, have had a few less-serious orthopedic problems in the last 10 years like a rotator cuff tear from heavy lifting.  But I seem to be free of the debilitating diseases of old age – cancers, dementias, diabetes, cardiovascular problems, etc.  I just had my blood lipids and C-reactive protein checked and they all came in normal.  My annual physical exams are boring.   I ask myself is this the result of blind luck, having a good initial set of genes, or following my anti-aging regimens?  I clearly can’t say for sure.  However if I am as active, alert, productive and disease-free at the age of 109 as I am now at 79, I will then know the answer.   The anti-aging firewalls will get most of the credit.  And, by that time the firewalls should be far more sophisticated and enable me to keep going for a long additional time.  I am betting on it and have to be careful not to ruin the program by getting run over by a bus.

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20. February 2009 by admin.

This news item is retro rather than forward looking, being concerned with life re-creation rather than life extension.  Life-extension may pose ethical problems, but how about bringing an extinct near-human species back to life?  German scientists have finished identifying the genome of Neanderthal Man, now extinct for 30,000 years. Further, there is discussion of creating a new live Neanderthal male (or female or both) using available technology.  A modern human genome would be modified so that its DNA matches the Neanderthal version. This DNA would be inserted into a chimpanzee cell which would then be reprogrammed to an embryonic state, and then introduced into a chimpanzee’s womb.  The chimp would give birth to a Neanderthal humanoid.

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20. February 2009 by admin.

A well-written article relating mitochondrial health to the use of antioxidants and can be found here.  Mitochondria are particularly susceptible to oxidative damage and such damage is implicated in many debilitating conditions including  cardiovascular disease, stroke, Parkinson’s disease, Alzheimer’s disease, fibromyalgia, schizophrenia, dementia, bipolar disorder, epilepsy, retinitis pigmentosa, and diabetes mellitus.  I continue to strongly believe that there is a central role for anti-oxidants in an effective longevity regimen.  Specifically, Co Q-10. Alpha-lipoic acid and acytl-l-carnitine are important antioxidants for maintaining the health of mitochondria.  An additional report came to my attention today confirming how the use of antioxidants can  support mitochondrial health, this one originated at the Stanford School of Medicine. Blood samples from 20 patients with various mitochondrial diseases uniformly showed depleted glutathione, indicating a lowering of those patients’ antioxidant defenses.  Apparently, mitochondrial disorders generate large numbers of free radicals.  On the other hand, those patients taking antioxidant supplements did not have depleted glutathione, they found, indicating stronger antioxidant defenses.

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20. February 2009 by admin.

A reported study about free radicals is radical in its conclusions.  The study was based on disabling five genes in mutant Caenorhabditis elegans worms.  The study’s authors suggest that damage due to free radicals may not be a cause of aging but rather is a consequence of aging and suggest instead that the aging process may originate in the mitochondria.  See my discussion on the Mitochondrial DNA mutation theory of aging.  It would seriously upset the anti-aging establishment’s applecart if oxidative damage turned out to be only a symptom.  However, I hesitate to accept such a broad conclusion given the preponderance of evidence that exposure to strong oxidative stress, such as massive doses of radiation, generates the overt symptoms of aging.  Most likely we are dealing with a chicken-and-egg causative process here where it is both the case that oxidative damage contributes to aging and that aging contributes to oxidative damage.  And the mitochondria play an important role in mediating the aging process.  See the previous blog post as well.

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20. February 2009 by admin.

Stress may increase the rate of progression of the most malignant form of melanoma, according to a report on a study conducted in New Zeeland of 1600 people diagnosed with that disease.  Small wonder given what we know about stress and how stress-generated cortisol suppresses the functioning of the immune system. Of course, some of the stress may come from the diagnosis itself.  This study  points again to the importance of the substances in the anti-aging firewalls that encourage regular sleep and mental calm like l-theanine and melatonin as well as a relaxed mental attitude that takes any problems in stride.

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