AGINGSCIENCES™ – Anti-Aging Firewalls™

I discussed the general topic of individual DNA testing in an earlier post.  There is an important twist that I cover here.  Low-cost consumer-oriented genetic testing is making personal genomic information available to individuals in a way not intermediated by the medical or any other professional establishment.  The result is an unprecedented opportunity for individuals to take more responsibility for their wellbeing and longevity.  However, there are certain associated problems and hazards. 

Up until recently, genetic testing was available through laboratories that mainly service professionals – medical people, crime specialists and genetic counselors for example.  If you had a genetic test it was ordered for you with a specific purpose in mind by somebody who also interpreted the results.  Now there are a number of direct-to-consumer web-based genetic testing services.  A person goes on a website, orders a test, receives a kit and sends a sample in.  He or she gets the result with no professional involved. At that point the person may or may not research the meaning of what was discovered further, may or may not decide to act on the results, and may or may not decide to consult a professional. The person may or may not share the result with his or her primary physician or spouse.

I have mentioned that a number of consumer companies do single-purpose tests, such as paternity testing or testing for HIV.  There is a growing number of companies that simultaneously scan for a number of possible disease or other susceptibilities.

A much-discussed low-cost example example company is 23andme. For $399 the company sends you a kit.  You spit into a tube and send it back to the 23andme lab and in 6-8 weeks the results are posted to a secure online site.  The test looks at genes related to 114 disease conditions and traits, a list that grows in time.  Examples of the conditions tested for include Parkinson’s Disease, Prostate Cancer, Psoriasis, Resistance to HIV/AIDS, Rheumatoid Arthritis, Sickle Cell Anemia & Malaria Resistance, Type 1 Diabetes and Type 2 Diabetes.  For each condition tested, certain basic information is provided.   The results provide an estimate of whether the genetic risk for a given condition is higher or lower than average, and background information on the condition and a list of counselors, links and condition-related support groups in the customer’s area.  The results for any given condition are based on one or several genetic markers, six of them in the case of rheumatoid arthritis.  Specific examples can be seen by clicking on any of the links just listed.  The service is an example of genotyping (looking at SNPs, sequence variations within a single nucleotide) to determine certain genetic variants a person possesses, which is very different than sequencing an individual’s entire genome. 23andme also offers updated clinical reports and research reports on the diseases, traits and conditions covered. 

Navigenics (www.navigenics.com) is another company in the consumer genomics game. It offers two levels of testing, one for $499 and its most comprehensive service for $2,499.  Both services suggest individual’s genetic predisposition to the common health conditions covered and “information and support to help you prevent, detect or diagnose them early,” including limited access to genetic counseling. Decodeme is another company in the consumer-oriented testing game offering a “cardiovascular” scan for $199 and charging $985 for its “complete scan” which scans over a million genetic variations for 38 conditions.  GeneDX is one of several specialized companies that scans for rare hereditary diseases.  The most comprehensive service seems to be Knome which offers complete genome sequencing looking at all 3 billion base pairs in the human genome.  “Each individual is assigned a complete team of bioinformaticians, geneticists and clinicians to conduct a comprehensive analysis of your complete genome.” The services are customized.  Costs are unpublished but I would guess they could range up to $100,000.

Heralding the emergence of consumer genomic testing as a highly competitive industry, a trade show for the industry is scheduled, The Consumer Genetics Show, Boston, Hynes Convention Center: June 9 – 11, 2009.

The hope of widespread consumer genetic screening is that individuals can identify disease susceptibilities and take appropriate actions.   If a person knows he has a susceptibility to cardiovascular disease or diabetes or he or she may make dietary and lifestyle changes to reduce the probability of the disease emerging.  People with susceptibility to arthritis may elect to take additional anti-inflammatory supplements, for example.  The individual is empowered to exercise preventative medicine on a personal level, clearly an important factor for enhancing longevity.  Further, if a couple does such testing before having children, they could possibly spot common negative inheritable traits that could emerge in an offspring.

Some genetic counselors are dubious about massive consumer genetic testing.  Reasons are 1. The state of research knowledge linking genetic markers to specific diseases is still very primitive and sketchy.  For the disease susceptibilities that are multigenic (involving multiple genes), in most cases the causative gene relationships are yet to be identified.  Scientific and medical researchers and practitioners have not agreed on appropriate diagnostic genetic biomarkers for most such conditions.  Further some important known biomarkers are proprietary and patented and can only be used by the company owning the rights to use them.  It is unclear who has the best biomarkers.  2.  Individuals are apt to misinterpret genetic results, either missing clues or suffering unnecessarily from worrying about a disease susceptibility that will never be realized.  For many of the conditions tested there is insufficient research evidence to justify firm conclusions.  Results need to be interpreted along with other important information including family history, health history, current health, environment, lifestyle, etc.  Providing such context and guidance to action is the role of genetic counselors.  I have heard one such counselor say the 23andme tests “only have entertainment value and it would be dangerous to read anything else into them.”

In all fairness, all of the consumer genetic testing services provide optional or built-in linkages to genetic counselors and attempt to identify the reliability of their findings in terms of the current state of research.  They also strive to keep up with such research and adjust their tests accordingly.  I expect that as time progresses we will have better and better underlying research to back up test result conclusions and that genomic consumer testing will become more and more commonplace.  Competition and lower-cost technology is likely to cause the tests to become ever cheaper, more comprehensive and cost-effective.  The cost of gene testing is rapidly dropping according to a variant of Moore’s Law.  (See the post on this Blog about the factors that drive Giuliano’s Law).  The latest generation of microfluidic gene-analysis chips are little bigger than a flake of dandruff and are getting down to costing less than a bottle of shampoo.  From $10, 000 down to $399 for a set of tests was a big drop.  The next drop may be down to $69.99.  And who knows if any bottom is in sight after that. 

There is a message here to medical and health professionals: you better get out there and learn about the gene tests and what they can mean if you want to maintain your creditability with your patients.  The same is true for longevity research, by the way. 

I published the first online version of the Anti-Aging Firewalls treatise a year ago and started this blog about six months ago.  A lot has happened on the longevity front during the period.  There have been 78 blog posts and the treatise has been updated dozens of times.  See Anti-Aging Firewalls V1.9 state of progress for a progress report as of two months ago.  The present version of the treatise is significantly expanded, corrected and far more comprehensive than the original.  Nonetheless a number of important developments have been reported in this blog and are not yet sufficiently covered in the treatise itself.  For me, it is important that the treatise at any time offers comprehensive coverage of what science knows about aging and what can be done about it.  Therefore I plan to focus my efforts during the next several days to bringing the treatise up to date.  You may not hear much from me here during that time.

I do want to share one thought from what I am writing, however.  There are the 14 theories of aging listed in the treatise and six additional candidate theories described in this blog that need to be described also in the treatise even though they don’t qualify as full aging theories yet.  They are Incorrect protein folding, Accumulation of progerin, Gene mutations leading to hellicase abnormalities, Aberrant mTOR signalling, The hypoxic response and Epigenomic changes in DNA methylation.  

Regarding these 20 theories or others that might come up, a single key theory of aging may not exist.  There are lots of biomolecular actions and genetic pathways that can lead to accelerated aging, and it appears there are also several that can delay aging at least somewhat.  Some may be more fundamental than others.  But it may well be that there is no one master theory or mechanism of aging that drives all the others.  It may be that we are looking at a large system of interacting feedback loops in which all the mechanisms of aging work together affecting each other in multiple ways.  All are primary. 

Think of a mechanical wrist watch.  It contains numerous gears, wheels, cogs and bearings.  Which is the main gear or wheel or bearing, the key component for operation of the watch?  Wrong question.  They are almost all needed.  Taking out or breaking almost any gear or cog or wheel or bearing will stop the watch or make it run screwy.  If you want a healthy functioning watch it is important that all the parts be in good shape and well-aligned with each other.  Same for us.

We have heard about so-called “longevity genes” that are over a billion years old.   A number of these in humans (15 or so) are also found in primitive species such as nematode roundworms (c-elegans), and are associated with the target of rapamycin (TOR) signaling pathway.  The mammalian counterpart of TOR is known as mTOR. My purpose here is to lay out a plain-language overview of TOR and mTOR-related longevity research and see what light this research might throw on the theories of aging in my Anti-Aging Firewalls treatise.   It turns out that the new findings are relevant to at least the Oxidative damage and Mitochondrial damage theories of aging.

Mammalian target of rapamycin (mTOR) is a protein encoded in humans by the FRAP1 gene.  As the name suggests, mTOR is targeted by the immunosuppressive drug rapamycin, a drug used clinically to treat graft rejection and restenosis and being tested as a treatment for autoimmune diseases.   “The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism(ref, ref).”   The mTOR pathway is “a central controller of cellular and organism growth that integrates nutrient and hormonal signals, and regulates diverse cellular processes(ref).”

The mTOR pathway plays important role in diseases.  Recent studies link mTOR to several age-related human diseases including diabetes, cancer, obesity, atherosclerosis, nephrotoxicity, cardiovascular diseases and neurological disorders. Inhibiting mTOR using rapamycin or derivative drugs offers a promising therapeutic approach for dealing with several diseases and cancer lines(ref,ref,ref).  “Dysregulation of mTOR signaling occurs in diverse human tumours, and can confer higher susceptibility to inhibitors of mTOR(ref).” 

Inhibiting mTOR may also offer an approach to enhancing human longevity.  Decreasing TOR signaling can extend the lifespans of flies and worms.  It does this by upregulation of mitochondrial gene expression resulting in decreased production of reactive oxygen species. “Reduced TOR Signaling Extends Chronological Life Span via Increased Respiration and Upregulation of Mitochondrial Gene Expression(ref)”  With respect to humans, much of the machinery of TOR signaling found in more primitive species is conserved.   “Recent data have also revealed that mTOR is involved in the regulation of lifespan and in age-related diseases(ref).” TOR also plays a role in the longevity-producing effects of calorie restriction(ref).

There are some tantalizing hints about how the mTOR pathway may relate to the other theories of aging.  For example, there are complex feedback interactions between the pathways involving NF-kappaB, mTOR and PI3K-Akt related to both treatment of cancers and longevity(ref).  A cancer treatment leads to simultaneous down-regulation of mTOR and telomerase activity in cancer cells(ref).  Inhibiting mTOR via rapamycin resulted in impairment of pluripotency and prevention of adult stem cell differentiation, among other effects(ref). As far as I can tell, however, discussions of human life extension via mTOR inhibition are at this point conjectural.  Based on what I have seen in fact, there have been no experiments so far to try mTOR inhibition for life extension on any mammals, even mice.  There are plenty of adverse effects associated with rapamycin, some possibly quite serious.  These are enough to throw cold water on any idea of healthy people using this substance in an effort to enhance their longevity

Does the mTOR story lend light on whether mitochondrial activity is more important than cell signaling or protection against oxidation damage for determining longevity?  The story actually lends light on the fact that this is the wrong kind of question to ask “Such notions are slowly giving way to a more nuanced view in which cellular signaling pathways intersect with the mitochondria, creating a two-way network of interactions between the consumer (the cell) and the supplier (the mitochondria) of energy(ref).” Instead of just focusing on the health of the inner operations of the cell or the mitochondria, perhaps we need to look more at what they are saying to each other.

So what does the mTOR story contribute to the longevity picture beyond what I have discussed before?  I see it as yet-another interesting area of the longevity puzzle still to be well-integrated with the other ones.

The most recent posts related to progeria diseases remind me again that when it comes to aging we seem to be dealing with different areas of a very large jigsaw puzzle where most of the pieces between the areas are still missing.  The best we can do is assemble different portions of the puzzle without worrying too much about how the portions will eventually fit together.   As we build those portions we find they have irregular shapes with holes in them where smaller collections of pieces are still missing.  We may have put together a portion of the puzzle and not know what it means – is the blue area sky, water or the side of a building?  Is the accumulation of progerin in cells with aging just another irrelevant buildup of a substance in cells with aging, a major cause of other aging effects, or what?  As we proceed we constantly keep looking for how one portion of the puzzle might be joined with another.  Being able to join up two major portions is a breakthrough event.  As time progresses a more and more coherent pattern emerges and the job gets easier.  If you have ever worked on a very large jigsaw puzzle you know what I mean.  

There are differences between the two kinds of puzzles, however.  You know what an assembled jigsaw puzzle looks like because the image is printed on the top of the box.  This image gives important color clues for putting the puzzle together.  And you know you the box should contain exactly the pieces you will need.  You know the pieces are accurately cut.  It might take a week off-and-on to finish a 3000 piece jigsaw puzzle but the job is finite. 

For the longevity puzzle we don’t know what the puzzle will look like when it is finished.  We have to be constantly fishing around in the world literature to find new pieces.  And some of the new pieces we find may be inaccurately shaped even if at first they seem to fit with some other pieces.  What works in a mouse study may not apply to humans.  If we put together a part of the puzzle with inaccurately shaped pieces that part won’t fit in with the rest of the puzzle and will eventually have to be taken apart and built over.  At any point, we don’t know how many pieces are still missing, and we don’t know whether we will live long enough to find them all. So, the longevity puzzle is open-ended and might take 5 years or a lifetime before the picture is reasonably clear.  What fun!

My last major post traced developments related to a form of progeria (premature aging) known as Hutchinson-Gilford progeria syndrome, or HGPS, for short.  The discussion and comments on this post are leading us down new paths, such as exploring the role of progerin and FTI therapies and seemingly away from the usual theories of aging.  There is also a different rare form of progeria known as Werner Syndrome (WS) that is worth looking at for what it might tell us about normal aging.

WS, sometimes called adult progeria, is characterized by the premature onset of age-related diseases, including inflammatory diseases, atherosclerosis and cancer.  People with WS may develop the symptoms of very old age by the time they turn 30 or 40, including “wrinkled skin, baldness, cataracts, muscular atrophy and a tendency to diabetes mellitus, among others(ref).”  Cells from people with WS when cultured have shorter life spans than cells from normal people.  “In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions(ref).”  It has recently been shown that WS is due to a mutation in a gene called WRN.  It is a hellicase deficiency disease.  Hellicases are enzymes important for many cellular processes including “DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis.”  Normally, the WRN gene “ functions as a key factor in resolving aberrant DNA structures that arise from DNA metabolic processes such as replication, recombination and/or repair, to preserve the genetic integrity in cells(ref).”

Unlike the case for HGPS, there appears to be a direct link between the aging mechanisms operating in WS patients and at least one of the usual theories of aging, the telomere shortning and damage theory. For example, regarding study of a mouse model of WS the authors write “Recent studies of the telomerase-Werner double null mouse link telomere dysfunction to accelerated aging and tumorigenesis in the setting of Werner deficiency. This mouse model thus provides a unique genetic platform to explore molecular mechanisms by which telomere dysfunction and loss of WRN gene function leads to the onset of premature aging and cancer(ref).”  Some researchers highlight the roles of cell senescence and telomeres in WS: “Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts(ref).”  Normal hellicase structures can be very important for assuring normal telomere structures(ref), a situation not present in WS.  Other researchers believe WS operates primarily through other than telomere erosion or damage:  “–  our data suggest that the abbreviated replicative life span of WS cells is due to a stress-induced, p38-mediated growth arrest that is independent of telomere erosion(ref).”

Looking for bridges between the genetic mechanisms operating in HGPS and those operating in WS:  1  It is easy to find commonality of end-results, specifically premature aging phenotypes like baldness, wrinkled skin and cardiovascular disease, and 2.  The underlying genomic mechanisms themselves are in the first instance quite different; they involve activation of different genes and the actions of different protein products. I do not see any easy “Ah hah, here is the common mechanism of aging involved in HGPS, WS and normal aging.”   Both HGPS and WS suggest means by which normal aging might work and possibly be slowed down, having to do with accumulation of progerin and possible treatment with FTIs in the case of HGPS, and having to do with P38, telomere shortening and telomerase activation in the case of WS.

HGPS, standing for Hutchinson-Gilford progeria syndrome is an extremely rare but well-studied genetic disease. Young children born with HGPS seem to age at an extraordinary rate, exhibit many of the symptoms of old age, become wrinkled and bald, are particularly vulnerable to cardiovascular diseases and usually die of a cardiovascular disease of old age by the age of 14.  Up until about five years ago neither the cause of the disease nor a cure were in sight.  Then a chain of exciting research developments emerged indentifying not only cause and possible cure but also what might amount to a new theory of normal aging.  The developments are complex and the puzzle is still far from complete.  I attempt to summarize them here in simple language and speculate on the implications involved.  I will study these matters further and embody this content into my Anti-Aging Firewalls treatise at some point, possibly as an extension of the 14^th theory, Decline in adult stem cell differentiation, possibly as a new 15^th theory.  So, here is the situation: 

1.    HGPS is caused by a mutation in the LMNA gene which is responsible for making lamin proteins which provide “scaffolding (supporting) components of the nuclear envelope, the structure that surrounds the nucleus in cells.”  The mutation produces a lamin that is “farnesylated but cannot be further processed to mature lamin A.(ref)”  That mutant farnesylated lamin is called progerin.  (Farnesylation is a post-translational chemical modification of a protein involving addition of a farnesyl group.) In progerin, a DNA sequence of 50 amino acids which would normally appear in the lamin is spliced out.

2.   Progerin targets itself to the nuclear envelope of a cell, “where it interferes with the integrity of the nuclear envelope and causes misshapen cell nuclei.” (ref),  There is strong reason to believe it is responsible for the symptoms of HGPS(ref).

3.   An obvious research idea was to see what could happen if the farnesylation of progerin was inhibited.  An exciting development was the discovery that, treating cells misshaped by the expression of progerin, inhibiting farnesylation with a farnesyltransferase inhibitor (FTI) could restore their normal cell shapes(ref,ref,ref,ref).  FTIs block the attachment of the farnesyl chemical group onto progerin. FTIs are a class of recently-developed anti-cancer drugs. 

4.   Sure enough and better yet, using the FTI  drug Tipifarnib (Zarnestra) in a progeria mouse model it was possible to prevent both the onset and late progression of cardiovascular disease(ref). This led to a hope that a cure for human HGPS might be based on use of an FTI.

5.   A clinical trial was launched on May 7, 2007 to test FTI therapy in HGPS patients(ref).  It was difficult finding patients because of the rarity of the disease.  Twenty eight children from 16 countries are participating and the trial is about halfway through.

6.   Progerin appears also to play possibly important similar roles in normal aging(ref).  Biochemical studies sugest that progerin may well cause similar effects in HGPS cells and normal cells and possibly a common molecular mechanism might underlie HGPS-type aging and normal physiological ageing. “Cell nuclei from old individuals acquire defects similar to those of HGPS patient cells, including changes in histone modifications and increased DNA damage.  Age-related nuclear defects are caused by sporadic use, in healthy individuals, of the same cryptic splice site in lamin A (progerin) whose constitutive activation causes HGPS. Inhibition of this splice site reverses the nuclear defects associated with aging(ref).”

7.   Supporting this idea, recent research indicates that progerin builds up in normal cells with age.  A powerful new technique has been developed for measuring the expression of the progeria gene. . A Swedish research group has found that both normal and progeria cells make larger and larger amounts of progerin RNA as they age(ref).

8.   Supporting this idea even further, research indicates that progerin creates all kinds of downstream biomolecular signaling mischief, including the introduction of errors in the normal differentiation of stem cells.  Progerin interferes with cell division in both HGPS and normal cells(ref).  In one key study(ref), the presence of progerin produced a profound impact on renewal and differentiation of adult mesenchymal stem cells, affecting the rates at which they mature into different tissues. “Our results support a model in which accelerated ageing in HGPS patients, and possibly also physiological ageing, is the result of adult stem cell dysfunction and progressive deterioration of tissue functions.”  

  There are strong hints here of important possibilities

:·        That a 15^th theory of aging exists, stating that aging is due to age-related accumulation of progerin in normal cells which creates age-related damage of all kinds similar to that observed in HGPS and inhibits the normal differentiation of adult stem cells into normal cells.  At present I am not sure the extent to which such progerin accumulation is the cause of or the result of other age-related collateral damage and how serious its impact is.·        That it may be possible to design a therapeutic intervention for normal aging based on use of FTIs.  I am not sure how safe it is to use these for anti-aging purposes  given that farnesylation is important for protein binding and happens as part of normal biochemical body functioning.  I have seen no research on the impacts taking FTIs may have on normal old people or even normal old mice for that matter.

I will be thinking about these matters further and on the lookout for additional research results.  You can expect to hear from me on this subject again soon.

Please chime in!

I have wonderful memories of spending summers at a rustic cottage on tiny Pleasant Lake in Michigan with my aunt Lila and my Uncle Gigi D’Augistino, back when I was a child in the 30s.  Gigi loved his red wine and would sprinkle dried red peppers generously over his pasta.  He would explain that his two doctors constantly gave him conflicting advice.  Dr. Gigante, our family’s traditional Italian-trained doctor, would tell Gigi that if he drank one or two glasses of red wine with every meal and partake of the capsicum pepper he would live a long and healthy life.  His modern American doctor told him that unless he cut out the wine and pepper he would surely die of stomach cancer.  Both doctors turned out to be right.  He died of stomach cancer back around 1965 I would guess at the age of 79, living a long life for back at that time.

Back in the 30s, health effects of red wine and hot peppers only existed in oral folk medicine.  There were no biomolecular theories of what these substances might do, animal experiments or clinical trials.  It was enough for Dr. Gigante to say “Red wine and hot peppers will aid your digestion and might help you live longer.”  Now of course we know about the polyphenols like resveratrol that exist in red wine and have a fairly good picture of how some of them limit inflammation, control apoptosis, fight cancers, affect “longevity genes,” and so forth.  A conflict about the longevity effects of wine still exists (see this post) but without any doubt red wine contains biochemical ingredients that are definitely health-promoting and potentially life-extending.

So much for red wine.  Now how about the red peppers?  It appears that a similar story exists.  Capsicum, the main ingredient in hot peppers, apparently can induce apoptosis in cancer cells (ref)(ref).  The American doctor back in the 30s was telling Gigi  the opposite of what was right about his pepper habits and cancer risk.  “It has been shown to exert biological activities (anticarcinogenic, antimutagenic and chemopreventive) in many cancer cell lines(ref).”  Red peppers are turning out to be hot stuff for cancer prevention.  Oh, a final note for any of you worrying about end-burns.  “There is no scientific evidence that a spicy meal based on red hot chili pepper may worsen hemorrhoidal symptoms and, therefore, there is no reason to prevent these patients from occasionally enjoying a spicy dish if they so wish.(ref)”   

Hmm. I am yearning for a good plate of pasta with meat sauce sprinkled with red peppers tonight!

As time rolls on and new research studies roll in, there appears to be more and more evidence for key role of the nuclear binding factor NF-kappaB in aging.  I have listed some updates on this subject in a previous blog post and treat it in my Anti-Aging Firewalls treatise under the Programmed epigenomic changes theory of aging.  I provide some additional thoughts and research citations on this important subject in this post.

First of all, a bit of additional clarification on what NF-kappaB is.  NF-kappaB  is not a single molecular substance but is “a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif”(ref).  What these proteins share in common is a motif, e.g. a characteristic DNA binding sequence.  In simple language NF-kappaB is a collection of proteins that can profoundly affect the transcription of DNA, that is the production of messenger RNA and the subsequent productions of proteins encoded by DNA.  It can target over 200 human genes in different kinds of cells.  It has positive roles in maintaining health and also can create disease conditions and accelerate aging.

According to a key study, the gene sequence motif most closely associated with aging is that of NF-KappaB.   “NF-kappaB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogramming of gene expression(ref). It is a very rapidly-acting substance, a “first responder” to harmful cellular stimuli.  NF-kappB tends to be plentiful in cells of older people. 

Normally, NF-kappaB lives in the cytoplasm of cells where it is bound up and kept out of the nucleus by a family of substances called IkB (inhibitor of kappaB).  When a harmful extracellular stimulus is perceived, the IkB inhibitor molecules are modified by a process called ubiquitination and destroyed by cellular processes known as proteolysis(ref).  The result is that the NF-kappaB is freed to translocate into the nucleus where it can bind to a variety of genes, activate them and produce a variety of impacts including vicious pro-inflammatory ones.  These processes are in fact quite complex involving many proteins, adapter, promoter and co-activator factors.

“Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate NF-kappaB activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1(ref).”   NF-kappaB plays a wide variety of roles going far beyond control of inflammation.  The aging process appears to involve changes in immune regulation and, among other things, NF-kappaB appears to be the master regulator of both the adaptive and the innate immune systems(ref). 

There is a large amount of research going on, basically focused on how inhibiting the expression of NF-kappaB can be used to prevent or control cancers, cardiovascular diseases and other inflammatory-related disease processes.  On a molecular level, there seems to be three possible strategies: 1 prevent the unbinding of NF-kappaB from IkB, 2, inhibit the translocation of NF-kappaB into the nucleus of cells, and 3.  prevent the activated NF-kappaB from binding onto and activating genes.  In a previous post I described an important experimental substance DHMEQ which acts through the second approach to inhibit the expression of NF-kappaB.  The third approach generally involves histone deacetylation.  That is, it involves coiling up the DNA in the neighborhood of genes so that those genes are not accessible for activation by the NF-kappaB. This appears to be the main mechanism used by curcumin, resveratrol and other dietary polyphenols for inhibition of gene activation by NF-kappaB(ref). 

I remind my reader that 39 of the supplements in my Anti-Aging Firewalls regimen are inhibitors of NF-kappaB expression.  Most of them work through this third mechanism.

One key challenge is finding therapeutic interventions that distinguish between the component NF-kappaB transcription factors: p50, p52, p65 (RelA), c-Rel, and RelB.  The research literature related to NF-kappaB is rapidly growing and increasingly difficult to follow.  A recent and excellent review and synthesis article can be found here.

The title of this post does not suggest a very noble undertaking. If a fruit fly has Parkinson’s- like shakes, so be it.  Who should care about the health of these pesky creatures and why?  A study reported in the May edition of Cell Metabolism suggests the answer.  The researchers introduced a gene called AOX into fruit flies (drosophila melanogaster), a gene that is found in a number of primitive species but not fruit flies, humans or other vertebrates for that matter.  We have lost the gene over the course of our evolutionary history.  The AOX gene reduced the number of free radicals and free radical damage in the mitochondria of the fruit flies, alleviated their Parkinson-like symptoms, and protected the flys from cyanide and other toxins.  There seemed to be no negative side effects to introducing the gene.   The gene affects mitochondrial electron chain transfer.  It “in essence acts as a bypass for blockages in the so-called oxidative phosphorylation (OXPHOS) cytochrome chain in mitochondria, ” a chain central to energy metabolism (ref)  That chain involves hundreds of proteins and complex interactions, but it appears that this single gene can significantly affect the whole chain.  The researchers had previously inserted the AOX gene into individual human cells and established that it found its way into the mitochondria where it was stress-protective.  The current study establishes the protectiveness of AOX for a whole organism – the fruit fly.  AOX is known to be related to longevity in some lower species.  If the approach worked for humans – restoring a historical gene to the genome that was deleted in the course of evolutionary history – benefits in both treating mitochondrial-related diseases and life extension might be realized.  Of course, experimentation must be done with caution.  The gene would have to be taken from the DNA of some lower species before it is inserted into human DNA.  Remember the horror-thriller B movie The Fly?

It has long been known that females tend to outlive males.  I have only to look at my own family’s history to see how that kept happening.  And apparently this also happens in a variety of other species as well. People have asked me “why?”  The best explanation seems to have to do with hormones and our old friends: longevity genes, antioxidants and mitochondria.  In this paper, the Spanish authors trace the phenomenon to “the beneficial action of estrogens, which bind to estrogen receptors and increase the expression of longevity-associated genes, including those encoding the antioxidant enzymes superoxide dismutase and glutathione peroxidase. As a result, mitochondria from females produce fewer reactive oxygen species than those from males.”  Looking at rats, “Oxidative damage to mitochondrial DNA in males is 4-fold higher than that in females(ref).”  Also see ref.  Estrogens are not particularly good for males.  However, I speculate we males might get some of the same longevity benefits by taking anti-oxidant combinations that strongly affect the mitochondria, like Co Q-10, actyl-l-carnitine and alpha-lipoic acid(ref).