AGINGSCIENCES™ – Anti-Aging Firewalls™

In anti-aging blog circles the answer seems to be YES, causing endless discussion of how people who want to take these substances and the telomerase activator astragaloside IV should time their doses so the effect of the expensive telomerase activator is not cancelled out.  But what does the actual research say?  I decided to spend a few hours having a fresh look at this question.  Personally, I have resistance to forgoing the cancer protection and other benefits of resveratrol, curcumin and other phyto substances for days at a time in order to benefit from the astragaloside IV.  I decided to focus on published experimental research results, not opinions.

To start with, as far as cancer cells are concerned the answer to the question seems definitely to be YES.  Here are a few of the many relevant citations: “Resveratrol down-regulates the growth and telomerase activity of breast cancer cells in vitro(ref),” “Effect of resveratrol on proliferation and telomerase activity of human colon cancer cells in vitro(ref).” “Curcumin inhibits telomerase activity in human cancer cell lines(ref),” “Curcumin-induced apoptosis in human leukemia cell HL-60 is associated with inhibition of telomerase activity(ref), Inhibition of telomerase activity and induction of apoptosis by curcumin in K-562 cells(ref),” “Molecular mechanism of curcumin induced cytotoxicity in human cervical carcinoma cells(ref),”  “EGCG down-regulates telomerase in human breast carcinoma MCF-7 cells,” leading to suppression of cell viability and induction of apoptosis(ref).” The tea polyphenols EGCG and EGC repress mRNA expression of human telomerase reverse transcriptase (hTERT) in carcinoma cells(ref).”  “Epigenetic and genetic mechanisms contribute to telomerase inhibition by EGCG(ref).” 

This is just a starting list of research studies for each of these substances that make two central points:  1. The substance leads to apoptosis in the cancer cell line studied, and 2. The substance down-regulates the expression of telomerase in that cancer cell line.  In other words the substance down-regulates the expression of telomerase induced by the cancer itself and leads the cancer to kill itself.  Note that these substances do NOT lead to apoptosis in normal cells.   

Although the research seems to be sparser for other phyto substances in my anti-aging firewalls regimen that are reputed to inhibit telomerase expression [like ginkgo biloba and ashwagandha (Withania somnifera)], the same two central points seem to apply to them as well.

So, what makes us think these substances down-regulate the expression of telomerase in normal cells?  Looking into that question, my first observation is that while there is a great deal of research linking the listed substances to telomerase inhibition in cancer cells, there is very little to no such research on how those substances relate to exogenously activated telomerase in normal cells.  A few studies jump out suggesting that these substances may do the opposite: promote telomerase activity at least in progenitor cells.  For example: “Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms(ref),” “Immortalization of epithelial progenitor cells mediated by resveratrol(ref), “Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity(ref).” A review study on cell growth regulation states “In addition, curcumin also exerts indirect control over cell division such as inhibition of telomerase activity. Remarkably, some studies point toward a selective growth-inhibitory effect of curcumin on transformed cell lines compared to nontransformed cell lines(ref).”

The bottom line of my mini-review is that I found:

1.   What appears to be many dozens or hundreds of articles that answer YES to the question in terms of experimental results but only for cancer cells,

2.   Several statements of YES opinion for normal cells, including opinions from reputable researchers, but without backup experimental evidence.

3.   Virtually NO actual experimental research studies that say YES for normal cells.  Such may well exist.  It is just that I could not find them in the time I set aside for looking.  My guess is that the opinions come from assuming that telomerase-inhibiting research on cancer cells applies to normal cells as well.

4.   A few experimental studies that definitely say NO for normal progenitor cells. At lease resveratrol and ginko activates telomerase expression in some progenitor cell lines.

My personal answer to the question is “I don’t know because there is no published research on what these substances do in normal cells when combined with a telomerase activator.  There seems to be no evidence for answering YES in the case of normal cells and some evidence for answering ‘NO, the opposite is true.’”  So I am not going to worry too much about taking resveratrol, curcumin, green tea, etc. the same day I take astragaloside IV.  Besides, it all seems to be working.  See my recent post How am I doing?

Suppose a simple genetic fix could allow us humans to gorge on fatty junk foods and avoid obesity.  Something like that has been tried on mice and apparently works according to research reported today(ref).  The idea was to introduce a plant-based genetic pathway in mice that increases metabolism of fatty acids and induces resistance to diet-related obesity.  Certain plants have a set of enzymes called the ‘glyoxylate shunt’ not present in mammals.  A team at UCLA “ —  cloned bacteria genes from Escherichia coli that would enable the shunt, then introduced the cloned E. coli genes into the mitochondria of liver cells in mice; mitochondria are where fatty acids are burned in cells.” 

“The researchers found the glyoxylate shunt cut the energy-generating pathway of the cell in half, allowing the cell to digest the fatty acid much faster than normal.  “Mice expressing the shunt showed resistance to diet-induced obesity on a high-fat diet despite similar food consumption. This was accompanied by a decrease in total fat mass, circulating leptin levels, plasma triglyceride concentration, and a signaling metabolite in liver, malonyl-CoA, that inhibits fatty acid degradation(ref).”

I imagine a similar approach might well work in humans, making us genetically a little more like plants.  I anticipate concerns about the practicality, safety and ethical aspects of such genetic modifications of humans, although the fast food people would probably love to see this one happen.  And it could be a great approach to solving the current obesity epidemic.

A year after first publishing the online treatise Anti-Aging Firewalls – The Science And Technology Of Longevity and six months after initiating this blog, it’s a good time to ask the question “How am I doing with my anti-aging firewalls program?”   First, there is the personal subjective response.  Coming up on 80:

·        I am experiencing high energy, good health and am feeling good about life.

·        My creativity, productivity, ability to think things through and social participation are as high as ever.

·        My level of activity including physical exercise remains high.

·        In photos, I look about the same age as in ones taken 10-20 years ago.

·        I pass my cholesterol, CRP and other annual blood tests and physical exam procedures with flying colors.

·        Compared to a year ago I believe my sexual libido is a bit increased, and my eyesight a bit better and keener.   

·        On the other hand, my hearing has gone a bit downhill.

·         There is definitely more grey hair growing on the top of my scalp now.  I started balding before 50 and there were hardly any hairs left on top a year ago.  At the current rate in another 18 months I will have a full head of hair again, for the first time since I was about 50.  

So, on the whole I feel very good about my anti-aging program so far.  Telomerase activation was one of the big changes in the last year and I think it might largely be responsible for some of the effects including improved eyesight and hair growth.   

From an intellectual viewpoint, I am also satisfied about how my view of aging has been maturing.  Devoting countless hours to reviewing the aging-related research literature, writing over 90 posts in this blog and generating numerous enhancements to my treatise, I have been learning a lot about the advanced sciences that are informing us about aging.  And, drawing on different viewpoints I have been increasingly seeing aging from a systems perspective.   

All of this is just a start though.  I not only want a full head of hair; I want it to be black instead of grey.   I want to look and move and hear like I did when I was 45.  And there is tons more for me to learn about biochemistry, molecular biology, genetics, genomics and the other omics.  And progress over the last year has sharpened my thirst for more basic breakthroughs, more understand of how the theories of aging interrelate and better anti-anti-aging interventions.  Please stay tuned.  There will be more.

In this blog and in my treatise Anti-Aging Firewalls – The Science And Technology Of Longevity I try to steer a mid course between scientific over-simplification and loosing readers because the content is too technical for them to fathom.  I am aware that many readers possibly have to struggle to follow the details of some of my posts.  The purpose of this particular post is to remind my reader that longevity science involves biomolecular and genetic complexity that is much deeper than what I discuss, or for that matter, that I am competent to discuss. 

It is pretty much agreed that extraordinary longevity will require activation of critical longevity-related cell signal transduction pathways. Yet, those pathways are incredibly complex.  As an example, here is a listing of papers in the current online issue of the Journal of Biological Chemistry having to do with Mechanisms of Signal Transduction.  I list the titles to illustrate the naked underlying complexity involved.  And there are thousands of other journals reporting research results every month of equal complexity that have potential relevance for longevity.  I am not suggesting you read these items but you might find the titles interesting for illustrating the biomolecular detail involved.  I am necessarily highly selective in what I cover in this blog. 

Subhashini Srinivasan, Fozia Mir, Jin-Sheng Huang, Fadi T. Khasawneh, Stephen C.-T. Lam, and Guy C. Le Breton The P2Y₁₂ Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a G_i-independent Increase in cAMP Levels.  J. Biol. Chem. 2009 284: 16108-16117. First Published on April 3, 2009; doi:10.1074/jbc.M809780200 [Abstract] [Full Text] [PDF] 

Matthew J. Betzenhauser, Larry E. Wagner, II, Hyung Seo Park, and David I. Yule ATP Regulation of Type-1 Inositol 1,4,5-Trisphosphate Receptor Activity Does Not Require Walker A-type ATP-binding Motifs
J. Biol. Chem. 2009 284: 16156-16163. First Published on April 22, 2009; doi:10.1074/jbc.M109.006452 [Abstract] [Full Text] [PDF]  

Xiang Li, George S. Baillie, and Miles D. Houslay Mdm2 Directs the Ubiquitination of β-Arrestin-sequestered cAMP Phosphodiesterase-4D5.  J. Biol. Chem. 2009 284: 16170-16182. First Published on April 16, 2009; doi:10.1074/jbc.M109.008078 [Abstract] [Full Text] [PDF] [Data Supplement 1]  

Chunmei Wang, Runzi Qi, Nan Li, Zhengxin Wang, Huazhang An, Qinghua Zhang, Yizhi Yu, and Xuetao Cao Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 Degradation and Up-regulating p53-dependent DR5 Expression
J. Biol. Chem. 2009 284: 16183-16190. First Published on April 17, 2009; doi:10.1074/jbc.M109.002105 [Abstract] [Full Text] [PDF] [Supplemental Data] 

Kam-Leung Siu, Kin-Hang Kok, Ming-Him James Ng, Vincent K. M. Poon, Kwok-Yung Yuen, Bo-Jian Zheng, and Dong-Yan Jin Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKK Complex
J. Biol. Chem. 2009 284: 16202-16209. First Published on April 20, 2009; doi:10.1074/jbc.M109.008227 [Abstract] [Full Text] [PDF]  

David Grandy, Jufang Shan, Xinxin Zhang, Sujata Rao, Shailaja Akunuru, Hongyan Li, Yanhui Zhang, Ivan Alpatov, Xin A. Zhang, Richard A. Lang, De-Li Shi, and Jie J. Zheng Discovery and Characterization of a Small Molecule Inhibitor of the PDZ Domain of Dishevelled
J. Biol. Chem. 2009 284: 16256-16263. First Published on April 21, 2009; doi:10.1074/jbc.M109.009647 [Abstract] [Full Text] [PDF] 

Philip J. Dittmer, Jose G. Miranda, Jessica A. Gorski, and Amy E. Palmer Genetically Encoded Sensors to Elucidate Spatial Distribution of Cellular Zinc
J. Biol. Chem. 2009 284: 16289-16297. First Published on April 10, 2009; doi:10.1074/jbc.M900501200 [Abstract] [Full Text] [PDF] [Supplemental Data]  

Sandra Mueller, Gunnar Kleinau, Mariusz W. Szkudlinski, Holger Jaeschke, Gerd Krause, and Ralf Paschke The Superagonistic Activity of Bovine Thyroid-stimulating Hormone (TSH) and the Human TR1401 TSH Analog Is Determined by Specific Amino Acids in the Hinge Region of the Human TSH Receptor
J. Biol. Chem. 2009 284: 16317-16324. First Published on April 22, 2009; doi:10.1074/jbc.M109.005710 [Abstract] [Full Text] [PDF]  

Alyson C. Howlett, Amy J. Gray, Jesse M. Hunter, and Barry M. Willardson Role of Molecular Chaperones in G Protein β5/Regulator of G Protein Signaling Dimer Assembly and G Protein β Dimer Specificity
J. Biol. Chem. 2009 284: 16386-16399. First Published on April 17, 2009; doi:10.1074/jbc.M900800200 [Abstract] [Full Text] [PDF]    

Petri Ala-Laurila, M. Carter Cornwall, Rosalie K. Crouch, and Masahiro Kono The Action of 11-cis-Retinol on Cone Opsins and Intact Cone Photoreceptors
J. Biol. Chem. 2009 284: 16492-16500. First Published on April 22, 2009; doi:10.1074/jbc.M109.004697 [Abstract] [Full Text] [PDF]    

Rosalyn P. Johnson, Ahmed F. El-Yazbi, Morgan F. Hughes, David C. Schriemer, Emma J. Walsh, Michael P. Walsh, and William C. Cole Identification and Functional Characterization of Protein Kinase A-catalyzed Phosphorylation of Potassium Channel Kv1.2 at Serine 449
J. Biol. Chem. 2009 284: 16562-16574. First Published on April 22, 2009; doi:10.1074/jbc.M109.010918 [Abstract] [Full Text] [PDF]  

Jonathan Barroso-González, Nabil El Jaber-Vazdekis, Laura García-Expósito, José-David Machado, Rafael Zárate, Ángel G. Ravelo, Ana Estévez-Braun, and Agustín Valenzuela-Fernández The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities
J. Biol. Chem. 2009 284: 16609-16620. First Published on April 22, 2009; doi:10.1074/jbc.M109.005835 [Abstract] [Full Text] [PDF] [Supplemental Data]  

  Mohammad Husain, Leonard G. Meggs, Himanshu Vashistha, Sonia Simoes, Kevin O. Griffiths, Dileep Kumar, Joanna Mikulak, Peter W. Mathieson, Moin A. Saleem, Luis Del Valle, Sergio Pina-Oviedo, Jin Ying Wang, Surya V. Seshan, Ashwani Malhotra, Krzysztof Reiss, and Pravin C. Singhal Inhibition of p66ShcA Longevity Gene Rescues Podocytes from HIV-1-induced Oxidative Stress and Apoptosis
J. Biol. Chem. 2009 284: 16648-16658. First Published on April 21, 2009; doi:10.1074/jbc.M109.008482 [Abstract] [Full Text] [PDF]  

Evgeny A. Zemskov, Elena Loukinova, Irina Mikhailenko, Richard A. Coleman, Dudley K. Strickland, and Alexey M. Belkin Regulation of Platelet-derived Growth Factor Receptor Function by Integrin-associated Cell Surface Transglutaminase
J. Biol. Chem. 2009 284: 16693-16703. First Published on April 22, 2009; doi:10.1074/jbc.M109.010769 [Abstract] [Full Text] [PDF] [Supplemental Data]   

Research reports continue to appear that identify linkages between theories of aging I have covered in the treatise Anti-Aging Firewalls – The Science And Technology Of Longevity.  The latest shows a link between the Telomere shortening and damage, the Programmed epigenomic changes, the Susceptibility to cancers and the Decline in adult stem cell differentiation theories.  The common element is epigenetic modification in the Ink4a-Arf locus.  These genes encode the proteins P16(Ink4a) and P19(Arf) which prevent inactivation of the tumor suppressor RB, and P19ARF, which stabilizes the tumor suppressor P53.    

According to the Telomere shortening and damage theory, when telomeres in somatic cells become too short as a result of successive cell divisions the cell is likely to go into a state of cell senescence where it can no longer divide and does not die. Senescent cells tend to strongly express the anti-cancer genes P16(INK4a) and P19(Arf).   So, these genes offer senescent cells an alternative to becoming malignant.  But senescent cells are likely to become bad neighbors sending out signals that can lead to organ dysfunction or degeneration.  Further, in discussing the Programmed epigenomic changes theory,   I mentioned how p16(INK4a) tends to be increasingly expressed with age and how it tends to inhibit the differentiation of adult stem and progenitor cells.  Thus, P16(INK 4a) plays a central role in the Decline in adult stem cell differentiation theory.  Also, it “induces an age-dependent decline in islet regenerative potential(ref).” Increasing expression of P16(INK4a) with age therefore tends to compromise organ repair and regeneration. P16(INK4a) provides a central defense against cancer in the case of senescent cells and is therefore important in the Susceptibility to cancers theory of aging.  

There is another side to cell senescence, however:   “Senescent cells, particularly senescent stromal fibroblasts, secrete factors that can disrupt tissue architecture and/or stimulate neighboring cells to proliferate. We suggest that senescent cells can create a tissue environment that synergizes with oncogenic mutations to promote the progression of age-related cancers(ref).”  I have mentioned the paradoxical role of P16(INK4a) in the Blog post Dr. Jekyll and-Mister Hyde Proteins. The new research, reported in a publication entitled Polycomb Mediated Epigenetic Silencing and Replication Timing at the INK4a/ARF Locus during Senescence provides a new link between the theories and hints at anti-aging intervention that can address all of these theories. 

The language of the publication like the title is highly technical, so I attempt a simplified explanation of the basic findings here.  Basically, in young cells, Polycomb group proteins act on the INK4/ARF gene regulatory domain so as to the keep the expression of P16(INK4a) turned off, the gene is silenced.  In senescent cells, however, there are epigenetic modifications (DNA and histone methylation changes) which block the inhibitory actions of the polycomb group proteins, so the P16(INK4a) and Arf genes are activated.  So, cell senescence leads to another pro-aging effect, the activation of the P16(INK4a) and Arf genes. Earlier, in the Anti-Aging Firewalls treatise I identified the increasing expression of P16(INK4a) with aging as a biomarker of aging and possible cause of age-related changes.  In fact, I identified this as possibly one of the major aging mechanisms according to the Programmed epigenomic changes theory.  At that time, however, I had no notion of how possibly to slow or halt the accumulation of INK4/ARF with age. 

The new results suggest two possible routes of intervention.  The first is to slow or stop cell senescence, something I am already attempting to do.  Since too-short telomeres is the primary cause of such senescence, according to the new research telomerase activation may address both the cell senescence and the accumulation of P16(INK4a) issues.  Personally, I am increasing my daily dose of Astragaloside IV to the 100mg a day provided in the new version of the Astral Fruit supplement. 

A second kind of possible anti-aging intervention with respect to slowing buildup of P16(Ink4a) with age comes to my mind as well.  It is to halt or block the cell and histone demethylation and deactylation patterns associated with cell senescence, specifically the histone deactylation patterns in senescent cells that are associated with blocking the inhibitory actions of Polycomb  proteins on expression of P16(Ink4a).  The molecular biology involved in this particular instance is quite complex(ref).  But it could be that histone deactylase promoters could be useful to limit the expression of P16(Ink4a).  See the recent blog post Histone acetylase and deacetylase inhibitors.  This is a speculation on my part but there could be something to it. 

Here is how it might work.  Suppose your child is born with an incurable disease due to a mutated gene.  After diagnosis, the cure would go like this:  Step 1: hair, blood or skin cells are collected from the patient and allowed to replicate.  This is a standard laboratory procedure. Step 2: the mutated genes in cells in the sample are replaced with corresponding normal genes.  This step involves using techniques from the field of gene therapy.  Several possible methods are being researched for deleting and introducing new genes.  Step 3: the cells are reprogrammed to create induced pluripotent cells, iPS cells that for all practical purposes are like patient-specific embryonic stem cells.  Reprogramming of any cells to pluripotent state, was discussed in a previous post on this blog, Rebooting cells and longevity. The resulting iPS cells are functionally equivalent to  the patient’s original stem cells, but no longer have the genetic defect.  They can differentiate into any cell type given the correct signaling conditions.  Step 4:  The iPS cells are introduced back into the body in such a way as to regenerate organs free of the disease.  For example, if an organ such as the heart has been damaged by the disease, the iPS cells could be introduced so as to regenerate healthy heart tissue.  While some success has been achieved with mice, Step 4 will require significant disease-related research if it is to be used in humans.  Introducing iPS cells into a live organism can lead to tumors such as teratomas if the signaling conditions are not correct.     

Research reported a few days ago shows that for one human genetic disease, Fanconi anemia (FA), steps 1-3 have been successful.  “FA is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C(ref).”  “Caused by mutations in one of 13 Fanconi anemia (FA) genes, the disease often leads to bone marrow failure, leukemia, and other cancers(ref).” 

The researchers started by collecting hair and skin cells from FA patients, and they ended up producing patient-specific iPS cells that were cured of FA.   Since blood cells are some of the worst affected by FA, they “tested whether patient-specific iPS cells could be used as a source for transplantable hematopoietic stem cells. They found that FA-iPS cells readily differentiated into hematopoietic progenitor cells primed to differentiate into healthy blood cells(ref)”  The researchers have set their sights on going forward to achieve Step 4. 

The prospect is for a simple and elegant approach to treating many, perhaps most, genetic diseases.  

Some time ago I posted an item Everything relates to everything else – at least in the science of longevity.  Recent research shows that applies to epigenomic information.  For some time it has been known that epigenomic information can be stored as either patterns of DNA methylation or in the form of histone modifications.  See the earlier posts Epigenetics, epigenomics and aging, DNA methylation, personalized medicine and longevity and Histone acetylase and deacetylase inhibitors.  Both DNA methylation and histone modification can serve to silence genes and play important roles in the development of an organism. One paper comments “These modifications seem to be programmed for carrying out two separate biological functions: histone methylation blocks target-gene reactivation in the absence of transcriptional repressors, whereas DNA methylation prevents reprogramming to the undifferentiated state(ref).”    Apparently, there can be significant crosstalk between these two forms of data storage. “It has recently become apparent that DNA methylation and histone modification pathways can be dependent on one another, and that this crosstalk can be mediated by biochemical interactions between SET domain histone methyltransferases and DNA methyltransferases. Relationships between DNA methylation and histone modification have implications for understanding normal development as well as somatic cell reprogramming and tumorigenesis(ref).”

A recent article*  appearing in Scientific American magazine points to several developments coming together to transform the practice of medicine as we know it.  I cover a few of the key points here and comment on their implications for both the practice of medicine and longevity.   

At some point in time, perhaps starting around 2025 certain key practices will be in place including: 

·        The practice of medicine will focus much more on prevention, anticipation of disease susceptibilities and taking early actions for disease avoidance by utilizing a wealth of information about an individual’s genetic makeup and health state at the moment in a systems context.  Specifically: 

o   It will economical and practical for individuals to have their entire genomes sequenced and kept on file.  Cost may be less than a few hundred dollars and virtually everybody will do this.  

o   It will be economical and practical to take snapshots at any given time of up to hundreds of thousands of  protein and mRNA (messengerRNA) molecules that are characteristic of the absence, presence or emergence of  most major known disease conditions in most organs.  No matter where the problem may be, much information as to disease states flows freely in the blood as mRNA and protein molecules and a single droplet of blood is all that are needed for testing.

·        Sophisticated computer models will exist that relate both an individual’s SNP gene variations and critical observed mRNA and protein-level patterns to disease susceptibilities, the state of health of an individual, the possible emergence of any disease condition, or the early-stage existence of a disease that is not yet overtly manifest. Medicine will become a systems science where diseases and disease susceptibilities are observable as signature molecular patterns.  The entire process of blood analysis and disease condition analyses and predictions will be automated and cheap.

·        The most important medical interventions will be preventative ones, taking actions early before serious diseases become manifest rather than trying to repair a situation where much of the damage is already done.  Costs for prevention will be vastly lower than later costs for treatment.

·        The result will be a much healthier longer-living population and much lower average health care cost. What is needed to get there?  Several things:

·        Great reduction in the cost of sequencing entire individual genomes.  The cost of sequencing has been following a version of Moore’s law (every year, cost of a given sequencing task drops by half), and if this trend continues sequencing an entire genome for a few hundred dollars will be practical in less than 10 years.

·        Technologies that allow massive scale mRNA and protein screening at very low cost.  It is likely that microfluidic chips will play a major role here, and these also are showing price-performance improvements according to a version of Moore’s law.   Critical to this path in evolution of medicine is “the extreme miniaturization of technologies for making diagnostic measurements from minuscule amounts of blood or even single cells taken from diseased tissues. These emerging tools, constructed at the scale of microns and nanometers (billionths of a meter), can manipulate and measure large numbers of biological molecules rapidly, precisely and, eventually, at a cost of pennies or less per measurement. That combination of cost and performance opens up new avenues for studying and treating disease by permitting the human body to be viewed as a dynamic system of molecular interactions(ref).”

·        Much additional research and computer modeling relating SNPs, critical protein and MRNA levels to disease susceptibilities, pre-disease and disease conditions and embodiment of this research into sophisticated predictive models. Therapeutic models are needed as well. It may take over a century for this task to be completed but I expect work should be well along in by 2025.

·        Much more personal participation in health related activities.

·        A context of proactivity for taking actions to protect against disease conditions before they are manifest.

·        A change in the model of practice of medicine will occur to focus on the five  Ps, personalization, prediction,  prevention, participation and proactivity It may take over a century for this task to be completed but the shift should be well underway in 15 years.  It is interesting that those of us concerned with extending our lives in a context of health are already there with most of these Ps.  What we are missing are good tools for prediction and personalization. 

An analogy can be made between maintaining health and keeping an automobile running well.  In 1952 you brought your car into a garage when it had a serious problem and tried to get it repaired.  That is what most medicine is like today.  A three year-old car with 50,000 miles was an old car headed soon for the junkyard.   If your brakes fail on the highway – well, too bad!   Now you bring in your car for scheduled maintenance and the mechanic with the aid of inboard computers checks for hundreds of possible problems.  You fix them before they become manifest.  If your brakes have recently been checked out with care, there is much less a chance they will fail on the highway.  That is like what medicine is becoming.  As to longevity, a three year-old Toyota or Honda with 50,000 miles today still has most of the value of a new car and is only a third of the way through its lifetime.  The age of 65 was once old; it is becoming mid-life and, if I am right about life extension, at some point will be seen as young.  You have to bring a car into a garage for an unforeseen problem rarely until the car gets very old.  The same should become true for hospital stays.  (Of course, improved quality of auto construction has a lot to do with the changed auto picture too, but the analogy still stands.)  

* The Feb 2009 Scientific American article is entitled Nanomedicine–Revolutionizing the Fight against Cancer, by  James R Heath, Mark E Davis and Leroy Hood.  It was interesting to me in that it brings forward the points covered above.

Readers, please don’t turn off on this post because the subject sounds too technical.  It relates to a major application area of epigenomics that has a lot to do with aging and anti-aging science.

First, a simplified review of a few key concepts.  Histones are spindles in a cell’s nucleus around which DNA is wrapped; they play important roles in gene activation.  Histone acetylation is a chemical modification of a portion of a histone which leads to selective unwrapping of the DNA making the exposed genes amenable to activation and expression.  Histone deacetylation is the opposite.  It is done by histone deacetylases and wraps up the DNA making the associated genes unreachable by activating proteins and therefore less amenable to expression.  Gene transcription is repressed.  Histone deacetylase inhibitors  prevent the actions of histone deacetylases, that is, they keep the DNA unwrapped and available for gene expression.  The enzymes controlling the state of histone acetylation in vivo are histone acetyltransferase (HAT) and histone deacetylases (HDAC).  HDAC enzymes catalyze the removal of acetyl groups from the amino-terminal lysine residues of core nucleosomal histones.  The result is gene silencing.  Exactly how the HAT and HDAC enzymes work is complex and only partially understood(ref).  There is a whole mammalian HDAC gene family and a corresponding HAT gene family. Patterns of histone acetylation are part of the epigenomic history of a cell.  For background see my previous posts Epigenetics, epigenomics and aging and DNA methylation, personalized medicine and longevity.  

One reason for the current interest in HAT and HDAC is that histone deacetylase inhibitors appear to act as powerful inducers of differentiation or apoptosis in cancer cells.  See this earlier review article and check out some of the articles citing it, particularly the more recent ones. It appears that inhibiting HDAC may become an important weapon in anti-cancer therapies(ref,ref).  HDAC inhibition may be effective against some skin cancers and leukemias.  HDAC inhibitors are reported to show promise against head and neck cancer.  The applications of HDAC and HAT inhibition extend to other medical conditions beyond cancers.   HDAC inhibitors may be useful for damping down the immune response in patients receiving bone marrow transplants(ref)(ref).   On another front. recent research suggesting that microRNAs and over-activity of histone deacetylases may be root causes of the auto-immune disease systemic lupus erythematosus (SLE).  The cited article reports there is “further rationale for the use of histone deacetylase inhibitors (HDIs) for the treatment of lupus.”  Further the researcher Nilamadhab Mishra is reported to be investigating “– two HDIs — TSA (Trichostatin A) and SAHA (suberoylaniide hydroxamic acid ) — in lupus patients and has reported positive results against a number of lupus symptoms and conditions.”   

Histone acetylation and deacetylation are implicated in a number of the theories of aging treated in my  ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY treatise, We find a number of HAT and HDAC inhibitors in the  anti-aging firewall dietary regimen.  (E )-Resveratrol appears to inhibit histone deacetylase activity in a concentration-dependent manner according to a recent research publication.  The publication suggests that for this reason, resveratrol “could be a promising candidate for the treatment of spinal muscular atrophy.”  Resveratrol’s actions are complex, however.  It activates protein deacetylase SIRT1, and this is thought to be the main reason why it has anti-aging activity(ref).   

In discussing the Programmed epigenomic changes theory of aging my in treatise, I have written about how inhibition of NF-kappaB expression is being considered as a treatment for cancers and other diseases and how this also qualifies as an anti-aging strategy. It appears that deacetylation and acetylation events are implicated in the regulation of NF-kappaB transcriptional activity at multiple levels(ref). There is is a longevity-related connection between histone H3 lysine 9 deacetylation and NF-kappaB gene expression, with SIRT6 playing an important linking role(ref). “SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters.”  The result is that even if NF-kappaB gets into a cell’s nucleus, the wrapped-up histones keep it from activating genes that lead to inflammation and other age-related damage. The HDAC inhibitor trichostatin A and vitamin D3 are synergistic in their anti cancer-proliferation capabilities.  Both work via the vitamin D3 receptor(ref)(ref).  Some of curcumin’s anti-cancer powers may be due to its capability to inhibit HDAC activity(ref).  In human hepatoma cells, curcumin treatment significantly inhibited the HAT activity both in vivo and in vitro(ref).   There are multiple other links to the aging theories and related to the suggested supplements as well.  Many  of the relationships are complex.  Curcumin, for example, works against cancer in multiple ways: to inhibit HDAC, to prevent degredation of IK-alpha (the substance that keeps NF-kappaB bound in the cell cytoplasm), to inhibit translocation of the NF-kappaB/p65 subunit into the nucleus, and to inhibit expression of th Notch1 gene(ref). 

The bottom line is that we can expect to hear more and more about HAT and HDAC inhibition in the course of future anti-aging science reporting and might as well get used to that. 

Thanks again to Res for suggesting the lead which led to this post. 

Adding to the list of rare genetic disorders affecting longevity recently discussed in this Blog, there is Wolfram Syndrome.  This is a disease long known to be associated with mitochondrial dysfunction that leads to a complex of symptoms including Type 1 diabetes and problems with eyesight and hearing.  Wolfram Syndrome 1 is caused by mutations in the WFS1 gene.  Recently reported research points to a novel gene CISD2, whose deficiency leads to Wolfram Syndrome 2 (WFS2).  The gene is located on chromosome 4q which is known to be a candidate region for human longevity genes(ref).  The new research using CISD2 knockout mice shows “ — that CISD2 is involved in mammalian life-span control. Cisd2 deficiency in mice causes mitochondrial breakdown and dysfunction accompanied by autophagic cell death, and these events precede the two earliest manifestations of nerve and muscle degeneration; together, they lead to a panel of phenotypic features suggestive of premature aging(ref).’  the authors of the study suggest “that mutation of CISD2 causes the mitochondria-mediated disorder WFS2 in humans.”

I have previously discussed so-called longevity genes, mTOR in particular.  It seems more concise to describe genes that accelerate aging when they are dysfunctional as “shortevity genes.” So, also harkening back to earlier posts we have:

·        WFS1 and CISD2 are shortevity genes associated with Wolfram Syndrome

·        Certain of the sheltrin-producing genes are shortevity genes associated with Hoyeraal-Hreidarsson Syndrome(ref)

·        WRN is a shortevity gene associated with Werner Syndrome(ref)

·        LMNA is a shortevity gene associated with Hutchinson-Gilford progeria syndrome(ref)

Whether any of the shorevity genes have anything to do with possible extraordinary longevity is a very interesting open question.