AGINGSCIENCES™ – Anti-Aging Firewalls™

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.

Is increasing longevity be good for the society or does it pose a burden on younger people?  I outline where I am on this issue here because it has a lot to do with what motivates me to continue generating this Blog and update my treatise AntiAging Firewalls – the Science and Technology of Longevity.

Let me start by stressing that the intent of life extension as I am pursuing it is to extend life in a condition of health permitting constructive contribution to society.   It is not to squeeze one or two more unproductive years out at the ends of lives.  I am not advocating life extension if the resulting quality of life precludes continuing social contribution.  I am not for keeping people alive as living vegetables in hospital or nursing home beds.  I am also not very interested in extending the lives of older people who have given up all hope of contributing to others and who are basically waiting to die.  It is no secret that a disproportionate share of medical costs in advanced society like ours are for advanced surgeries and expensive drugs for older people, treatments that are very limited in their effectiveness against age-related diseases.  I am arguing not for such treatments but rather for measures that postpone or eliminate the typical diseases of aging.  The result should be more productive years and hopefully a larger average ratio of productive years to unproductive years of life.

Now, let’s look at some of the key arguments against extending longevity.

The argument from evolution is perhaps the most respectable.  It goes like this:  Each species, humans included, has evolved characteristic life-spans designed to optimize the survival of that species taking into account resource limitations, a need for protection against predators and diseases, and environmental conditions.  Scarce resources need to be devoted to providing for the young and raising new generations and fighting off predators and diseases during the years of rearing the young.  According to this argument, need for individual survival diminishes after child-rearing years.  Younger animals are stronger and can better fight off predators and diseases than older ones. From the viewpoint of the human species, then, resources are better devoted to raising and protecting children than to keeping old people around, people who are no longer part of the reproductive-child-rearing cycle.  According to this argument, finding means to extend lives of old people leads to a misallocation of resources that is counter to survival of the species. 

The problem with this argument is that it takes biological evolution into account but not social evolution.  The argument  does not take into account the ever-increasing complexity of our society, the ever-increasing requirement for education that is necessary to function well in society, the ever-increasing cost of rearing young including education, the increase in the time required for young people to become fully functional in society, and the need for people to spend more years working to cover the ever-growing costs for educating their young.  As social evolution advances at an exponentially increasing rate and society continues to become more complex, there is an ever-increasing need for people to draw on vast resources of information, deep knowledge and wisdom to survive and advance the society.  The time required for basic education continues to grow and continuing education becomes a lifelong necessity.   Longer life spans therefore serve the need of social evolution by increasing mobilization of knowledge and wisdom. 

In fact, social evolution has been working hard to extend our longevity in recent times.  A few hundred years ago people typically died before 40.  Now, life expectancy has roughly doubled, to about 78 for US males and 80 for females.  All the other typical age-marking numbers have also roughly doubled.  Once young males could join their fathers as hunters or warriors or farmers or artisans at the age of 15 and start fully contributing to society shortly thereafter.  About twice as much time (30 years) is now required in an advanced society for a male to become a doctor or lawyer or physicist, to become fully engaged in his profession, to get married and have children.  Females used to start having babies when they were biologically capable, around 15.  Now for educated Western women, the age is roughly 30.  The investment required for rearing a child has become enormous – $300,000 – $500,000 or more for a thirty year period when including the cost of preparatory education.  All this change has happened in less than 400 years.  The key thing to focus on is that the number of productive years – the years between completion of education and retirement – has doubled too. Instead of 20 good working years now the average is more like 40. 

So, social evolution requires longer life spans because people have to become ever more sophisticated to accommodate to ever more-complex social conditions.  Now as social evolution continues to accelerate at an exponential pace, it is appropriate that life spans also become extended at an accelerating rate.  That is what my work is about.

My main point is this:  as society becomes exponentially more complex, so a need arises for exponential growth in life expectancy.  Life extension is not about older people surviving unproductively longer in retirement communities in Florida or nursing homes.  It is about keeping an increasingly complex society workable.

A simplistic variant of the argument from evolution is to say extending lives is not natural.  If nature or God wanted us to live to 150 or beyond, he or she would have set it up that way, the argument goes.  My response is: who says what is natural?  From the viewpoint of the year 1600, living lives as long as the ones we enjoy now would have been seen as highly unnatural. 

Another argument against life extension is the burden on the young argument.  It is another variant of the argument from evolution stating that extending the lives of older people will lead to more and more unproductive older people, an unfair burden on the young people.  My response to this is that there should be no such burden.  The young, by virtue of their requirement for a long and expensive period of rearing and education are already a burden on their working parents – those in their productive years.  I am arguing for further extending the productive years so as to give more time for amortizing the investments in the young and minimizing the burden for those in their productive years due to having to take care of the young as well as the debilitated and unproductive old.

Another argument against life extension is that a society consisting of much older people will lack vibrancy, stress conformity and be uncompetitive compared with societies consisting of younger people.  The opposite is true.  In most countries in Africa and the Middle East where the population has recently exploded, the average age is now under 25.  Educational level per capita is minimal, the societies and their people cannot compete on the world stage, and there appears to be a chronic condition of poverty and social hopelessness.  In those countries lives are not seen to be worth much and average life spans are relatively short.  In advanced Western countries where there is large investments in education and life spans are long, lives are worth a lot.  It just takes a lot of years for people to come up to speed so they can compete in the world economy today.

The final argument against life extension I will deal with here is it will drive our social security and retirement systems broke.  True, if people live longer and longer on the average and we don’t adjust our retirement ages and expectations for retirement upwards,  We need to readjust our thinking about older people working.  I am one of possibly a million people around 80 who is perfectly capable of handling a full-time job.  As it happens to be, I am working 50-70 hours a week, self-employed and basically concerned with longevity science.  However, virtually no businesses, government agencies or health institutions are willing to employ people my age in regular jobs.  Twenty five years ago, 60 was the mandatory retirement age.  Now it is 65 and possibly going on 70.  As longevity increases and larger number of people are taking anti-aging measures, we need to change the culture so these people are not automatically thrown out of the work force when they reach an arbitrary chronological age.

Here is my vision:  A society where people live longer and more healthily, where the average period of suffering from end-of-life disability grows shorter and shorter compared to the total, where the knowledge and wisdom of older people is put fully to work, and where longevity translates into productivity that helps all. 

Exotic genetic diseases often provide important clues for the aging process, and I have previously discussed implications of Hutchinson-Gilford progeria and Werner Syndrome in this Blog.  This time, a research item on Hoyeraal-Hreidarsson Syndrome(HHS)  came to my attention.  “Hoyeraal-Hreidarsson syndrome is a multisystem disorder affecting males and is characterized by aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia, and growth retardation. HHS is a severe variant of dyskeratosis congenita(ref).”(ref).  HHS is “mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency(ref).”  Telomere shortening and damage is the 12^th theory of aging covered in my Anti-Aging Firewalls Treatise.

The key conclusion of the new research is “Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR (DNA damage response) and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease(ref).”  The problem in the case of HHS is apparently due to diminished 3′ overhangs which are part of telomeric DNA, that is, defective telomere caps.  Telomerase works by adding telomeric repeats off of the 3” overhangs and, if the overhangs are not normal, cannot do its job of extending telomeres. The researchers tracked the problem down to mutations in the telomerase subunits and in the Shelterin component Tin2.  Shelterin is a protein complex that is essential for shaping and protecting human telomeres.  It has six components: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.  Shelterin is important for enabling cells to distinguish telomeres from sites of DNA damage.

The study demonstrates the complexity involved in telomerase activation and that many pathways can contribute to either telomere extension or shortening. The devil is in the details.  The results are related to those posted in previous blog entries: More research progress on telomerase, and Stem cells, telomeres and telomerase and DNA repair.

I searched the news this morning for items related to stem cell disease therapies.  I found over 60 items.  My impression is that the situation is a bit like commercial aviation was in 1926: everybody is talking about it, visionaries are sure it will be a very big thing, there is a lot of disconnected activity going on all over the place, and safety is a big question.  And, the regulatory rules-of-the-game still have to be worked out.  Most potential stem cell therapies are still far from being part of mainline medicine and it is difficult to make sense about where things stand.   

The most practiced approach to stem cell therapy is to take autologous (a patient’s own) mesenchymal or hematopoietic stem cells from the patient’s bone marrow, grow the numbers of them in culture, and reintroduce them into the body in a way that hopefully leads to cure of a diseases or organ regeneration.  Use of a patient’s own stem cells avoids problems of immune system rejection encountered when other people’s stem cells are used.  Mesenchymal stem cells (MSCs) “ – are multipotent stem cells that can differentiate into a variety of cell types. Cell types that MSCs have been shown to differentiate into in vitro or in vivo include osteoblasts, chondrocytes, myocytes, adipocytes, and, beta-pancreatic islets cells(ref).”  Hematopoietic stem cells (HSCs)  are also multipotent cells that can differentiate into “all of the blood cell types including myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes/platelets, dendritic cells), and lymphoid lineages (T-cells, B-cells, NK-cells)(ref).” 

There are also other approaches, such as using other autologous stem cells (like nerve or hair stem cells), stem cells transplanted from other people, fetal stem cells, amniotic stem cells, and stem cells made by reprogramming ordinary cells.  But I am mainly not concerned with those here. 

The technology of harvesting stem cells from bone marrow is well worked out.  The challenge is to re-introduce the cells in the right place under the right conditions so that they produce the intended results.  Whether stem cells differentiate and what cells stem cells differentiate into depends very much on local inter-cellular signaling and in most cases that signaling is not well understood.  Here is a sampling of scattered items intended to give a flavor of what is happening: 

·        A few “classical” stem cell therapies based on using other people’s cells are in routine use today, such as for treatment of leukemia(ref).

·        The FDA apparently wants to subject new stem cell therapies to the same approval procedures required of new drugs.  This means they must pass through a controlled bureaucratic process that is likely to cost tens or hundreds of millions of dollars and require seven to ten years of clinical trials for completion.

·          A group of US doctorsis challenging that position(ref).  They claim that introducing a patient’s own cells back into the body is very different than introducing a foreign drug substance.  Accusations have been made that the FDA is killing approval of stem cell therapies by slowing down autologous stem cell transplants and therefore killing patients(ref).  How this will play out on the political and medical stages is difficult to predict.

·        Private clinics and hospitals have set up stem cell therapy shops in other countries where regulations permit.   This article in Forbes outlines overseas stem cell treatment options for Parkinson’s Disease, Alzheimer’s Disease, Multiple Sclerosis, Cardiovascular Disease, and Diabetes in countries such as China, Costa Rica, Ukraine, Republic of Georgia,  Russia, India, Germany, Israel, Mexico, Thailand, Argentina, Panama, Singapore, the Dominican Republic and countries in  Eastern Europe.  Costs typically range from $10,000 to $35,000. An example of a private stem cell clinic is the Xell Center in Germany. Xell only does autologous transplants, offers treatments for a variety of conditions, and claims there is no associated tumor risk.

 ·        Pet and animal stem cell therapy is starting to thrive.  Treating dogs for arthritis and horses for orthopedic injuries seem to be favorites.(ref)(ref).

·        A small Phase II European study suggests that autologous stem cell therapy is effective in treating congestive heart disease(ref).

·        NIH has launched a study of hematopoietic stem cell transplantation for severe, treatment-resistant lupus(ref).  This approach may show promise for this formerly intractable disease.  The idea is to reboot one’s immune system(ref).

·        One branch of autologous stem cell therapy research involves genetically modifying the stem cells before they are re-inserted.  See the recent post on this blog Trojan horse stem cells might offer an important new cancer therapy.  Stem cell transplants can be used to transfer new genes into patients, for example to protect them from some of the negative effects of chemotherapy treatments(ref).

·        Based on work with 9 patients, it appears that autologous Mesenchymal stem cells might be employed as part of a process to cure painful chronic fingertip ulcers experienced by many patients with scleroderma(ref).  A cultured stem cell mixture is externally applied to the would along with bioengineered skin.

·        A search of the website ClinicalTrials.gov using the search term stem cells retrieved 2572 studies, a few completed, some ongoing and many now recruiting.  Of course not all of these involve use of autologous cells. The disease conditions addressed cover nearly every area of medicine.

·        Reports of failures and in some cases deaths resulting from stem cell therapies continue to create doubts about them in the minds of many medical professionals.  For example, in one case of using human fetal stem cells, brain and spine tumors emerged(ref).  Some researchers feel the risks of such things happening are less when autologous transplants used.  Also, stem cell clinical trials have been discontinued for safety reasons.  Just a few days ago, Aastrom Biosciences Inc. suspended a clinical trial after received a report that a patient died some time after treatment with autologous stem cells for congestive heart failure. It is not known whether the patient’s death is related to the treatment(ref). The FDA is placing the trial on hold pending an investigation.

If all of this leaves you a bit unclear about where things really are, please be comforted by knowing that I am unclear too.  I was that way back in 1969 when I was trying to keep up with developments in the computer field.  So, perhaps the situation is not so bad.  It can only bring good news for longevity.

I have written previously on the difference between brute-force cancer therapies and highly focused new- generation ones in the pipeline.  See the post From four-pound hammer to smart molecules – on cancer treatments.  Radiation therapy and most forms of chemotherapy kill normal cells along with cancer cells – like the four-pound hammer approach to swatting flies.  Suppose there were 1. a protein that would selectively kill cancer cells but be harmless to normal cells, and  2.  safe and easy ways existed  for triggering the action of that protein in cancer cells.  The comment made yesterday by Res in response to my post Trojan-horse stem cells might offer an important new cancer therapy set me on the trail of TRAIL which appears to be just such a protein.  TRAIL stand for tumor necrosis factor–related apoptosis-inducing ligand.   TRAIL is also called APO-2L and consists of 281 amino acids.   As pointed out earlier, “TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells(ref).”    “ — TRAIL delivery in anticancer experiments does not result in any deleterious effect on normal cells. Therefore, many oncologists predict that TRAIL has the potential to be developed as an anticancer drug that selectively restricts primary as well as metastatic tumours(ref)” 

TRAIL appears to be the mechanism of anti-cancer action of the potential stem cell therapy mentioned in the previous post, where mesenchymal stem cells are loaded with TRAIL warheads and act as missiles that home in on cancer cells.  Certain of the supplements in the Susceptibility to Cancer Firewall, particularly curcumin(ref), resveratrol(ref) and green tea, owe at least some of their anti-cancer effects to the operation of TRAIL.  In the case of prostate and other cancers, curcumin inhibits the activation of NF-kappaB which makes them more sensitive to apoptosis by TRAIL(ref,ref,ref). Resveratrol appears to have the same effect in certain tumors(ref)(ref). The same appears to be true for EGCG, the major active constituent of green tea(ref).   I speculate that other plant-derived polyphenols in the anti-cancer firewall might have similar effects, enhancing TRAIL-mediated death receptor activation in cancer cells. Possibly, most of the 39 inhibitors of NF-kappaB in the firewall might work to empower TRAIL and fight cancers in the same way. 

It appears that combating cancers via TRAIL is now a major approach under research investigation.  However, some cancer cells offer resistance to TRAIL-induced death receptor apoptosis.  Using TRAIL with another anti-cancer therapy might be helpful in such cases.  Velcade, a proteasome inhibitor, sensitizes cancer cells to TRAIL.  It has been suggested that TRAIL might be combined with the anti-cancer drug Velcade to achieve a synergistic effect(ref). 

The Anti-Aging Firewalls treatise is now a year old.  It is sometimes updated weekly, sometimes daily and has undergone several major revisions.  As expected when I first published the treatise, it is now very different from the original.  The latest version embodies a new section ADDITIONAL CANDIDATE THEORIES OF AGING that integrates material formally published on this blog with existing and other new material.  Now there are six additional candidate theories of aging in addition to the original 14 theories – views of what might drive aging in most cases suggesting possible intervention strategies.   I intend to continue reporting on relevant topics and news here in this blog and to updating and maintaining the treatise as important new developments come to my attention.  Again, my intention is that the treatise will continue to be a comprehensive and definitive document on what science knows about aging and on corresponding science-based anti-aging interventions.  Achieving this may become harder and harder as the pace of progress continues to pick up, but for the present I am enjoying the challenge this task poses.

There is a constant stream of news stories on new possible approaches to curing cancers.  Cancer research institutions love to see these.  They help to impress the funding sources.  But most of these press releases describe incremental progress on existing therapeutic approaches.  It is rare to see a news story on a basically new and promising way to control  or cure cancers.  I think such a news story may have appeared today.  (See ref and ref). 

The therapeutic concept is simple and based on two observations.  The first observation is that for some reason mesenchymal stem cells (MSCs which are normally found in bone marrow) circulating in the body seek out cancer cells.  I conjecture that this is because cancers excrete signaling molecules that cause the circulating MSCs to home in on them, a strategy cancers use to achieve rapid growth(ref). The second observation is that it is possible to attach a payload molecule to mesenchymal stem cells which cause them to kill cancer cells but not normal cells, a molecule called TRAIL (A TNF-related apoptosis-inducing ligand in case you wanted to know).  “TRAIL induces apoptosis via death receptors (DR4 and DR5) in a wide variety of tumor cells but not in normal cells(ref).”  

The new research involves genetically engineering mesenchymal stem cells to be “Trojan horses” carrying TRAIL.  The stem cells seek out cancer cells and the TRAIL kills them.  The approach is reported to work in-vitro for a number of different cancers and in-vivo in a mouse model of breast cancer.  “In culture, the stem cells caused lung, squamous, breast and cervical cancer cells to die (all p< 0.01), even at low stem cell/tumor cell ratios (1:16). In mice, the researchers showed that the stem cells could reduce the growth of subcutaneous breast tumors by approximately 80 percent (p< .0001). The stem cells could also be injected intravenously as therapy for mice with lung metastases and could eliminate lung metastases in 38 percent of mice compared to control mice, all of which still had metastases (p=0.03)(ref).”  

It will probably take a few years before this cancer therapy approach is tried out in humans but it sounds promising to me.  Unlike blunderbus chemotherapy approaches the approach would be highly targeted, first in that the treated stem cells specifically seek out cancer cells, and second in that the payload kills only cancer cells not normal ones. Result should be minimal collateral damage. Most likely a patient’s own mesenchymal stem cells would be used to avoid any problem of immune system rejection so the therapy would be minimally problematic or toxic for the patient.