When I first learned about computers in 1950, there were probably less than a three dozen people in the world doing computer programming, and I soon joined their ranks.  At that time, to suggest that computer programming would become an occupation involving tens of millions of people would have gotten me labeled as a crazy visionary.  Yesterday I started to wonder about how many people are involved now with genetic reprogramming of body cells.  At first I guessed that the number is anywhere from a few hundred to a few thousand.  Then, later last night, I realized that the number is about 6.8 billion people, the world’s population.  Everybody is constantly involved in reprogramming their own genes. 

Gene reprogramming can involve two quite different things: modifying genes themselves or modifying the epigenomic information that determine what the genes do.  You are born with a set of genes, those same genes are in every cell of your body and, without an extraordinary intervention you will die with the same genes.  It is possible to change some of your genes in some of your cells using sophisticated gene splicing techniques, for example to correct a genetic disease-creating defect.  See the blog post Treating genetic diseases with corrected induced pluripotent stem cells.  However, changing genes is not something that can be done lightly and almost all of us will live our lives out with the same genes we started out with.

Gene reprogramming is mostly about is modification of epigenetic information in the DNA which affects gene expression. After all, the differences between all the different kinds of cells in our body are due to gene expression.  So, “gene reprogramming” usually involves altering epigenomic markers (e.g. DNA methylation, histone acetylation and protein folding) so as to affect gene expression in cells with some objective in mind, such as curing a disease created by a gene polymorphism.   (Why the “re” in reprogramming?  For two reasons: first because computer researchers have pre-empted the term “genetic programming” to describe a fundamentally different algorithmic approach to computing, one that is vaguely based on genetics but not necessarily useful for dealing with what goes on with the DNA in real biological cells.  The other reason is that the cells worked with in reprogramming are already behaving according to some kind of epigenetic program and the objective is to alter that program.)

The big enchilada of genetic reprogramming today is reverting cells to induced pluripotent stem cell (iPSC) status, a matter I have touched on in several previous posts, starting with the post Rebooting cells and longevity. In a matter of only months the tiny initial stream of research in this area is already growing into a river.  New ways are being discovered for turning stem cell genes off and on, for example, ones like manipulation of culture conditions that do not require virus vectors or transgenes(ref).    Here is a recently compiled list of articles related to deliberate cell reprogramming.

But deliberate gene reprogramming using sophisticated laboratory techniques is only a very tiny part of the picture.

Gene reprogramming goes on constantly in the process of aging and is a feature of many disease processes. For example, a 2003 publication, Growth Hormone, Acromegaly, and Heart Failure: The Gene Reprogramming Theory, states “When the myocardium hypertrophies to face an increased mechanical load, extensive gene reprogramming occurs in the cardiomyocytes. Some genes are downregulated, whereas others are upregulated. A distinct feature of this process is the re-emergence of an ensemble of fetal genes that are normally quiescent in the adult myocardium. It was theorized that the hypertrophic cardiomyocytes are sentenced to death, as an inherent consequence of the new gene programme (Katz, 1994)” The 1999 publication Adrenergic induction of bimodal myocardial protection: signal transduction and cardiac gene reprogramming states “The delayed adaptive response is associated with the expression of cardiac genes encoding fetal contractile proteins, and PKC-I may transduce the signal for reprogramming of cardiac gene expression.”  Another article related to gene reprogramming in heart tissues is Myocardial gene reprogramming associated with a cardiac cross-resistant state induced by LPS preconditioning.  Many other studies also relate to gene reprogramming in specific tissues and under particular disease conditions. 

Cancers do masterful jobs of gene reprogramming, sometimes changing the expression of hundreds of different genes. One of the central things most cancers do, for example, is to reprogram so as to inactivate expression of the p53 apoptosis gene.  According to a recently-suggested line of thought “–  cancer could begin when normal cells spontaneously reprogram themselves, for reasons yet unknown, beginning the process that results in a cancerous tumor(ref).”

Gene reprogramming can also occur due to environmental or stress conditions.  In May 2009 it was reported “Breathing polluted air for even a short period of time can cause some genes to undergo reprogramming, which may affect a person’s risk of developing cancer and other diseases, say Italian researchers. — Comparisons of blood DNA samples from healthy workers who were exposed to high levels of airborne particulates at a foundry near Milan revealed that after only three days of exposure, changes occurred in four genes that have been linked to tumor suppression.” – “This finding indicates “that environmental factors need little time to cause gene reprogramming, which is potentially associated with disease outcomes.”

The situation is not always simple.  For example, the reprogramming introduced by stress may be beneficial or harmful dependent on a cell’s capability to mobilize a response to the stress.  See the blog post Stress and Longevity.

What you eat reprograms your genes.  The blog post Recent research on the Mediterranean diet cites research indicating that the cell reprogramming resulting from following this diet results in multiple health and longevity benefits.  Cigarette smoking affects gene reprogramming, probably in several ways(ref) (ref).  So does exercise(ref)(ref). So does taking resveratrol(ref) and taking curcumin(ref)(ref).  In fact all of the dietary supplements in the combined anti-aging supplement firewall induce gene reprogramming to one extent or the other.  So what else can reprogram your genes? Just about everything you experience and do and your emotional and mental states.  See the post Optimism and epigenomic activation.  Simply put, research shows that optimism enhances longevity.  Your mental state can create epigenomic modifications, DNA methylation on your chromosomes and histone acetylation/deacetylation modifications, and therefore alter your gene expression pattern and therefore affect your longevity.The Anti-aging lifestyle Regimen section of my treatise contains numerous “conventional wisdom” suggestions for keeping yourself young.  All of these suggestions – every one of them – is a suggestion about how you can reprogram your genes so as to enhance the prospects for longevity. 

Eating a tripple-cheeseburger whopper with a double order of fries and a giant coke reprograms your genes one way.  Exercising 47 minutes a day (my target) reprograms your genes another way.  You are a gene-reprogrammer!

It is now official; telomerase is really for-real.  A Nobel Prize was just granted to Carol Greider, Elizabeth Blackburn and Jack Szostak, for discovery of the telomerase enzyme 25 years ago.  Greider was a 23-year-old first-year graduate student back then.  My impression was that very few scientists paid any attention to telomerase at that time.  Yet, the awesome potential of telomerase is what got me interested in anti-aging research back in 1994. 

Monday, the world’s press was full of reports on the anti-aging potential of telomerase and the use of telomerase inhibition to cure cancers.   There is a danger now that hype and irresponsible commercialization of telomerase activators will start to obscure what is actually known about telomerase – similar to what has happened in the last two years with respect to resveratrol.   Since I have written extensively on the telomere-shortening theory of aging and the possible anti-aging roles of telomerase, I thought this might be a good time to provide annotated links to what I have written.

·        The write-up in my treatise of the Telomere Shortening and Damage theory of aging is a complete and current introduction to telomeres, their roles in aging and the key properties and roles of telomerase.   Telomerase achieves a lot more than simply extending telomeres.

·        The Telomere Shortening and Damage Firewall  section of the treatise discusses the activation of telomerase as a possible anti-aging intervention, one I have been using personally.

·        On October 5, 2008 I added a note to the treatise On telomerase expression and nervous system cells.

·        My first blog entry with respect to telomerase was A January 28, 2009 item Geron in the news again.  Geron was and continues to be the biotech company most heavily invested in telomere technology.

·        In This week’s anti-aging news Jan 31, 2009, and related to the discovery of a new telomerase-related protein TCAB1.

·        The February 18, 2009 blog post You may be able to keep your telomeres long reports on a Swedish large-population study of telomere lengths.

·        The February 22, 2009 post Updated discussion of the Telomere shortening theory of aging covered changes up to that point due to what I learned about telomeres and telomerase since I first drafted the Anti-Aging Firewalls treatise about a year earlier.  These changes have been since embodied in the treatise.  

·        The March 1, 2009 blog entry More telomerase tidbits discusses telomere length as  a predictor of susceptibility to coronary artery disease and discusses birds who have long telomeres and who live a very long time for birds.

·        The March 13, 2009 post From the fringe to the center discusses earlier and lesser prizes received by Blackburn and Greider and the emerging acknowledged relevance of telomerase.

·        In the June 5, 2009 blog post Linking up the theories of aging, I discuss links between the Telomere shortening and damage, the Programmed epigenomic changes, the Susceptibility to cancers and the Stem Cell Supply Chain Breakdown theories of aging.

·        In my June 9, 2009 blog post How am I doing I said  ”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.”  

·        A June 11, 2009 post deals with the question Do resveratrol, curcumin and EGCG from green tea really inhibit the expression of telomerase? 

·   The July15, 2009 blog post Telomerase activation – upside and downside relates to another major update of the telomerase discussion in my treatise and mentions a possible danger involved with telomerase activation, that being promotion of the differentiation of cancer stem cells.

·        The September 30 blog post Revisiting telomere shortening yet-again reports on finding a treasure trove of recent publications which shed light on three issues: the relationship between two of the theories of aging (Telomere Shortening and Damage, and Stem Cell Supply Chain Breakdown),  the role of telomere shortening in multiple disease processes, and the nature of telomere shortening. 

Although at the moment I am most excited by the newest theory of aging, the Stem Cell Supply Chain Breakdown theory, I see the Telomere Shortening and Damage to be a very important complementary theory.  And I plan to continue taking a telomerase-activating daily supplement.

A team at the Whitehead Institute has taken a step towards finding a cure for Parkinson’s disease (PD) following an approach similar to but falling short of the approach outlined in my blog post Treating genetic diseases with corrected induced pluripotent stem cells.  The report’s headline is Breakthrough produces Parkinson’s patient-specific stem cells free of harmful reprogramming genes.  “Deploying a method that removes potentially cancer-causing genes, Whitehead Institute researchers have “reprogrammed” human skin cells from Parkinson’s disease patients into an embryonic-stem-cell-like state. Whitehead scientists then used these so-called induced pluripotent stem (iPS) cells to create dopamine-producing neurons, the cell type that degenerates in Parkinson’s disease patients.” 

The main innovation in this work was removal of the genes used for induction of reprogramming from the DNA of the produced iPSCs.  The researchers used an approach employed “since August 2006 for reprogramming adult cells into iPS cells by using viruses to transfer four genes (Oct4, Sox2, c-Myc and Klf4) into the cells’ DNA. Although necessary for reprogramming cells, these genes, the known oncogene c-Myc in particular, also have the potential to cause cancer. In addition, the four genes interact with approximately 3000 other genes in the cell, which may change how the cell functions. Therefore, leaving the genes behind in successfully reprogrammed cells may cause unintended alterations that limit the cells’ applicability for therapeutic use, for drug screens or to study disease in cell culture.” In recent months, incidentally, several other approaches to creating iPSCs have been reported that do not require use of these genes, including approaches that do not require insertion of genes at all(ref).

The approach the Whitehead researchers used is a good example of gene editing.  “In the current method, Whitehead researchers used viruses to transfer the four reprogramming genes and a gene coding for the enzyme Cre into skin cells from Parkinson’s disease patients. The reprogramming genes were bracketed by short DNA sequences, called loxP, which are recognized by the enzyme Cre.  After the skin cells were reprogrammed to iPS cells, the researchers introduced the Cre enzyme into the cells, which removed the DNA between the two loxP sites, thereby deleting the reprogramming genes from the cells. The result is a collection of iPS cells with genomes virtually identical to those of the Parkinson’s disease patients from whom original skin cells came.”  Clever!

“After removing the reprogramming genes, the — researchers differentiated the cells from the Parkinson’s disease patients into dopamine-producing nerve cells. In Parkinson’s disease patients, these cells in the brain die or become impaired, causing such classic Parkinson’s symptoms as tremors, slowed movement, and balance problems.”

Those cells might be very useful for testing out various treatments for PD in-vitro but of course retain any genetic defects that may have led to PD in the first place.  These cells are therefore questionably suitable for stem-cell replacement therapy.  The next step in developing a stem cell therapy for PD would be to strip out faulty genes that lead to PD susceptibility and replace them with healthy ones, as suggested in my post.  There has been some progress in identifying genes related to PD susceptibility(ref)(ref), with several genes having been identified that, when mutated, have to do with forms of PD, genes like alpha-synuclein,  parkin, DJ1, PINK1, and LRRK2.  However, my impression is that not enough is known about these genes yet to allow such gene correction. 

This work exemplifies hundreds of studies demonstrating modest steps of progress but aimed ultimately at stem-cell cures for diseases.   An earlier blog post Gene therapy for fruit flies with Parkinson’s Disease  discusses a different possible therapeutic approach, re-introducing a gene that has been lost on the process of evolution.    For an approach that might be more immediately useful for prevention of PD, check out my blog entry Mitochondria and Parkinson’s Disease

Conventional wisdom says that you will live healthier as you reach an advanced age if you live with a partner. A Scandinavian study published in July 2009 confirms that wisdom with respect to cognitive capability. The study, Association between mid-life marital status and cognitive function in later life: population based cohort study, had the objective of looking at whether mid-life marital status is related to cognitive function in later life. The study looked at a previously-researched sample of 1449 individuals from the Kuopio and Joensuu regions in eastern Finland with an average follow-up period of 21 years.

“Results:  People cohabiting with a partner in mid-life (mean age 50.4) were less likely than all other categories (single, separated, or widowed) to show cognitive impairment later in life at ages 65-79. Those widowed or divorced in mid-life and still so at follow-up had three times the risk compared with married or cohabiting people. Those widowed both at mid-life and later life had an odds ratio of 7.67 (1.6 to 40.0) for Alzheimer’s disease compared with married or cohabiting people. The highest increased risk for Alzheimer’s disease was in carriers of the apolipoprotein E e4 allele who lost their partner before mid-life and were still widowed or divorced at follow-up. The progressive entering of several adjustment variables from mid-life did not alter these associations(ref).”

I find these statistics impressive; three times the risk is way beyond a marginal effect.  If  you are living successfully with a partner you probably have to exercise your mind more.  The report concludes “Living in a relationship with a partner might imply cognitive and social challenges that have a protective effect against cognitive impairment later in life, consistent with the brain reserve hypothesis. The specific increased risk for widowed and divorced people compared with single people indicates that other factors are needed to explain parts of the results. A sociogenetic disease model might explain the dramatic increase in risk of Alzheimer’s disease for widowed apolipoprotein E e4 carriers.”

It is Sunday evening now and I am going to stop writing so I can hang out with my wife. 

Regular readers of this blog are familiar with the crucial importance of signaling molecules and transcription factors in life-related biological processes.  However, traditional mass spectrometry may have difficulty detecting such molecules which are produced in low numbers.  Although mass spectrometry is a very important technique for determining the presence of proteins in cells, the observations it produces produced are averages, often over millions of cells in a culture.  Information related to important subpopulations of cells or what is going on in a single cell is lost.  “Mass spectrometry (MS) has become a preeminent methodology of proteomics since it provides rapid and quantitative identification of protein species with relatively low sample consumption. Yet with the trend toward biological analysis at increasingly smaller scales, ultimately down to the volume of an individual cell, MS with few-to-single molecule resolution will be required(ref).”

A typical laboratory mass spectrometry system is the size of a supermarket food freezer.  Recently-reported research indicates that it may be possible to mass-produce mass spectrometers on microchips, ones that can analyze the proteins in individual cells. “A prototype for a mass spectrometer with single-molecule sensitivity has prospects for single-cell proteomics.   – – With new work from Michael Roukes’s group at the California Institute of Technology, however, this could potentially all change. Roukes and his colleagues recently reported a nanoelectromechanical system (NEMS)-based method that can be used to detect molecular mass with single-molecule sensitivity. — NEMS sensors are nanoscale devices that resonate at frequencies close to the microwave range(ref).”  According to Roukes “We report the first realization of MS based on single-biological-molecule detection with nanoelectromechanical systems (NEMS). NEMS provide unparalleled mass resolution, now sufficient for detection of individual molecular species in real time. However, high sensitivity is only one of several components required for MS. We demonstrate a first complete prototype NEMS-MS system for single-molecule mass spectrometry providing proof-of-principle for this new technique(ref).”“

“The next question is, that’s a lot of molecules that you need to measure one by one, and how the heck are you going to do that?” says Roukes. He envisions an elaborate microfluidics-based front-end separation system, which would distribute the contents of a single cell to a chip consisting of thousands of individual NEMS sensors, each one a tiny mass spectrometer(ref).”  Proof-of-concept has been established but the engineering challenge of building such a device remains. “Roukes is collaborating with researchers at CEA (French Atomic Energy Commission) Leti in Grenoble, to make such chips with thousands or even millions of NEMS sensors. Another challenge they must tackle is pushing the mass resolution to below a single dalton; their current mass resolution is about 1,000 daltons. “This will require us to scale down [the size of] the individual NEMS resonators,” says Roukes(ref).”

This stream of development is another example of what I talked about in my blog post Factors that drive Giuliano’s Law. You may recall that Giuliano’s Law is:

·        Starting now, every seven years will see the emergence of practical age-extension interventions (ones that have a potential of leading to extraordinary longevity) that double the power of the interventions available at the start of the 7 year period.  That is, on an average basis, the practical anti-aging interventions available at the end of a seven-year period will enable twice the number of years of life extension than did the interventions available at the start of the period.  Life extension is measured in years of life expectancy beyond those actuarially predicted for a given population. 

In that post I said “This law is valid for the same reason Moore’s Law for integrated electronics is valid – the law that the number of transistor elements on a chip at a given price point doubles roughly every two years.  This law has held for 40 years and is responsible for the corresponding increase in cost-effectiveness of computers, cell phones and all other electronics.  This law was the result of a strong positive feedback relationship between societal need, market, economic contribution, market vehicles, user applications, marketing channels, changes in user expectations advancement in the relevant basic science, advancement of technology, advancement of manufacturing capability and an entrepreneurial environment.”  And there is yet-another factor I did not mention before, and that is massive government investment in health sciences research.  Advances in basic research technology like spectrometry is one of the key factors driving life extension, a factor that works in close interplay with the other factors mentioned. 

The first computer I worked on, the UDEC at Wayne State University in 1952, was some 60 feet long, weighed several tons and filled a gigantic room under the dome of the old Victorian-design main building.  The computer chip in my Blackberry phone is the size of a large dandruff  flake and is tens of thousands of times more powerful and useful.   And I remember when powerful computers got to be the size of supermarket freezers, in the early 80s.  I wonder if someday we will carry pen or pin-sized mass spectrometers as part of our personalized medicine health monitoring system.

I love reporting on research that supports my favorite theories, and also on research that challenges them.  In the post The anti-antioxidant side of the story I reported on research suggesting a couple of possible downsides to antioxidant supplementation.  A just-published research publication suggests another possible downside: Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment.  “Normal epithelial cells require matrix attachment for survival, and the ability of tumour cells to survive outside their natural extracellular matrix (ECM) niches is dependent on acquisition of anchorage independence. Although apoptosis is the most rapid mechanism for eliminating cells lacking appropriate ECM attachment, recent reports suggest that non-apoptotic death processes prevent survival when apoptosis is inhibited in matrix-deprived cells.”  Specifically “detachment of mammary epithelial cells from ECM causes an ATP deficiency owing to the loss of glucose transport.”  The ATP deficient cells being in a state of stress had high levels of ROS expression and eventually died off, a good thing.  This kind of cell death is important because many cancers suppress the expression of apoptotic genes.  However, exposing the detached cells to antioxidants tended to restore ATP production and rescue the rouge cells, a bad thing.  

Another report on the same research states “Can antioxidants also promote cell transformation? MCF-10A cells expressing oncogenes that promote proliferation and suppress apoptosis (either human papillomavirus E7 and BCL-2, or ERBB2) exhibit limited colony formation in soft agar, but antioxidant treatment increased both the number and the size of colonies.” – “–antioxidants may promote tumours by suppressing the ability of ROS to prevent outgrowth of cells that are displaced from their natural microenvironment.” I have no idea as to whether the concern is a valid one for the health of live organisms, and, if so, the dimensions of the problem.

Repeating what I said in my earlier post, I stress that taking antioxidants is only one component of what is likely to be an effective anti-aging program such as that identified in my treatise ANTI-AGING FIREWALLS –  THE SCIENCE AND TECHNOLOGY OF LONGEVITY.  Further, taking certain antioxidants in excess quantities could conceivably be dangerous to health or longevity.

This post relates to the Stem Cell Supply Chain Breakdown theory of aging, and is about getting somatic stem cells in mature individuals to keep up their rate of differentiation with aging.  The central issue is how safely to nudge multipotent stem cells (Type B cells in my classification, like hematopoietic stem cells) which live in niches using the Notch signaling pathway so they continue to differentiate and provide a stream of new mature (Type D) cells, such as working blood or immune system cells.  I was stimulated to look into this topic by a long comment to the blog post The stem cell supply chain – closing the loop for very long lives posted by eric25001.  I suggest readers to review that comment as background before going further into this post.  The comment incidentally is a news item that should have been attributed to UCBerkeley News. “A study led by researchers at the University of California, Berkeley, has identified critical biochemical pathways linked to the aging of human muscle. By manipulating these pathways, the researchers were able to turn back the clock on old human muscle, restoring its ability to repair and rebuild itself.”

The grist of this post deals with both new research and a couple of complicated cell signal-transduction pathways that have been extensively studied for over 15 years now, known as Notch and MAPK.  I also discuss a new and interesting role of old friends – antioxidants.  I will start with rudimentary introductions to Notch and MAPK, although these are subjects that could fill up a 4-year graduate school program in biochemistry and molecular biology.

About Notch and MAPK

Notch is an ancient signaling pathway that has been inherited from primitive multi-cellular organisms and has to do with signaling between cells, such as when stem cells decide to differentiate.  Ever wonder how whole bunches of cells work together to generate new blood vessels or new nerve tissue?  Look into Notch. “Because Notch often acts in concert with other signaling pathways, it is able to regulate a diverse set of biological processes in a cell-context dependent manner(ref). “  Notch protein receptors (there are 4 different ones) sit on the surfaces of cells and communicate between adjacent cells via Notch ligands.   Ligand binding to a receptor alters the chemical conformation, that is the three dimensional shape of the receptor protein(ref).” Intracellular proteins transmit Notch signals into the cell’s nucleus where they can activate genes, including ones that initiate differentiation in stem cells. Notch signaling can play an important role in determining the morphology of organs.  For example see ref. Also Notch plays several important roles in stem and progenitor cell differentiation, particularly ones that maintain balance during development. “Notch signaling is a powerful means of turning adult CNS precursor cells into astrocytes(ref).”   “In the developing nervous system, the balance between proliferation and differentiation is critical to generate the appropriate numbers and types of neurons and glia. Notch signaling maintains the progenitor pool throughout this process(ref).”

MAPK/ERK is another very complicated signal transduction pathway way that couples intracellular responses to the binding of growth factors to cell surface receptors.  MAPK signaling is important for cell growth and differentiation, inflammation and apoptosis.  A diagram showing all the ways MAPK signaling can work would fill a large wall.  For example this diagram shows four different MAPK cascades.  Clicking on the individual bubbles in the diagram reveal more-detailed diagrams, showing cascades such as for growth, differentiation and inflammation.

Both Notch and MAPK signaling are deeply involved in embryogenesis and stem cell differentiation.  It is no surprise that there is crosstalk between the Notch and MAPK pathways.  For example, this report  states: “Here we show that Notch signaling activation in C2C12 cells suppresses the activity of p38 MAPK to inhibit myogenesis. Our results show that Notch specifically induces expression of MKP-1, a member of the dual-specificity MAPK phosphatase, which directly inactivates p38 to negatively regulate C2C12 myogenesis.” 

So much for background. 

Going back to the recent UCBerkeley news item, the idea of the research was to regenerate old muscle cells by using Notch and MAPK signaling to re-invigorate old pools of stem cells.  “The researchers further examined the response of the human muscle to biochemical signals. They learned from previous studies that adult muscle stem cells have a receptor called Notch, which triggers growth when activated. Those stem cells also have a receptor for the protein TGF-beta that, when excessively activated, sets off a chain reaction that ultimately inhibits a cell’s ability to divide. — The researchers said that aging in mice is associated in part with the progressive decline of Notch and increased levels of TGF-beta, ultimately blocking the stem cells’ capacity to effectively rebuild the body. — This study revealed that the same pathways are at play in human muscle, but also showed for the first time that mitogen-activated protein (MAP) kinase was an important positive regulator of Notch activity essential for human muscle repair, and that it was rendered inactive in old tissue. MAP kinase (MAPK) is familiar to developmental biologists since it is an important enzyme for organ formation in such diverse species as nematodes, fruit flies and mice. — For old human muscle, MAPK levels are low, so the Notch pathway is not activated and the stem cells no longer perform their muscle regeneration jobs properly, the researchers said. — In practical terms, we now know that to enhance regeneration of old human muscle and restore tissue health, we can either target the MAPK or the Notch pathways. The ultimate goal, of course, is to move this research toward clinical trials.”

The research related to MAPK and Notch described below suggests to me that this avenue of pursuit for invigorating old stem cells is likely to be very worthwhile but also very tricky.  Some studies relate to the hopefulness of the approach:The 2006 study report Notch signaling regulates stem cell numbers in vitro and in vivo states:  “In both murine somatic and human embryonic stem cells, these positive signals are opposed by a control mechanism that involves the p38 mitogen-activated protein kinase. (MAPK) Transient administration of Notch ligands to the brain of adult rats increases the numbers of newly generated precursor cells and improves motor skills after ischaemic injury. These data indicate that stem cell expansion in vitro and in vivo, two central goals of regenerative medicine, may be achieved by Notch ligands through a pathway that is fundamental to development and cancer.”No surprise,  Notch and MAPK signaling are also intimately involved in the development of cancers, and herein lay the rub.

A November 2009 (e-publication in advance) research report Emerging role of Notch signaling in epidermal differentiation and skin cancer states “Signaling mediated by the Notch receptor governs tissue development during embryonal organogenesis, while in adult tissues it contributes to maintenance of cellular differentiation, proliferation and apoptosis. In addition, control by the Notch pathway of stem cell self-renewal and multi-potency points to an expanding role of Notch signaling in the progression of solid tumors. — Notch signaling has a dual action (either as an oncogene or as a tumor suppressor), depending on the tumor cell type and the synchronous activation of other intracellular signaling mechanisms.” Notch signaling that promotes stem cell differentiation can also promote tumorgenesis.  Beware!

This June 2009 study Emerging role of Notch in stem cells and cancer relates a similar message: “The Notch signaling pathway is known to be responsible for maintaining a balance between cell proliferation and death and, as such, plays important roles in the formation of many types of human tumors. Recently, Notch signaling pathway has been shown to control stem cell self-renewal and multi-potency. As many cancers are thought to be developed from a number of cancer stem-like cells, which are also known to be linked with the acquisition of epithelial-mesenchymal transition (EMT); and thus suggesting an expanding role of Notch signaling in human tumor progression.”

A 2008 study relates to the role of Notch signaling in promoting the differentiation of cancer stem cells: Notch activation promotes cell proliferation and the formation of neural stem cell-like colonies in human glioma cells.  “We hypothesized that  Notch signaling might play roles in cancer stem cells and cancer cells with a stem cell phenotype. In this study, we accessed potential functions of the Notch pathway in the formation of cancer stem cells using human glioma. — These data suggest that Notch signaling promote the formation of cancer stem cell-like cells in human glioma.”

This 2008 report again emphasizes the dual role of Notch signaling, this time with respect to the brain, and points out an additional interesting fact:  Notch, neural stem cells, and brain tumors.  “During neocortical development, Notch signaling inhibits neuronal differentiation and maintains the neural stem/progenitor cell pool to permit successive waves of neurogenesis, which are followed by gliogenesis. In addition, recent evidence suggests that Notch signaling is not uniformly used among distinct proliferative neural cells types, with the canonical cascade functional in neural stem cells but attenuated in neurogenic progenitors. Although the role of Notch in neural development is increasingly well understood, it has recently become evident that Notch also has a role in brain tumor biology. Notch receptors are overexpressed in many different brain tumor types, and they may have an initiating role in some. Stem-like cells in brain tumors share many similarities with neural stem/progenitor cells and may require Notch for their survival and growth.”   The additional fact is that Notch signaling can serve to inhibit rather than promote differentiation in the interest of maintaining healthy pools of stem cells.  Its action can be selectively to promote or inhibit stem cell differentiation.

The same point, that Notch activity is involved in both cell differentiation and tumorgenesis, appears in many other studies, for example Notch signaling at the crossroads of T cell development and leukemogenesis.

An interesting discovery for me was that Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells (HSCs)  but, as pointed out in the same report  “prolonged treatment with an antioxidant or an inhibitor of P38 MAPK extended the lifespan of HSCs from wild-type mice in serial transplantation experiments.”  These seem to be key points from an anti-aging viewpoint linking up the Oxidative Damage and the Stem Cell Supply Chain Breakdown  theories of aging and pointing to a different role for antioxidants than those discussed before.

The idea of inhibiting P38 MAPK via antioxidants to treat vascular smooth muscle cell hypertrophy goes back to 2001(ref).  Other studies have also implicated activated p38 MAPK in disease progression and suggest that its inhibition may represent a rational strategy for therapeutic intervention(ref)(ref).  However, the linkage of inhibiting p38 MAPK to health of stem cell pools appears to be fairly new. A 2004 in-vitro study of rabbit cells telegraphed the punch:  “We show that the inactivation of p38 kinase leads to the stimulation of proliferation, the extension of life span, and a delay in the onset of senescence, thus implying that p38 kinase limits the life span of rabbit articular chondrocytes in vitro(ref).”

For me, bottom-lines from the above are:

1.    Stimulating Notch signaling as a way of increasing stem cell differentiation in older folks is likely to turn out to be tricky for three reasons, first because the stimulation can also stimulate cancer stem cells and carcinogenesis, second because too much stimulation can cause exhaustion of stem cell pools and third and most basic: because the multipotent Type B cells in stem cell pools are subject to replicative senescence, a more basic approach to stem cell renewal is probably needed.  See my recent post The stem cell supply chain – closing the loop for very long lives.

2.    There appears to be another positive role for antioxidants beyond those commonly discussed: inhibiting p38 MAPK to help preserve the life spans of hematopoietic and possibly other multipotent stem cells and to assist in the prevention of a number of disease processes.

After coming up from burying myself for a month in the research leading to the Stem Cell Supply Chain Breakdown theory of aging, I decided to check on recent research relating this theory to the Telomere Shortening and Damage theory of aging.  I found a treasure trove of recent publications which shed light on three issues: the relationship between the two theories, the role of telomere shortening in multiple disease processes, and the nature of telomere shortening.  I report on these here.

Stem cells and telomere shortening

The two theories actually fit together hand-in-glove. A number of studies suggest that a main cause for depletion of pools of stem cells and deterioration of the ability of stem cells in those pools to differentiate is shortened stem cell telomeres due to replicative senescence.  Except for embryonic stem cells, somatic stem cells and progenitor cells (Types B and C according to my theory) are subject to telomere shortening due to continuing replication.  Quoting from different research studies:

1.     Somatic stem cells lose telomere length on replication

·        “– the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells(ref).”

·        “–telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth, and resulted in suppression of stem cell proliferative capacity in vitro(ref).” 

·        “– telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice(ref).”

·        “The proliferative life-span of the stem cells that sustain hematopoiesis throughout life is not known. It has been proposed that the sequential loss of telomeric DNA from the ends of human chromosomes with each somatic cell division eventually reaches a critical point that triggers cellular senescence. We now show that candidate human stem cells with a CD34+CD38lo phenotype that were purified from adult bone marrow have shorter telomeres than cells from fetal liver or umbilical cord blood. We also found that cells produced in cytokine-supplemented cultures of purified precursor cells show a proliferation-associated loss of telomeric DNA. These findings strongly suggest that the proliferative potential of most, if not all, hematopoietic stem cells is limited and decreases with age, a concept that has widespread implications for models of normal and abnormal hematopoiesis as well as gene therapy(ref).”

·        “Progressive telomere shortening limits stem cell divisions and probably acts as a tumor suppressor mechanism. Using a sensitive PCR method to detect the length of individual telomere repeats on specific chromosomes, we confirmed that telomere length decreases from primitive to more differentiated human cell types within the hematopoietic hierarchy(ref).”  

 2.     Telomere length regulation and telomere attrition are very complex matters involving many other factors besides the availability of telomerase.  

·        “The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells(ref).”

·        “ Telomere length in peripheral blood mononuclear cells is associated with folate status in men. — Telomere length is epigenetically regulated by DNA methylation, which in turn could be modulated by folate status. — We propose that folate status influences telomere length by affecting DNA integrity and the epigenetic regulation of telomere length through DNA methylation(ref).”

·        “With aging, long telomeres decrease and short telomeres increase, and the contents of the telomeres with methylated subtelomere increase in long telomeres, thus leading us to postulate that telomeres with less methylated subtelomeres tend to become shortened faster.  —   The subtelomeric methylation of peripheral blood cells is also indicated to be an indicator for aging-associated genomic changes(ref).

See my treatise for more discussion of the complexities related to telomere lengths.  One study cited there showed that over a 9-11 year period, telomere lengths actually increased in about a third of 959 individuals as they aged.

3.     Disease conditions and cancers can lead to stem cell supply chain failures

·        “We have found heritable hypomorphic TERT mutations in other cancers as well, and we propose that such mutations result in short telomeres and premature loss of stem cells. Loss of normal stem cells could provide strong selection for abnormal cells incapable of responding to DNA damage signals originating from short telomeres(ref)”

4.     Genetic mutations in telomerase and shortened telomeres are implicated in a number of diseases.

·        “Genetic mutations in the components of telomerase (the RNA template sequence hTERC, reverse transcriptase hTERT, and Syskerin DKC1) have recently been implicated in a variety of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and more recently, acute myeloid leukemia (AML)(ref).”

·        “The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer(ref).”

·         “Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by cutaneous symptoms, including hyperpigmentation and nail dystrophy. Some forms of DC are caused by mutations in telomerase, the enzyme that counteracts telomere shortening, suggesting a telomere-based disease mechanism. — These results provide experimental support for the notion that DC is caused by telomere dysfunction, and demonstrate that key aspects of a human telomere-based disease can be modeled in the mouse(ref).”

·        “These results suggest that marrow failure in DC is caused by a reduction in the ability of hematopoietic stem cells to sustain their numbers due to telomere impairment rather than a qualitative defect in their commitment to specific lineages or in the ability of their lineage-restricted progeny to execute normal differentiation programs(ref).” Again, there is a direct link between the two theories of aging Stem Cell Supply Chain Breakdown and Telomere Shortening and Damage. 

·        ”Loss of (stem) cells via telomere attrition provides strong selection for abnormal cells in which malignant progression is facilitated by genome instability resulting from uncapped telomeres(ref).” 

·        “Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability(ref).”

·        “Although we could not find a statistical difference in the mean telomere length of peripheral leukocytes between the PD (Parkinson’s Disease) patients and the control participants, we found the mean telomere lengths to be shorter than 5 kb in only the PD patients and a significant PD-associated decrease in the telomeres with a length ranging from 23.1 to 9.4 kb in the patients in their 50s and 60s. These observations suggest that telomere shortening is accelerated in PD patients in comparison to the normal population(ref).”  I note that telomere shortening is observed in many disease processes where the body’s response is speeding up cell division and differentiation, as may be the case in this instance.  Such a situation is different than one in which shortened or impaired telomeres are causative of the disease such as those described above.

·        “Studies in white people have shown that telomere length, a marker of biological ageing, is shorter in individuals with coronary artery disease (CAD). South Asian Indians have a high prevalence of CAD, especially premature CAD. — Subjects of Indian ethnicity with CAD have shorter telomeres than subjects without such a history. The finding provides further evidence that telomere biology is altered in subjects with CAD(ref).”

5.     Telomere attrition probably plays a key role in immunosenescence

·        “Macrophages from aged mice showed increased susceptibility to oxidants and an accumulation of intracellular reactive oxygen species. In these macrophages STAT5a oxidation was reduced, which led to the decreased phosphorylation observed. Interestingly, the same cellular defects were found in macrophages from telomerase knockout (Terc–/–) mice suggesting that telomere loss is the cause for the enhanced oxidative stress, the reduced Stat5a oxidation and phosphorylation and, ultimately, for the impaired GM-CSF-dependent macrophage proliferation(ref).

I upgraded the Telomere Shortening and Damage theory in my treatise on July 14 2009 and stand by what I said there.

Some of the above citations suggest how another of the theories of aging Susceptibility to Cancers integrates with the Stem Cell Supply Chain Breakdown and the Telomere Shortening and Damage theories.  And, I have argued that the Programmed Epigenomic Changes theory and the candidate Epigenomic Changes in DNA Methylation and Histone Acetylation theories of aging are completely compatible and complementary with the Stem Cell Supply Chain Breakdown theory.  We are in the process of converging on a unified systems model of aging.

On a personal note, for telomerase activation as soon as my current bottle of astragaloside IV is used up I will be switching to cycloastragenol as my primary telomerase-activating supplement, a new RevGenetics product.

Stem Cell Supply Chain Breakdown is the newest theory of aging described in my treatise and the one I am currently most excited about.  According to a simplified model of this theory a newly-conceived human embryo consists of pluripotent stem cells (Type A), ones that can potentially divide into any body cells.  With growth, these proliferate and, in a remarkably articulated manner, progressively differentiate into multipotent stem cells (Type B), progenitor cells (Type C), mature body somatic cells (Type E), and many eventually become senescent cells (Type E). 

According to the best current understanding of stem cells this is an open-loop process.  The above list is in order of increasing cell-type specificity and decreasing cell-type potency to differentiate into other cell types.  Starting at conception and throughout life, all cells on this list except the senescent ones will selectively reproduce and possibly differentiate into cells of types further down in the list.  The state of the body in terms of makeup of cell types continues to change through life and the process goes inexplicably from start (conception) leading to end (death).   

At conception, the embryo is all Type A cells.  At maturity there are relatively very few Type A cells and a mix of Type B, C and D cells,  Type B and C cells typically live in protected stem cell niches where they reproduce and, as-needed differentiate to become the normal working body Type D cells.  As Type D cells die from trauma or apoptosis they are replaced by new cells resulting from differentiation of Type B and Type C cells.  Stem cell gene expression evolves with age.  “In newborn mice, blood-forming cells (hematopoietic stem cells, HSCs) rely on a transcription factor known as Sox17 for self-renewal, but adult HSCs rely on a different transcription factor, Bmi-1(ref).”  At an advanced age, the pools of Type B and Type C cells become depleted in part because of replicative senescence and the cells remaining in the pools lose their ability to differentiate as necessary to replace Type D cells.   

Although in principle stem cells can replicate indefinitely, in fact they age as the organism ages, continuing to change their gene expression.  And the gene expression changes in a way that favors protection against cancer over differentiation capability, e.g. expression of p16ink4a increases.  Many Type D cells senesce and become Type E cells which make the corresponding organs shrivel and be susceptible to cancers and other disease processes. 

That is the essence of the Stem Cell Supply Chain Breakdown theory of aging.  In essence, early-on the body sets up pools of stem and progenitor cells to replace lost somatic cells.  Cells in those pools replicate and differentiate throughout life.  But when these pools become compromised or depleted or the cells in them lose their capability to differentiate –  well – to be blunt soon its curtains.  “Every day, billions of new blood cells are produced in the body, each one derived from a hematopoietic stem cell (HSC). Because most mature blood stem cells have a limited life span, the ability of HSCs to perpetuate themselves through self-renewal and generate new blood cells for the lifetime of an organism is critical to sustaining life(ref).”  I suggest here the possibility that the stem cell supply chain process could someday be made into a continuing closed loop one where at some point in life the balance of the difference types of cells reaches an equilibrium and stays at that equilibrium and that the consequence could possibly be extremely long lives.

To get the full depth of this post, please review the Stem Cell Supply Chain Breakdown section of my treatise.  There is a lot of research background described there that I cannot repeat here. 

This post picks up with the closing remark in my treatise regarding stem cells: There is a possibility of keeping the stem cell supply chain active indefinitely.  The key idea is to use induced Pluripotent Stem cells (iPSCs) which are fully pluripotent and equivalent to embryonic stem cells(ref)(ref)(ref) as feedstock Type A cells in adults to make the stem cell supply chain as a continuous loop process instead of a once-through process.  I have described the process several times before.  1.  A few human skin, fat, blood or spit cells are corrected for any known genetic diseases defect are taken from an individual, 2. These cells are reverted by known means to a state of epigenomic ground-zero, that is into iPSCs for that individual, 3.  These corrected cells are replicated outside the body, and 4.  They are re-introduced into the body of the same individuals so as to differentiate into vital Type B and Type C stem cells in their niches refreshing the existing pools of stem cells and revitalizing the cells in them.  Because they are cells derived from the same individual, there should be no graft versus host disease immune system rejection or reaction to them.  The stem cell supply chain becomes closed loop. Further, the Type A source cells are free of any original genetic disease susceptibility. Steps 1-3 have been tried out although many issues connected with them are still being worked out.   

The balance of this post is devoted to reviewing the state of research progress related to such an overall loop-closing process focusing on Step 4 where the major challenge is.  I discuss issues connected with the proliferation and differentiation of Type B and C cells extensively in my treatise and will not repeat those discussions here.  Finally I comment on the kinds of research needed to allow closing the loop.

Some known things:

·        Both proliferation and differentiation of Type A, B, and C stem and progenitor cells decreases with aging.

·        Adult stem cells live in niches – stem cell microenvironments and the health of the stem cells and their ability to reproduce or differentiate both depend upon and condition the states of their niches. 

These last two points are discussed further in the Stem Cell Supply Chain Breakdown section of my treatise, as are the following points.

·        iPSCs can be cured of genetic defects, induced to produce hematopoietic and other Type B and C stem and progenitor cells, and re-introduced into the same animal so as to cure diseases.  For example, they have been used to cure mice of sickle cell anemia(ref).  Other researchers recently reported “Here we show that, on correction of the genetic defect, somatic cells from Fanconi anaemia patients can be reprogrammed to pluripotency to generate patient-specific iPS cells. These cell lines appear indistinguishable from human embryonic stem cells and iPS cells from healthy individuals. Most importantly, we show that corrected Fanconi-anaemia-specific iPS cells can give rise to haematopoietic progenitors of the myeloid and erythroid lineages that are phenotypically normal, that is, disease-free(ref).”  Very recently, research has been reported in applying this general approach to “familial dysautonomia (FD), a rare but fatal neuropathy that has been impervious to functional analysis and drug validation(ref).”

·        “Embryonic stem (ES) cells have the potential to serve as an alternative source of hematopoietic precursors for transplantation and for the study of hematopoietic cell development(ref).”  Also, “hESCs possess indefinite proliferative capacity in vitro, and have been shown to differentiate into the hematopoietic cell fate, giving rise to erythroid, myeloid, and lymphoid lineages using a variety of differentiation procedures(ref)”.  The same point is made in this research report. Since iPSCs are relatively new, there is a lot more research out there on ESCs than on iPSCs.

·        To the extent that iPSCs are truly equivalent to ESCs, they should have the same differentiation potential.  This report is on a study that looked at the hematopoietic and endothelial differentiation potential of different  iPSC lines.  “Although we observed some variations in the efficiency of hematopoietic differentiation between different hiPSCs, the pattern of differentiation was very similar in all seven tested lines obtained through reprogramming of human fetal, neonatal, or adult fibroblasts with three or four genes(ref).”

·        Technologies have been developed for generating a number of specific cell types from ESCs in-vitro using hematopoietic cell intermediaries and probably can be adopted for generating those cell types starting with iPSCs. “–  we have developed a protocol for efficient generation of neutrophils, eosinophils, macrophages, osteoclasts, DCs, and Langerhans cells from human embryonic stem cells (hESCs). As a first step, we generated lin-CD34+CD43+CD45+ hematopoietic cells – “Morphologic, phenotypic, molecular, and functional analyses revealed that hESC-derived myelomonocytic cells were comparable to their corresponding somatic counterparts. In addition, we demonstrated that a similar protocol could be used to generate myelomonocytic cells from induced pluripotent stem cells (iPSCs)(ref).

In other words, techniques have been worked out to get ESCs to transform into hematopoietic progenitors and a variety of other stem types in-vitro, and these techniques will probably work equally well with iPSCs.  This is not quite the same, however, as getting iPSCs to regenerate new supplies of multipotent and progenitor cells in their in-vivo niches.  There the situation is much more complex involving niche-dependent signaling, age-dependent gene expression and related epigenomic DNA transformations in both stem cells and their supporting cells.  

One approach might involve in-vivo creation of iPSCs through forced gene induction, as outlined in this research plan.  “Here we propose that one important application is to produce neural stem cells from differentiated neurons in vivo in the central nervous system, and to repair the dysfunctional neural circuits, whether caused by aging, disease or a knife cut.” – “The first step will be the induction of neurons or glial cells in culture into neural stem cells or pluripotent stem cells, using similar transcription factors that have succeed in skin cells, for example, or to indentify extra transcription factors required. Then either viral transfection or electroporation could be adopted for in vivo gene transfer, “inducing” neural cells inside the brain into stem cells. Lastly the therapeutic values of these newly generated neurons have to be tested, to see if they can bring any functional outcomes(ref).”  If this approach works, it could conceivably be applied to renewing Type B cells in their niches.  

I will be looking for research news on using iPSCs to regenerate new supplies of multipotent and progenitor cells in their in-vivo niches.  For now, closing the loop in the natural stem cell supply chain is an incomplete story, to be continued. 

“Cordyceps militaris is pretty much the coolest mushroom ever(ref).”  It is a caterpillar killer that gets inside a pupa or larva (usually of a butterfly or moth).  From there it grows inside and bursts outside the insect shell in a horror scene that could have been in an Aliens movie.  The fungus has also long been known as a delicacy and as a medicinal substance.  “Perhaps one of the most fascinating Cordyceps is C.sinensis found in China and Tibet. This is a highly prized edible fungus found in the mountains of Yunnan, Sichuan and Tibet. It is made into soup and the best specimens will still be attached to their parasitised pupae. More than a culinary delicacy, it is one of the best medicinal mushrooms. It is known in Chinese as Dong Chong Xia Cao, (winter insect, summer grass). It grows in grasslands over 3000m in altitude and is usually collected at the summer equinox before the last snows have melted. In former times, its use was restricted to the Emperors’ palace due to its rarity(ref).’  Its history goes back to the Tang Dynasty in China and is “Considered particularly beneficial to kidneys and lungs in traditional Chinese Medicine(ref).”Western-style science in its quest for new cancer cures has taken an interest in Cordyceps militaris.  I recapitulate some recent research reports here.   

·        The title of the 2009 research report, Induction of apoptosis and inhibition of telomerase activity in human lung carcinoma cells by the water extract of Cordyceps militaris, tells the basic story.  “Taken together, the data from this study indicate that WECM induces the apoptosis of A549 cells through a signaling cascade of death receptor-mediated extrinsic and mitochondria-mediated intrinsic caspase pathways. It was also conclude that apoptotic events due to WECM (water extract of C. militaris) were mediated with diminished telomerase activity through the inhibition of hTERT transcriptional activity.

·        This 2005 research report, Growth inhibition of U937 leukemia cells by aqueous extract of Cordyceps militaris through induction of apoptosis, says that more or less the same story is true for leukemia cells.  “It was found that AECM (aqueous extract of C. militaris) could inhibit cell growth of U937 cells in a dose-dependent manner, which was associated with morphological change and apoptotic cell death such as formation of apoptotic bodies and DNA fragmentation.– Taken together, these results indicated that the anti-proliferative effects of AECM were associated with the induction of apoptotic cell death through regulation of several major growth regulatory gene products such as Bcl-2 family expression and caspase protease activity, and AECM may have therapeutic potential in human leukemia treatment.”

·        Another 2998 research report suggests the same story holds for breast cancer cells: Induction of apoptosis by aqueous extract of Cordyceps militaris through activation of caspases and inactivation of Akt in human breast cancer MDA-MB-231 Cells.  “Exposure to AECM induced apoptosis, as demonstrated by a quantitative analysis of nuclear morphological change and a flow cytometric analysis. AECM increased hyperpolarization of mitochondrial membrane potential and promoted the activation of caspases. — The results indicated that AECM-induced apoptosis may relate to the activation of caspase-3 and mitochondria dysfunctions that correlate with the inactivation of Akt.”

·        The PowerPoint presentation The anti-proliferation effect of Cordyceps militaris on human mucoepidermoid pulmonary carcinoma discusses the molecular mechanisms involved in the anti-cancer effects of Cordyceps militaris and makes a strong case for considering use of this substance as a therapy. 

Research has also been conducted on other possible medicinal properties of Cordyceps fungi.  For example”

·        Study on effect of Cordyceps sinensis and artemisinin in preventing recurrence of lupus nephritis reports” Cordyceps and artemisinin could prevent the recurrence of LN and protect kidney function.”

·        Antifibrotic effect of extracellular biopolymer from submerged mycelial cultures of Cordyceps militaris on liver Fibrosis induced by Bile duct ligation and scission in rats.  “These results indicate that EPC (extracellular biopolymers from myceiial liquid culture of Cordyceps militaris) (30 mg/kg/day for 4 weeks, p.o.) has an antifibrotic effect on fibrotic rats induced by BDL/S (bile duct ligation and scission).” 

It remains to be seen if, when and how the mainline cancer establishment will embrace therapies or adjunct therapies based on Cordyceps militaris. 

In the interim, many different cordyceps-derived supplement products are sold in the US and in China and other Asian countries. For example, a Korean company manufactures Codycepin, derived from Cordyceps militaris which it sells as a supplement and purports to be an “anti-cancer substance.”*  * Note that in this blog I do not support any claims made by supplement companies related to the ability of a supplement to treat or cure any disease.  Please also note the Medical Disclaimer for this blog.