AGINGSCIENCES™ – Anti-Aging Firewalls™

While embryonic stem cell therapies are still barely getting off the ground (see the post It’s a long  way to stem cell treatment), several important therapeutic applications of Mesenchymal stem cells (MSCs) are now getting to be well along in the development pipeline and could soon become part of mainline medicine.  

In this post I first enumerate some recently-discovered and exciting properties of MSCs that make these applications possible.  Then, to illustrate that mesenchymal stem cell therapies are going prime-time, I provide a current listing of clinical trials involving MSCs with hyperlinks to further information about each trial.     

Mesenchymal stem cells are multipotent cells that can differentiate into a variety of cell types including chondrocytes, osteoblasts,  myocytes, adipocytes and beta-pancreatic islets cells.  “Mesenchymal stem cells (MSC) represent a population of the bone marrow microenvironment, which participates in the regulation of haematopoietic stem cells (HSC) self-renewal and differentiation. MSC are multipotent non-haematopoietic progenitors, which have been explored as a promising treatment in tissue regeneration(ref).” Some of the properties of these cells are amazing, making them a good platform for a variety of new emerging disease therapies. 

Properties of Mesenchymal stem cells 

·        “MSCs are rare in bone marrow, representing approximately 1 in 10,000 nucleated cells. Although not immortal, they have the ability to expand manyfold in culture while retaining their growth and multilineage potential(ref).”

·        MSCs inhibit immune response.  “Both in vitro and in vivo, the MSC inhibit the T, B, NK and dendritic cell functions(ref).” MSCs suppress lymphocyte proliferation(ref).   Implications are that MSCs might be useful in treating autoimmune diseases,  and that MSCs could work in treating Graft vs Host Disease (GvHD), a major problem encountered in organ transplantation.

·        Because of their freedom from immune responses, MSCs work fine no matter where you get them.  “ Most interestingly, there was no difference in the response rates or side effects between patients receiving mesenchymal stem cells from third-party mismatched donors compared with those patients receiving cells from HLA-identical siblings or from haploidentical family members(ref).

·        MSCs tend to inhibit the inflammatory response. “Based on the observations that mesenchymal stem cells (a) develop into joint tissues and (b) in vitro and in vivo show immunosuppressive and anti-inflammatory qualities indicating a transplant-protecting activity, these cells are prominent candidates for future tissue engineering approaches for the treatment of rheumatic diseases(ref).”

·        MSCs prolong the survival of haemopoietic stem cells(ref).

·        MSCs automatically home in on diseased or damaged tissues requiring regeneration.  “It has been shown that MSCs, when transplanted systemically, are able to migrate to sites of injury in animals, suggesting that MSCs possess migratory capacity. However, the mechanisms underlying the migration of these cells remain unclear(ref).”

·        Arriving at a site having tissue damage and requiring regeneration, MSCs can and “know how to” differentiate into a variety of different types of cell tissues as needed, ranging from heart muscle cells to cartilage osteoclasts, and integrate themselves into a functioning organ so as to renew it.  

·        A 2010 study suggests that one of the communications strategies utilized by MSCs is that they they secrete therapeutic paracrine factors (signaling molecules that affect nearby cells) and also secrete RNA-containing microparticles(ref).

·        There is strong evidence that a number of known medical conditions can be treated with MSCs, and new ones are still being discovered.  “Experimental and clinical data gave encouraging results, showing that MSC injection allowed controlling refractory GVHD, restoring bone development in children with osteogenesis imperfecta or improving heart function after myocardial infarction(ref).”

·        Amazingly, Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology.  This means that the MSCs from an old person with osteoarthritis whose knee or hip cartilage is severely eroded by that osteoarthritis can be used to regenerate new cartilage.  “We conclude that, irrespective of age and OA etiology, sufficient numbers of MSCs can be isolated and that these cells possess an adequate chondrogenic differentiation potential. Therefore, a therapeutic application of MSCs for cartilage regeneration of OA lesions seems feasible.”  This will be the subject of another blog post to follow within a few days.

·        Several non-surgical ways are being experimented with for working with MSCs including site injection, topical application possibly with a structure matrix, and injection with substances that accelerate the natural migration of MSCs to a site requiring restoration. “Harnessing the migratory potential of MSCs by modulating their chemokine-chemokine receptor interactions may be a powerful way to increase their ability to correct inherited disorders of mesenchymal tissues or facilitate tissue repair in vivo(ref).” 

·        I even speculate that one of the main ways acupuncture could work is by creating minor damage that generates chemical messages that attract MSCs to an injury site requiring attention.

Previous blog posts have highlighted various aspects and other potential applications of MSCs.  See the blog posts Terminator stem cells in the early pipeline, Stem cell differentiation and nanotubes, Trojan-horse stem cells might offer an important new cancer therapy.  The blog post State of autologous stem cell therapies is relevant.  However it is already partially obsolete though only 8 months old.  Also, MSCs can be found in other body locations besides bone marrow, like in teeth.  See the post Dental Pulp Stem Cells – the big needle vs the tooth fairy.

Clinical trials involving Mesenchymal stem cells 

A good sign that  a drug or technology is probably headed for big-time medical use is when it is in several clinical trials.  The following  listing is mostly based in information from www.clinicaltrials.gov, “a registry of federally and privately supported clinical trials conducted in the United States and around the world.”  Clicking on any trial heading will lead you to further information about the objectives, methodology and status of the trial involved.   

1.     Safety Study of Adult Mesenchymal Stem Cells (MSC) to Treat Acute Myocardial Infarction  Also see ref.

2.     A Phase I Clinical Trial of the Treatment of Crohn’s Fistula by Adipose Mesenchymal Stem Cell Transplantation

3.     Mesenchymal Stem Cell Transplantation in Decompensated Cirrhosis

4.     Allogeneic Mesenchymal Stem Cell for Graft-Versus-Host Disease Treatment (MSCGVHD

5.     Mesenchymal Stem Cell Infusion as Treatment for Steroid-Resistant Acute GVHD or Poor Graft Function

6.       Prochymal™ Adult Human Mesenchymal Stem Cells for Treatment of Moderate-to-Severe Crohn’s Disease

7.     Safety and Efficacy Study of Umbilical Cord Blood-Drived Mesenchymal Stem Cells to Promote Engraftment of Unrelated Hematopoietic Stem Cell Transplantation (for treating acute leukemia).     

8.  Mesenchymal Stem Cell Infusion as Prevention for Graft Rejection and Graft-Versus-Host Disease (for treating Hematological Malignancies)

9.     Mesenchymal Stem Cells and Subclinical Rejection (related to Organ Transplantation)

10.            Autologous Transplantation of Bone Marrow Mesenchymal Stem Cells on Diabetic Foot

11.   Allogeneic Mesenchymal Stem Cells Transplantation for Primary Sjögren’s Syndrome (pSS)

12.            Mesenchymal Stem Cells in Multiple Sclerosis (MSCIMS)

13.            Mesenchymal Stem Cells in Critical Limb Ischemia

14.            The Use of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Articular Cartilage Defects (for treating Degenerative Arthritis; Chondral Defects;  Osteochondral Defects)

15.  Safety and Efficacy Study of Allogenic Mesenchymal Stem Cells to Treat Extensive Chronic Graft Versus Host Disease ((for combined treatment with prednisone and cyclosporine as primary treatment) 

16.            Mesenchymal Stem Cell Transplantation in the Treatment of Chronic Allograft Nephropathy  (for Kidney Transplant; prevention of Chronic Allograft Nephropathy)

17.            Extended Evaluation of PROCHYMAL[tm] Adult Human Stem Cells for Treatment-Resistant Moderate-to-Severe Crohn’s Disease

18.  Autologous Transplantation of Mesenchymal Stem Cells (MSCs) and Scaffold in Full-Thickness Articular Cartilage (for treating Knee Cartilage Defects;   Osteoarthritis)

19.            Evaluation of the Role of Mesenchymal Stem Cells in the Treatment of Graft Versus Host Disease

20.            Mesenchymal Stem Cell for Osteonecrosis of the Femoral Head

21.            Mesenchymal Stem Cells Under Basiliximab/Low Dose RATG to Induce Renal Transplant Tolerance

22.            Intravenous Stem Cells After Ischemic Stroke

23.            Effect of Mesenchymal Stem Cell Transplantation for Lupus Nephritis

24.            Safety and Efficacy Study of Adult Human Mesenchymal Stem Cells to Treat Acute GHVD

This listing may not be complete but should make the point that MSC therapies are probably heading for big-time.  Yet, I need point out that most of these trials are either just getting off the ground or are Phase I studies focused on safety and dosage rather than on efficacy.  And some of the trials could produce negative results and be aborted.  So it may be a while before most of these therapeutic applications are actually integrated in as part of mainline medicine. 

A few of the studies are in or already beyond Phase II, however, and moving along nicely through the pipeline.  The following is from a report in Medical News Today on a Phase II study:  “A phase II multicenter study performed within the European Group for Blood and Marrow Transplantation (EBMT) Mesenchymal Stem Cell Expansion Consortium, shows that mesenchymal stem cells provide a therapeutic potential for the treatment of acute steroid-refractory GvHD (graft-versus-host disease). — Allogeneic stem-cell transplantation is the treatment of choice for many malignant and non-malignant disorders. Severe graft-versus-host disease (GvHD) is a life-threatening complication which could arise following this treatment. Especially if patients with GvHD do not respond to steroids, therapeutic options are limited and the success uncertain. This publication in one of the leading scientific journals opens new exciting possibilities for patients with GvHD. — The study was launched to assess whether mesenchymal stem cells could reduce the risk of GvHD after stem cell transplantation. Between October 2001 and January 2007, 55 patients were treated. From this, 30 patients had a complete response and nine showed improvement. No patients had side effects during or immediately after infusions of mesenchymal stem cells. This response was not related to donor HLA-match. Three patients had recurrent malignant disease and one developed de-novo acute myeloid leukaemia of recipient origin. — This phase II study shows that the infusion of mesenchymal stem cells expanded in vitro, irrespective of donor, might be an effective therapy for patients with steroid-resistant, acute GvHD. Most interestingly, there was no difference in the response rates or side effects between patients receiving mesenchymal stem cells from third-party mismatched donors compared with those patients receiving cells from HLA-identical siblings or from haploidentical family members. This finding makes the logistical requirements for this approach more convenient, because the establishment of local banks of mesenchymal stem cells would enable unproblematic and rapid availability of mesenchymal stem cells without the need of HLA typing.”

I am optimistic.  In a follow-up blog post, I will focus on research relating to one specific possible therapeutic role of MSCs – cartilage regeneration, an application for those who are suffering from lost cartilage in their knees, hips or elsewhere, a cure that can be done without need for surgery.  It works even if the patient has ongoing osteoarthritis which caused the problem in the first place.  I believe we are finally entering the new era of regenerative medicine. What incredible good news for longevity!

In the Part I post  I described several recent studies relating to calorie restriction (CR), mainly ones exploring the pathways through which CR limits the development of cancers.  I cite a background study on the somatotropic axis and a few additional recent studies here, with focus this time on the gene activation pathways that seem to be involved.  And I touch lightly on how taking resveratrol supplements appears to mimic many of the effects of CR.  

The somatotropic axis and IGF-1 

As background, I begin by commenting on the somatotropic axis, a subject covered well in the 2005 paper Minireview: Role of the Growth Hormone/Insulin-Like Growth Factor System in Mammalian Aging.  “THE SOMATOTROPIC AXIS, consisting of pituitary derived GH (growth hormone) and IGF-I, the main mediator of GH actions, is the key determinant of somatic growth and adult body size. Moreover, the GH/IGF-I system is involved in the regulation of puberty and gonadal function and influences body composition as well as structural and functional maintenance of adult tissues.” This pathway and its associated genes seem to be evolutionary conserved across a multiplicity of species including unicellular yeast, through insects, worms, rodents, and other mammals including humans.   

The pathway seems also very relevant to aging.  The key thing to note is that across many species including fruit flies, roundworms, mice and rats, inhibition of IGF-1 signaling is generally associated with smaller-sized animals and longer lifespans.  Some people take human growth-hormone promoting supplements  because they think it may extend their lives, but the evidence seems to point in the opposite direction.  “– administration of GH is often advocated as an “anti-aging” therapy. In sharp contrast to these findings, GH deficiency, GH resistance, and reduced IGF-I signaling in mice are associated with symptoms of delayed aging and markedly extended longevity.  Although most normal mice die at approximately 2 yr of age, hypopituitary and GH-resistant mutants often survive beyond the age of 3 yr and occasionally past the age of 4 yr, i.e. outside the range encountered in various laboratory strains of this species.  — Association of reduced somatotropic signaling with extended longevity in laboratory stocks of house mice (Mus musculus) is robust, reproducible, and consistent across several mutants, genetic backgrounds, and diets (ref).”  The same can be said for other more primitive species and “it seems entirely reasonable to expect that the involvement of these signaling pathways in the control of aging is universal and includes humans.” 

From the viewpoint of the current discussion, there is strong evidence that the somatotropic axis, i.e., limiting of IGF-1 signaling  is involved in the life-extending actions of calorie restriction. This is pointed out in several publications cited in the Part I post(ref).  “The group’s analysis points to a connection between calorie intake and a protein called Insulin-like Growth Factor (IGF) -1, with obesity increasing and calorie restriction decreasing levels of IGF-1(ref).” 

DAF-16, SMK-1 and PHA-4  It appears, however, that IGF-1 signaling is not necessarily the only or even the most important longevity-related pathway involved in calorie restriction.  .   According to a 2007 Science Daily posting:  “–  Initially, researchers thought that the effect of calorie restriction on aging was mediated through insulin-like signaling pathways in the roundworm Caenorhabditis elegans (C. elegans), but experiments by graduate student Siler Panowski in Dillin’s lab suggested otherwise. — In the worm, signals passed down the insulin/IGF-1 pathway regulate a DNA-binding protein called DAF-16 that belongs to what is called the forkhead family. It was believed that DAF-16 then regulated expression of genes associated with longevity. Dillin had also identified a co-regulator in the pathway called SMK-1 that apparently worked with DAF-16 to regulate longevity. — “When we asked whether DAF-16 and SMK-1 proteins were both necessary for CR-mediated longevity, DAF-16 turned out to be unnecessary but, somewhat surprisingly, SMK-1 was,” says first author Panowski. — Since 15 other forkhead-like factors are expressed in C. elegans, graduate student Suzanne Wolff and former post-doctoral fellow Hugo Aguilaniu, Ph.D., now an assistant professor at the École Normale Supérieure de Lyon, France, set out to determine if any of them teamed up with SMK-1 to delay aging in the CR-response. They did this by knocking out each gene separately and observing whether the genetically altered worms still showed enhanced longevity when calorie-restricted. — Loss of only one of the genes, a gene encoding the protein PHA-4, negated the lifespan-enhancing effect of calorie-restriction in worms.  And, when researchers undertook the opposite experiment–by overexpressing pha-4 in worms–the longevity effect was enhanced. “PHA-4 acts completely independent of insulin/IGF-1 signaling and turns out to be essential for CR-mediated longevity,” says Panowski.”  CREB, CBP, SATB-1 and histone acetylation Again alas , these are not the only pathways involved.  The 2009 publication Role of CBP and SATB-1 in Aging, Dietary Restriction, and Insulin-Like Signaling points out “Here we report that hypothalamic expression of CREB-binding protein (CBP) and CBP-binding partner Special AT-rich sequence binding protein 1 (SATB-1) is highly correlated with lifespan across five strains of mice, and expression of these genes decreases with age and diabetes in mice.”  The same publication states “drugs that enhance histone acetylation increase lifespan and reduce Aβ42-related pathology, protective effects completely blocked by cbp-1 RNAi. Other factors implicated in lifespan extension are also CBP-binding partners, suggesting that CBP constitutes a common factor in the modulation of lifespan and disease burden by DR and the insulin/IGF1 signaling pathway.”  This landmark publication is well worth perusing and I quote a few other passages from it.

“Elucidation of mechanisms mediating lifespan extension and reduction of disease burden, including cancer and neurodegenerative diseases, by DR is a major goal of aging research [1]. Recent studies have implicated sirtuins [2], SKN-1 [3], SMK-1 and PHA-4/Foxa [4], AMPK [5], RHEB-1 [6], daf-16/Fox1a [5], and HSF-1 [7] in mediating lifespan extension by some, but not all [8],[9], protocols of DR in Caenorhabditis elegans. However, a role for expression of these genes in mammalian lifespan has not been addressed, nor, with rare exceptions [7], has a role for expression of these genes in reduction of age-related pathologies by DR. The purpose of the present studies was to discover genes whose expression predicts lifespan and whose expression decreases with age and disease in mammals, whose expression is induced by DR, and whose inhibition attenuates life extension by several distinct protocols of DR. We report that among genes implicated in lifespan extension by DR or the insulin-like signaling pathway, only CBP meets these criteria.”

“In the present study we have discovered that DR induces a transcription factor, CBP, and additional factors that work with CBP to control the expression of other genes involved in determination of lifespan. When we blocked the DR-mediated increase in CBP and associated factors, we blocked all the protective effects of DR on lifespan extension, on the slowed rate of aging, and on protection against pathology in a model of Alzheimer’s disease. Further, in mice expression of CBP and a CBP-interacting factor positively predicted lifespan, and expression of both factors decreased with age and in diabetes. Finally, pharmacological manipulations that mimicked enhanced CBP activity increased lifespan and reduced pathology in a model of Alzheimer’s disease.”

“Mechanisms linking cbp-1 expression to increased lifespan and reduced age-related pathology are therefore of great interest. It is suggestive that all genes implicated in the present screens are either CBP or CBP-binding co-activators [29]–[31]. Similarly, genes recently implicated in mediating lifespan extension by DR, skn-1 and pha-4, also code for transcriptional factors that interact with CBP [37],[38]. Furthermore, transgenic overexpression of cbp-1 did not significantly increase lifespan (Figure S6), suggesting that effects of CBP on lifespan requires increased expression of other factors. Uniquely among factors implicated in mediating lifespan extension by DR, RHEB-1 is not known to interact with CBP [6]. However, RHEB-1 mediates lifespan extension by intermittent fasting-induced longevity [6], which, in contrast to other protocols of DR (including those examined in the present studies), increases lifespan by reducing initial mortality rate, not by reducing age-related acceleration of mortality rate.”

Glucose metabolism

A study cited in the Part I post implicates glucose metabolism in DR, in that healthy cells in-vitro lived longer and had better health indicators when deprived of a glucose nutrient, while the opposite was true of cancer cells(ref).

Epigenetic effects, Akt, mTOR, P16 and hTERT

The Part I post  touched on how these too are involved in CR.

Resveratrol and calorie restriction

Resveratrol supplementation appears to partially mimic some of the longevity-promoting effects of CR, possibly via the IGF-1 channel, possibly via other mechanisms.  This is the probably-good news for us longevity aficionados.  In a mouse study: “We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR(ref).” There is a lot more that can be said about this subject, however, and that will be the subject of a future post.

Wrapping it all up

Researchers are developing ever-better understanding of the underlying molecular/epigenetic mechanisms of CR.  Further – and that is what is most exciting – it appears that with resveratrol and new resveratrol homologs, we may already have a practical anti-aging intervention that takes advantage of the CR pathways nature have given us.  And, stay off of the glucose!

If you are a supplement follower, you may have already read a newspaper article today on the major study on Ginkgo and cognition just reported in JAMA.  Here is a firsthand copy of the abstract of the original article Ginkgo biloba for Preventing Cognitive Decline in Older Adults – A Randomized Trial:

“Context  The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.  

Objective  To determine whether G biloba slows the rates of global or domain-specific cognitive decline in older adults.

Design, Setting, and Participants  The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.

Intervention  Twice-daily dose of 120-mg extract of G biloba (n = 1545) or identical-appearing placebo (n = 1524).

Main Outcome Measures  Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.

Results  Annual rates of decline in z scores did not differ between G biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P = .71; for ADAS-Cog, P = .97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P > .05).

Conclusion  Compared with placebo, the use of G biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.”

Because of the size and controlled nature of the study, I can find no reason to challenge its conclusions.  In fact the conclusions are compatible with those of a January 2007 review study Ginkgo biloba for cognitive impairment and dementia. “AUTHORS’ CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and we cannot exclude publication bias. The evidence that Ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing.”

The completely negative results are somewhat puzzling to me however, given a number of earlier research studies indicating that ginkgo biloba extract EGb 761, the same one used in the latest study,  has a capacity to promote neurogenesis in the hippocampus and improves cognitive functioning in small-animal models of Alzheimer’s disease.  For example:

·          The 2008 article Ginkgo Extract Has Multiple Actions on Alzheimer Symptoms, for example, states:  “In ongoing studies, a research team led by Luo found that giving mice with the human Alzheimer’s gene the ginkgo extract called EGb 761 improved the process of making new nerve cells in part of the brain much affected by the disease. The team found evidence that the protective effect of the extract also could be due to decreasing senile plaques or the clumping of beta-amyloid in the brain tissues.”  

·         Another relevant research report is the 2007 publication EGb 761 enhances adult hippocampal neurogenesis and phosphorylation of CREB in transgenic mouse model of Alzheimer’s disease. “The present findings suggest that 1) enhanced neurogenesis by EGb 761 may be mediated by activation of CREB, 2) stimulation of neurogenesis by EGb 761 may contribute to its beneficial effects in AD patients and improved cognitive functions in the mouse model of AD, and 3) EGb 761 has therapeutic potential for the prevention and improved treatment of AD.” 

·         The 2003 report Prenatal exposure of rats to Ginkgo biloba extract (EGb 761) increases neuronal survival/growth and alters gene expression in the developing fetal hippocampus states “These findings, which have provided the first genetic profile of the effects of EGb 761 on the developing rat hippocampus, increase our understanding of the molecular and genetic programs that are activated by the extract. These effects of EGb 761 may underlie its neuroprotective properties.” 

·         Studies of the neuroprotective effects of EGb 761 relating to Alzheimer’s Disease go back some time.  For example the 2000 publication The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid reported test-tube findings.  “We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells, this area being severely affected in AD. A co-treatment with EGb 761 concentration-dependently (10-100 microg/mL) protected hippocampal neurons against toxicity induced by Abeta fragments, with a maximal and complete protection at the highest concentration tested.” 

·          The 2009 report Stimulation of Neurogenesis and Synaptogenesis by Bilobalide and Quercetin via Common Final Pathway in Hippocampal Neurons “Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and, brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-β oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation.”

This all leaves me is thinking:

·        Despite the negative clinical studies related to cognition and dementia, there is much more to ginkgo biloba extract EGb 761 than vitamin-marketing smoke-and-mirrors.

·        I find the results of the large-scale human clinical study hard to understand given the results of the earlier animal studies but, hey, we are not rats and science is science.

·        For the present, I want to avoid any further claim that ginkgo biloba extract supplementation can prevent dementia or enhance cognition.

·        Until I can review the issue in more detail, I am leaving ginkgo biloba extract  as part of my Anti-aging firewalls supplement regimen because of possible health-giving actions the substance may have above and beyond cognition enhancement or dementia prevention.  For example, see Studies on the effect of Ginkgo biloba extracts on NF-kappaB pathway,  Ginkgo biloba Extract Inhibits Tumor Necrosis Factor- –Induced Reactive Oxygen Species Generation, Transcription Factor Activation, and Cell Adhesion Molecule Expression in Human Aortic Endothelial Cells and Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity.

A number of interesting studies related to calorie restriction (CR) have shown up recently.   I will discuss a few of these studies here, particularly ones relating CR to cancers.   I will discuss additional studies relating CR to gene activation in a Part II post and speculate there on what I think these studies mean. 

Calorie restriction  involves systematic dietary restriction of calorie intake.  It has long been known to work as an effective longevity-enhancing intervention.  “CR when not associated with malnutrition,^[1] improves age related health and slows the aging process in some animals and fungi. CR is one of the few dietary interventions that has been documented to increase both the median and maximum lifespan in a variety of species, among them yeast, fish, rodents and dogs. There are currently ongoing studies on primates to show if CR works on primates, and even though they are showing positive indications^[2][3] it is still not certain that CR has a positive effect on longevity for primates and humans, due to the very lengthy time required for the completion of such lifespan studies(ref).^[2][3] “ 

The news this week in interesting since it describes effects of limiting glucose on the cellular level on both normal and precancerous cells.  The online pre-publication is entitled Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression.  “We analyzed normal WI-38 and immortalized (precancerous) WI-38/S fetal lung fibroblasts and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells.” (Both sets of cells were exposed to either normal or reduced levels of glucose (sugar) while being grown in the laboratory.)  “Moreover, in WI-38/S (precancerous) cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16INK4a. Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction.”   

Said differently, reducing glucose decreased telomerase expression and increased apoptosis in precancerous cells leading them to die off, and produced the opposite effect in normal cells. 

The observed effects were epigenetic.  “The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as anti-aging approaches(ref).”  

A 2008 report in Science Daily Calorie Restriction Limits — And Obesity Fuels — Development Of Epithelial Cancers  further examines the CR-cancer connection.  “A restricted-calorie diet inhibited the development of precancerous growths in a two-step model of skin cancer, reducing the activation of two signaling pathways known to contribute to cancer growth and development,–“ –“ This study employed four diets, two representing calorie reductions of 30 percent and 15 percent, a control diet including 10 percent kilocalories from fat, and an obesity-inducing diet consisting of 60 percent kilocalories from fat.  Agents were then given to the mice to induce premalignant lesions called papillomas, which are precursors to cancer. — Those on the calorie restricted diets had statistically significant inhibition of papilloma formation compared with the other two diets. — In a separate experiment the development of carcinomas and the effect of dietary energy balance on conversion of papillomas to carcinomas was evaluated. This study demonstrated that dietary energy balance determines the number of carcinomas found through its effects on the number of premalignant lesions but does not affect the rate of malignant conversion.” 

The molecular signaling pathways involved in the CR-cancer link appear to be ones discussed several times previously in this blog, namely IGF-1, Akt and mTOR(ref)(ref)(ref).  “Epithelial cancers arise in the epithelium – the tissue that lines the surfaces and cavities of the body’s organs. They comprise 80 percent of all cancers.  “Calorie restriction and obesity directly affect activation of the cell surface receptors epidermal growth factor (EGFR) and insulin-like growth factor (IGF-1R),” Moore said. “These receptors then affect signaling in downstream molecular pathways such as Akt and mTOR.” – “increased Akt and mTOR signaling are linked to the growth, proliferation and survival of many human cancers.”  These findings provide the basis for future translational studies targeting Akt/mTOR pathways through combinations of lifestyle and pharmacologic approaches to prevent and control obesity-related epithelial cancers in humans,” DiGiovanni said(ref).” 

It is interesting that CR inhibiting the Akt-mTOR pathways as mentioned in this study and glucose limitation inhibiting expression of hTERT and promoting P16 in cancer cells as mentioned in the other study seem on the surface to be independent effects.  No doubt, on a deeper level these effects are linked.   

Several other research reports highlight the association between CR and lower levels of cancer.  One research study  reported in 2008 “sheds light on the connection between obesity, calorie intake and pancreatic cancer by comparing a calorie restricted diet, an overweight diet and an obesity-inducing diet in a strain of mice that spontaneously develops pancreatic lesions that lead to cancer. – “Our findings indicate that calorie restriction hinders development of pancreatic cancer, which could have implications for prevention and treatment of pancreatic tumors caused by chronic inflammation and obesity.”–  The group’s analysis points to a connection between calorie intake and a protein called Insulin-like Growth Factor (IGF) -1, with obesity increasing and calorie restriction decreasing levels of IGF-1. IGF-1 is an important growth factor known to stimulate the growth of many types of cancer cells. Inflammatory signaling proteins also were found to be reduced in the blood of the calorie-restricted mice.”

“Mice on the heavier diets had significantly more lesions and larger lesions than those on the restricted calorie diet, — These lesions develop into pancreatic cancer and virtually all of these mice die within six to eight months.   The researchers fed the calorie restricted group a diet that was 30 percent lower in calories than that consumed by the overweight group and 50 percent lower than the obese group. Only 7.5 percent of mice on the calorie-restricted diet developed pancreatic lesions at the end of the experiment, and these lesions were so small that none exhibited symptoms of illness. For mice on the overweight diet, 45 percent developed lesions, as did 57.5 percent of those on the obesity-inducing diet. Lesions were also much larger in the overweight and obese mice than the calorie restricted mice. –. Pancreatic cancer is the fourth leading cause of cancer death and remains mostly intractable to existing treatments(ref). 

Sex differences and hormonal factors may also impact on the results of CR.  Regarding a 2008 study (ref) done by Spanish and Italian researchers, “Using lab rats as stand-ins for humans, the researchers found that the livers of both female rats and calorie-restricted rats produced different levels of 27 proteins than male rats or those on a normal diet. — The findings suggest that a previously unrecognized set of cellular pathways may be involved in the longevity boost from being female and eating a sparse diet, the study says, suggesting that these insights could lead to new ways of boosting human longevity(ref).” 

I will continue this discussion in the follow-up post, Calorie restriction research roundup – Part II.

A news item appeared this week citing mortality and morbidity statistics for patients who undergo abdominal surgery.  This led me to probe a bit into how surgery risks increase with age and even to speculate on why. 

First of all, to be clear on terminology, morbidity relates to ongoing disease, sickness or poor health and mortality describes the probability of death, usually measured in numbers of death per thousand individuals.  Both are cause-independent, that is, if mortality connected with  cancer surgery is counted in terms of deaths in the year following the operation, deaths due to pneumonia, stroke or other causes would be counted along with deaths due to cancer.  Comorbidity refers to the presence of one or more additional diseases or disorders, such as pneumonia and hypertension going along with lung cancer. 

In the latest study Impact of advancing age on abdominal surgical outcomes “Nader N. Massarweh, M.D., and colleagues at University of Washington School of Medicine, Seattle, examined complication and death rates of 101,318 adults age 65 or older who underwent common abdominal procedures such as cholecystectomy (gall bladder removal), hysterectomy and colectomy from 1987 to 2004. Complications were recorded within 90 days of discharge and deaths were recorded within 90 days of hospital admission(ref).” 

A review of the publication states:  “Older adults have a higher risk of complications and early death after common abdominal surgeries than doctors thought, a new study found.”

“Among patients 65 and older, the 90-day complication rate after abdominal surgery was 17.3% and the 90-day death rate was 5.4%, according to an online report in the Dec. 21 Archives of Surgery.”

“The likelihood of complications increased as patients aged beyond 65 years, with the researchers finding the following associations between age and complication frequency (trend test, P<0.001):

• 65 to 69 years, 14.6%
• 70 to 74 years, 16.1%
• 75 to 79 years, 18.8%
• 80 to 84 years, 19.9%
• 85 to 89 years, 22.6%
• 90 and older, 22.7%

Similarly, older patients were at higher risk of mortality. Death rates by age group were (trend test, P<0.001):

• 65 to 69 years, 2.5%
• 70 to 74 years, 3.8%
• 75 to 79 years, 6.0%
• 80 to 84 years, 8.1%
• 85 to 89 years, 12.6%
• 90 and older, 16.7%”

“Among older adults, the risk of complications and early death after commonly performed abdominal procedures is greater than previously reported,” Nader N. Massarweh, MD, of University of Washington School of Medicine, Seattle, and colleagues concluded(ref).”  What I find interesting is the rapid acceleration of death rates with age.  Comparing the 65-69 range with the 85-89 range, over a 20 year age interval the death rate associated with a surgery has gone up by a factor of five.

Reading this report led me to wonder if the reported  magnitudes of increase in risks with advancing age are typical or whether they are unique to the kinds of surgery studied.  So, I set out to look for other large scale studies of age-related morbidity and mortality associated with different surgical procedures.  One such study is reported in the 2005 paper Early mortality among Medicare beneficiaries undergoing bariatric surgical procedures.  “Results:  A total of 16,155 patients underwent bariatric procedures (mean age, 47.7 years [SD, 11.3 years]; 75.8% women). The rates of 30-day, 90-day, and 1-year mortality were 2.0%, 2.8%, and 4.6%, respectively. Men had higher rates of early death than women (3.7% vs 1.5%, 4.8% vs 2.1%, and 7.5% vs 3.7% at 30 days, 90 days, and 1 year, respectively; P<.001). Mortality rates were greater for those aged 65 years or older compared with younger patients (4.8% vs 1.7% at 30 days, 6.9% vs 2.3% at 90 days, and 11.1% vs 3.9% at 1 year; P<.001).   After adjustment for sex and comorbidity index, the odds of death within 90 days were 5-fold greater for older Medicare beneficiaries (aged 75 years; n = 136) than for those aged 65 to 74 years (n = 1381; odds ratio, 5.0; 95% confidence interval, 3.1-8.0).”  Normally, the risk of death associated with bariatric surgery is low (0.5%), but apparently the risk rises very steeply with advanced age, much as observed in the first-mentioned study.

Both of the above studies were concerned with surgeries of the GI track.  Turning to a different kind of operative procedure the report Coronary arteriography and coronary artery bypass surgery: morbidity and mortality in patients ages 65 years or older. A report from the Coronary Artery Surgery Study, ‘Of 2144 patients age 65 years or older entered into the registry of the Coronary Artery Surgery Study (CASS) who had coronary arteriography, 1086 underwent isolated coronary artery bypass grafting. Complications of angiography included death in four patients and nonfatal myocardial infarction in 17. Eight patients suffered neurologic complications, which were transient in five. The perioperative mortality was 5.2% (57 of 1086), which is significantly greater than the perioperative mortality of 1.9% (151 of 7827) in patients younger than 65 years entered in CASS (p less than 0.001). There was a trend toward an increased mortality rate with age; it was 4.6% (37 of 803) in patients age 65-69 years, 6.6% (16 of 241) in those 70-74 years and 9.5% (four of 42) in those 75 years or older. The duration of hospital stay after operation was significantly longer for the patients 65 years or older than for the patients younger than 65 (13.3 vs 11.4 days; p less than 0.001).”  Again, the observed increase of mortality with age was drastic and consistent with that reported in the other studies.

I checked out one more study Effect of patient age on increasing morbidity and mortality following urogynecologic surgery.  “There were 264,340 women in our study population. Increasing age was associated with higher mortality risks per 1000 women (<60 years, 0.1; 60-69 years, 0.5; 70-79 years, 0.9; ≥80 years, 2.8; P < .01) and higher complication risks per 1000 women (<60 years, 140; 60-69 years, 130; 70-79 years, 160; ≥80 years, 200; P < .01). Using multivariable logistic regression, increasing age was associated with an increased risk of death (60-69 years, odds ratio [OR] 3.4 [95% CI 1.7-6.9]; 70-79 years, OR 4.9 [95% CI 2.2-10.9]; ≥80 years, OR 13.6 [95% CI 5.9-31.4]), compared with women <60 years. The risk of peri-operative complications was also higher in elderly women 80 years of age and older (OR 1.4 [95% CI 1.3-1.5]) compared with younger women.”  Again, a similar pattern was observed, 5.6 times he mortality risk in the oldest group compared to that that in the younger group.  Amazing how similar these rates are to those observed in the first-mentioned study above, and amazing the difference that 20 years makes at the end of life! 

These results are not surprising given what we know about aging.  Vulnerability to multiple causes of illness and death starts to accelerate around 50, picks up in the 60s, accelerates further in the 70s and goes into warp overdrive in the 80s – resulting in everybody in known history being dead by age 123.  There are many ways to explain this effect, the 14 theories of aging and seven candidate theories in my treatise being the main ones from a scientific viewpoint.  The darkest view is that given in my blog entry Homicide by DNA methylation.   According to that view, lifelong progression of DNA methylation causes accumulation of irreversible DNA mutational damage.  Even if you could reverse the methylation at old age you could not undo the mutations so its soon curtains for us old folk, no matter what.  End of discussion.  The other theories of aging to some extent allow more hope for the prospect of extending life.  Discovering where the best realistic hope lies is an ultimate objective I have in following and understanding the research described in this blog.

Genetics, genomics, epigenetics and epigenomics are important recurrent topics in the writing of this blog.  The discussions have included many examples of longevity-related  genes, “shortivity” genes, cancer and inflammation-related genes, gene silencing and gene mutations.  For reference purposes I list the genes I have discussed or mentioned with pointers to the corresponding blog entries.

Telomerase genes

·        “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).”

·        See also the blog entry Hoyeraal-Hreidarsson Syndrome and telomere dysfunction

VHL-1 gene:  See the blog entry Another longevity-related biochemical pathway.

P-53 gene:  See the blog entry P53 gene, normal and mutant, in the news.  Also see the blog entry: Senesco and the Factor 5A1 gene.

P-50/65 and NF-kappaB: See the blog entry Autoimmune diseases and lymphoma – Part II: focus on inflammation

P16 and P19 genes: See the blog entries Linking up the theories of aging and Revisiting the naked mole rat – two factors we can emulate for longevity 

WFS1, CISD2, WRN and LMNA genes: See the blog entry Another rare genetic disease, and shortevity genes   

LMNA gene: See the blog entry Progerin, HGPS and a possible new theory of aging. 

AOX gene:  This is a possibly-protective gene missing in humans.  See the blog entry Gene therapy for fruit flies with Parkinson’s Disease 

FRAP1 gene and mTOR:  See the blog entry Longevity genes, mTOR and lifespan. 

FA gene:  See the blog entry A simple treatment for human genetic diseases. 

CFTR, GSTZ1_02 ,pG42R), AKR1C3_35), TYR_02, SCARB1_03, SLC23A1_05. CD80_04, BCL2L1_03, CASP9, EPHX1_15, and ERCC4_01 genes:  See the blog entry Gene variations and diseases – far from simple. 

PINK1 gene:  See the blog entry Mitochondria and Parkinson’s Disease. 

RAS2 and SCH9 genes: See the blog entry Life extension by a factor of 10.

APOE4 and TOMM40  genes: See the blog entry APOE4 gene variant, memory loss and Alzheimer’s Disease risk  

Fas and FasL genes: See the blog entry: Fascinating dance of death and life – Fas, FasL and diseases.  See also : Autoimmune diseases and lymphoma: Part I: focus on Lupus.

TREX1 gene: See the blog entry: Autoimmune diseases and lymphoma: Part I: focus on Lupus.

TNF superfamily of genes within chromosome 6p21.3 and Bcl-2 gene: See the blog entry: Autoimmune diseases and lymphoma – Part III: focus on lymphomas.

P13k gene: See the blog entry: Big pharma is targeting cancer stem cells.  Also see Nrf2 and cancer chemoprevention by phytochemicals, Rosmarinic acid, and Breakthrough telomere research finding.

FTO gene: See the blog entry: The “skinny” about the “fatso” gene FTO. 

FOXO genes:  See the blog entry: FOXO genes and protecting stem cells — What does resveratrol do?  

KLOTHO gene: See the blog entry: Klotho anti-aging gene in the news. 

NRG1 gene: See the blog entry: The NRG1 Gene – an important new tumor suppressor gene? And press sensationalism about it. 

BRCA1, BRCA2, APC, RB1. WIF1, MLH1, TIMP3, PTEN, APC, CD95, RASSF1A, E cadherin, RECK and GSTP1 genes:  See the blog entry: DNA demethylation – a new way of coming at cancers.

Factor 5A1 gene:  See the blog entry: Senesco and the Factor 5A1 gene. 

RPE65 gene: See the blog entry: A gene therapy home run. 

UCP1, PRDM16 genes: See the blog entry: Getting skinny from brown fat.

A news item appeared this week saying that British researchers have succeeded in creating complete genome mappings for normal tissues, lung-cancer tissues and melanoma tissues in a single patient.  While the result is an exciting breakthrough in one sense, it also highlights the very long way there is still to go in decoding cancer genomes and using this information practically to identify cancer susceptibilities, to identify cancer preventative measures and to identify new anti-cancer therapies. I will say a few words about the background of this work, describe the new finding and mention a practical use of existing knowledge of cancer-related gene polymorphisms.

The website of the The Cancer Genome Project of the Wellcome Trust Sanger Institute in the UK provides an introduction:  “All cancers occur due to abnormalities in DNA sequence. Throughout life, the genome within cells of the human body is exposed to mutagens and suffers mistakes in replication. These corrosive influences result in progressive, subtle divergence of the DNA sequence in each cell from that originally constituted in the fertilised egg. Occasionally, one of these somatic mutations alters the function of a critical gene, providing growth advantage to the cell in which it has occurred and resulting in the emergence of an expanded clone derived from this cell. Acquisition of additional mutations, and consequent waves of clonal expansion result in the evolution of the mutinous cells that invade surrounding tissues and metastasise. One in three people in the Western world develop cancer and one in five die of the disease. Cancer is therefore the commonest genetic disease. — The identification of genes that are mutated and hence drive oncogenesis has been a central aim of cancer research since the advent of recombinant DNA technology. The Cancer Genome Project is using the human genome sequence and high throughput mutation detection techniques to identify somatically acquired sequence variants/mutations and hence identify genes critical in the development of human cancers. — –“.  “The census is not static but rather is updated regularly/as needed.  — Currently, more than 1% of all human genes are implicated via mutation in cancer. Of these, approximately 90% have somatic mutations in cancer, 20% bear germline mutations that predispose to cancer and 10% show both somatic and germline mutations.”

The site classifies known cancer genes as follows by type of genetic error:

Clicking on any of the error categories will show the oncogenes in the category. 

A discussion of genetic errors can be found in my blog entry Gene variations and diseases – far from simple.

The new findings

The 16 December advance online publication by members of the Wellcome Trust Sanger Institute is entitled A comprehensive catalogue of somatic mutations from a human cancer genome. By sequencing the entire genome of one patient with lung cancer and melanoma three times: once in healthy cells, once in lung cancer cells and once in melanoma cells, it was possible to identify the mutated genes associated with each of the two types of cancer. Amazing numbers of mutations were found:  33,000 in the melanoma genome, 23,000 in the lung cancer genome.

A fascinating aspect of this work is discovery of traces of pre-disease history in the mutated genes including the efforts of the body’s genetic repair mechanisms.  “These are the two main cancers in the developed world for which we know the primary exposure,” explains Professor Mike Stratton, from the Cancer Genome Project at the Wellcome Trust Sanger Institute. “For lung cancer, it is cigarette smoke and for malignant melanoma it is exposure to sunlight. With these genome sequences, we have been able to explore deep into the past of each tumour, uncovering with remarkable clarity the imprints of these environmental mutagens on DNA, which occurred years before the tumour became apparent. — “We can also see the desperate attempts of our genome to defend itself against the damage wreaked by the chemicals in cigarette smoke or the damage from ultraviolet radiation. Our cells fight back furiously to repair the damage, but frequently lose that fight(ref).”

A companion December 16 advance online publication A small-cell lung cancer genome with complex signatures of tobacco exposure relates to the mutational process leading from tobacco smoking to lung cancer and how the footprints of this process can be found in the mutated genes found in the cancer cells. “Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident.” Lung cancer kills about 1.3 million people a year worldwide.“

“In the melanoma sample, we can see sunlight’s signature writ large in the genome,” says Dr Andy Futreal, from the Wellcome Trust Sanger Institute. “However, with both samples, because we have produced essentially complete catalogues, we can see other, more mysterious processes acting on the DNA. Indeed, somewhere amongst the mutations we have found lurk those that drive the cells to become cancerous. Tracking them down will be our major challenge for the next few years(ref).”

The work leaves many questions still to be answered such as:  One is “Which gene mutations are primary and essential to the cancer and which ones are just going along for the ride?” Which gene mutations lead to which others, how, when and why?”  Expanding the research to include more people with the same cancers and people with other cancers may help to answer the questions.  There are perhaps 100 other kinds of cancer that can be studied in the same way, so there is a long ways yet to go. 

Benefits of genomic profiling of cancers could be enormous in the realm of personalized medicine, such as:

·         identification of cancer susceptibilities long before occurrence of actual cancers,

·         being able to know how far along a cancer-susceptible person is from actually manifesting the disease,

·         knowing how to stop disease progression at that point,

·         new lifestyle, drug, genetic and epigenetic interventions to prevent occurrence of and cure of specific cancers.

There is already some payoff being realized from knowledge of certain specific gene mutations, for example the BRCA1 and BRCA 2 mutations. These mutations are both known to be associated with increased risk for breast and ovarian cancers. The December 17, 2009 report Gene Mutation in Cancer Patients Leads to Earlier Diagnosis “Breast cancer patients with a particular gene mutation are diagnosed years earlier than the previous generation who also had the disease, according to a study conducted at The University of Texas M.D. Anderson Cancer Center.  — Background information provided in the study’s paper revealed that it is estimated that 5% to 10% of all breast cancers are associated with either the BRCA1 or 2 mutation, both of which are associated with an increased risk for breast and ovarian cancers. Furthermore, according to the American Cancer Society (ACS), women with BRCA1 or 2 have a 60% lifetime risk of developing breast cancer, compared to a 12% risk for women in the general population.”

I have covered a number of new-science approaches to detecting, preventing or curing cancers in this blog and in other writings.  The context was set in an early blog entry From four-pound hammer to smart molecules – on cancer treatments.  Here is a listing of the new approaches and twists on old ones, citing relevant blog and writing entries:

*  DNA demethylation:  See DNA demethylation – a new way of coming at cancers.  Also Homicide by DNA methylation, and Embryonic Stem cell research news.  In my treatise see the candidate theory of aging Epigenomic Changes in DNA Methylation and Histone Acetylation and the blog entry Epigenetics, Epigenomics and Aging.

*  Use of terminator stem cells:  See Terminator stem cells in the early pipeline.  See also Trojan-horse stem cells might offer an important new cancer therapy, and Progress in fighting glioblastoma.

*  Using TRAIL to kill cancer cells: See On the TRAIL of a selective cancer treatment.  Also note Terminator stem cells in the early pipeline.

*  Keeping telomeres long:   See Revisiting telomere shortening yet-again.  The discussion in the treatise section Telomere Shortening and Damage is relevant for background.

*  Telomerase activation affect on cancer stem cells:  See Extra-telomeric benefits of telomerase – good news for telomerase activators. 

*  Gene therapy: See for example A Fascinating dance of death and life – Fas, FasL and diseases. 

*  Targeting the Factor 5A1 gene: See Senesco and the Factor 5A1 gene

* Inhibition of expression of NF-kappaB:  See in my treatise discussions in the Susceptibility to Cancers Firewall and in the Programmed Epigenomic Changes Firewall.

*  Taking advantage of the NRG1 GENE:  See The NRG1 Gene – an important new tumor suppressor gene?, Also see DNA demethylation – a new way of coming at cancers

*  Targeting the Nrf2 gene: see Nrf2 and cancer chemoprevention by phytochemicals.  Also Phytochemicals – focus on caffeic acid and Health and longevity benefits of dark chocolate.

* Targeting cancer stem cells:  see News on disabling cancer stem cells, Big Pharma is targeting cancer stem cells, Update on cancer stem cells, and On cancer stem cells.

*  Plant-derived substances:   See Progress in fighting glioblastoma re curcumin,  see Cordyceps militaris and cancer, and Blueberries and health – the research case.

*  Chemotherapy combinations and substances in clinical trials for lymphomas: see Autoimmune diseases and lymphoma – Part III: focus on lymphomas 

*  Cancer immunotherapy:  See Dendritic cell cancer immunotherapy 

*  DHMEQ:  See More on DHMEQ and a no-no mind bender and DHMEQ.

* Prevention of oncogenic radiation-induced DNA damage:  See my paper Protection Against Radiation – The Second Line of Defense.

For the time being it appears that the multiple forms of cancer offer multiple challenges and that multiple approaches  will be needed to deal with these challenges.  Thus, each of the above approaches and others yet may turn out to have their roles. I will continue to monitor these and other emerging developments.

Newly-reported research involves progress in disabling cancer stem cells via the notch pathway.  Regarding cancer stem cells, see the blog entry Big pharma is targeting cancer stem cells. “As I wrote in my July 2009 post On cancer stem cells, most cancer therapies are based on killing cancer cells – as many cells as possible.  But cancers frequently and persistently recur after bouts of radiation or chemotherapy.  The culprit is thought to be cancer stem cells, where any surviving ones simply go about making new cancer cells.  A new therapeutic concept is therefore to focus on killing the cancer stem cells.  “While normal stem cells are essential for development, play a key role in tissue maintenance, and aid in repair, cancer stem cells are believed responsible for tumorigenesis, metastases, and cancer recurrence(ref).”  I reported further research regarding cancer stem cells in my August 2009 blog post Update on cancer stem cells.”  

I also briefly discussed how the Notch pathway is involved in tumorgenesis in the blog post Niche, Notch and Nudge.

A news report appeared yesterday indicating “Studies in animals and women with advanced breast cancer showed the experimental compound MK-0752, under development by Merck & Co Inc, was able to kill off cancer stem cells that linger in the breast after chemotherapy. — In the latest study, supported by funding from Merck, Chang and colleagues injected mice with breast cancer cells taken from patients and grew human tumors in the mice that were identical to those growing in women. The team then studied the specific properties of the cancer stem cells, and focused on the Notch pathway, which is important for normal development of breast tissue.  “We found this was also active in cancer stem cells,” Chang said in a telephone interview. Chang said breast cancer stem cells were dependent on the Notch pathway for survival. Merck’s drug MK-0752, a compound called a gamma-secretase inhibitor, blocks that pathway. When the team combined the drug with regular chemotherapy in mice, “we found we managed to hit cancer stem cells,” Chang said.”

The team also did a small human study involving 35 women with advanced breast cancer. Breast cancer biopsies before and after treatment show the MK-0752 treatment reduces the number of breast cancer stem cells.  “In the human studies, the researchers evaluated the stem cells or tumor initiating cells in biopsies taken before and after treatment. In both human and animal studies, inhibition of the pathway reduced the population of these tumor-originating cells that would otherwise remain after chemotherapy. — The next step in research is to take this into larger studies involving patients (Phase III clinical studies), Chang said. “If what we believe is true, we would eventually start using this therapy earlier in treatment,” said Chang(ref).”

The nanotechnology and epigenomics fields are barely 10 years old.  Both show enormous future potential.  An important application has recently emerged that involves both of them as pointed out in a recent research announcement New DNA Test Uses Nanotechnology to Find Early Signs of Cancer. 

I have discussed DNA methylation several times before.  See the blog posts Epigenetics, Epigenomics and Aging and DNA methylation, personalized medicine and longevity in this blog.  Also the blog entry Homicide by DNA methylation which discusses the possibility that DNA methylation may be the cause of aging and death in higher organisms. DNA methylation involves the chemical attachment of a methyl group to a cytosine nucleotide in the DNA on chromosomes.  DNA methylation happens throughout life and modifies the epigenomic state of a cell, that is, helps determine which genes are turned on and which genes are turned off.  In general, methylation silences genes, that is turns them off.  When key tumor-suppressor genes are silenced due to methylation, vulnerabilities to cancers exist.  Knowledge that tumor suppressor genes are methylated is potentially valuable to alert disease susceptibility and to allow preventive measures to be taken.

Tests for silenced tumor suppressor genes exist but they are awkward, involve multi-step laboratory procedures, and less sensitive than the new method.  The new discovery possibly opens the door for widespread economic testing for multiple cancer-related methylation patterns.

“Using tiny crystals called quantum dots, Johns Hopkins researchers have developed a highly sensitive test to look for DNA attachments that often are early warning signs of cancer. This test, which detects both the presence and the quantity of certain DNA changes, could alert people who are at risk of developing the disease and could tell doctors how well a particular cancer treatment is working.  — When the quantum dots are exposed to certain types of light, they transfer the energy to fluorescent molecules, shown as pink globes, that emit a glow. This enables researchers to detect and count the DNA strands linked to cancer(ref).”

The new testing method is reported in the paper MS-qFRET: A quantum dot-based method for analysis of DNA methylation in the August issue of Genome Research. Samples were collected by spitting on a chip.  “Here we report an ultrasensitive and reliable nanotechnology assay, MS-qFRET, for detection and quantification of DNA methylation. Bisulfite-modified DNA is subjected to PCR amplification with primers that would differentiate between methylated and unmethylated DNA. Quantum dots are then used to capture PCR amplicons and determine the methylation status via fluorescence resonance energy transfer (FRET). Key features of MS-qFRET include its low intrinsic background noise, high resolution, and high sensitivity. This approach detects as little as 15 pg of methylated DNA in the presence of a 10,000-fold excess of unmethylated alleles, enables reduced use of PCR (as low as eight cycles), and allows for multiplexed analyses. The high sensitivity of MS-qFRET enables one-step detection of methylation at PYCARD, CDKN2B, and CDKN2A genes in patient sputum samples that contain low concentrations of methylated DNA, which normally would require a nested PCR approach. The direct application of MS-qFRET on clinical samples offers great promise for its translational use in early cancer diagnosis, prognostic assessment of tumor behavior, as well as monitoring response to therapeutic agents.”  

While this post describes a better means for detecting cancer-related DNA methylation, my November 1 post discusses the hope of reversing such methylation once it is detected DNA demethylation – a new way of coming at cancers.

This work is another example of how technologies from diverse disciplines are coming together so as to accelerate the state-of-the-arts of disease prevention, detection, and therapy.  And, of course, these will also extend average longevity.  Like a multitude of other developments, the practical benefits of the most basic discoveries are probably 4-15 years out.  See, for example, yesterday’s post Terminator stem cells in the early pipeline, the December 6 post Personalized medicine and genetic drug interaction, the November 24 post It’s a long way to stem cell treatment, and the November 11 item A gene therapy home run.