AGINGSCIENCES™ – Anti-Aging Firewalls™

Perhaps you have been wondering about this too.  I have been spending a good deal of time in research, thought and writing recently in order to generate long technical blog posts such as those in the recent three-part series on Auto-immune diseases and lymphomas.  This has led me to ask myself again why I am doing this work.  What I am up to with this blog and the Anti-aging firewall treatise in general?  I am not being paid to do the work and I am not getting university or institutional credit for doing it.  And I am not accepting advertising on my web sites.  So why am I doing it?  I could be seeing good movies instead.  I share the answers I came up with here.

Having defined myself as a research-synthesizer in the longevity sciences, the work I do, the researching, the thinking and writing the blog entries and updating my treatise serves me in several ways.  The work helps me:

·        To develop a working familiarization with the basic scientific disciplines relevant to longevity, including human biology, organic chemistry, biochemistry, molecular biology, genetics, nutrition, genomics, and several areas of medicine  What I am learning would require many years of undergraduate and graduate study, important for me since my college and graduate school study back eons ago was concerned with other topics.

·        To develop a working understanding of the forefront areas of longevity science and relevant developments in the many collateral fields and research areas involved (like advanced molecular biology, genomics, proteomics and the other “omics”) including a capability to read, understand and digest relevant research publications in these areas.

·        To be comprehensive in my coverage of longevity sciences.  This entail exploring and developing familiarity with important areas peripheral to longevity, be these specific disease processes, bimolecular pathways, genomic and stem cell developments, methods of biotechnology engineering, or nutritional substances with extraordinary capabilities.

·        To develop a capability to synthesize understanding across several disparate fields and areas of scientific research so as to be able to see emerging new patterns in the longevity sciences and what it will take to achieve extraordinary longevity.

·        To communicate my understandings, realizations and new syntheses freely to others who might be interested, documenting what I write meticulously with research citations and maintaining a high standard of intellectual integrity.  My writing is targeted to health professionals and individuals seriously concerned with the sciences of aging.

·        Through this process to gradually build up a constituency of readers who follow my work.  As of the time of this writing between 500 and 800 people with unique URL identifiers visit my blog and treatise sites and view at least two web pages every day.  (My whole treatise is defined as a single page).

·        Through this process, to realize feedback, suggestions, encouragement and collegial relationships with concerned parties.

·        Through this process to achieve a growing level of legitimacy in the anti-aging science community which will in time allow me to develop institutional affiliations, speaking and consulting engagements, and income streams.   

·        To maintain and expand my own intellectual capability as I age through applying it on a daily basis in a most-challenging area of emerging knowledge. 

My commitment to researching, thinking, writing and publishing an almost-daily blog has been a way of forcing myself into the discipline necessary to move forward as above.  Writing for purposes of sharing forces me to think clearly.  And having a significant reader constituency is forcing me to be creative, relevant and interesting.  My readers, I thank you for being my professors.  And please let me know what you think and what you would like to see more of.

This is Part III of three lengthily posts involving autoimmune diseases and lymphomas.  In the Part I post, I focused on a particular autoimmune disease, Lupus erythematosus, its genetic causes and new therapies intended to address it.  The Part II post was concerned with the association between Lupus and other autoimmune diseases with lymphomas, what this association is telling us, and the key role of inflammation. Further, I discussed the key role of NF-kappaB, a cell nuclear factor, in autoimmune-related inflammation.  This Part III post focuses on lymphomas, their classification, causes, and conventional and emerging therapies for lymphomas. Finally, I include a few comments and speculations about where lymphoma treatments may be going.

Classifications of lymphomas

Lymphoma is a class of cancers that originates in lymphocytes (particularly, T cells and B cells) of the immune system(ref).  One such cancer is Hodgkin’s disease, named after the person who discovered it, and there are 16 other lymphoma cancers known as non-Hodgkin lymphomas (NHL’s). These can affect either T cells or B cells.  A classification of NHLs listing the general properties of each can be found here.  B cell lymphomas represent about 85% of occurrences of NHLs including those that emerge in patients with autoimmune dysfunctions. “The principal functions of B cells are to make antibodies against antigens, perform the role of Antigen Presenting Cells (APCs) and eventually develop into memory B cells after activation by antigen interaction. B cells are an essential component of the adaptive immune system(ref).”   “The human body makes millions of different types of B cells each day that circulate in the blood and lymphatic system performing the role of immune surveillance. They do not produce antibodies until they become fully activated. Each B cell has a unique receptor protein (referred to as the B cell receptor (BCR)) on its surface that will bind to one particular antigen. The BCR is a membrane-bound immunoglobulin, and it is this molecule that allows the distinction of B cells from other types of lymphocyte, as well as being the main protein involved in B cell activation. Once a B cell encounters its cognate antigen and receives an additional signal from a T helper cell, it can further differentiate into one of the two types of B cells listed below (plasma B cells and memory B cells)(ref).”  So, there is a lot that can go wrong with B cells and their functioning resulting in lymphomas.

The American Cancer Society web site offers excellent summaries of the risk factors for NHL, what is known about causes for NHL, possible preventative measures, and explains treatments, providing information on Surgery,  Radiation Therapy, Chemotherapy, Immunotherapy, Bone Marrow or Peripheral Blood Stem Cell Transplantation, Clinical Trials, Complementary and Alternative Methods, Treatment of Specific Lymphomas, and More Treatment Information.  This general information is too extensive to repeat here but I touch on a few high points.

Causes of lymphoma

Causes of lymphoma are traditionally viewed as complex and not well understood.  There are several known risk factors such as having an autoimmune disease or certain other diseases such as HIV.  At the root level, the cause is thought to be involved with DNA errors that are inherited or, in the case of NHLs, mutations or DNA copying errors acquired in the process of living.  See the July blog post Gene variations and diseases – far from simple.  In that post I said “In some cases gene families are known to indicate increased disease susceptibility, for example as recently reported for non-Hodgkin lymphoma: “Our results provide consistent evidence that variation in the TNF superfamily of genes and specifically within chromosome 6p21.3 impacts lymphomagenesis. Further characterization of these susceptibility loci and identification of functional variants are warranted(ref).”” 

According to the ACS web site “DNA mutations related to non-Hodgkin lymphoma are usually acquired after birth, rather than being inherited. Acquired mutations may result from exposure to radiation, cancer-causing chemicals, or infections, but often these mutations occur for no apparent reason. They seem to happen more often as we age, and lymphomas for the most part are a cancer of older people.” – “Translocations are a type of DNA change that can cause non-Hodgkin lymphoma to develop. A translocation means that DNA from one chromosome breaks off and becomes attached to a different chromosome. When this happens, oncogenes can be turned on or tumor suppressor genes can be turned off. Some lymphomas tend to have specific chromosomal defects. For example, most cases of follicular lymphoma have a translocation between chromosomes 14 and 18, which results in the turning on of the bcl-2 oncogene. This stops the cell from dying at the right time(ref).”   I expect much more will be learned about the genetics of lymphomas in the next few years and, already, a few genetics-oriented therapies such as targeting the bcl-2 oncogene are in clinical trials.

NHLs vary widely in their etiology, prognosis and available treatment options.  For some low-grade lymphomas like Low Grade Diffuse B-Cell Lymphomas and Waldenström’s macroglobulinemia, there can be good news and bad news for the patient.  The good news is that the disease may develop very slowly and not impact seriously on the patient for many years.  The bad news is that in several cases there is no good available treatment until the patient takes a turn for the worse.  Low-grade disorders may begin to progress rapidly after five to 10 years to become aggressive or high-grade, and at that point effective treatment options could be limited    “Taken as a whole, low grade lymphomas (diffuse and follicular, B-cell and T-cell) make up from 20-45% of lymphomas and have a median survival of 5 years or more. Patients are often left untreated until morbidity occurs. While combination chemotherapy usually secures a complete or partial response, the relapse rate is 10-15% per year thereafter(ref).”

Chemotherapy

Chemotherapy appears to be the mainline traditional approach for treating NHLs, specifically favoring the CHOP and more recently R-CHOP protocols.  CHOP consists of four drugs:  Cyclophosphamide (also called Cytoxan/Neosar), Doxorubicin (or Adriamycin), Vincristine (Oncovin) and Prednisolone.  R-CHOP adds Rituximab. 

·        Cyclophosphamide “works by slowing or stopping cell growth. It also works by decreasing the immune system’s response to various diseases.” – “Phosphoramide mustard forms DNA crosslinks between (interstrand crosslinkages) and within (intrastrand crosslinkages) DNA strands at guanine N-7 positions. This leads to cell death(ref).”

·        Doxorubicin “is a cytotoxic anthracycline antibiotic(ref).” It is used therapeutically against many cancers.  “The exact mechanism of action of doxorubicin is complex and still somewhat unclear, though it is thought to interact with DNA by intercalation^[14]  and inhibition of macromolecular biosynthesis.^[15] This inhibits the progression of the enzyme topoisomerase II, which unwinds DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication(ref).”  The drug has several potentially serious side effects. 

·        Vincristine is an alkaloid that “ binds to tubulin dimers, inhibiting assembly of microtubule structures. Disruption of the microtubules arrests mitosis in metaphase. The vinca alkaloids therefore affect all rapidly dividing cell types including cancer cells, but also intestinal epithelium and bone marrow(ref).  This drug too has potentially serious side effects.

·        Prednisolone is a powerful anti-inflammatory.  “Prednisolone is a corticosteroid drug with predominantly glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions –(ref)” Again, prolonged therapy with prednisolone can lead to serious side effects.

·        Rituximab is a chimeric monoclonal antibody that wipes out B cells by targeting the pan-B-cell surface marker CD20. 

Radiation therapy

Radiation therapy can be useful in certain instances, such as for early-diagnosed low grade localized follicular lymphoma, where it might provide a cure. It can also be used in conjunction with other therapies.  Of course, it can have life-shortening side effects.

Stem cell therapy 

Recently, stem cell therapies are also being tried as NHL therapies, often in combination with chemotherapies.  Normally stem cell therapies involve using hematopoietic stem cells derived from blood or bone marrow and can be of two kinds: autogolous which means using stem cells derived from the patient, and allogeneic which means using cells derived from a donor.  There are advantages and disadvantages to each.   On the one hand, relapse seems to be a serious issue when using allogeneic stem cells.  In one study identifying “Characteristics of relapse after autologous stem–cell transplantation for follicular lymphoma,”  looking at the 10-year history of 241 patients, “one hundred and three relapses occurred. The 10-year relapse probability was 47%. Median time from autoSCT to relapse was 20 (2–128) months(ref).” (I comment on this high relapse rate and what will probably be done about it in the future at the end of this post)  On the other hand, “Graft-versus-host disease (GVHD) occurs in up to 60 percent of those who have a transplant of blood stem cells — called hematopoietic cell transplantation — from the bone marrow or peripheral blood of unrelated donors. In GVHD, the immune system or T-cells from the donor recognize the recipient’s tissues as foreign and attack(ref).”  Various treatments for minimizing the chance of GVHD are under investigation.  Sometimes, stem cell therapy may be combined with myeloablative therapy, e.g. a very intense regimen of chemotherapy to destroy all cells that divide rapidly, before transferring in the stem cells.

Clinical trials

There is a broad quest underway for improved cancer treatments and cures, and NHL lymphoma is one of the prime targets. A search of clinical trials for treatments on adult NHLs within 500 miles of my home in the National Cancer Institute’s database reveals 243 entries.   I note a few of these to illustrate the mix and diversity of what is going on in NHL cancer treatment research.

·        This trial, like many others, involves testing combinations of existing chemotherapy agents possibly with additional agents for particular NHL diseases or disease stages: Phase III Randomized Study of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) Versus Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin and Rituximab (EPOCH-R) in Patients With Previously Untreated De Novo Diffuse Large B-Cell Non-Hodgkin’s Lymphoma

·        Trial of another combination of well-known chemotherapy agents for specific lymphoma conditions: Phase I/II Randomized Study of Bortezomib, Rituximab, Cyclophosphamide, and Prednisone in Patients With Relapsed or Refractory Indolent B-Cell Lymphoproliferative Disorders or Mantle Cell Lymphoma

·        One of many trials looking at Rituximab-centered therapy approaches: A Study of Rituximab Alternative Dosing Rate in Patients With Previously Untreated Diffuse Large B-Cell or Follicular Non-Hodgkin’s Lymphoma (RATE)

·        This trial looks at a relatively new substance CMC-544 in conjunction with Rituximab.  :  Study Evaluating CMC-544 Administered in Combination With Rituximab in Subjects With Non-Hodgkin’s Lymphoma (NHL).  CMC-544 has previously been shown to be potent against systemically disseminated B-cell lymphoma in mice. 

·        This trial involves testing a novel monoclonal antibody substances when the patient is refractory to use of a usual one: HuMax-CD20 in FL Patients Refractory to Rituximab

·        This trial tests chemotherapy alternatives when used in conjunction with stem cell transplantation, in this case using autologous stem cells: Comparison of Rituxan Versus Bexxar When Combined With Carmustine, Etoposide, Cytarabine and Melphalan (BEAM) With Autologous Hematopoietic Stem Cell Transplantation (ASCT)

·        Another study looking at chemotherapy regimens to combine with stem-cell transplantation, allogenic stem cells this time: Tacrolimus/Sirolimus/Methotrexate Versus Tacrolimus/Methotrexate or Cyclosporine/Mycophenolate Mofetil for GVHD Prophylaxis After Reduced Intensity Allogeneic Stem Cell Transplantation for Patients With Lymphoma.  The emphasis here is prevention of GVHD.

·        Another trial with emphasis on GVHD prevention after allogenic stem cell transplantation is Bortezomib Plus Tacrolimus and Methotrexate to Prevent GVHD After Mismatched Allogeneic Non-Myeloablative Blood Stem Cell Transplantation .

·        This trial seems to combine two familiar themes, use of Rituximab and prevention of GVHD: Rituximab for Prevention of Chronic GVHD .

·        Fatigue is often an important issue for patients who have undergone intensive cancer chemotherapy.  This trial looks at a dietary supplement:  Phase III Randomized Study of American Ginseng (Panax quinquefolius) in Patients With Cancer-Related Fatigue.  The title is self-explanatory.

·        This trial looks at a different “alternative” approach to treating post-chemotherapy fatigue: Acupuncture for the Treatment of Chronic Post-Chemotherapy Fatigue: A Randomized, Phase III Trial 

·        An early-phase trial of a relatively new potential chemotherapy substance SB-743921:  A Study of SB-743921 in Non-Hodgkin’s Lymphoma.  Initial clinical findings were recently published(ref).

·         Another early-phase trial of yet-another potential chemotherapy agent Phase I/II Study of ABT-263 in Patients With Relapsed or Refractory T-cell or B-cell Lymphoid Malignancies.  ABT-263 is an orally bioavailable inhibitor of Bcl-2 family members(ref).  This trial is one of several trials concerned with relapsed or refractory lymphomas.

I cannot do justice to all the clinical trials but the list above is illustrative and leads to a few observations:

·        A great many of the trials involve alternative combinations of known cancer chemotherapy agents for alternative lymphoma conditions.

·        Several trials involve rituximab and other monoclonal antibody therapies, possibly in combination with other conventional chemotherapy agents

·        Certain “old favorite” chemotherapy agents show up in the trials over and over again, including prednisolone, rituximab, methotrexate, doxorubicin , mycophenolate mofetil, often variations of R-CHOP or other cancer chemotherapy protocols.

·        Stem cell clinical trials for NHLs seem to focus on using chemotherapeutic agents to prevent GVHD in the case of allogeneic transplants and relapses in the case of autologous transplants

·        A number of trials are focused on relapsed or refractory lymphomas.  Driving these trials is the fact that existing therapies don’t always work and many are subject to relapse.

Comments and speculations

I have no doubt that the existing clinical trials will lead to improved treatment schedules for NHL’s; how much improved I do not know. 

My impression is that therapies specifically targeting cancer stem cells have not yet entered clinical trials.  As long as cancer stem cells are doing their thing and continuing to differentiate, therapies that mainly kill off normal cancer cells are likely to lead to relapse.  See my recent post Update on cancer stem cells and the post On Cancer stem cells. 

I speculate that the high rate of relapses in cases of autologous stem cell transplants in treatments of NHLs is due to the fact that the patient’s own stem cells contain the same genetic defects that led to the lymphoma condition in the first place.  The transplant takes the patient back to an earlier epigenomic state but the gene-determined cancer susceptibility remains the same.  I speculate further that an ultimate therapy might involve restoring selective cells from a patient to induced pluripotent stem cell( iPSC) state, repairing the genetic defect in these iPSCs to remove the cancer susceptibility, and then using these corrected cells for stem cell therapy.  This process is described in the August 2009 blog post Treating genetic diseases with corrected induced pluripotent stem cells.  I expect at some point to learn about clinical trials of this approach.

Yesterday, the National Center for Health Statistics in its preliminary 2007 statistical report on deaths indicated that average life expectancy (at birth) in the US was up 73 days in 2007 from 2006, up to 77.9 years.  The report indicated life expectancy rose from 75.1 to 75.3 years for men and from 80.2 to 80.4 years for women. The 5.1- year difference in male and female life expectancy was year-to-year the same though it is down from 7.8 years back in 1979.

The age-adjusted death rate in the United States continued its steady year-by-year decline and fell to 760.3 deaths per 100,000 in 2007, about half of what it was 60 years ago.

“Mortality rates declined significantly for eight of the 15 leading causes of death, including —  8.4 percent decline from influenza and pneumonia, 6.5 percent decline from homicides, 5 percent decline from accidents, 4.7 percent from heart disease, 4.6 percent from stroke, 3.9 percent from diabetes, 2.7 percent from high blood pressure and 1.8 percent drop from cancer. — There was also a 10 percent drop in deaths from HIV and AIDS between 2006 and 2007 — the biggest one-year fall since 1998. HIV, however, remains the leading cause of death among 25 to 44 year olds(ref).” 

Of relevance from an anti-aging viewpoint, the 15 leading causes of death in 2007 were reported to be: 

1. Diseases of heart 615,651

2. Malignant neoplasms 560,187

3. Cerebrovascular diseases 133,990

4. Chronic lower respiratory diseases 129,311

5. Accidents (unintentional injuries) 117,075

6. Alzheimer’s disease 74,944

7. Diabetes mellitus 70,905

8. Influenza and pneumonia 52,847

9. Nephritis, nephrotic syndrome and nephrosis 46,095

10. Septicemia 34,851

11. Intentional self-harm (suicide) 33,185

12. Chronic liver disease and cirrhosis 28,504

13. Essential hypertension and hypertensive renal disease 23,769

14. Parkinson’s disease 20,136

15. Assault (homicide) 17,520

All other causes 465,089        

In the May 2009 blog entry Social ethics of longevity I argued that social evolution requires that people live longer – and is in fact leading to longer and longer life spans. “As social evolution advances at an exponentially increasing rate and society continues to become more complex, there is an ever-increasing need for people to draw on vast resources of information, deep knowledge and wisdom to survive and advance the society.  The time required for basic education continues to grow and continuing education becomes a lifelong necessity.   Longer life spans therefore serve the need of social evolution by increasing mobilization of knowledge and wisdom.”    Increase in average life span of 73 days in the course of just one year is not doing badly at all. 

Anti-aging science, the subject of this blog, is part of this broad stream of social and human evolution leading to longer and longer lives.  I welcome you who are joining me in exploring the scientific frontier of this stream!

This is the second of three lengthily posts involving autoimmune diseases and lymphoma.  In the first post I focused on a particular autoimmune disease, Lupus erythematosus, its genetic causes and new therapies intended to address it.  This Part II post is concerned with the association between Lupus and other autoimmune diseases with lymphoma, what this association is telling us, and the key role of inflammation. Further, I discuss the key role of NF-kappaB), a cell nuclear factor, in autoimmune-related inflammation and possibly in the transition to lymphoma.

Autoimmune diseases, inflammation and lymphoma

It has long been observed that certain autoimmune diseases convey an increased risk of malignant lymphomas, but the nature and cause of this risk seemed unclear.  A 2006 review study publication by a Swedish team cast some light on the situation: Malignant Lymphomas in Autoimmunity and Inflammation: A Review of Risks, Risk Factors, and Lymphoma Characteristics .  “Recent results clearly indicate an association between severity of chronic inflammation and lymphoma risk in RA (rheumatoid arthritis) and Sjögren’s syndrome. Thus, the average risk of lymphoma in RA may be composed of a markedly increased risk in those with most severe disease and little or no increase in those with mild or moderate disease.” – “Furthermore, RA, Sjögren’s syndrome, systemic lupus erythematosus, and possibly celiac disease may share an association with risk of diffuse large B-cell lymphoma, in addition to well-established links of Sjögren’s syndrome with risk of mucosa-associated lymphoid tissue lymphoma and of celiac disease with risk of small intestinal lymphoma(ref).” 

Several parallel and subsequent reports confirm and further clarify the association, such as this study relating autoimmune diseases to Waldenström macroglobulinemia (WM), a non-Hodgkin lymphoma subtype.  That study looked at histories of 4 million US veterans, of which 361 were identified to be patients with WM. “In the largest investigation of WM risk factors to date, we found a 2- to 3-fold elevated risk of WM in persons with a personal history of autoimmune diseases with autoantibodies – (ref).”  These two (ref)(ref) 2009 reports review epidemiological studies that relate autoimmune diseases to lymphomas and other pathologies.

It seems that presence of intense inflammation is a predictor of susceptibility to lymphoma in patients with an autoimmune disease, and that control of the inflammation can lessen the probability of a lymphoma emerging.   This report concludes “Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.”    Another Swedish report based on the same data looked at the impact of long-term anti-inflammatory treatment of RA patients with steroids on susceptibility to lymphoma.  The study compared a population of 378 individuals with both RA and associated lymphoma with a matched population of individuals with RA but without lymphoma.  The study concluded that “Increased duration of corticosteroid use (more than 2 years) was associated with a reduced risk of lymphoma (particularly large B-cell lymphoma) in RA patients(ref).”  While the result is interesting, prolonged use of a powerful steroid like prednisone may not be a good thing.  John Hopkins medical editors caution “–  that any benefit of prolonged steroid treatment on the prevention of lymphoma must be balanced against known detrimental side effects (i.e. ischemic heart disease, insulin resistance, osteoporosis, etc…) that are more common and may result in greater group morbidity and mortality than lymphoma(ref). 

Lymphoma and lupus are both diseases that involve B-cell pathologies and control of inflammation via prednisone is a common feature of the conventional treatment approaches for both.  This report - The treatment of lymphoma complicating autoimmune disease: two birds with one stone?   – looks at the vexing issue of how best to treat a non-Hodgkin lymphoma in the context of an auto-immune disease and discusses using R-CHOP as a common protocol addressing both disease conditions. R-CHOP stands for a chemotherapy regimen of five drugs used to treat aggressive non-Hodgkin lymphomas(ref).

What are autoimmune diseases at a cellular level?  Different autoimmune diseases correspond to different immune system abnormalities, and these are in most cases quite complex and only partially understood.  For example, in the case of SLE:  “Although tissue-bound antigen-antibody complexes are the principal effectors of this inflammatory process, a fundamental disorder of the immune system that permits the inappropriate production of autoantibodies exists at the cellular level.   It is currently held that T-lymphocyte effector dysfunctions contribute to this altered immune response in SLE. Indeed, diverse T-cell dysfunctions have been well described in SLE. Among these are (a) exaggerated CD4 T-helper (Th) activity; (b) diminished CD8 T-cytotoxic/regulatory (Tc) function; (c) imbalanced production of Th1 and Th2 cytokines, and (d) reduced proliferative responses to antigens/mitogens. These diverse T-cell dysfunctions lead to an imbalance between helper and cytotoxic/regulatory functions that promote B-cell proliferation, differentiation and antibody production. Due to the loss of effective Tc regulatory feedback to B cells, forbidden B-cell clones can produce autoantibodies directed against an array of intra- and extracellular autoantigens(ref).” 

Role of NF-kappaB

Given that rampant inflammation plays such an important role in autoimmune diseases, in the genesis of autoimmune-related lymphoma, and in lymphomas themselves, what can be said about the process that leads to such inflammation?   I look at that issue here from a particular vantage point, examining the role nuclear factor NF-kappaB in the inflammatory process of an autoimmune disease. 

(As background, expression of NF-kappaB plays an important role in the Programmed Epigenomic Changes theory of aging covered in my treatise.   NF-kappaB is also discussed in several previous blog entries including Updates on NF-kappaB, DHMEQ, A further update on NF-kappaB, On the TRAIL of a selective cancer treatment, Histone acetylase and deacetylase inhibitors,  Spices of life, Anti-inflammatory effects of the hormone alpha-MSH, and More on DHMEQ and a no-no mind bender. )

For purposes of this post, I draw heavily from a 2006 report A role for transcription factor NF-kappaB in autoimmunity: possible interactions of genes, sex, and the immune response.  “Gene and hormone alterations of the NF-kappaB signaling cascade provide a unifying hypothesis to explain the wide-ranging human and murine autoimmune disease phenotypes regulated by NF-kappaB, including cytokine balance, antigen presentation, lymphoid development, and lymphoid repertoire selection by apoptosis.”  The discussion in this paper is complex but worth following for readers seriously interested in grasping what is going on.  In simplified terms some of the main points are:

·        Most autoimmune diseases including lupus are expressed much more frequently by females than by males, “– women account for 80% of cases.”  — “hormonal shifts in pregnancy, menopause, and aging are associated with fluctuations in the course of autoimmune disease(ref).”  

·        “NF-kappaB appears to be a central player in several autoimmune diseases, according to recent studies of genetic defects in autoreactive lymphoid cells (the immune cell types responsible for autoimmunity) in both murine models of autoimmunity and humans with diverse forms of autoimmunity.”  “– in autoimmune diseases “both genes and sex hormones may exert their effects through the same general mechanism, dysregulation of transcription factor NF-kappaB –(ref).” 

·        “Although the genes altering NF-kappaB appear to vary in different autoimmune diseases, usually decreased NF-kappaB activity in response to select cell surface cytokines is commonly observed.”  — “In a normal immune cell in the periphery, exposure to TNF (tumor necrosis factor) triggers a complex pathway of NF-kappaB activation that culminates in an active NF-kappaB dimer entering the nucleus, i.e., the p50/p65 complex. This NF-kappaB complex ensures that the cell will survive(ref).”  It does this by activating genes that protect the cell from apoptosis.     “As shown, studies in autoimmunity have identified mutations and functional blocks in the NF-kappaB signaling pathway in autoimmune disease. These mutations alter the autoreactive T cells signaling due to disruptions in NF-kappaB activation.”  In the presence of such a mutation there is no NF-kappaB activation there is no protection against apoptosis induced by TNF and the cell dies.  “NF-kappaB controls cell death (apoptosis) and life decisions in immune cells in the periphery. If the NF-kappaB pathway is intact in the periphery, activated NF-kappaB enters the nucleus and results in the transcription of genes for survival. If the NF-kappaB pathway via is blocked, the cell will die instead with TNF exposure. TNF is essential in the peripheral in maintaining cell life and death decisions and control of T cell populations(ref).”

·         “In lupus, activation of NF-kappaB signaling is attenuated in T cells due to the absence of the p65 appearance in the nucleus, one of the NF-kappaB subunits that binds to DNA .This is compounded in lupus by a polymorphism in TNF receptor 2, a version of the TNF receptor restricted to activated CD8 T cells. This mutation affects TNF-induced apoptosis by decreased NF-kappaB signaling and thus the set point for death(ref).”

At this point I flag what appears to be a paradox: 1. The above says the pathology underlying lupus and several other autoimmune diseases is connected with attenuated NF-kappaB signaling and insufficient translocation of the p65 subunit into the nucleus in immune cells, 2. Glucocorticoids like prednisone (used for treating lupus, other autoimmune diseases and many forms of lymphoma) work by inhibiting the nuclear transport of  NF-kappaB (ref).  If the initial problem is too much inhibition, how does further inhibition help as a key step in controlling inflammation? Clearly, there are many other signaling pathways involved besides NF-kappaB.

Implications for the anti-aging firewalls regimen In the light of the above, a question arises as to the roles of some of the substances in the firewall regimen for individuals who have inflammatory autoimmune diseases.  I am thinking of substances that are at the same time anti-inflammatories, anti-oxidants, pro-apoptosis agents in cancers and promoters/inhibitors of NF-kappaB.  Green tea extract, curcumin and resveratrol are examples.   What is the net effect of taking such supplements on individuals having an autoimmune disease?  

The answer may vary by disease and substance but curcumin may offer an example.  “Recent studies have shown that curcumin ameliorates multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease in human or animal models. Curcumin inhibits these autoimmune diseases by regulating inflammatory cytokines such as IL-1beta, IL-6, IL-12, TNF-alpha and IFN-gamma and associated JAK-STAT, AP-1, and NF-kappaB signaling pathways in immune cells(ref).”  “Traditionally known for its antiinflammatory effects, curcumin has been shown in the last two decades to be a potent immunomodulatory agent that can modulate the activation of T cells, B cells, macrophages, neutrophils, natural killer cells, and dendritic cells. Curcumin can also downregulate the expression of various proinflammatory cytokines including TNF, IL-1, IL-2, IL-6, IL-8, IL-12, and chemokines, most likely through inactivation of the transcription factor NF-kappaB(ref).” See also these additional references with respect to the potential roles of curcumin for treating autoimmune diseases.   And such references also exist for the potential role of curcumin in lymphoma prevention, such as “Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53”.  So it appears that for curcumin at least, its impact on autoimmune diseases is likely to be positive.  A similar conclusion appears to be the case for green tea(ref)(ref)(ref)(ref) and resveratrol(ref)(ref)(ref) and may also be true for several other of the firewall substances. Again, please see the medical disclaimer in the previous post.

Inhibition of the expression of NF-kappaB is a general strategy for retarding aging according to the 14^th  theory of aging covered in my treatise Programmed Epigenomic Changes.  There appears to be a solid research basis for that strategy.  In fact, 36 substances in my combined anti-aging supplement regimen inhibit the expression of  NF-kappaB.

This Part II post has focused on the relationship of autoimmune diseases to lymphoma, the critical role of inflammation in that relationship, the roles that TNF, NF-kappaB and cell death play in autoimmune diseases, and the potential role a few of the anti-aging firewall substances can play in controlling autoimmune diseases.  A final Part III post will focus on lymphomas, their classifications and conventional and emerging therapies for lymphomas.

FROM TIME TO TIME, THIS BLOG DISCUSSES DISEASE PROCESSES.  THE INTENTION OF THOSE DISCUSSIONS IS TO CONVEY CURRENT RESEARCH FINDINGS AND OPINIONS, NOT TO GIVE MEDICAL ADVICE.  THE INFORMATION IN POSTS IN THIS BLOG IS NOT A SUBSTITUTE FOR A LICENSED PHYSICIAN’S MEDICAL ADVICE. IF ANY ADVICE, OPINIONS, OR INSTRUCTIONS HEREIN CONFLICT WITH THAT OF A TREATING LICENSED PHYSICIAN, DEFER TO THE OPINION OF THE PHYSICIAN. THIS INFORMATION IS INTENDED FOR PEOPLE IN GOOD HEALTH.  IT IS THE READER’S RESPONSIBILITY TO KNOW HIS OR HER MEDICAL HISTORY AND ENSURE THAT ACTIONS OR SUPPLEMENTS HE OR SHE TAKES DO NOT CREATE AN ADVERSE REACTION.

There is more hard evidence coming in to support the notion that if we want to get somewhere with preventing and curing cancers, the best approach invoves broadening focus from what is going on inside and among cancer cells to also include what is going on inside and among cancer stem cells.  For background, see the July 6 blog post On Cancer stem cells. 

In fact, going back to when I was just starting this blog, in the february 5 post From four-pound hammer to smart molecules – on cancer treatments, I said “The idea is to discover genetics-based and bio-molecular therapies which go after and kill the cancer stem cells, turning off the source of new cancer cells. “New therapies designed to target stem cells could eliminate cancer without the risks and side effects of current treatments that also destroy healthy cells in the body. Destroying cancer stem cells in the original tumor could reduce the risk of deadly metastasis, where malignant cells move from the primary tumor to other places in the body. Finally, by killing the cells driving the tumor’s growth, treatments targeted at cancer stem cells could eliminate recurrences of the disease(ref).”   The hope is for approaches that prevent or cure cancers that work by killing cancer stem cells, or causing them revert to benign form or preventing their differentiation into cancer cells.

The new research reported yesterday in the world press shows two advances with respect to cancer stem cells (CSCs): first, development of a high-throughput screening approach for agents that have high toxicity for epithelial cancer stem cells; second, identification of a compound that has very high toxicity for breast cancer stem cells.  “A critical aspect of our work was to generate relatively homogenous and stable populations of cancer stem-like cells that could then be used for screening,” says Tamer Onder, — co-first author of the study(ref).”  “The technique works by coaxing adult cells to undergo a critical change (known as an “epithelial-to-mesenchymal transition”) that alters their shape and motility. At the same time, the cells also adopt similar properties as stem cells(ref).”

Of the 16,000 chemical compounds tested, only a small subset showed toxicity against cancer stem cells. One particular substance, salinomycin, showed high toxicity.  “– salinomycin, reduces the proportion of CSCs by >100-fold relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug. Treatment of mice with salinomycin inhibits mammary tumor growth in vivo and induces increased epithelial differentiation of tumor cells. In addition, global gene expression analyses show that salinomycin treatment results in the loss of expression of breast CSC genes previously identified by analyses of breast tissues isolated directly from patients(ref)”  “Salinomycin is an ionophore antibiotic used in farming for the prevention of coccidiodomycosis in poultry and to alter gut flora in order to improve nutrient absorption in ruminants(ref).”  

Of course, there is a long road of clinical trials that must be traveresed before salinomycin can be used for treating humans with breast cancer.  In an important recent post in this blog, I suggested that there was an important new way to look at aging: to focus not only on what goes on with normal body cells but also on what is happening with the stem cells in the supply chain that replenishes those body cells.  The same holds when it comes to cancers.

This is the first of three blog posts I intend to create relating to recent research on autoimmune diseases, Lupus in particular, the links between autoimmune diseases and lymphoma cancers, and such cancers themselves.  This Part I post is focused on recent research regarding one particular autoimmune disease, Lupus erythematosus, its genetic causes and new therapies intended to address it.  The Part II post will be concerned with the association between Lupus and other autoimmune diseases with lymphoma and what this association is telling us.  The final Part III post will review some recent research on lymphomas and emerging treatments for them. 

Autoimmune diseases

An autoimmune disease is “An illness that occurs when the body tissues are attacked by its own immune system(ref).”  Autoimmune diseases, including Lupus erythematosus , Crohns Disease, Graves’ Disease, Rheumatoid arthritis, Scleroderma, Pulmonary Fibrosis,  and Sjogren’s Syndrome affect hundreds of millions of people worldwide, are the cause of untold suffering, and are the subjects of intense research from multiple viewpoints.  Well over 70 autoimmune diseases and conditions have been discovered, some of which are close cousins of one another.  Many patients have symptoms of multiple autoimmune diseases.  In fact there is a category known as “mixed connective tissue disease.”  “It has been estimated that autoimmune diseases are among the ten leading causes of death among women in all age groups up to 65 years(ref).”   Moreover, as I will discuss in a next blog post, patients with autoimmune diseases have a significant susceptibility to developing lymphoma cancers.   

Systemic Lupus erythemetosus (SLE)

Patients with SLE are subject to severe inflammatory conditions that can occur in Lupus flares and that can possibly affect many different body systems including blood cells, joints, skin, kidneys, heart, and lungs.  About 1.5 million people in the US and at least 5 million worldwide are affected by lupus(ref).  The majority of those affected by SLE are women, perhaps 90% of the patients, and blacks and Latinos are significantly more susceptible than whites. . When the disease first strikes, the victims are usually in their 30s and 40s.   The manifestations of SLE and how and when they will emerge vary widely from patient to patient.  External symptoms can include  fatigue, Raynaud’s syndrome, fever, joint pain, stiffness and swelling, rashes, arthritic attacks, skin lesions, chest pain, and mouth sores.  A patient may go many years in a relatively benign condition between inflammatory flares.  On the other hand SLE can attack many internal organs, leading to death. In case of a flare the disease is usually treated aggressively with a strong anti-inflammatory drug, particularly Prednisone.  Otherwise a low-level of the disease may be treated with a more benign anti-inflammatory drug like Plaquinil.

SLE diagnosis

A common feature shared by SLE patients is the presence of antibodies that can be identified by tests, like ANA and anti-dsDNA(ref). These antibody tests, clinical manifestations and other blood tests like sedimentation-rate are used in diagnosis of lupus.  Lupus comes in multiple manifestations and is sometimes confused or compounded with other autoimmune diseases.

How does SLE work?

Basically, SLE involves immune cells attacking normal body cells.  But what are the underlying genetic/bimolecular mechanisms?  On a general level, SLE appears to be a disease of faulty B-cell signaling(ref).  “Although the cause of SLE remains unsolved, the research accumulated thus far points to numerous aberrations in antigen-receptor mediated signaling events exhibited by SLE B cells and highlights signaling defects that presumably play a central role in the pathogenesis of the disease. Abnormal B cell signaling certainly plays a significant role in the breakdown of B cell tolerance and subsequently the pathogenesis of SLE.”

There are several interesting possibilities undergoing research investigation relating to the basic processes underlying SLE.  For example:

•  I discussed an underlying genetic conditions thought to be important to SLE in a blog post earlier this month: A Fascinating dance of death and life – Fas, FasL and diseases. I said: “Defects in the Gene encoding Fas is correlated with systemic lupus erythematosus (SLE).  “In the murine MRL/Ipr-Ipr model of systemic lupus erythematosus (SLE), the lymphoproliferation (lpr) mutation results in defective transcription of the gene that codes for the Fas protein.” – “Interest in the importance of Fas in SLE has risen with the observation that 60% of human subjects with lupus have elevated levels of the soluble Fas receptor in their serum and that the abnormal presence of this molecule may protect lymphocytes from undergoing apoptosis(ref).”  The link of FAS to autoimmune diseases goes back over a decade, considering the 1998 paper Human autoimmune lymphoproliferative syndrome, a defect in the apoptosis-inducing Fas receptor: a lesson from the mouse model. 

• Abnormal editing of gene-produced messages in T cells may be a causal factor in Lupus(ref).  “Dama Laxminarayana, Ph.D., assistant professor of internal medicine and senior author, said that in systemic lupus erythematosus, the normal editing process goes awry, causing a shift in the balance of proteins that results in impaired functions in T cells, a type of white blood cell involved in the regulation of immune functions.”  — “150-kDa ADAR1, one of the three enzymes involved in editing gene messages, is higher in the T cells of lupus patients compared to those without lupus. ADARs are adenosine deaminases that act on RNA(ref).”

• Aberrant differentiation of T helper cells into T follicular helper cells (Tfh cells) under the influence of Bc16 (a gene and transcription factor B-cell lymphoma 6), a might play a role in the manifestation of SLE as well as B-cell lymphomas.  “Tfh cells and germinal centers have been implicated in antibody-mediated autoimmune diseases such as lupus and rheumatoid arthritis, Dong noted. In these diseases, the germinal centers are likely producing the wrong type of antibody at great volume(ref).”

• Variations in the TREX1 gene may be related to susceptibility to SLE, according to a study reported in 2007(ref).  “The study involved 417 lupus patients from the United Kingdom and Germany. Mutations were found in nine patients with lupus and were absent in 1,712 people without lupus. “Our data identify a stronger risk for developing lupus in patients that carry variants of the gene,” said Lee-Kirsch.” – “The gene manufactures a protein, also known as TREX1, whose function is to “disassemble” or “unravel” DNA, the strand of genetic material that controls processes within cells. The “unraveling” occurs during the natural process of cells dying and being replaced by new cells. If a cell’s DNA isn’t degraded or unraveled during cell death, the body develops antibodies against it. “If the TREX1 protein isn’t working to disassemble the DNA, you make antibodies to your own DNA and can end up with a disease like lupus,” said Perrino(ref).” 

•  Lupus gene-discovery results are being reported more and more frequently.  For example, see New Batch of Lupus Genes Discovered.  A January 2008 review study analyzes the Significance And Limitations Of New Lupus Gene Expression Research.   

• Finally, Lupus research is surfacing some interesting curiosities, such as revealed in the report Sex-Dependent Effect of Melatonin on Systemic Erythematosus Lupus Developed in Mrl/Mpj-Faslpr Mice: It Ameliorates the Disease Course in Females, whereas It Exacerbates It in Males.  Clearly, SLE appears to be sex-hormone linked. 

New therapeutic approaches are being investigated for SLE.  For example:

•  In 2004, “researchers at the Department of Health and Human Services’ National Institutes of Health (NIH) launched a five-year study to see whether a therapy using transplantation of hematopoietic stem cells, blood stem cells found in bone marrow, can produce long-term remission for patients with severe, treatment-resistant systemic lupus erythematosus(ref).”  The study was extended for another two years and no results have yet been published. The approach uses powerful immunosuppressive drugs to wipe out patients’ immune system cells, an approach that is potentially quite dangerous because for a week or two a patient undergoing the treatment has no operational immune system.  However, the treatment approach might-well work.  The idea is that autologous hematopoietic stem cells may have the same genes as mature immune system cells in a given individual, but that they might not have the epigenetic experience that leads to manifestation of SLE.   So, it may well be possible to reset an individual’s immune system to an earlier state, before development of SLE.  Besides showing that the technique works, the study could provide important information since it was designed with an intent to investigate how B and T cells function in the immune systems of lupus patients.  The results of this study will not be known for a couple of years although the results of other studies using the same approach are likely to be known earlier. 

• Treatment with Rituximab is another semi-experimental approach for dealing with SLE, particularly in episodes of severe inflammation where more conventional treatments like prednisone are not doing the job(ref).  Rituximab is a chimeric monoclonal antibody that wipes out B cells by targeting the pan-B-cell surface marker CD20.  The results of this approach appears to be a mixed bag.  A 2005 report indicates that for Lupus  “A total of 100 rituximab-treated patients with severe disease, refractory to major immunosuppressive treatment, have been reported so far. Within a median follow-up period of 12 months rituximab was well tolerated, which is compatible with the experience accumulated from its use in more than 500 000 lymphoma patients. About 80% of patients achieved marked and rapid reductions in global disease activity. Because of the clinical heterogeneity, dosing differences, and concomitant treatments, including cyclophosphamide in 35% of patients, a proper evaluation of the clinical efficacy or rituximab is difficult. Variable degrees of clinical benefit have been reported for all clinical systemic lupus erythematosus manifestations, including active proliferative nephritis.” – “The findings reviewed point to a growing optimism for targeting B cells in the treatment of systemic lupus erythematosus; therefore double-blind studies comparing rituximab with existing immunosuppressive therapies are needed.”  Many studies have involved only one or a few patients, such as described in this report.  A 2007 report on a study involving 2000 patients is headlined Over One-third of Refractory Lupus Patients Remain Stable After Receiving B-cell Depletion Therapy.  A March 2009 report indicates that a Phase III clinical trial was discontinued because the therapy that included rituximab for lupus nephritis was ineffective.  “March 11, 2009 –  Genentech, Inc. (NYSE: DNA) and Biogen Idec (Nasdaq: BIIB) announced today that a Phase III study of Rituxan® (rituximab) plus mycophenolate mofetil (MMF) and corticosteroids in patients with lupus nephritis did not meet its primary endpoint of significantly reducing disease activity at 52 weeks.”  That conclusion seems to be in conflict with this study report released about the same time suggesting that rituximab may indeed be a useful treatment for patients with severe lupus nephritis.  Of course, the treatment protocols were not the same.  Finally, rituximab treatment may have serious side effects, some of which are life-threatening(ref).   

• Therapy involving mycophenolate mofetil may be useful for reducing the frequency of lupus flares, according to a 2007 study(ref).  “The research team evaluated mycophenolate mofetil (MMF) to see if it would reduce the number of flares in SLE, which is both chronic and relapsing.  In the retrospective study, researchers studied 88 patients treated with MMF at Mayo Clinic over a two-year period. They also studied patient histories and data on lupus flares going back two years. The patients, whose average age was 44, had lupus for an average of 10 years. The majority of participants were women. Before the MMF, lupus flares in the group totaled 155 compared to 99 after treatment. For severe flares, the improvement was even more dramatic, from 98 to 54.” – “”Our findings show this therapy reduces lupus flares overall and is especially effective in reducing severe flares by roughly half,” says Mayo rheumatologist Kevin Moder, M.D., who led the research(ref).”

• Laboratory experiments reported in May 2009(ref) suggest that class R inhibitory oligonucleotides may be useful for controlling inflamation in patients experiencing a lupus flare.  The idea is to suppress lupus-related inflammation without generally suppressing the entire immune system.  “Using human cell lines and isolated mouse cells, Lenert and his colleagues showed that the DNA-like compounds were able to selectively reduce the activity of two types of immune cells called autoreactive B cells and dendritic cells. When given to mice with lupus, the compounds delayed death and reduced kidney damage, proving their effectiveness.” – “”With further testing, we hope that class R inhibitory oligonucleotides may become another weapon in the fight against lupus,” Lenert said(ref).” 

• Finally, the big recent news in the world press was interim success in a Phase III clinical trial of Benlysta, a new drug for lupus created by Human Genome Sciences(ref).  “Belimumab is a monoclonal antibody which targets and inhibits the activity of BLyS (B cell lymphocyte stimulator). BLyS is a naturally occurring protein which is normally involved in the survival of antibody producing B cells. When present in excess it can lead to the development of autoimmune diseases like lupus(ref).”  The drug may not turn out to be a blockbuster for lupus, but the announcement tripled the price of HGSI stock(ref).  That says something about the world’s hunger for an effective new treatment for SLE.

This has been a sampling of what is known about SLE and some emerging treatments for it.  The next post in this series will look more deeply at SLE and inflammation, and the relationship of SLE to lymphomas.  It is Summer and I am on a slowed-down work schedule so this next post may be a few days in coming.

It is pretty clear to most people when they are in pain and when they have a bothersome itch, and if you want to live a long life you don’t want either as a chronic condition.  However, the neurological events that lead to the experience of having a pain or having an itch have been only partially understood.  General information on pruritus (itchiness) can be found here and here.  “Studies have been done to show that itch receptors are only found on the top two skin layers, the epidermis and the epidermal/dermal transition layers. — Itch is never felt in muscle, joints, or inner organs, which show that deep tissue does not contain itch signaling apparatuses(ref).”  Itch is a serious topic of continuing study as you could find out from the Report from the 4th International Workshop for the Study of Itch attended by more than 130 scientists and physicians from throughout the world. 

For some time, researchers have thought that pain signals and itch signals traveled to the brain through two different pathways. “Unmyelinated nerve fibers for itch and pain both originate in the skin; however, information for them is conveyed centrally in two distinct systems that both use the same peripheral nerve bundle and spinothalamic tract(ref) .”  The spinothalamic tract consists of a set of cells that travel up the spine to the brain’s thalamus.

Two years ago, a team at the Washington University School of Medicine in St. Louis, Missouri discovered a gene that, expressed in neurons, appeared to be necessary for itch, but not pain, called the gastrin-releasing peptide receptor (GRPR) gene. Neurons expressing GRPR were thought possibly to be itch neurons.  Interestingly, GRPR – is involved in regulation of “–numerous functions of the gastrointestinal and central nervous systems, including release of gastrointestinal hormones, smooth muscle cell contraction, and epithelial cell proliferation and is a potent mitogen for neoplastic tissues. — The receptor is aberrantly expressed in numerous cancers such as those of the lung, colon, and prostate(ref).”  Also curiously, “ – the presence of 2 expressed copies of the GRPR gene in females may be a factor in the increased susceptibility of women to tobacco-induced lung cancer(ref).” 

In a  new study reported in the Aug 6  issue of Science Express, the same Washington University team focused on whether neurons expressing GRPR were the long-sought itch-only neurons.  The team selectively killed GRPR-expressing lamina I neurons and then exposed the mice to all kinds of itchy stimuli that would normally cause them to scratch themselves like crazy.  The mice did not scratch but responded as usual to various kinds of induced pain.  So, the inference is that GRPR-expressing neurons are the itch response neurons(ref).  “This finding has very important therapeutic implications,” says Zhou-Feng Chen, Ph.D., the study’s principal investigator. “We’ve shown that particular neurons are critical for the itching sensation but not for pain, which means those cells may contain several itch-specific receptors or signaling molecules that can be explored or identified as targets for future treatment or management of chronic itching(ref).”

There is still a lot more to be learned about itch.  ““We’ve shown that these GRPR neurons are important for itching sensation and not for pain, but we really don’t know much more about them,” Chen says.  “We still have a lot of questions, and we are very interested to find more answers(ref).”

It is summertime and I needed a little break from heavy-duty research today.  So, this time I picked an easy subject – folk remedies.  I do not know if any of the cures I list here really work and don’t vouch for any of them, but I do find them interesting 

• Warts?  Rub them with a banana skin to make them go away.  See this link.
• Feeling down with poor circulation or want to speed up your metabolism?  You could try a Russian steam bath (Shvitz in Eastern European Jewish culture).  See this link
• Curing a hangover.  Don’t drink so much in the first place and eat while you are drinking.  See this link.
• How to numb a toothache.  Use oil of clove.  See this link.
• Do you have night leg pains?  You could try camphor, oil of mustard, steam baths, red flannel, walnuts, cod liver oil, fenugreek and saffron.  Or, another approach is to sleep with a bar of soap.  See this link.
• Suffering from body odor?  “Just rub vinegar under the armpit instead of deodorant. The vinegar smell will disappear shortly. — Baking soda is one of the best alternatives to using commercial deodorants available. Just dust baking soda under the armpits on dry skin and it will absorb moisture as well as kill odor causing bacteria.”  See this link
• Want to keep colds and flu away”  A lot of interesting suggestions are on this site, including “ Put your toothbrush in a glass of hydrogen peroxide. This will keep you from reinfecting yourself.”
• Suffering from an unfaithful spouse?  You could try XXX-Triple Strength Spiritual Candles.  See this link.  There are several other traditional folk treatments for this condition.  According to the Qur’an An-Nur, for example(ref)  “The woman and the man guilty of illegal sexual intercourse, flog each of them with a hundred stripes. Let not pity withhold you in their case, in a punishment prescribed by Allâh, if you believe in Allâh and the Last Day. And let a party of the believers witness their punishment. (This punishment is for unmarried persons guilty of the above crime but if married persons commit it, the punishment is to stone them to death, according to Allâh’s Law).”
• Suffering from arthritis?  There are no end to ideas like “Blend 1-2 large Celery sticks with an Apple and a Carrot. Add a little water and take as a drink once or twice a day(ref).” 
• Can’t stop vomiting?  Here is a remedy based on onion juice and peppermint tea that “should stop vomiting within 15 minutes.”
• Skin problems?  Several ideas can be found here, including this one: “Take fresh cucumbers wash, dry and cut into pieces, put the pieces in a bottle filled with vodka and keep in a warm place for two weeks. (if you haven’t guessed (vodka) this, and the others in this paragraph, are Russian recipes). After two weeks the solution is strained, the cucumbers are discarded and the liquid is used as a lotion to soften the skin, eliminate pimples and shrink enlarged pores.”
• Athlete’s foot?  Several interesting folk remedies can be found here, including this one:  “CHAPARRAL – Mix six tablespoons of dried chaparral to one quart of boiling cheap whiskey or wine; reduce and simmer for 20 minutes; remove and steep for 8 hours. DO NOT use aluminum cookware! Soak your feet in this solution.”
• You can, by the way, buy used copies of the Folk Remedy Encyclopedia: Olive Oil, Vinegar, Honey and 1,001 Other Home Remedies from Amazon.com for $5.38. (link)

Research studies sometimes suggest remedy approaches that seem just as weird as the folk ones.  For example:

• Want to live a very long healthy life?  Here is a link to an earlier blog post that points to research saying that if you are a man, polygamy might help.

Many traditional folk remedies have been researched using the tools of contemporary science and have been found to make excellent sense, for example drinking green tea and eating foods with turmeric to ward off cancers. Traditional remedies listed as part of the combined anti anti-aging firewall suggested in my anti-aging treatise include astragalus root, ashwagandha, boswellia seratta, curcumin, ginger, billberries, olive leaf extract, grape seed extract, blueberries, saw palmetto, ginko biloba, stinging nettle, garlic, chocolate, olive oil, coffee and green tea. While use of these substances can be found in Chinese, Indian, Mediterranean and other traditions, they have all been the subject of recent Western-style research and have been found to possess valuable properties.  I have discussed many of these substances in my treatise and blog posts. 

Readers of this blog are likely to take the value of antioxidants for granted.  And indeed, a part of my overall anti-aging regimen is the firewall against oxidative damage which includes a number of antioxidants.  Research studies supporting the value of antioxidants are frequently cited both in this blog and in my longevity treatise.  However, serious research publications also appear from time to time that question the value or even the safety of antioxidant consumption.  I cite and comment on two of these here.

One such study, published in 2007 in the Journal of the American Medical Association (JAMA), is entitled Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention.  The study was a meta-analysis based on synthesizing data from other studies.  “We included 68 randomized trials with 232 606 participants (385 publications).”  The data for the entire sample of trials reported showed that there was no significant impact of taking antioxidant supplements on mortality, one way or the other.  However, when the trials were separated into two categories “high-bias risk trials” and “low-bias risk trials,” the data for the low-bias trials showed a significant association between taking antioxidants with increased mortality – the opposite of the hoped-for result.  “Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.05-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality(ref).”  Several letters cited on the JAMA website page along with the abstract for this study question the validity of the approach used in the analysis.  One such letter written by two doctors at the National Cancer institute states “We believe that the approach used in the meta-analysis of mortality in randomized trials of antioxidant supplements by Dr Bjelakovic and colleagues1 erred in several important ways, probably resulting in biased conclusions(ref).”  The implication is that deciding what studies were “low bias risk” was actually an exercise of bias.

Another recent study publication is entitled Antioxidants prevent health-promoting effects of physical exercise in humans. “ Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.”  In a experiment involving 49 healthy young men it was found that “Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants –“  Also, “ Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation(ref).”  The study does not deal with the critical question of whether the total impact of both exercising and taking antioxidant supplements is more or less health-producing than exercise or taking antioxidant supplements alone.

Personally I do not know what to make of these two studies except to be open to further research that corroborates or negates the views that they express.  I continue to see taking antioxidants as an important part of an anti-aging program.  But 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.