AGINGSCIENCES™ – Anti-Aging Firewalls™

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.

This is a long and important blog entry, going to the heart of “What is aging and what can be done about it?”

Stem cell research, churning along at a ferocious rate, is revealing a new view of aging from the cellular level – one that renders older concepts obsolete.  While that view is still being formed, my purpose here is to identify what that view generally looks like and some of the research evidence supporting it. I also look at a few of the existing theories of aging from this new viewpoint and touch on implications for anti-aging interventions.

The new view looks at aging as a cellular supply-chain phenomenon.  In a simplified model, think of the 210 kinds of cells found in the human body as falling in five categories:

A.  Human embryonic stem cells (hESCs) which are pluripotent and capable of differentiating into any cells; induced pluripotent stem cells (iPSCs) are also in this category,

B.  Relatively undifferentiated multipotent somatic stem cells, such as may exist in bone marrow or vascular walls (e.g. hematopoietic stem cells, mesenchymal stem cells and pericytes).  These multipotent cells are each capable of differentiating into a variety of kinds of somatic cells.

C.  More differentiated stem and progenitor cells (e.g. endothelial progenitor cells, myoblasts or satellite cells in muscle tissue).  These are cells capable of differentiating only into specific somatic cell types.  

D.  Normal body somatic cells (e.g.  cardiomyocytes, red blood cells, leukocytes, keratinocytes, melanocytes, and  Langerhans cells)

E.  Senescent cells, ones which no longer can divide.

Cells in all categories except Type E can divide to make new cells.  They are all subject to mutation, cell damage, oncogenesis and, it is thought, are subject to replicative senescence due to telomere attrition.  Cells of Type A in the early embryo progressively differentiate to make all cells of Types B, C or D. All cells of Type D result from differentiation of cells of Type A, B and/or C, possibly via intermediary stem cell types. Some cells of Type B may differentiate through several intermediate forms before creating Type D cells.  Hierarchy in differentiation is always preserved under natural conditions, although it may or may not necessarily be the case that intermediate stem cell types are involved depending on the kind of cell.

An early embryo consists of mostly A-Type cells.  This supply-chain process continues through life although in aging there may be more and more cells of Types D and E and fewer and fewer active cells of Types B and C. and virtually no active Type A cells left.  Healthy normal aging is thus a matter or cellular supply chain management.  The body must assure that there are not too many Type E cells around for they create havoc.  Type D cells are the workhorses of day-to-day functioning and the key factors involved are insuring a good supply of them by avoiding damage-related or replicative senescence, taking care of their need for nutrition and a healthy intra-cellular environment, and making sure that damaged or proto-cancerous cells are eliminated through proper apoptosis.  Also, it is important to assure that Type B and C cells are able to differentiate properly to provide a reliable source of replacements for them. 

The issues for Types B and C cells include seeing that they are in sufficient supply and health so as to be able to differentiate into Type D cells and making sure that the differentiating option is readily available when needed.  Other issues for Types B and C cells are similar to those for Type D cells – preventing damage-related or replicative senescence, and preventing oncogenesis.  The unique problem is that in aged individuals there are few active Type A cells around to replace them.

Before looking further at anti-aging interventions given this new perspective, let’s review some of the recent relevant research.

• Both proliferation and differentiation of Type A, B and C stem and progenitor cells decreases with aging due to the existence of niches (stem cell microenvironments) of more-differentiated cells.  That is, they reduce their regenerative potential.  “Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches(ref).”  This is important because it says that the very existence of differentiated cells in their niches acts to inhibit the proliferation and differentiation of stem cells. “– the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches(ref).”
• Although the mobilization responsiveness of Type C stem cells declines with age, it appears that their regenerative capability can be restored through environmental messages or induction of Notch activity.  “In adult skeletal muscle, where the resident dedicated stem cells (“satellite cells”) are capable of rapid and highly effective regeneration in response to injury, there is just such a loss of regenerative potential with age. Satellite cell activation and cell fate determination are controlled by the Notch signaling pathway that is initiated by the rapid increase in expression of the Notch ligand, Delta, following injury. In old muscle, this upregulation of Delta is blunted and thus satellite cell activation is markedly diminished. However, by indirectly inducing Notch activity, the regenerative potential of aged satellite cells can be restored.  In old muscle, this upregulation of Delta is blunted and thus satellite cell activation is markedly diminished. However, by indirectly inducing Notch activity, the regenerative potential of aged satellite cells can be restored. Furthermore, exposure of aged satellite cells to serum from young mice, either in vivo by heterochronic parabiotic pairings or in vitro, rejuvenates the satellite cell response. This restorative potential suggests that tissue-specific stem cells do not lose their ability to participate in tissue maintenance and repair. Therefore, it may be that even very old stem cells may be capable of maintaining and repairing aged tissues if provided with optimal environmental cues (ref).”

• The gene expression profiles in Type A human embryonic stem cells offer regenerative anti-aging potential not found in more mature stem cells.  “Significantly, this work establishes that hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo (ref).”  I comment at this point that the same regenerative potential is likely to be found in induced pluripotent stem cells.  See the post Rebooting cells and longevity and additional discussions of iPSCs in other posts in the blog.
• More is being learned about the relationships between stem cells and their niches and environmental messaging relating to stem cell division and differentiation.  Stem cells of Types B and C have been known for some time to live and thrive within specific tissue stem cell niches, microenvironments that interact with stem cells and are necessary for their survival and mobilization for differentiation.  Recently it was discovered that stem cells of type A in vivo also live in their autonomously derived niches(ref).  “Understanding how extrinsic factors control hESC self-renewal and differentiation will allow us to culture and differentiate these pluripotent cells with higher efficiency. This knowledge will be essential for clinical applications using human pluripotent cells in regenerative medicine(ref).”
• Stem cells are subject to replicative senescence, although niche signaling and telomerase expression may have strong influences on their replicative lifespan.  This 2008 study looked at replicative senescence of mesenchymal stem cells in vitro and found it to be “a continuous and organized process.”  “Within 43 to 77 days of cultivation (7 to 12 passages), MSC demonstrated morphological abnormalities, enlargement, attenuated expression of specific surface markers, and ultimately proliferation arrest. Adipogenic differentiation potential decreased whereas the propensity for osteogenic differentiation increased. mRNA expression profiling revealed a consistent pattern of alterations in the global gene expression signature of MSC at different passages. These changes are not restricted to later passages, but are continuously acquired with increasing passages. Genes involved in cell cycle, DNA replication and DNA repair are significantly down-regulated in late passages.”  This form of replicative senescence occurring at each reproduction cycle appears to be absence-of-niche related and not to be driven by telomere shortening, the usual cause of replicative senescence. It highlights the importance of understanding what is going on in stem cell niches. Proliferation and differentiation of stem cells involves a bimolecular dance with their niches.
• Highlighting the importance of stem-cell environment signaling, a recent finding is that Co-Culture with Mesenchymal Stromal Cells Increases Proliferation and Maintenance of Hematopoietic Progenitor Cells.  Stem cells seem to be very social animals.
• As I have previously pointed out, buildup of levels of Ink4a/P16 associated with aging slows down the rate of differentiation of adult stem cells.  “Recent evidence shows that loss of Bmi-1, a polycomb transcriptional repressor of theInk4a-Arf locus, results in progressive loss of HSCs in adult mice with subsequent failure of hematopoiesis.” – “ These results show that either both p16Ink4a and p19Arf can inhibit HSC self-renewal in a serial transplant setting, or that only p16Ink4a is necessary(ref).“
• Researchers are starting to look harder at the links between cellular senescence, aging, and bone marrow-derived cells.  See this review article.
• See the recent blog post Research evidence for the Decline In Adult Stem Cell Differentiation theory of aging.

Implication for anti-aging interventions

First of all, the required shift in emphasis seems to be expansion from what is going on with normal body cells to encompass also what is going on with stem cells in the supply chain.  If this view of aging is correct, a program of effective anti-aging interventions is needed that applies across the entire cell supply chain.   Simply extending the telomeres of Type D cells and extending their replicative life spans is unlikely to lead to extraordinary longevity if they are not being reliably replaced by stem cell differentiation.  And convincing Type B and Type C cells to differentiate more readily into Type D cells won’t achieve that end either if these stem cell stocks are aging and losing inherent capability.  Of course, both of these interventions could still help.  See the discussions for the Telomere shortening and damage and the Decline of adult stem cell differentiation theories of aging in my treatise.

Of the interventions in the combined anti-aging firewalls dietary regimen, a key one seems to be taking supplements that enhance the expression of telomerase.  That may have three positive anti-aging effects: 1. promoting differentiation of stem cells through a mechanism independent of telomere extension, 2.  extending the replicative lifespan of Type D somatic cells through extending their telomeres, and 3.  possibly similarly extending the replicative lifespan of Type B,  C and even possibly A stem cells through telomere extension.  The last point is a conjecture on my part since I am not aware of any direct research on that topic.  See the blog post Extra-telomeric benefits of telomerase – good news for telomerase activators.

The above-cited research also suggests a new possible anti-aging supply chain intervention: re-activating Type A cells at the head end of the entire supply chain to start producing new and vital Type B and Type C stem cells in a controlled fashion.  Whether this is to be accomplished by factors that enable the controlled expression hESCs already in the body or through use of iPSCs is yet to be seen.  The above-cited research provides clues.  For example, rejuvenating hESCs through increasing the expression of Oct4 in them to overcome mature niche signaling, hESC proliferation and differentiation might be increased. Oct4 is one of the transcription factors introduced to generate iPSCs from normal somatic cells.

Other supply chain anti-aging interventions may be possible, such as induction of notch activity in satellite cells to restore their regenerative capabilities.  Also, the fact that serum from young mice rejuvenates stem cell activity in old mice provides important clues for where to look further.

I expect there will be a lot more to say regarding this supply chain view of longevity interventions.

In the human body, of course everything is connected to everything else.  But some of these connections are intelligent and keep body parts working well together.  In particular, there are certain systems that detect problems such as the presence of disease or other stressors, compute solutions designed to maximize the survival of the organism, and send messages out to other body systems and components telling them what to do to get in step with a new or revised survival system. 

One such system is the hypothalamic-pituitary-adrenal axis. “The stress system coordinates the adaptive responses of the organism to stressors of any kind. The main components of the stress system are the corticotropin-releasing hormone (CRH) and locus ceruleus-norepinephrine (LC/NE)-autonomic systems and their peripheral effectors, the pituitary-adrenal axis, and the limbs of the autonomic system. Activation of the stress system leads to behavioral and peripheral changes that improve the ability of the organism to adjust homeostasis and increase its chances for survival.”  The effects of signaling from this system are widespread. “The CRH and LC/NE systems stimulate arousal and attention, as well as the mesocorticolimbic dopaminergic system, which is involved in anticipatory and reward phenomena, and the hypothalamic beta-endorphin system, which suppresses pain sensation and, hence, increases analgesia. CRH inhibits appetite and activates thermogenesis via the catecholaminergic system. Also, reciprocal interactions exist between the amygdala and the hippocampus and the stress system, which stimulates these elements and is regulated by them (ref).”  If you get badly startled the adrenalin kicks in and the whole cascade process is kicked off.

Recent research is revealing that the skin provides another quite similar system.  “Described as the body’s largest organ, the skin is strategically located at the interface with the external environment where it has evolved to detect, integrate and respond to a diverse range of stressors. A flurry of recent findings has established the skin as an important peripheral (neuro)endocrine organ that is tightly networked to central stress axes. This capability is contributing to the maintenance of body homeostasis, and in this way could be harnessed for therapeutic strategies(ref).”

Central actors in this regard are our old friends, melanocytes.  “More than 15 years ago, we have proposed that melanocytes are sensory and regulatory cells with computing capability, which transform external and/or internal signals/energy into organized regulatory network(s) for the maintenance of the cutaneous homeostasis. This concept is substantiated by accumulating evidence that melanocytes produce classical stress neurotransmitters, neuropeptides and hormones, express corresponding receptors and these processes are modified and/or regulated by ultraviolet radiation, biological factors or stress(ref).” Melanocortins produced by melanocytes have widespread impacts including cardiovascular regulatory effects(ref).  Regarding melanocytes, also see the previous posts Anti-inflammatory effects of the hormone alpha-MSH and  More research insight on gray hair and adult stem cell reproduction .

In fact, hair follicles just by themselves play an important role(ref)(ref).  And see Human hair follicles display a functional equivalent of the hypothalamic-pituitary-adrenal axis and synthesize cortisol.   “Thus, even in the absence of endocrine, neural, or vascular systemic connections, normal human scalp hair follicles directly respond to CRH stimulation in a strikingly similar manner to what is seen in the classical HPA axis, including synthesis and secretion of cortisol and activation of prototypic neuroendocrine feedback loops(ref).”  Who would think a lowly hair follicle could do things like that  – things that regulate my temperament and how I react?

To sum it up: “We are currently experiencing a spectacular surge in our knowledge of skin function both at the organ and organismal levels, much of this due to a flurry of cutaneous neuroendocrinologic data, that positions the skin as a major sensor of the periphery. As our body’s largest organ, the skin incorporates all major support systems including blood, muscle and innervation as well as its role in immuno-competence, psycho-emotion, ultraviolet radiation sensing, endocrine function, etc. It is integral for maintenance of mammalian homeostasis and utilizes locally-produced melanocortins to neutralize noxious stimuli. In particular, the cutaneous pigmentary system is an important stress response element of the skin’s sensing apparatus—(ref).”

I am planning another blog entry where I will discuss another topic related to melanocytes – the afamelanotide analog of alpha-MSH that has been in clinical trials and the “melanotan” commercial products that may or may not work like alpha-MSH and may or may not be safe.

This morning, several news items appeared in the world press on a study relating the impact of mental exercises to the incidence of dementia in the elderly.  The new study, reported the Aug. 4 issue of the journal Neurology, involved following 488 elderl y people aged 75 to 85 (mean age 79.5)  for an average of five years.  The participants did not have dementia when they enrolled in the study and 101 of them developed dementia during the study period. “We assessed the influence of self-reported participation in cognitively stimulating leisure activities on the onset of accelerated memory decline.” (The activities reported on were daily reading, writing, group discussions, playing music, doing crossword puzzles, and playing board or card games.)  “Results: Each additional self-reported day of cognitive activity at baseline delayed the onset of accelerated memory decline by 0.18 years (66 days)(ref).”  “”The point of accelerated decline was delayed by 1.29 years for the person who participated in 11 activities per week compared to the person who participated in only four activities per week,” said study author Charles B. Hall of Albert Einstein College of Medicine in Bronx, NY(ref).”

The link between mental activity and a reduced risk of dementia is not new.  “In one study, Dr Valenzuela, a clinical neuroscience research fellow at the University of NSW school of psychiatry, looked at almost 29,000 people.”   (The study combined data from 22 studies worldwide.) “He found that a lifetime of complex mental activity almost halved the risk of dementia. — A separate study conducted over three years used repeated brain scans of healthy people aged over 60. It found those who led mentally stimulating lives had “less shrinkage of the hippocampus”, the area of the brain associated with memory and the first area affected by Alzheimer’s(ref).”

I have written about mental exercise before in this blog.  See the post Brain fitness, Google and comprehending longevity.  Repeating something I said there, “Try and get your arms around longevity research and I can personally guarantee you will get ample mental exercise.” Physical exercise too powerfully helps postpone or prevent dementia – but that will be the subject of another blog posting.

The brain contains white matter, grey matter and black matter.  “White matter is composed of bundles of myelinated nerve cell processes (or axons), which connect various grey matter areas (the locations of nerve cell bodies) of the brain to each other, and carry nerve impulses between neurons(ref).”  “A 20 year-old male has around 176,000 km of myelinated axons in his brain.^[1]”  Stretched end-to-end, that would be enough to go around the world more than four times. 

Health of white matter in older people seems to be a strong predictor of general functionality and probability of death.  A few weeks ago, a report appeared on a “3 year follow-up study of 639 non-disabled older patients (mean age 74.1 (SD 5.0), 45.1% men) in whom brain magnetic resonance imaging showed mild, moderate, or severe age related changes in white matter.”  –“The annual rate of transition or death was 10.5%, 15.1%, and 29.5%, respectively, for patients with mild, moderate, or severe age related changes in white matter.”   The conclusion of the study was “The three year results of the LADIS study suggest that in older adults who seek medical attention for non-disabling complaints, severe age related changes in white matter independently and strongly predict rapid global functional decline.(ref)”

The relationship between age-related white matter change and serious health problems is multi-faceted.  For example, age-related white matter changes stroke death(ref) and such changes negatively affect cognitive functioning(ref). 

From an anti-aging viewpoint the three critical questions appear to be 1.  What are the typical age-related changes in the white matter?  2.  What causes the changes?  and 3. What can be done to avert the changes?

As to the first question, one answer is “– the appearance, starting around age 60, of “white-matter lesions” among the brain’s message-carrying axons — significantly affect cognitive function in old age. White-matter lesions are small bright patches that show up on magnetic resonance imaging (MRI) of the brain(ref).  The technical term for the change is Leukoaraiosis, involving  “changes in the cerebral white matter that can be detected with high frequency by CT and MRI in aged individuals. It is a descriptive term for rarefaction of the white matter. It is also commonly referred to as white matter hyperintensities (WMH) due to its bright white appearance on T2 MRI scans(ref).”  Myelin degeneration appears to be another cause of age-related white matter changes(ref).  There appears to be a correlation between Leukoaraiosis and  small vessel disease.

As to the second question, what exactly causes the white matter changes is only now being established.  An earlier hypothysis is that leukoaraiosis may be associated with decreaserd cortical oxygen metabolism(ref). “The result is consistent with the view that primary cortical hypoperfusion (decreased blood flow) plays a role, at least in part, as a pathogenesis of impaired cortical metabolism in hypertensive patients with extensive deep white matter lesions.”   That view is also supported by this study.  Whatever the basic cause of leukoaraiosis may be, those who have it seem to have decreased regional cerebral blood volume and, most likely, circulation. One research report colorfully states about the cereberal vascular system “Adding to the difficulties, tortuosities develop in some of these vessels with aging. According to some calculations, hypertensive levels of blood pressure would be required to maintain irrigation through some of these vessels.”  Also, it appears that “Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well.”

Another earlier hypothysis links the white matter lesions with apoptosis(ref). “Nonetheless, because the number of oligodendroglia within the area of leukoaraiosis is greatly depleted, the percentage of cells caught in the act of apoptosis is actually quite high(ref).”   A 2009 report links the vascular-defect hypothysis with the apoptosis hypothysis giving a more complete picture.   “We explain the vascular changes in LA (leukoaraiosis) as follows. LA induces apoptosis with loss of oligodendrocytes. Capillaries and neuropil are lost. Increased oxygen extraction from the blood in the deep white matter in LA implies that there are too many cells for the remaining capillaries. Thus, the capillaries appear to die first(ref).”  Oligodendrocytes play a central role in the white matter.  They are a kind of neuroglia cells that provide insulation of and protection for the axons.  Oliodendrocytes play a role in the central nervous system similar the role that Schwann cells play in the peripheral nervous system, a topic I discussed in the previous post on Nerve regeneration.  

Without going on further about the causes of leukoaraiosis, let me turn to the third question: what can be done to prevent or mimize it?  Looking at the causes of this condition it seems that what would help includes:

·        Insuring good circulation to the brain.  This implies maintaining a healthy vascular system.  For practical steps, have a look at my Susceptibility to cardiovascular disease firewall.

·        Maintaining healthy oliodendrocytes.  This implies continuing regeneration of oliodendrocytes: assuring differentiation of oliodendrocyte progenitor/precursor cells – a partially diffferentiated type of adult stem cell.  For a practical approach have a look at the firewall for the Decline in Adult Stem Cell Differentiation theory of aging. 

·        Maintaining  a balanced pattern of oligodendroglial apoptosis.  A number of research studies suggest that the effects of TNF-alpha and inflammation often play key roles in initiating unwanted oligodendroglial apoptosis(ref)(ref).  “These results demonstrate that aberrant local TNF/p55TNF receptor signaling in the central nervous system can have a potentially major role in the aetiopathogenesis of MS demyelination, particularly in MS subtypes in which oligodendrocyte death is a primary pathological feature, and provide new models for studying the basic mechanisms underlying oligodendrocyte and myelin loss(ref).”  Again, practical measures are suggested in the firewall for the Chronic or Excess Inflammation theory of aging.  Also inflammatory gene-activation associated with TNF-alpha activation can be inhibited by inhibiting the expression of NF-kappaB, an effect of 36 substances in the combined anti-aging firewall.  This topic is discussed as part of the firewall for the Programmed Epigenomic Changes  theory of aging.

The bottom line is that the combined anti-aging firewall program should provide protection for the heath of white brain matter in aging individuals.  How much protection I cannot say, but it may well be a lot.