AGINGSCIENCES™ – Anti-Aging Firewalls™

In a July blog post Warding off Alzheimer’s Disease and things in my diet, I talked about My usual breakfast: a sugar-free bran cereal with blueberries, walnuts and a sliced half-banana.  I cited research on the health benefits of the walnuts.  But what about the blueberries, the cupful or so I consume each morning?  It is common knowledge that they have strong antioxidant properties and “are good for you.” But what is known about their actual health benefits?  Actually, a great deal if animal models are to be trusted.  I reviewed some recent research on this subject and share the results here, mostly by listing quotes from the publications cited. I end each item with a simple summary of my own which is italicized.

·        Dietary blueberry attenuates whole-body insulin resistance in high fat-fed mice by reducing adipocyte death and its inflammatory sequelae, a new study, August 2009. “Salutary effects of BB on adipocyte physiology and ATMPhi gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-kappaB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology.” Blueberries can combat obesity and its problems.

·        Blueberries make their mark on cardiovascular and diabetes risks, U-M animal study finds, April 2009. “The researchers studied the effect of blueberries (freeze dried blueberries crushed into a powder) that were mixed into the rat diet, as part of either a low- or high-fat diet. They performed many comparisons between the rats consuming the test diets and the control rats receiving no blueberry powder. All the rats were from a research breed that is prone to being severely overweight. — In all, after 90 days, the rats that received the blueberry-enriched powder, measured as 2 percent of their diet, had less abdominal fat, lower triglycerides, lower cholesterol, and improved fasting glucose and insulin sensitivity, which are measures of how well the body processes glucose for energy. — While regular blueberry intake reduced these risks for cardiovascular disease and metabolic syndrome, the health benefits were even better when combined with a low-fat diet.” Blueberries can reduce risk of cardiovascular disease.

·        A blueberry-enriched diet protects rat hearts from ischemic damage,  June 2009. “CONCLUSION: A blueberry-enriched diet protected the myocardium from induced ischemic damage and demonstrated the potential to attenuate the development of post MI chronic heart failure.” Blueberries can help protect against heart attack damage.

·         Antiobesity and antidiabetic effects of biotransformed blueberry juice in KKAy mice, August 2009.  This study is based on Juice extracted from North American lowbush blueberries which has been biotransformed with Serratia vaccinii, a bacteria from the skin of the fruit.  The KKAy mice provide a rodent model of leptin resistance.  “Incorporating BJ (the biotransformed blueberry juice)in drinking water protected young KKAy mice from hyperphagia and significantly reduced their weight gain. Moreover, BJ protected young KKAy mice against the development of glucose intolerance and diabetes mellitus.” “Results of this study clearly show that biotransformed blueberry juice has strong anti-obesity and anti-diabetic potential,” says senior author Pierre S. Haddad, a pharmacology professor at the Université de Montréal’s Faculty of Medicine. “Biotransformed blueberry juice may represent a novel therapeutic agent, since it decreases hyperglycemia in diabetic mice and can protect young pre-diabetic mice from developing obesity and diabetes(ref).”  Biotransformed blueberry juice can be protective against obesity and diabetes.

·        Wild Blueberries May Help Protect Arteries, Reduce Risks From Cardiovascular Disease, November 2003. “The apparent benefit of the blueberry enriched diet carried over to older rats which received blueberries later in the study. The implication is that the addition of wild blueberries to the diet later in life may still have a protective effect on arteries.” Wild blueberries can protect against cardiovascular disease in the old as well as young.

·        Blueberry polyphenols attenuate kainic acid-induced decrements in cognition and alter inflammatory gene expression in rat hippocampus, “These results indicate that blueberry polyphenols attenuate learning impairments following neurotoxic insult and exert anti-inflammatory actions, perhaps via alteration of gene expression.” It was observed that blueberries attenuated the expression of NF-kappaB induced by the neurotoxic kainic acid and augmented the expression of IGF-1. Blueberries can be protective of mental capability when exposed to brain toxins.

·        Inhibition of cancer cell proliferation and suppression of TNF-induced activation of NFkappaB by edible berry juice, March-April 2007.  “The potential chemopreventive activity of a variety of small berries cultivated or collected in the province of Québec, Canada were evaluated here. — RESULTS: The growth of various cancer cell lines, including those of stomach, prostate, intestine and breast, was strongly inhibited by raspberry, black currant, white currant, gooseberry, velvet leaf blueberry, low-bush blueberry, sea buckthorn and cranberry juice, but not (or only slightly) by strawberry, high-bush blueberry, serviceberry, red currant, or blackberry juice. No correlation was found between the anti-proliferative activity of berry juices and their antioxidant capacity (p > 0.05). — juice of 6 significantly inhibited the TNF-induced activation of COX-2 expression and activation of the nuclear transcription factor NFkappaB.” Blueberry and other berry juices can be protective against some cancers. 

·        Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro, December 2006.  “The berry extracts were evaluated for their ability to inhibit the growth of human oral (KB, CAL-27), breast (MCF-7), colon (HT-29, HCT116), and prostate (LNCaP) tumor cell lines at concentrations ranging from 25 to 200 micro g/mL. With increasing concentration of berry extract, increasing inhibition of cell proliferation in all of the cell lines were observed, with different degrees of potency between cell lines.”  Blueberry and other edible berry extracts can kill cancer cells.

·        Berry fruits: compositional elements, biochemical activities, and the impact of their intake on human health, performance, and disease, February 2008.  “An overwhelming body of research has now firmly established that the dietary intake of berry fruits has a positive and profound impact on human health, performance, and disease.” Blueberries and other berries are great for health.

·        Whole berries versus berry anthocyanins: interactions with dietary fat levels in the C57BL/6J mouse model of obesity, February 2008.  “After 8 weeks, mice fed the HF60 (high fat) diet plus purified anthocyanins from BB in the drinking water had lower body weight gains and body fat than the HF60-fed controls. Anthocyanins fed as the whole blueberry did not prevent and may have actually increased obesity. However, feeding purified anthocyanins from blueberries or strawberries reduced obesity.”  The berries used in the study were blueberries and strawberries.This study is interesting because it suggests the additional calories from the whole berries possibly led to weight gain but the anthocyanin extracts led to weight loss.  If this result is further confirmed, it would provide an argument for consuming berry anthocyanin extracts supplements instead of the whole berries themselves. Berry anthocyanin supplements might be better for weight loss than the berries themselves.

·        Purple Berries’ Rank High In Antioxidants, USDA Study Says, November 2003.  Some berries may be even better for you than blueberries, ones like elderberries, black currants and chokeberries.  “In preliminary laboratory studies, the researchers found that the elderberry, black currant and chokeberry — collectively known as the “purple berries” due to their dark color — are as much as 50 percent higher in antioxidants than some of the more common berry varieties and have the potential to provide more health benefits, such as protection against cancer, heart disease and Alzheimer’s.”  The darker and more purple the berry colors the better thay are for you, possibly.

Defined-benefit pension plans (DBPPs) are ones that pay out a fixed monthly amount for the life of the pensioner, possibly with a cost-of-living adjustment for inflation.  Social Security in the US is a prime example.  There are thousands of other defined-benefit pension plans worldwide sponsored by governments and government agencies, corporations, insurance companies, not-for-profits, unions, financial trusts, etc.  What DBPPs share in common is being financially ambushed by rapidly increasing longevity in the general population.

These plans traditionally have been designed so that income and outgo of a pension fund would balance for the population concerned taking multiple variables into account, among these being actuarial statistics for longevity of a plan’s participants.  Traditionally these life-expectancy statistics have been slow-changing.  So, in setting up a new plan changes in life expectancy could be ignored or accommodated by a built-in general contingency margin.  That is the way it was in the 1930s and 1940s. So what happens when the plans are faced with “runaway longevity,” life expectancy growing to be far beyond that expected?   The answer is financial crises and unsustainability for the DBPPs concerned. 

Even without extraordinary longevity as advocated in this blog, many existing DBPPs are already having serious financial problems with their participants living longer than expected.  According to an article appearing yesterday in the UK Times Online, “Directors and pension trustees have already been cruelly mauled by the British population’s habit of living longer than expected, drawing extra pension payments in the process. In the past 12 months UK longevity forecasts have risen by a year, sufficient to increase the combined FTSE 100 pension deficit by £1m an hour, according to Hewitt Associates, a firm of actuaries(ref).”  If that rate of longevity increase is correct and keeps up – growing by a year in 12 months, it sounds like pension funds that expected participants to behave right and die off in 15 years might have to keep paying them off forever.

One response of DBPPs has been to close down to new participants; another has been to cap cost-of-living increases; many have gone into deep deficit. “Some groups with large deficits in their defined-benefit schemes have gone farther, stopping existing members from accruing new benefits. Others have chosen a middle course. Royal Bank of Scotland last week said it would cap increases in benefits at the rate of inflation or 2%, whichever was the lower. The news did not go down well with the 60,000 affected employees, who had watched Sir Fred Goodwin, the chief executive, leave with a £17m retirement package.” – “Longevity, however, has silently crept up on trustees and companies, and has provided a nasty surprise.  — Pension schemes are, at the moment, having to deal with a “bulge” in longevity caused by the health improvements made in the past 20 years. Once this spurt has been dealt with, trustees think they should be all right if they assume perhaps an increase of 1% or 2% each year. They might not. “The problem with estimating longevity is that many of the judgments are subjective. You don’t know how long people will live,” said Martin Bird, the UK lead on longevity at Hewitt(ref).”

I also think it might be a mistake to view the current rate of longevity increase as a “bulge” or “spurt.”  I suspect the rate may actually grow higher instead of going down. See the May 2009 blog entry The Social ethics of longevity. There I argued that social evolution requires that people live longer – and is in fact leading to longer and longer life spans. Also see the blog entry Average US life expectancy is up 73 days in one year.  (I am not sure, by the way, the Times article was correct in stating that life expectancy in Great Britain increased a year over a year-long period even though the main point of the article is correct.)

DBPPs have been on their way out for several years now, being replaced by defined-contribution plans.  These are plans like IRAs where the retiree benefits are not fixed but are based on what the retiree wishes to draw out from a pot of money put into the plan during working years and invested.  In the US at least, money in such a plan can be grown tax-free.   Nonetheless, DBPPs have a long history and strong supportive constituencies.  A history of Social Security in the US going back to 1600 can be found here.  Keeping the existing DBPPs going in the face of increasing longevity is likely to become a very contentious process, pitting “entitled” pensioners against “realist” financial managers.  I expect the future political process associated with social security reform in the US will make the current health-system reform fight seem like a very tame game. 

A major impediment to developing drugs that affect the brain, such as new treatments for Alzheimer’s Disease, Meningitis , Epilepsy, Parkinson’s disease and Multiple sclerosis, has been determining whether and how effectively a drug substance can cross the blood-brain barrier (BBB).  The barrier separates cerebrospinal fluid surrounding the brain from circulating blood and is highly selective in the molecules it lets through.  Physically, the barrier is created by “tight junctions between endothelial cells in CNS vessels that restricts the passage of solutes.”   The cells line some 400 miles of tiny capillary vessels throughout the brain. The barrier is neuroprotective and keeps out many common bacteria, but “In its neuroprotective role, the blood-brain barrier functions to hinder the delivery of many potentially important diagnostic and therapeutic agents to the brain. Therapeutic molecules and genes that might otherwise be effective in diagnosis and therapy do not cross the BBB in adequate amounts(ref).”

The blood-brain barrier stands in the way of new drug development(ref).  Specifically, most large-molecule drugs cannot pass through it, so testing the safety and efficacy of many possible new therapeutic agents for the brain poses a serious challenge.

Triple quadrupole mass spectrometry offers a way of working around this problem.  A triple quadrupole mass spectrometer is a sophisticated laboratory device about the size of a table-top refrigerator.  Technically, “A triple quadrupole mass spectrometer is a tandem mass spectrometer (TQMS) consisting of two quadrupole mass spectrometers in series, with a (non mass-resolving) radio frequency (RF) only quadrupole between them to act as a collision cell for collision-induced dissociation. The first (Q₁) and third (Q₃) quadrupoles serve as mass filters, whereas the middle (q₂) quadrupole serves as a collision cell(ref).”  

A TQMS can help determine exactly how much of a substance is getting through to the brain and is being used, for example, in research on drug treatments for Alzheimer’s disease.  As reported in the Aug 1 issue of GEN, “Another state-of-the-art tool, triple quadrupole mass spectrometry, gives scientists at Mithridion an advantage for working in the Alzheimer’s drug arena. Triple quadrupole mass spectrometry measures accurately and quantitatively small amounts of drugs in an extract of blood or brain tissue during preclinical studies. In Alzheimer’s disease research, it’s critical to confirm that new drug candidates are capable of crossing the blood-brain barrier to work in the brain. “The blood-brain barrier is quite an obstacle, and many drugs fail to get through,” Dr. Twose notes. — Not only does triple quadrupole mass spectrometry confirm that compounds enter the brain, but the technology also defines chemical structures required for this to happen. “We know many of the rules, so we can carry out an in silico process before we synthesize compounds,” continues Dr. Twose. Mithridion’s semi-rational approach to drug design provides a good estimate of whether compounds will pass into the brain, and triple quadrupole mass spectrometry verifies that this occurs(ref).”

The triple quadrupole mass spectrometer is an example of hundreds of new technologies that are helping accelerate the pace of medical and life sciences research and facilitating discoveries that will at some point allow us to live for centuries.  In proposing Giuliano’s Law which relates to the prospects for breaking through the 122 year human age limit, I asserted that improving technology was combining with several other factors to constantly accelerate the rate of discovery and availability of anti-aging interventions.  For a complete discussion of how these factors are combining to drive the acceleration, see the blog post Factors that drive Giuliano’s Law.  Finally if you want to get a sense of some of the other emerging technologies that are being put to work for life sciences discovery, development, and production, I suggest you browse through a copy of GEN (Genetic Engineering & Biotechnology News), a biotechnology industry trade newspaper-magazine.  Our daily newspapers are getting skinnier, but GEN seems constantly to be getting fatter.

New cohort studies were published in the last few weeks on the impact of following the Mediterranean diet on the risk of senile dementia.  This led me to do a quick review of the research behind the general wisdom that the diet “is good for you.”  I summarize what I found here.

I suggest following the Mediterranean diet in numerous places in my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY.   I wrote “Consider a Mediterranean Diet which features eating lots of vegetables and fruits, lean protein, fish, whole-grain pasta, lots of olive oil and moderate amounts of red wine.”  Actually the Mediterranean Diet (MeDi) is a family of somewhat similar diets commonly followed in different countries bordering the Mediterranean.  Key components of the diet from a health viewpoint are described here and include:

§  “Getting plenty of exercise and eating your meals with family and friends

§  Eating a generous amount of fruits and vegetables

§  Consuming healthy fats such as olive oil and canola oil

§  Using herbs and spices instead of salt to flavor foods

§  Eating small portions of nuts

§  Drinking red wine, in moderation, for some

§  Consuming very little red meat

§  Eating fish or shellfish at least twice a week(ref)” 

First, as to the new research relating the diet to risk of dementia:  An August 12 study 2009 report in JAMA Adherence to a Mediterranean diet, cognitive decline, and risk of dementia is a “ cohort study of 1410 adults (> or = 65 years) from Bordeaux, France, included in the Three-City cohort in 2001-2002 and reexamined at least once over 5 years.” – “CONCLUSIONS: Higher adherence to a Mediterranean diet was associated with slower MMSE (Mini-Mental State Examination) cognitive decline but not consistently with other cognitive tests(ref).”  The conclusions were reached based on data adjusted  “for age, sex, education, marital status, energy intake, physical activity, depressive symptomatology, taking 5 medications/d or more, apolipoprotein E genotype, cardiovascular risk factors, and stroke.” 

A second report in the same issue of JAMA Physical activity, diet, and risk of Alzheimer disease looks at the impact of following the Mediterranean diet in combination with substantial physical activity.  This is a “Prospective cohort study of 2 cohorts comprising 1880 community-dwelling elders without dementia living in New York, New York.  Standardized neurological and neuropsychological measures were administered approximately every 1.5 years from 1992 through 2006.”  Again, the data was adjusted for numerous variables. “Compared with individuals neither adhering to the diet nor participating in physical activity (low diet score and no physical activity; absolute AD (Alzheimer Disease) risk of 19%), those both adhering to the diet and participating in physical activity (high diet score and high physical activity) had a lower risk of AD (absolute risk, 12%; Hazard Ratio, 0.65 [95% CI, 0.44-0.96]; P = .03 for trend). – Conclusion”  In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for AD(ref).”

A July 2009 study report looks at Mediterranean diet and mild cognitive impairment.  The study is based on data from a multi-ethnic community in New York. “There were 1393 cognitively normal participants, 275 of whom developed MCI (mild cognitive impairment) during a mean (SD) follow-up of 4.5 (2.7) years (range, 0.9-16.4 years).”  Subjects were divided into tertiles with respect to their adherence to a Mediterranean diet. “CONCLUSIONS: Higher adherence to the MeDi is associated with a trend for reduced risk of developing MCI and with reduced risk of MCI conversion to AD(ref).”

I mention two other studies relating the MeDi to dementia risk.  A 2007 study report of 192 individuals looked at Mediterranean diet and Alzheimer disease mortality . “ CONCLUSION: Adherence to the Mediterranean diet (MeDi) may affect not only risk for Alzheimer disease (AD) but also subsequent disease course: Higher adherence to the MeDi is associated with lower mortality in AD. The gradual reduction in mortality risk for higher MeDi adherence tertiles suggests a possible dose-response effect(ref).”  Another 2007 study was on Mediterranean diet, Alzheimer disease, and vascular mediation.  “CONCLUSIONS: We note once more that higher adherence to the MeDi is associated with a reduced risk for AD. The association does not seem to be mediated by vascular comorbidity(ref).”

All five of these cohort studies show a consistent correlation between following a MeDi and lower risk of age-related dementia. The studies correlating Mediterranean Diet to lower mortality are even more impressive. Of many relevant publications I cite only two important studies.  The first is a 2007 report Mediterranean dietary pattern and prediction of all-cause mortality in a US population: results from the NIH-AARP Diet and Health Study.  “Study participants included 214,284 men and 166,012 women. — During follow-up for all-cause mortality (1995-2005), 27,799 deaths were documented. In the first 5 years of follow-up, 5,985 cancer deaths and 3,451 cardiovascular disease (CVD) deaths were reported.” – “The Mediterranean diet was associated with reduced all-cause and cause-specific mortality.” – “. In women, an inverse association was seen with high conformity with this pattern: decreased risks that ranged from 12% for cancer mortality to 20% for all-cause mortality (P = .04 and P < .001, respectively, for the trend). — CONCLUSION: These results provide strong evidence for a beneficial effect of higher conformity with the Mediterranean dietary pattern on risk of death from all causes, including deaths due to CVD and cancer, in a US population(ref).”

The second cohort study looking at MeDi and mortality is Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. The study “includes 1507 apparently healthy men and 832 women, aged 70 to 90 years in 11 European countries. This cohort study was conducted between 1988 and 2000.” – “CONCLUSION: Among individuals aged 70 to 90 years, adherence to a Mediterranean diet and healthful lifestyle is associated with a more than 50% lower rate of all-causes and cause-specific mortality(ref).”

These and similar reductions in mortality and other benefits of a Mediterranean diet reported in other publications are quite impressive to me.  The reasons for following a Mediterranean diet and a healthy lifestyle are not just New-Age fluff.

This is about alpha melanocyte-stimulating hormone tripeptide K(D)PT.   In the blog post Anti-inflammatory effects of the hormone alpha-MSH, I discussed a line of research linking the human hormone alpha-melanocyte-stimulating hormone (alpha-MSH) to reduction of inflammation.  Alpha-MSH is synthesized in human hair follicles and acts upon melanocytes, cells which produce the pigment melanin which gives color to the skin, eyes and hair.  In that post I discussed how alpha-MSH effectively controls systemic inflammation through acting on the central nervous system and inhibiting the expression of NF-kappaB.   “The anti-inflammatory effects of alpha-MSH have been confirmed by means of animal models of inflammation such as irritant and allergic contact dermatitis, cutaneous vasculitis, asthma, inflammatory bowel disease, rheumatoid arthritis, ocular and brain inflammation(ref).”

Another substance closely related to alpha-MSH is attracting increasing interest as a possible anti-inflammatory agent, that being K(D)PT   “Most of the anti-inflammatory activities of alpha-MSH can be attributed to its C-terminal tripeptide KPV. K(D)PT, a derivative of KPV corresponding to the amino acid 193–195 of IL-1beta, is currently emerging as another tripeptide with potent anti-inflammatory effects. The anti-inflammatory potential together with the favourable physiochemical properties most likely will allow these agents to be developed for the treatment of inflammatory skin, eye and bowel diseases, allergic asthma and arthritis(ref).”  K(D)PT is identical to interleukin (IL)-1beta193-195.  Like alpha-MSH, K(D)PT appears to be an anti-inflammatory that inhibits the expression of NF-kappaB. K(D)PT “ameliorates endotoxin-induced nuclear factor kappaB translocation(ref)” 

Regular readers of this blog know I have an interest in the role of hair follicle melanocytes in hair pigmentation, a subject I discussed in the blog posts Why does your hair turn gray, and More research insight on gray hair and adult stem cell reproduction.  K(D)PT appears to be capable of stimulating hair pigmentation under inflammatory conditions that would normally turn colored hair gray.  “The alpha-melanocyte stimulating hormone-related tripeptide K(D)PT stimulates human hair follicle pigmentation in situ under proinflammatory conditions.”  “Conclusions: The IL-1beta- and alpha-MSH-related tripeptide, K(D)PT, displays interesting hair pigmentation-stimulatory activities under proinflammatory conditions. These might become exploitable for innovative antigreying strategies, notably in postinflammatory poliosis (regrowth of white hair, e.g. during recovery from alopecia areata), where no effective clinical therapy is yet available(ref).”

The research relating K(D)PT to human hair pigmentation is still in an early stage.  It is possible that this substance could turn out to be a useful new anti-inflammatory and could also play a role in restoring natural color to gray hair under certain stress circumstancces.

A new study just published  in the New England Journal of Medicine points out yet-again the growing risk due to low-level radiation associated with the increasing use of CAT scans and other sophisticated radiological procedures.  The study looked at the cumulative radiation received by “952,420 nonelderly adults (between 18 and 64 years of age) in five health care markets across the United States between January 1, 2005, and December 31, 2007.”  — “Computed tomographic and nuclear imaging accounted for 75.4% of the cumulative effective dose, with 81.8% of the total administered in outpatient settings.” – “Conclusions: Imaging procedures are an important source of exposure to ionizing radiation in the United States and can result in high cumulative effective doses of radiation(ref).”

As most readers here probably know, oxidative damage is the oldest and most established theory of aging and ionizing radiation is a prime source of free radicals (reactive oxidative species, or ROS).  In short, the medical radiation can be a prime source of aging.  The increase in use of CAT scans is part of a shift in the general practice of medicine.  The orders for the CAT scans come not from the radiologists who read the results but from other doctors who see them as part of their regular diagnostic toolkit, like cardiologists, oncologists, pulmonologists, rheumatologists and especially emergency room doctors.  Some patients with chronic diseases may undergo a half-dozen or more CAT scans a year.

While avoiding the CAT scans and the associated radiation may be difficult or unwise given the change in the practice of medicine, there is another approach that can contribute to minimizing the radiation damage.  I wrote a paper treating this subject in 2008 which is available online Protection Against Radiation – The Second Line of Defense.  Basically, the protective idea is to take antioxidants.  I suggest reading this paper for anyone expecting to undergo extensive diagnostic x-radiation.  I repeat the summary of this paper here.

SUMMARY 

The increasing use of diagnostic radiology is unquestionably beneficial.  However, per-capita exposure to medical radiation has grown some six fold in the last two decades and appears to be still increasing.  The issue of medical radiation protection is therefore achieving central importance for the health of both patients and radiation professionals.   It is well established that the effects of radiation are cumulative and lead to increased incidence of cancers, cell deaths, genetic damage and numerous forms of body tissue pathology.   

The first line of defense against gamma and X radiation damage, long established in clinical practice, is simply radiation avoidance such as by use of shorter exposure and more sensitive film, carefully focused beams, lead aprons and other shielding. 

This paper is concerned with a second and complimentary line of defense one not yet established in clinical practice but potentially of great importance.  That is, radiation damage minimization by interfering with the biological mechanism of radiation damage, that is, interfering with the propagation in tissues of free radicals created by X-rays.  This kind of protection can be achieved through using commonly-available antioxidant supplements.   

Despite the large body of research supporting the effectiveness of antioxidants to quench radiation-induced free radicals, this second line of defense against radiation damage is neither taught to radiology students in medical schools nor is embodied in general clinical radiology practice. The author discusses the research basis for widespread adoption of this “second line of defense” for radiation protection and provides some 60 research citations to support his points. 

The paper also discusses the use of specific antioxidants for radiation protection and cites some 60 studies on the radioprotectivity of specific antioxidants.  The paper is relevant not only to patients but also to interventional radiologist, radiation technicians and atomic-technology workers who are repeatedly exposed to low doses of ionizing radiation.

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.