AGINGSCIENCES™ – Anti-Aging Firewalls™

One of the headlines this week describing a population study in Denmark reads:  “Men’s key to longevity: have sex with younger women: Study.”  Another headline reporting on the same study reads “Daily sex with woman 15 yrs younger cuts death risk by 20%.”   “The study reveals that a man’s chances of dying an untimely death are cut by one-fifth if his bedpartner is 15 to 17 years younger to him.”  — “Men who took care of children and put food on the table lived longer, found the study that examined deaths between 1990 and 2005 for the entire population of Denmark.  The higher life expectancy in case of men having sex with younger women was attributed possibly not to having the sex itself, but rather to having a younger woman around to take care of you as you grow old and have increasing problems.   Hmm. 

But is having sex really irrelevant?  There is the Caerphilly Cohort Study which relates frequency of sexual orgasims to mortality, a 10-year cohert study of 918 men living in Caerphilly, South Wales and adjacent villages aged 45-59 at time of enrollment in the study.  “RESULTS: Mortality risk was 50% lower in the group with high orgasmic frequency than in the group with low orgasmic frequency, with evidence of a dose-response relation across the groups(ref).” 

Living with and having frequent sex with a female probably adds to longevity in other species in addition to humans.  Back some time ago in this blog posting I reported research that indicates that living and mating with a female adds up to 20% in the longevity of fertility of male mice.  See also the post Polygamy helps men live longer  and the post Use it or lose it and sexual intercourse.  Hmm again.  Seems like having women around, younger ones and perhaps more than one, and having frequent sex contribute to male longevity. 

Another study casts light on the issue from an evolutionary point of view. “It turns out that older men chasing younger women contributes to human longevity and the survival of the species, according to new findings by researchers at Stanford and the University of California-Santa Barbara(ref).  The study looked at contemporary primitive societies, investigating “ longevity and fertility data from two hunter-gatherer groups, the Dobe !Kung of the Kalahari and the Ache of Paraguay, one of the most isolated populations in the world. They also looked at the forager-farmer Yanomamo of Brazil and Venezuela, and the Tsimane, an indigenous group in Bolivia. “They’re living a lifestyle that our ancestors lived and their fertility patterns are probably most consistent with our ancestors.” – “In the less developed, traditional societies, males were as much as 5-to-15 years older than their female partners. In the United States and Europe, the age spread was about two years. “It’s a universal pattern that in typical marriages men are older than women,” Puleston said. “The age gaps vary by culture, but in every group we looked at men start [being sexually reproductive] later.”  — “The paper noted that the age gap is most pronounced in societies that favor polygyny, where a man takes several wives, and in gerontocracies, where older men monopolize access to reproductive women. The authors also cite genetic and anthropological evidence that early humans were probably polygynous as well(ref).”The researchers argue that older males mating with younger women provides an evolutionary advantage because it enables safer pregnancies of women in stable marriages before menopause and because: “the fatherhood of a small number of older men is enough to postpone the date with death because natural selection fights life-shortening mutations until the species is finished reproducing(ref).”  So, an old man fathering a child with a younger woman may not personally receive any longevity benefit, but his offsprings might. 

As a personal note, I have fathered five children with four different women.  One of these wonderful women, one wife back, is 16 years younger than me and another, my current wife, is 17 years younger than me.

According to a news release yesterday; “TOKYO — Japanese people are living longer than ever, with the average life expectancy now 86.05 years for women and 79.29 years for men, the health ministry said Thursday.  Japanese women extended their life expectancy by almost 22 days in 2008 from the previous year, while men added another 37 days, the ministry said.”   

It seems like an immense increase in lifespan to happen in just one year. It is interesting to ask how could this happen.   The usual theories are related to improvements in public health and nutrition: changes that happened 70-90 years ago that affected the survival rate of infants, public sanitation systems, less air and water pollution, better balanced diets, improvements in the Japanese health care system and more public awareness about health.  I speculate here that something else more profound could also be involved – physical evolution of our species.

First I want to comment that the trend to longer life expectancy has been going on for many centuries now and has been happening in all developed countries. This table provides government statistics for “Life expectancy at birth, at 65 years of age, and at 75 years of age, by race and sex: United States, selected years 1900–2005.”  All the numbers have been going up every year.  A woman born in 1900 could expect to live 48.3 years; a woman born in 2005 can expect to live 80.4 years – a 66% increase.  In Germany life expectancy at birth increased from 78.42 years in 2003 to 79.1 years in 2008(ref).  The trend of increasing expectancy has been a very long one.  This Table suggest that average life expectancy at birth in Medieval Britain was 20-30 years, in the early 20^th century 30-40 years. This Table from the CIA World Factbook lists 2008 life expectancy at birth for 191 countries.  At the top of the list is Macau with 84.38 combined male-female life expectancy at birth and at the bottom is Swaziland with 39.6 years combined life expectancy.  The US ranks 45^th on the list with 78.06 years.  At the same time as life expectancy has increased there have been other shifts in average human body characteristics, such a towards greater height, particularly in advanced countries(ref).

My speculation is that human cultural evolution is leading to species evolution via epigenomic modifications in inheritable DNA that makes for longer longevity, and that this process is ongoing right now..  Specifically:

·        As human industrial and post-industrial societies become more and more complex it takes longer and longer for young people to achieve the education and skills for them to become fully-functioning members of society.  In Neolithic societies, at the age of about 15 children could start taking full adult responsibilities for hunting and gathering, bearing children and taking on the roles required for society to work.  Nowadays, if a young person is pursuing a professional path, about twice as many years are required before that person is a fully-functioning doctor, lawyer, or other skilled professional.  Instead of starting to have children at 15-16, the tendency in advanced countries now is for childbearing to be postponed until women are in their 30s or 40s(ref). 

·        While there are clearly class differences, the individual and societal investment required to bring young people up to speed has been growing and in the US may be nearing a half-million dollars for advanced professionals like doctors, lawyers, scientists and diplomats.  While few finished high school a century ago, yesterday President Obama advocated that everyone should be provided at least a 2-year college education.  Everything connected with full social maturation takes longer, is more complex and is more expensive

·        From a viewpoint of simple cultural economics, it makes sense that this greatly expanded investment in initial maturation of individuals be accompanied by a much longer productive lifespan over which that investment is amortized. 

In other words, arguing purely from an evolutionary viewpoint, it would make excellent sense for cultural evolution to induce species evolution so that people live longer.  That is exactly what has been happening, but the exact mechanisms involved are unclear.  There are probably several mechanisms at work including advances in public health knowledge and developments such as decline in cigarette smoking.   Another mechanism may be greater dissemination of knowledge as to what makes for health and longevity, this blog playing a tiny part. 

My speculation is that, in addition, inheritable epigenomic changes are happening in our DNA that are leading to greater longevity.  That is, our genes themselves are not being changed but that there are modifications in our histone acetylation and DNA methylation patterns and other chromatin changes that on the whole help us live longer. 

The general process of epigenomic modification is described in my February blog entry Epigenetics, Epigenomics and Aging.  My speculation is feasible, given what we know about epigenomics.  In fact, as I have speculated before, aging itself may largely be an epigenomic phenomenon.  However, my speculation remains a speculation for now because I cannot say how and when longevity-promoting epigenomic reprogramming is taking place.  For a possible hint, see also my previous blog post Longevity Genes and Two Fantasies.  See also this reference for how hormonal mechanisms may affect longevity genes via epigenomic modifications. 

A study published in the July 16 issue of the New England Journal of Medicine indicates that people who inherit the ApoE4 gene allele are likely to experience signs of early dementia.  815 subjects were followed for about five years, 317 of which were carriers of the APOE4 Gene SNP, and 498 noncarriers.  “Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele–dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status.” —  “Conclusions Age-related memory decline in APOE 4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status(ref).“

For some time, abnormalities in the APOE gene has been known to be associated with susceptibility to dementia and Alzheimer’s disease(ref)(ref).  Aberrations in that gene have also been associated with susceptibility to multiple sclerosis(ref). Back in 2000, a project was set up to investigate common SNPs in the APOE gene and to look at dementia-related disease associations(ref).  One perception was that there was a relationship between the presence of APOE4, mitochondrial and oxidative damage and cognitive dysfunction.  “The results suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients who carry APOE4 than in those who do not(ref).”  Later it was confirmed that mitochondrial dysfunction and the TOM40 gene are also associated with accumulation of amaloid and the development of Alzheimer’s Disease(ref). 

Until recently, however, it was not clear how the presence of the APOE4 Gene variant impacted on the prognosis for developing Alzheimer’s Disease.  “In research presented Sunday at the International Conference on Alzheimer’s Disease in Vienna, Dr. Roses and his team looked at the area of DNA surrounding the APOE gene. They found that a gene linked to APOE called TOMM40 had mutations that involved a small number of extra copies of a particular building block of DNA in some individuals and a large number of extra copies in others.” – “Individuals with the large number of extra copies — known as the “long repeat” version of TOMM40 — coupled with APOE3 develop Alzheimer’s an average of seven years earlier — about age 70 — compared with APOE3 individuals with a “short repeat” version of TOMM40(ref).”  The extra-copy alteration in TOMM40 is known as a copy number variation (CNV).  The recent blog post Gene variations and diseases – far from simple provides an overview of CNVs and how they can affect disease conditions.

And, in case you are confused, as near as I can tell TOM40 and TOMM40 appear to be different names for the same gene.

I need a little break from heavy-duty research.  So, it is time for lighter stuff and junk.  I continue to monitor the news and web for insights related to longevity.  Here are a few recent tidbits:

·        As a longevity exercise: “The lips and cheeks can be exercised by smacking your lips several times, blowing in and out of a narrow straw or pipe, inflating your cheeks, and then keeping them that way for a few seconds and deflating, or even simply chewing bubble gum(ref).”

·        You can see what the Cat in The Hat has to say about aging by clicking here. 

·        If you are interested in the Qi Gong traditional Chinese system of meditative exercises for longevity, you can find out about it here.  The system has been in use for over 2,000 years.

·        If you are old, avoid extreme heat and humidity.  See here. 

·        One of my favorite sayings is “It’s not the heat that gets to me; it’s the stupidity.”  See this on older people choosing the path of learning vs the path of stupidity.

·        Interested in shoe fitting and longevity?  Check it out here on tutu.com.

·        Does practicing cannibalism enhance longevity? Yes, at least for some mosquitoes.  Check out this research paper.  As to human cannibalism it may be part of a rational diet.  Check this out.

First of all, today I updated the discussion related to the Telomere Shortening and Damage theory of aging. The treatise now has a more comprehensive and up-to-date discussion of the topic with more literature citations.  Not a lot new is included for regular readers of this blog, however. 

Second, a personal item.  Since switching to the 100mg dose of astragaloside IV a couple of months ago I have reported continuing to experience wellbeing and more and more hairs appearing on my previously-bald scalp.  Yesterday I found out another thing.  A biopsy report indicated that a rapidly-growing growth removed from my armpit was a basal-cell carcinoma.  I had had a couple of such small carcinomas removed some 5 years ago but they stopped developing then  when I increased my resveratrol, curcumin and aswagandha supplements to their current levels.  The growth was easily removed and in no-way was life-threatening.  However, I found out that my current “firewall against cancers” is not now bulletproof.

One possibility is that the skin cancer development was correlated with the increased dosage of astragaloside IV.  As you may have noted in my recent post On Cancer Stem Cells, more and more researchers are looking to cancer stem cells as being the key targets for anti-cancer therapy rather than mature cancer cells.  Enhanced expression of telomerase, as I have pointed out, increases differentiation and proliferation of normal stem cells through a pathway independent of telomere extension.  There are hints in the research literature that telomerase activation may be doing the same for cancer stem cells.  I will be seeing what I can turn up in the research literature relevant to this.  And I may suggest shifts in my anti-cancer firewall regimen for people taking telomerase activators.

Joe’s Wife:  Jerry just called from Brown’s Boat Basin. 

Old Joe:  Who fell down?  Did you say Larry or Mary? And what’s that about a brown raisin in your throat?

Joe’s Wife:  “YOUR SON JERRY PHONED.  Said he wants to talk with you about coming over for dinner.

Old Joe:  “Oh.  OK.  I would love to go for a walk with him.  And Rover can come too.  He is really a winner.”

Joe’s Wife:  “You mostly don’t get it.  YOU NEED TO GET YOUR HEARING CHECKED.”

Old Joe:  “My hearing is fine.  You need to speak up more clearly.  Now, what were you trying to say?

Joe’s Wife:  Never mind.  Forget it.   I am going shopping.

Social isolation is only one likely consequence of hearing loss(ref) for an older person. “More than 28 million people in the United States have a significant loss of hearing. Almost half of these individuals are under the age of 65, and 54% of the population over 65 years of age have hearing loss. Hearing loss is the third most prevalent chronic health condition in the older population, following arthritis and high blood pressure. The impact of hearing loss can be far reaching and involve many different aspects of one’s life. Hearing impaired individuals may have difficulty localizing sounds, understanding speech in noisy environments, and contributing to conversations. This can lead to social isolation, confusion, frustration, tension, stress and depression. There is mounting evidence that untreated hearing loss has enormous impact on the overall health of individuals(ref). “ 

I set out to research age-related hearing loss and what if anything can be done about it.  This is what I came up with including some relatively good news.

The classical explanation is that hearing loss is something that often comes with the territory of growing older.  It is called Presbycusis and if you have it there is probably nothing that can be done about it except to get a hearing aid or a cochlear implant if you want to go that far.  Hearing loss is mostly at higher frequencies resulting in fricatives and sibilants often being misrecognized and involves multiple changes in hair cells, nerve fibers and molecular markers(ref).  A simplified view is “Tiny hairs inside your ear help you hear. They pick up sound waves and change them into the nerve signals that the brain interprets as sound. Hearing loss occurs when the tiny hairs inside the ear are damaged or die. The hair cells do not regrow, so most hearing loss is permanent(ref).”  Also, hearing loss can be accelerated by repeated exposure to loud noises such as in a rock concert, cigarette smoking and some drugs and diseases. “About half of all people over age 75 have some amount of age-related hearing loss(ref).”  If an older person experiences hearing loss the first step is to confirm that the problem is not just accumulated ear wax, then to get tested by an audiologist to confirm the loss, and then most-often to get fitted with a hearing aid. 

Starting in the 1990s, a large number of studies have established that antioxidants can partially or even in large measure reduce the loss of hearing induced by loud noise, disease or other events traumatic to hearing in a variety of animal models(ref).  “The hearing loss from exposure to noise and ototoxic drugs share a number of audiological and pathological similarities. Recent research has shown that reactive oxygen species (ROS) may be a common factor in both noise- and drug-induced hearing loss. This review describes three experiments that point to ROS as a causative factor in both noise- and drug-induced hearing loss and antioxidants as a protective agent(ref).”  “The pathways of necrotic and apoptotic cell death are also reviewed. Interventions are discussed that target the prevention of noise-induced hair cell death: the use of antioxidants to scavenge and eliminate the damaging ROS, pharmacological interventions to limit the damage resulting from ROS, and new techniques aimed at interrupting the apoptotic biochemical cascade that results in the death of irreplaceable hair cells(ref).”  “– animals treated with MLT (melatonon) experienced an improvement in their hearing functionality. This effect, which is probably linked to MLT’s ability to reduce c-fos and TNF-alpha gene expression thereby preventing outer hair cell (OHC) loss, was even more pronounced in week 3(ref).”  “In this study, experiments provide compelling evidence that long-term treatment with compounds that block or scavenge reactive oxygen metabolites attenuate age-related hearing loss and reduce the impact of associated deleterious changes at the molecular level(ref).”  

·        The view of age-related hearing loss started to shift then too, to where it was seen to a large extent to be the result of accumulated oxidative damage.  This view brings hearing loss into very familiar territory, as being associated with the Oxidative Damage theory of aging.  It also strongly suggests that taking antioxidants might be very useful for staving off age-related hearing loss.  See the supplement firewall for the oxidative damage theory of aging.  Substances in the combined anti-agingfirewall experimentally demonstrated to reduce noise-trauma hearing loss include Vitamins A, C, E,  magnesium, resveratrol, acety l-carnitine, melatonin, folic acid, and R-alpha lipoic acid.  

·         As a variation on this oxidative damage theory of hearing loss, some researchers started to suspect mitochondrial damage as being a serious culprit(ref), bringing us to another island of familiar territory, the Mitochondrial Damage theory of aging.  Again, substances in the firewall for the mitochondrial damage theory of aging appear to be effective against hearing loss. “Acetyl-l-carnitine and alpha-lipoic acid reduce age-associated deterioration in auditory sensitivity and improve cochlear function. This effect appears to be related to the mitochondrial metabolite ability to protect and repair age-induced cochlear mtDNA damage, thereby upregulating mitochondrial function and improving energy-producing capabilities(ref).” 

·        Starting in the 2000s, yet-another view of age-related hearing loss has been emerging, seeing presbycusis as a result of decline in the rate of differentiation of hair follicle stem cells in the cochlear canal.  All along it has been known that hearing is the result of movement by sounds of delicate hairs in the cochlea and that presbycusis is directly associated with decline in the numbers of such hairs and corresponding hair cells.  More and more of the hair cells die out with age and are not replaced and hearing goes downhill.  And cochlear hair cells do not live in isolation; their wellbeing is correlated with the wellbeing of associated nerve cells like spiral ganglion neurons.  “- – neurotransmitter release from the hair cells drives membrane electrical activity in spiral ganglion neurons which also supports their survival(ref).  “The recent discovery of stem cells in the adult inner ear that are capable of differentiating into hair cells, as well as the finding that embryonic stem cells can be converted into hair cells, raise hope for the future development of stem-cell-based treatment regimens(ref).  This new stem-cell view of hearing loss leads to yet-another island of familiar territory – the Decline in Adult Stem Cell Differentiation theory of aging.   

·        Various means(ref) are being considered to remedy this situation in old folks, one being to make new cochlear hair follicle cells out of induced pluripotent stem cells and re-introduce them into the cochlea(ref).  This might be a good idea for the longer run but in the shorter run a simpler approach may be use of telomerase activation to increase the rate of differentiation of the existing hair follicle stem cells.  We know that telomerase can increase the rate of differentiation of hair stem cells via a process independent of telomere extension(See the shaggy mouse story). 

And I know from personal experience (N=1) that since starting telomerase activation many months back I am slowly getting more and more grey hairs on my previously-bald scalp.  Now, am I also getting more hairs in my cochlea?  Possibly; it is hard to count them.  Is my hearing improving?  Not insofar as I can tell.  My hearing right now is definitely not as good as it was back 5 years ago when I was only 74 but my immediate problem could simply be ear wax.   I will be cleaning my outer ear and watching carefully (actually listening carefully) to see what direction my hearing is going in.

If a life-extension technology works well with yeast, fruit flies and nematodes, will it also work well with us humans?  It would take a very long time to prove this through controlled lifelong experiments.  And such experiments might never happen. 

We know of several things that experimentally extends the life spans of fruit flies and nematodes and a few things that demonstrably extend the life spans of mice and rats.  However, there is very little firm experimental evidence on what can for-sure extend the life spans of primates: apes and chimpanzees.  And no such experiments for humans.  This is because of the lengths of time required to measure fully the impacts of anti-aging interventions on life spans – a few days in the case of fruit flies, two years in the case of mice, 40 years in the case of many monkeys and 90 years in the case of humans. 

Calorie  restriction has long been known to be the most sure-fire intervention for achieving  life extension.  It has been shown to work for a number of primitive species and has been shown to confer up to 40% life extension for smaller animals like mice and rats.  Moreover, the associated genetic pathways are starting to be understood and are known to be similar across species including our own.  Some 20 years ago, two US research groups set out to show that calorie restriction works also for extending the lives of primates.  Yesterday, another interim report appeared that lends credence to this hypothesis, this time for rhesus monkeys.  Studying aging in monkeys takes a lot of patience.  “Mice and rats only live for a couple of years, while these monkeys can live to 40, and the average life span is 27 years. Now that the surviving monkeys have reached their mid- to late 20s, the Wisconsin group could glean how calorie restriction was affecting their life span. Sixty-three percent of the calorie-restricted animals are still alive compared to only 45% of their free-feeding counterparts. For age-related deaths caused by illnesses such as cardiovascular disease and cancer, the voracious eaters died at three times the rate of restricted monkeys: 14 versus five monkeys, respectively. Another seven control and nine lean monkeys died from causes not related to aging such as complications from anesthesia or injuries. Leaner diets also reduced muscle and brain gray matter deterioration, two conditions associated with aging. (The team has not yet studied cognitive differences between the two groups.) (ref).”

The indications are plain but the real bottom line won’t be in for the monkey study until another 10 years have passed. Then it would take another 80-90 years of the same kind of experiment  to prove that calorie restriction works to extend lives in humans. 

Calorie restriction is not to most people’s taste, so such an experiment will probably never happen.  Instead, we rely on other interventions to delay aging, such as taking resveratrol which is shown by studies to activate some of the same genetic pathways activated by calorie restriction.  We are relying on knowledge of underlying mechanisms of molecular biology, genomics, and the other “omics,” plus experimental results with small animals which we infer should apply more or less to us as well.  For those of us interested in life extension now, this is the best we can do. 500 years from now we should have much firmer evidence of what delays aging in people.  Personally, I strongly prefer not to wait for that before taking anti-aging actions.

Some 288 news articles appeared in the last two days with headlines like Anti-age pill comes closer to reality and  Is Man’s Quest For Longevity Hidden in Antibiotics?  They are about the latest experimental discovery related to the  mTOR gene activation pathway and the drug Rapamycin .  In May, I posted a blog entry providing background on this subject called Longevity genes, mTOR and lifespan.  Also Aberrant mTOR signalling  is described in my treatise as one of the Additional Candidate Theories of Aging.  So, I will focus here only on the new finding except to repeat “Mammalian target of rapamycin (mTOR) is a protein encoded in humans by the FRAP1 gene.  As the name suggests, mTOR is targeted by the immunosuppressive drug rapamycin, a drug used clinically to treat graft rejection and restenosis and being tested as a treatment for autoimmune diseases.“ The generic name for rapamycin is sirolimus; it is a serine/threonine kinase inhibitor.

The study that excited the news reports is entitled Rapamycin fed late in life extends lifespan in genetically heterogeneous mice . “Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age. On the basis of age at 90% mortality, rapamycin led to an increase of 14% for females and 9% for males. The effect was seen at three independent test sites in genetically heterogeneous mice, chosen to avoid genotype-specific effects on disease susceptibility. Disease patterns of rapamycin-treated mice did not differ from those of control mice. In a separate study, rapamycin fed to mice beginning at 270 days of age also increased survival in both males and females, based on an interim analysis conducted near the median survival point. Rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both(ref).”  “The results were pooled from three independent studies–at Jackson Laboratory, in Bar Harbor, ME; the University of Texas Health Science Center, in San Antonio; and the University of Michigan, in Ann Arbor–and coordinated by the National Institute of Aging’s Interventions Testing Program (ITP). Rapamycin is the first success story to emerge from the ITP, which systematically evaluates anti-aging drug candidates for effectiveness in mice(ref) .”

The study is important for it is the first experimental evidence of life extension via rapamycin in mammals.  It is also important for old folks like me because the treatment was started late in the lives of the mice, equivalent to the age of 60 for humans. If the results can be extrapolated to humans it would mean something like 8 years of life extension for  males, 10 years more life for males.  Long live (with) rapamycin!!

Now for the caveats.  First of all, several of the supplements in the combined anti-aging firewall in my Anti-Aging Firewalls treatise have been reported at various times to extend the lives of mice by comparable or even greater amounts.  Would the effects of taking rapamycin provide additional life extension or simply be redundant  with the life extension already provided by those substances?  The answer is unknown.  Second, rapamycin/sirolimus can be dangerous stuff to play around with.  It is a powerful immune-system suppressant and may increase the risks of infections caused by viruses and bacteria, lymphoma, skin cancer, elevated blood lipids (cholesterol and triglycerides) and decreased kidney function(ref).  Third, we are not mice kept in a controlled cage away from most infections.  We do not know what the result would have been for mice in the wild and we don’t  know what the results of sustained intake of rapamycin would be for humans.  Caveat (beware of) rapamycin!

The basic idea of cancer immunotherapy is to get a patient’s own immune system to attack and destroy cancer cells or cancer stem cells or both. There are several approaches to doing this and one important general approach involves the use of dendritic cells (DCs).  Dendritic cells are immune system cells that help determine the adaptive immune response.   In simple language dendritic cells identify pathogens and then go tell the T cells what those pathogens are so the T cells can go out and kill cells harboring those pathogens.   “Immature dendritic cells constantly sample the surrounding environment for pathogens such as viruses and bacteria. This is done through pattern recognition receptors (PRRs) such as the toll-like receptors (TLRs). — Once they have come into contact with a presentable antigen, they become activated into mature dendritic cells and begin to migrate to the lymph node.”  There, “they act as antigen-presenting cells: they activate helper T-cells and killer T-cells as well as B-cells by presenting them with antigens derived from the pathogen, alongside non-antigen specific costimulatory signals(ref).” Finally, the helper and killer T-cells go out and kill any cells presenting the antigens. 

So, the general strategy in dendritic cell cancer immunotherapy (DCCI) is to make sure a significant subpopulation of dendritic cells are primed with antigens unique to cancer stem cells or cancer cells of the kind concerned.  There are various ways to make this happen.  In the case of skin cancers one approach is to paint the surface of the cancer with an “eat me” substance that will be recognized by already-circulating dendritic cells(ref). “In mice, topical application of phosphatidylserine-containing ointment over melanoma induced tumor-specific CTL, local and systemic antitumor immunity, and inhibited tumor growth. Thus, labeling of tumors with phosphatidylserine is a promising strategy for cancer immunotherapy(ref).”  A second DCCI approach is to collect a sample of a patient’s dendritic cells (normally from bone marrow), label these cells with the cancer antigen, and then inject them back into the patient(ref).  A third and new DCCI approach reported only yesterday is to start with embryonic stem cells, engineer these so they become dendritic cells, label these cells with the cancer antigen and inject them into the patient. According to a press release: “Geron Corporation (Nasdaq: GERN) today announced the publication of data demonstrating that dendritic cells (DCs) scalably manufactured from human embryonic stem cells (hESCs) exhibit the normal functions of naturally occurring human DCs found in the bloodstream. These findings support the use of hESC-derived DCs in therapeutic vaccine applications for cancer and other diseases. Substituting standardized, off-the-shelf hESC-derived DCs for current approaches using DCs obtained from individual patients may result in more cost effective and reliable approaches to cancer immunotherapy(ref).“

Research related to DCCI  has been going on for over 10 years now and despite several problems that have been encountered shows potential promise against several cancer types.  These articles review progress and problems in developing an effective dendritic cell vaccine against melanoma(ref)(ref). A recent publication suggests a variant of DCCI where dendritic cells are pulsed with RNA(ref).  A 1999 publication suggested the application of DCCI to two incurable diseases: Dendritic cell immunotherapy for cancer: Application to low-grade lymphoma and multiple myeloma.  A 2008 report indicates “The clinical studies have shown that DC administration to patients is safe and induces antigen-specific immunity. However, it seldom elicits objective clinical responses in patients with advanced-stage malignancies. Novel insights into DC and lymphocyte regulation are expected to lead to more effective vaccines in the near future(ref).”  In other words, the desired therapeutic effectiveness is mostly not there yet for people with advanced cancers but there is hope that more effective DCCIs can be developed.

I need point out again that there are other approaches to cancer immunotherapy besides use of dendritic cells, for example ones based on using monoclonal antibodies.  These too are potentially promising and in some cases have been shown to be successful.  But these will have to be topics of another blog post.

I thought I would poke into what the research literature says about things in my diet and associated risk of Alzheimer’s disease or late-onset dementia.  I came up with the following”

My morning cups of coffee (3-4 cups, half-caffeinated, half decaff): 

“Coffee drinkers at midlife had lower risk of dementia and AD later in life compared with those drinking no or only little coffee adjusted for demographic, lifestyle and vascular factors, apolipoprotein E ε4 allele and depressive symptoms. The lowest risk (65% decreased) was found in people who drank 3-5 cups per day(ref).” “Middle-aged people who drank between three and five cups of coffee a day lowered their risk of developing dementia and Alzheimer’s disease by between 60 and 65 percent later in life,” said lead researcher on the project, Miia Kivipelto, a professor at the University of Kuopio in Finland and at the Karolinska Institute in Stockholm(ref). A just-out study goes further and suggests that lots of coffee can possibly reverse symptoms of Alzheimer’s Disease: “New research from the US and Japan showed that giving the caffeine equivalent of five cups of coffee a day to aged mice with symptoms of Alzheimer’s reversed two signs of the disease: it reversed memory impairment and reduced the hallmark protein in the animals’ blood and brains(ref).”  See my earlier post Phytochemicals – focus on caffeic acid.

My usual breakfast: a sugar-free bran cereal with blueberries, walnuts and a sliced half-banana.

From Science News: Diet Of Walnuts, Blueberries Improve Cognition; May Help Maintain Brain Function(ref): “Diets containing two percent, six percent, or nine percent walnuts, when given to old rats, were found to reverse several parameters of brain aging, as well as age-related motor and cognitive deficits, says James Joseph, PhD, of the U.S. Department of Agriculture Human Nutrition Research Center at Tufts University in Boston.” – “Diets containing two percent, six percent, or nine percent walnuts, when given to old rats, were found to reverse several parameters of brain aging, as well as age-related motor and cognitive deficits, says James Joseph, PhD, of the U.S. Department of Agriculture Human Nutrition Research Center at Tufts University in Boston.” “This information, coupled with our previous studies, shows that the addition of walnuts, berries, and grape juice to the diet may increase ‘health span’ in aging and provide a ‘longevity dividend’ or economic benefit for slowing the aging process by reducing the incidence and delaying the onset of debilitating degenerative disease.” Six percent walnuts is equivalent to about an ounce a day which is what I have been eating. A British study reported in April 2009 confirms the value of walnuts for enhancing the ability of the connections between neurons to change in strength and function in aging rodents, and also to limiting oxidative damage to neural tissue. In aged rodents(ref).  Oh yes, and then there is the half- banana.  Another research report indicates “”Our results suggest that fresh apples, banana and orange in our daily diet along with other fruits may protect neuron cells against oxidative stress-induced neurotoxicity and may play an important role in reducing the risk of neurodegenerative disorders such as Alzheimer’s disease,” Lee concluded(ref).”

My daily fruit snacks (apple, cherries, plum, grapes, nectarine)

Previous reference applies.

My daily chocolate snack

“Oxidative stress induced by reactive oxygen species has been strongly associated with the pathogenesis of neurodegenerative disorders, including Alzheimer’s disease. In this study, we investigated the possible protective effects of a cocoa procyanidin fraction (CPF) and procyanidin B2 (epicatechin-(4beta-8)-epicatechin) – a major polyphenol in cocoa – against apoptosis of PC12 rat pheochromocytoma (PC12) cells induced by hydrogen peroxide.  — These results suggest that the protective effects of CPF and procyanidin B2 against H(2)O(2)-induced apoptosis involve inhibiting the downregulation of Bcl-X(L) and Bcl-2 expression through blocking the activation of JNK and p38 MAPK(ref).”  So, chocolate might help too and reduce cardiovascular risk as well(ref).

Glass of red wine (1-2 days a week)

“We recently found that moderate consumption of two un-related red wines generate from different grape species, a Cabernet Sauvignon and a muscadine wine that are characterized by distinct component composition of polyphenolic compounds, significantly attenuated the development of Alzheimer’s disease (AD)-type brain pathology and memory deterioration in a transgenic AD mouse model. Interestingly, our evidence suggests that the two red wines attenuated AD phenotypes through independent mechanisms. In particular, we previously found that treatment with Cabernet Sauvignon reduced the generation of AD-type amyloid-β (Aβ) peptides. In contrast, evidence from our present study suggests that muscadine treatment attenuates Aβ neuropathology and Aβ-related cognitive deterioration in Tg2576 mice by interfering with the oligomerization of Aβ molecules to soluble high-molecular-weight Aβ oligomer species that are responsible for initiating a cascade of cellular events resulting in cognitive decline. Collectively, our observations suggest that distinct polyphenolic compounds from red wines may be bioavailable at the organism level and beneficially modulate AD phenotypes through multiple Aβ-related mechanisms(ref).”  See my previous post in this blog Half glass of wine a day – good for longevity or bad because of increased cancer risk?   

Salami, prosciutto or corned beef sandwich, hot dog, bacon, hamburger, Polish or Italian sausage- once a week?

It would not be honest to represent everything I eat as good for me.  Occasionally, perhaps once or twice a week, I will partake of processed meat.  Usually this is in a restaurant, ball park or other place where I cannot check on the preservatives used. “Preservatives added to cured meats, bacon and ground beef have been linked to dementia diseases such as Alzheimer’s and Parkinson’s.”  — “Scientists say sodium nitrite, which is added to meat and fish to destroy toxins, reacts with proteins in the meat, damaging human DNA cells similar to aging(ref).” “U.S. researchers say they have found a substantial link between increased levels of nitrates in the environment and in food and increased deaths from Alzheimer’s, Parkinson’s and Type 2 diabetes. –The study, published this month in the Journal of Alzheimer’s Disease, found “strong parallels” between age-adjusted increases in the death rate from those diseases and the progressive increases in human exposure to nitrates and nitrosamines through processed and preserved foods, as well as through fertilizers(ref).