AGINGSCIENCES™ – Anti-Aging Firewalls™

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

Telomerase genes

·        “Genetic mutations in the components of telomerase (the RNA template sequence hTERC, reverse transcriptase hTERT, and Syskerin DKC1) have recently been implicated in a variety of bone marrow failure syndromes, idiopathic pulmonary fibrosis, and more recently, acute myeloid leukemia (AML)(ref).”

·        “The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer(ref).”

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The new findings

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

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

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

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

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

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

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

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

·         knowing how to stop disease progression at that point,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

*  Cancer immunotherapy:  See Dendritic cell cancer immunotherapy 

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The concept here is engineering stem cells so they differentiate into body cells that target, go after and kill “bad” cells, such as cells infected with HIV or cancer cells.  It is a fairly new approach.  Since stem cells have an uncanny ability to be welcomed in the body and get around in it, they potentially make very attractive seek-and-destroy cells.

A December 8 2009 Science Daily story Stem Cells Can Be Engineered to Kill HIV, Scientists Show is a this-week example.  “Researchers from the UCLA AIDS Institute and colleagues have for the first time demonstrated that human blood stem cells can be engineered into cells that can target and kill HIV-infected cells –.  Taking CD8 cytotoxic T lymphocytes — the “killer” T cells that help fight infection — from an HIV-infected individual, the researchers identified the molecule known as the T-cell receptor, which guides the T cell in recognizing and killing HIV-infected cells. These cells, while able to destroy HIV-infected cells, do not exist in enough quantities to clear the virus from the body. So the researchers cloned the receptor and genetically engineered human blood stem cells, then placed the stem cells into human thymus tissue that had been implanted in mice, allowing them to study the reaction in a living organism.  — The engineered stem cells developed into a large population of mature, multifunctional HIV-specific CD8 cells that could specifically target cells containing HIV proteins. The researchers also found that HIV-specific T-cell receptors have to be matched to an individual in much the same way that an organ is matched to a transplant patient. — The next step is to test this strategy in a more advanced model to determine if it would work in the human body –“This approach could be used to combat a variety of chronic viral diseases,” said Zack, who is also a professor of microbiology, immunology and molecular genetics (at UCLA). “It’s like a genetic vaccine.”” 

A May 2009 Science Daily story Adult Stem Cells From Bone Marrow Made To Kill Metastatic Lung Cancer Cells In Mice describes another example.  “Researchers in London have demonstrated the ability of adult stem cells from bone marrow (mesenchymal stem cells, or MSCs) to deliver a cancer-killing protein to tumors. — The genetically engineered stem cells are able to home to the cancer cells, both in culture and in mouse models, and deliver TNF-related apoptosis-inducing ligand (TRAIL), destroying the tumor cells while sparing normal cells.”  This story was covered in the blog entry Trojan-horse stem cells might offer an important new cancer therapy.  And, regarding the payload TRAIL, see the blog entry On the TRAIL of a selective cancer treatment.

A 2005 Science Daily story Researchers Use Human Embryonic Stem Cells To Kill Cancer Cells described an earlier related development.  In this case, human embryonic stem cells were coaxed to differentiate into NK (natural killer) cells.  “Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte that constitute a major component of the innate immune system. NK cells play a major role in the rejection of tumors and cells infected by viruses. The cells kill by releasing small cytoplasmic granules of proteins called perforin and granzyme that cause the target cell to die by apoptosis(ref).”

A related but not quite terminator-cell approach is described in an October 2009 Science Daily story The Stem Cells Which ‘Fool Immune System’ May Provide Vaccination For Cancer.  In this case “Scientists from the United States and China have revealed the potential for human stem cells to provide a vaccination against colon cancer, reports a study published in Stem Cells. — “This finding potentially opens up a new paradigm for cancer vaccine research,” said Dr. Zihai Li. “Cancer and stem cells share many molecular and biological features. By immunizing the host with stem cells, we are able to ‘fool’ the immune system to believe that cancer cells are present and thus to initiate a tumor-combating immune program –‘ .The team vaccinated laboratory mice with human embryonic stem (hES) cells and discovered a consistent immune response against colon cancer cells. The team witnessed dramatic decline in tumor growth within the immunized mice. This revealed that immunized mice could generate a strong anti-tumour response through the application of hES cells.”

These four stem-cell approaches to disease immunization or cure show potential promise but each is still in an early stage of development and is yet to be tested in humans.   I would guess that 8-15 years will be required for any of them to become part of clinical practice.

I remember an old Star Trek movie where severely debilitated people without functional vocal chords could readily speak to each other by merely thinking their sentences.  Recent research is bringing us closer to having such a capability.  The article A Wireless Brain-Machine Interface for Real-Time Speech Synthesis in the current issue of Plos One lays out the progress.

“Brain-machine interfaces (BMIs) involving electrodes implanted into the human cerebral cortex have recently been developed in an attempt to restore function to profoundly paralyzed individuals. — In the current study we use a novel approach to speech restoration in which we decode continuous auditory parameters for a real-time speech synthesizer from neuronal activity in motor cortex during attempted speech. —  Neural signals recorded by a Neurotrophic Electrode implanted in a speech-related region of the left precentral gyrus of a human volunteer suffering from locked-in syndrome, characterized by near-total paralysis with spared cognition, were transmitted wirelessly across the scalp and used to drive a speech synthesizer. A Kalman filter-based decoder translated the neural signals generated during attempted speech into continuous parameters for controlling a synthesizer that provided immediate (within 50 ms) auditory feedback of the decoded sound. Accuracy of the volunteer’s vowel productions with the synthesizer improved quickly with practice, with a 25% improvement in average hit rate (from 45% to 70%) and 46% decrease in average endpoint error from the first to the last block of a three-vowel task.”

I take this to mean that machine-training is necessary and that generating normal fluent speech is not yet possible.  My impression is that a lot more needs to be done to understand and encode the relationships between neural events and continuous speech.  This may take some time.  Computer speech recognition research started in the 1950s and decent recognition of continuous speech was not achieved until around 2000.  The authors conclude “Our results support the feasibility of neural prostheses that may have the potential to provide near-conversational synthetic speech output for individuals with severely impaired speech motor control. They also provide an initial glimpse into the functional properties of neurons in speech motor cortical areas.”

I speculate that if and as this technology is perfected it would have a number of additional applications for normal non-debilitated people including:

·         Telephone calls without talking aloud for privacy or in noisy places or so as not to disturb others,

·         Rapid writing or recording of thoughts for people who can think faster than they can talk,

·         Private voice conversations not obvious to those you are with, even sneakier than text messaging can be, and

·         Controlling machinery or even driving a car with just internally vocalized thoughts.

In the future the situation could get even more extreme when electronics also can short-circuit the human hearing apparatus and thoughts can fly electronically from one brain into another.  I don’t want to go there for now.  If I live as long as I want to, however, there will surely come a point when I will have to decide whether or not to have a brain implant for voiceless speech synthesis.

It is time for a bit of humor.  I receive several advertiser-supported health, longevity and vitamin-promoting magazines in the mail.  I am not sure why they are getting sent to me since I don’t pay for them.  I usually have trouble finding much substance in them.  My intent here is to poke fun at them by constructing eleven cover-story titles and lead lines for a new magazine of that ilk which I will call AVOIDANCE.

AVOIDANCE

Live longer – the Dr. Goldstone method

Doctor Goldstone outlines his revolutionary approach to living longer, an extract from his book The Sure Way to Live Longer.  Long life is a matter of context, and the secret is ongoing death prevention.  “I guarantee you that if you succeed at avoiding death, you will live longer.”  Dr. Goldstone is a practicing coroner who knows his business and a frequent contributor to AVOIDANCE.

Flatten your bulgy belly

A simple guide based on the artichoke-lime juice diet, step climbing and squat jumps.  Blend boiled artichokes with the lime juice, refrigerate, and consume nothing but 3 cups a day for 2 weeks.  If A is your age and W is your weight you must climb |3*(W-A)| steps a day except on Fridays and do |(W-A)/3| squat jumps daily except on Tuesdays.  If you don’t follow instructions and your stomach stays bulgy, it’s your own fault.

Living with Zybbrignowski’s Symptom

It does not have to drive you crazy if you are willing to be bit nuts in the first place and chew a bunch of crunchy Forgouh Pain™ tablets whenever you feel an attack coming on.   Available in seven flavors, anti-allergenic.  Doctor-recommended.  Arsenic-free.  Convenient order form is below.  Order now.  Two bottles for the price of one.

Avoiding diseases of old age – a simple sports approach that is guaranteed to work

The solution is to die young, and this can likely be accomplished by pursuing a combination of dangerous sports.  We suggest parachute-free skydiving, ocean shark polo, motorcycle daredevil racing and Himalayan mountaintop skiing.

Forget your aging wrinkles with Azerbaijan koodo root slime grease

It burns and stings, smells terrible, won’t wash off, stains everything, ruins clothes and definitely makes your wrinkles seem like minor matters to be concerned about.

The six best ways to lose weight – and the 283 worst ways

Describes an annotated document you can buy for only $18.99 and keep by your refrigerator.  If you “act now” a dozen colorful anti-weight pebbles will be included for free.  Turns out, you better have strong eyeglasses or a magnifying glass handy to read the document.  It is written by the same lawyers that write contracts for software products, the ones where you have to click the “I agree” box to get the software to work.  You keep the anti-weight pebbles in a glass on the kitchen table to remind you not to eat.

Step up your sex life with exotic radish-garlic-spicy pepper soup

Five chopped up cloves of garlic, a generous sprinkling of dried red pepper flakes and a bottle of Tabasco sauce tops off the serving.  If you can manage to consume it and keep it down, in 24 hours you should be ready for a torrid sex experience.

Living simply for health

In other words, live simply for health and forget everything else.  It may not make you better but it can give you focus, purpose, and keep you reading Vince’s Blog.  And you can get so boring that you drive other pesky people away.  Hint:  if you are going to do this, be sure to get somebody else to pay your bills.

Bargain diet software makes healthy meal planning easy

Easy-to-use software for preparing tasty and healthful dishes, only $2.99 a disk.  Available formatted for Osborn I, Apple II, CPM, DOS, Commodore 64 and Atari 400 operating systems only. 

Dr Saps on how to forget your Alzheimer’s problems

His advice is to avoid unnecessary stress and worry.  Just ignore your dementia concerns and sooner or later you will surely forget them all.

Taking care of your hippocampus 

A nontechnical guide written in plain language for ordinary people who have heard of how important hippocampuses are. A clean, well-organized and well-functioning hippocampus is important for your emotional health and wellbeing, and for taking care of your hippo if you have one.  Emphasis should be on mitochondrial health and on a big enough hippocampus for your hippo to wander around in with African-type wallowing holes. 

I set out two days ago to see what updated research I could find on diet and cognition.  I found a bewildering array of items, some somewhat contradictory.  It has been a cognitive challenge to make sense of them, especially while having to deal with variety of other challenges like figuring out how to bring two virus-infected computers back to life, what to tell my investment adviser, how to take care of the house given that a big tree branch has crashed through a window, keeping things going during a couple of  storm-related power outages, and what I need to do to continue keeping a bunch of family members happy.  The question at hand is “What is the impact of diet on cognitive functioning and memory, especially for older people?”  So I report on a few selected 2009 studies and end up giving my own bottom line. 

Mediterranean diet and risk of dementia

The August 2009 report in JAMA Adherence to a Mediterranean Diet, Cognitive Decline, and Risk of Dementia. “ Objective:  To investigate the association of a Mediterranean diet with change in cognitive performance and risk for dementia in elderly French persons.   Design, Setting, and Participants:  Prospective cohort study of 1410 adults (65 years) from Bordeaux, France, — Adherence to a Mediterranean diet (scored as 0 to 9) was computed from a food frequency questionnaire and 24-hour recall. Main Outcome Measures”  Cognitive performance was assessed on 4 neuropsychological tests: Main Outcome Measures:  Cognitive performance was assessed on 4 neuropsychological tests: the Mini-Mental State Examination (MMSE), Isaacs Set Test (IST), Benton Visual Retention Test (BVRT), and Free and Cued Selective Reminding Test (FCSRT). Incident cases of dementia (n = 99) were validated by an independent expert committee of neurologists.  ^– Conclusions:  Higher adherence to a Mediterranean diet was associated with slower MMSE cognitive decline but not consistently with other cognitive tests. Higher adherence was not associated with risk for incident dementia.”  At least one commentary on the article in JAMA suggested that at least one of the other rests also may also indicate cognitive decline(ref).  Not much surprise here.

The DASH diet may slow cognitive decline – it you can get people to follow it

There is not much surprise for me in this July 2009 item either.  “A diet rich in fruits and vegetables and low in salt, sweets, and red meats — the Dietary Approaches to Stop Hypertension (DASH) model — appears to slow cognitive decline, researchers said here at the International Conference on Alzheimer’s Disease(ref).” “The patients received a score based on how closely they followed the diet, which requires seven to eight servings of grains; four to five servings of fruit; four to five servings of vegetables, two to three servings of low fat dairy, two or fewer servings of meat a day, and five servings of nuts or legumes or seeds a week.”  

“The groups were divided into quintiles, and the results showed that those patients in the highest quintile — the individuals who were closest in following the diet — had the slowest decline in cognitive functioning, while the patients in the lowest quintiles had the most rapid decline in functioning.  — Over the 11-year time frame of the study, the difference between the most diet-adherent individuals was about 3.73 points (P<0.001) on the Modified Mini Mental State Examination, a standard instrument that measures cognitive decline. The examinations were given at baseline and as many as four times during the study period.”

I think that the proponents of this diet are correct in pointing out that getting compliance with it is likely to be very difficult, even if it does offer benefits.

Rats on junk food become lazy and stupid

The August 2009 study Deterioration of physical performance and cognitive function in rats with short-term high-fat feeding seems to say that for rats at least, a high-fat diet leads not only to long-term cognitive decline but also to short-term decline as well.  “We found that rats ran 35% less far on a treadmill and showed cognitive impairment in a maze test with 9 d of high-fat feeding, with respiratory uncoupling in skeletal muscle mitochondria, associated with increased uncoupling protein (UCP3) levels. Our results suggest that high-fat feeding, even over short periods of time, alters skeletal muscle UCP3 expression, affecting energy production and physical performance.”

The Science Daily coverage of the research is headlined Do High-Fat Diets Make Us Stupid And Lazy? Physical And Memory Abilities Of Rats Affected After 9 Days.  According to it “All 42 rats were initially fed a standard feed with a low fat content of 7.5 per cent. Their physical endurance was measured by how long they could run on a treadmill and their short-term or ‘working’ memory was measured in a maze task. Half of the rats were then switched to a high-fat diet where 55 per cent of the calories came from fat. After four days of getting used to the new diet, the endurance and cognitive performance of the rats on the low- and high-fat diets was compared for another five days. — “With the standard feed, 7.5 per cent of the calories come from fat. That’s a pretty low-fat diet, much like humans eating nothing but muesli,” says Dr Murray. “The high-fat diet, in which 55 per cent of the calories came from fat, sounds high but it’s actually not extraordinarily high by human standards. A junk food diet would come close to that. — Some high-fat, low-carb diets for weight loss can even have fat contents as high as 60 per cent. However, it’s not clear how many direct conclusions can be drawn from our work for these diets, as the high-fat diet we used was not particularly low in carbs,” he adds. — On the fifth day of the high-fat diet (the first day back on the treadmill), the rats were already running 30 per cent less far than those remaining on the low-fat diet. By the ninth day, the last of the experiment, they were running 50 per cent less far. — The rats on the high-fat diet were also making mistakes sooner in the maze task, suggesting that their cognitive abilities were also being affected by their diet. The number of correct decisions before making a mistake dropped from over six to an average of 5 to 5.5.”

So, if people’s metabolisms are like rat’s, a steady diet of junk food could make us fat and lazy.  Some times when I am in a junk food chain late at night and noticing that everyone in sight is obese, I have had the same thought, a thought I quickly repress as being politically incorrect.

Unlike rats, airline pilots cognition is made better with a high fat or high carb diet

This next report is a mind-bender because it seems to contradict the previous one and to go against what we think we know.  The report is entitled High-Carb, High-Fat Diets Superior to High-Protein Diets in Improving Cognitive Performance.*   “Diets high in carbohydrates or fat can lead to significantly better cognitive-performance and in-flight-testing scores in pilots than diets high in protein, according to results reported in a poster presentation at the Military Health Research Forum (MHRF) 2009 in Kansas City, Missouri. — In addition, a high-carbohydrate diet helped study pilots sleep better, and a high-fat diet appeared to lead to significantly faster short-term memory. — Eating a diet that’s high in protein just isn’t going to help you perform optimally.   Results showed that overall flight-performance scores for the pilots consuming a high-protein diet were significantly worse (P < 05) than for those consuming a high-carbohydrate or a high-fat diet. A hierarchical regression analysis indicated that this was due in part to dietary protein intakes, serotonin levels, and irritability scores. — The response time on the Sternberg test of short-term memory was significantly faster for participants who ate the high-fat diet (P < .05) than for those who ate the protein and control diets, especially at higher memory loads. No significant impact was observed on the Vandenberg test.”

So does a high fat diet make cognition worse or improve it? Hmm.  Perhaps airline pilots can get smarter on junk food and rats can’t?  I doubt it.  Reminds me of the climate change studies.  Most of these say that CO2 is responsible for global warming, but a few say the opposite.  And I remember the old days when most research reports said cigarette smoking was very harmful and a few said the opposite.  In any event the presenter tempered the findings a bit.  “We’re certainly not saying you always have to eat high fat,” said Glenda Lindseth. “The take-away message is that a diet that is well balanced and has a lot of carbohydrates and a reasonable amount of fat in it is best for pilots to perform well cognitively(ref).”

What do I make of these reports?  Basically that nutrition research marches on, and that in general a single study or research report an important theory does not prove or disprove.  I think that there is plenty of additional evidence that the Mediterranean diet offers many health benefits likely to include increased cognitive clarity, and that high-fat diets are likely to create health problems.  See the blog post Recent research on the Mediterranean diet.  So most of these studies tend to confirm what is already known except for the airline pilot study.  Either that study will provide a breakthrough new perspective if the results are supported by additional studies, or additional research will cast doubt on or significantly narrow its conclusions. 

•  If you don’t belong to Medscape and want to read this item, do a Google search on the entire title and then click on it in the search results.

One hope for personalized medicine is that individuals would have their major gene variations profiled and that drug interactions with critical genes would also be profiled.  Thus, a person with a particular disease could determine whether a particular drug is efficacious given their gene variations, or whether that drug would be likely to produce an adverse reaction.  Fulfilling this hope requires both profiling of gene variations present in individuals and pharmacogenetic studies of drugs, that is, analyses and  clinical testing of how drugs behave in the presence of genetic variations.   I have discussed individual profiling in the blog entry Individual DNA testing. It is starting to get off the ground but has a very long way to go.  This blog posting is about progress/lack of progress in pharmacogenetic drug profiling. 

My comments are mainly based on a review article  that appeared in PloS ONE four days ago Fulfilling the Promise of Personalized Medicine? Systematic Review and Field Synopsis of Pharmacogenetic Studies.  The authors looked systematically at the published literature in an attempt to determine the current state of pharmacogenetic knowledge.  “From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25:1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40–222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of ≥4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points.” 

The state of progress appears to be underwhelming.  The authors conclude “The high expectation but limited translation of the pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines.” 

So, more or less the same thing can be said about the pharmacogenetic profiling aspect of the personalized medicine hope:  It is starting to get off the ground but has a very long way to go. It is a long long way to Tipperary, to stem cell treatment and to drug-response related personalized medicine.  At least, we are on our way.