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).

A relatively new approach to looking at and treating cancers is to focus on cancer stem cells, a small subpopulation of cancer cells in a tumor that are capable or reproducing indefinitely and differentiating into mature cancer cells.  “Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample(ref).”

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. 

For example, there is recent news of research related to cause acute myeloid leukemia (AML), a blood disease that is highly treatment-resistant and prone to relapses.  “Researchers created an antibody (7G3) that recognizes and binds to a molecule called CD123, which is expressed at high levels on leukemia stem cells (LSCs), but not on normal blood cells. —When AML-LSCs from human patients were transplanted into mice, those treated with 7G3 survived longer than mice that didn’t receive the antibody. The researchers found that 7G3 blocked a signaling pathway in tumor cells, impaired migration of AML-LSCs to bone marrow and activated the immune system to destroy AML-LSCs(ref).”

On another front, researchers at the University of Michigan are going after breast cancer stem cells(ref).  “Researchers at U-M were the first to identify stem cells in breast cancer. These cells represent fewer than 5 percent of the cells in a tumor but are believed to be responsible for fueling a tumor’s growth and spread. Researchers believe that the ultimate cure of cancer will require killing these cancer stem cells. — In the current study, researchers looked at a drug called perifosine, which inhibits the Akt pathway. Tumors in mice were treated with perifosine or docetaxel, a standard chemotherapy drug. The docetaxel alone showed no effect on the number of cancer stem cells in the tumor. But adding perifosine reduced the cancer stem cell population by up to 90 percent. What’s more, the cells treated with perifosine – either with or without docetaxel – were less likely to grow a secondary tumor, compared to the cells treated with just docetaxel(ref).”  Perifosine affects pathways associated with the PTEN gene.

In another research study, breast cancer stem cell proliferation and differentiation is linked to faulty regulation in the Notch signaling pathway. “First, Notch helps restrict breast stem cell number, so that when Notch is ‘switched off’, there is a resultant expansion in breast stem cells. Second, Notch is important for ensuring that stem cells produce the sleeve of cells that normally line breast ducts. These ‘luminal’ cells may be the cells that give rise to common types of breast cancer. Thus, Notch helps to orchestrate the formation of breast tissue: it plays an important role in controlling stem cell number and instructs stem cells to produce luminal cells. Significantly, Dr Bouras and colleagues found that errant activation of Notch resulted in uncontrolled growth of luminal precursors, leading to the formation of breast tumours(ref).”  Yet-another related study shows that a protein called cyclin d1 is required for growth of breast cancer in the mouse model and negatively regulating Notch signaling and targeting cyclin d1may block the expansion of breast cancer stem cells(ref).

Research on cancer stem cells is proceeding on a variety of additional fronts.  “Researchers at Yale School of Medicine have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer’s recurrence and its resistance to chemotherapy(ref).” ‘Stem cell-like glioma cancer cells that share many characteristics with normal stem cells propel the lethal growth of brain cancers by promoting tumor blood vessel formation, and may hold the key to treating these deadly cancers(ref).” “Brain tumor researchers have found that brain tumors arise from cancer stem cells living within tiny protective areas formed by blood vessels in the brain. Killing those cells is a promising strategy to eliminate tumors and prevents them from re-growing. The researchers have found that drugs that block new blood vessel formation can destroy the protected areas and stop cancer from developing(ref).”  An earlier study had indicated “Brain tumors appear to arise from cancer stem cells (CSCs) that live within microscopic protective “niches” formed by blood vessels in the brain; and disrupting these niches is a promising strategy for eliminating the tumors and preventing them from re-growing  –(ref).”  Existing angiogenesis inhibitors like Avastin might be therapeutically useful.

A few days ago a report appeared indicating  “a molecule called telomerase, best known for enabling unlimited cell division of stem cells and cancer cells, has a surprising additional role in the expression of genes in an important stem cell regulatory pathway, say researchers at the Stanford University School of Medicine. The unexpected finding may lead to new anticancer therapies and a greater understanding of how adult and embryonic stem cells divide and specialize(ref).”  We have known for some time that telomerase promotes the differentiation of somatic stem cells through a mechanism independent of telomere extension(ref). 

My impression of this cancer stem cell research at this point is that:

·        Involved researchers believe this area holds great promise for developing targeted and more-effective cancer therapies.

·        Those therapies will involve targeting cancer stem cells rather than cancer cells in general.

·        Those therapies are likely to be less destructive of healthy tissues than existing radiation and chemotherapies and are less likely to lead to relapse and recurrence of the cancer

.·        Few if any of those cancer stem cell therapies have yet been developed sufficiently to become part of regular clinical practice.  Many are still in the cell-level and small-animal stages of experimentation.

The genome of an individual normally exhibits variations from the reference human genome identified by the Human Genome Project.  Some of these variations are inherited, some are due to mutations, some may be harmful, some are beneficial and some may indicate disease susceptibilities. 

The most familiar kinds of gene variations are SNPs, single-nucleotide polymorphisms,” a variation occurring when a single nucleotide — A, T, C, or G — in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual(ref).  Another kind of variation of increasing interest is a CNV, a copy number variation, meaning a missing sequence of DNA, incorrectly-inserted DNA or too many copies of a given DNA sequence.  

SNPs and CNVs occur much more commonly than once thought and are not necessarily harmful.  A 2006 study of 270 individuals revealed an average of 47 CNVs per person(ref).  More-recent research indicates that there may be as many as 1,000 CNVs in the average person(ref).

Defects in some individual genes are known to confer specific disease susceptibilities, perhaps the best known of these being BRCA1 and BRCA2, tumor suppressor genes.   Mutations of these are linked to hereditary breast and ovarian cancer(ref).  Another example is cystic fibrosis which is associated with a mutation in (or two copies of) the CFTR gene(ref). Down’s Syndrome is caused by a CNV in which an extra copy of chromosome 2, in whole or in part, is inherited.

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).”

In most cases the relationships between genetic variations and specific diseases are complex, probabilistic and still being explored.  Only rarely is there the situation “one bad gene, one disease.” For example, for a recent study relating bladder cancer to SNPs it is reported(ref):  “These authors evaluated the role of single nucleotide polymorphisms (SNPs) and bladder cancer risk and case survival. The authors used a panel of SNPs in potential cancer regulatory pathways, including cell cycle, cell growth, detoxification, telomerase, and apoptosis. They ranked causative or survival-associated single gene and multi-gene-combinations using a large, population-based case-control study in New Hampshire, USA. There were 832 cancer patients and 1,191 controls. The vast majority had non-invasive bladder cancer. 1,421 SNPs were evaluated, representing 400 cancer related genes. Bladder cancer risk was associated with altered genes in detoxification (GSTZ1_02 and pG42R), PAH metabolism (AKR1C3_35), pigmentation (TYR_02), lipid metabolism (SCARB1_03), and metabolism (SLC23A1_05). Altered genes associated with bladder cancer survival included surface antigens (CD80_04), apoptosis (BCL2L1_03 and CASP9), detoxification (EPHX1_15), and DNA repair (ERCC4_01)(ref). “A single-nucleotide polymorphism (SNP, pronounced snip) is a DNA sequence variation occurring when a single nucleotide — A, T, C, or G — in the genome (or other shared sequence) differs between members of a species (or between paired chromosomes in an individual)(ref).

The situation with respect to schizophrenia and bipolar disease is even more complex.  According to news reports this week: “Researchers at Stanford and 14 other institutions carried out a study of common DNA variations throughout the genome, and then combined forces with two independent studies to complete a pooled analysis of 27,000 individuals. The largest genetic differences between the study participants with and without schizophrenia were found on a stretch of chromosome 6 containing numerous genes associated with immune response (and some with other roles). This raises the possibility that immune function plays a role schizophrenia(ref).” The three studies found 30,000 common gene variations linked with the mental illness(ref).” While the research appears to be solid, the researchers are still far from being able to relate susceptibility to schizophrenia or bipolar disease to gene variation patterns.

Discoveries are coming at a fast pace and there are many tantalizing clues.  For example a 20 kilobase deletion CNV upstream of the IRGM gene is known to contribute to Crohn’s disease susceptibility according to a multi-species study(ref)(ref).  CNVs are associated with bone density based on a study of 6,865 Icelanders 8,510 subjects of European descent (ref).  CNVs at seven loci are identified with obesity(ref).  And here in one issue of Nature Genetics are reports of other studies relating CNVs to coronary heart disease risk, polygenic dyslipidemia, body mass index, type 2 diabetes, sclerosing skeletal dysplasia, and reticular dysgenesis.

  There is a great deal of ongoing research focused in linking SNP and CNV variation patterns with diseases such as is described here, and multiple  SNP and CNV databases are being built.  Because of the complexity, discovering disease relationships may be increasingly a task of applying computational genomics to databases.  See this listing of medical genetics databases. I expect there will be a lot more to report about this topic as time progresses.

The headline in the Reuters news release yesterday is Two-thirds of American adults are too fat: study, and the lead is “CHICAGO (Reuters) – Obesity rates continued to climb in the past year with 23 U.S. states reporting adults in their states are fatter now than they were a year ago, two advocacy groups said on Wednesday.” Obesity leads to heart disease, diabetes and cancer and other diseases, is a major cause for continuing rises in health care costs, debilitates the productivity of those affected with it, and shortens life spans.  The occasion is release of a study entitled F as in Fat: How Obesity Policies Are Failing in America 2009 conducted by the Robert Wood Johnson Foundation and the Trust for America’s Health, So what are some of the main things that can be said about obesity in the US?

Where it is happening:  Obesity is a serious problem throughout the United States but according to the new report appears to be worst in the most staunch “Red States “ The annual ranking of obesity rates in U.S. states found Mississippi continues as the state with the fattest residents, with nearly a third of adults considered obese. The U.S. state has topped the list for the past five years.”  “Three other states — West Virginia, Alabama, and Tennessee — now have obesity rates above 30 percent, according to the report(ref).”  Next-worst states are South Carolina, Oklahoma, Kentucky, Lousiana, Arkansas, Michigan and Ohio, all having a greater than 28.5% current obesity rate.  The State with the best score is Colorado with 18.9%  and the second best is Massachusetts I surmise that obesity correlates negatively with socio-economic status and level of education, positively with poverty and ignorance.  Increasing childhood obesity is an important aspect of the problem and even in Massachusetts 30% of the children are obese or overweight.

Change in obesity:  Despite public education efforts, the obesity pandemic is growing worse.  “The top state in 2009 is Mississippi, which in 2005 was 28.1% obese, and is now 32.5% obese. In 1991, every state was less than 20% obese(ref).”  Michigan is a case-in-point: “Nearly two-thirds of the state is battling either obesity or being overweight, considered a BMI of 25 to 29.9. The obesity percentage has steadily increased since 2005, when 25.3% of the state was obese. The state is now spending upward of $3 billion a year dealing with obesity-related medical issues.” – “About 25% of Michiganders 65 and older are obese(ref).”

Causes of obesity.  There are multiple possible causes for weight gain and obesity.  This article summarizes the better-known causes. 

Eating and lifestyle habits seem to be the two major controllable factors that cause obesity.  It is a question not only of the number of calories consumed but also of the kind of food.  One well-publicized cause is consumption of trans fats and saturated fats in processed foods.  “Trans fats are used widely by the food industry because they are up to 85% cheaper than natural fats such as butter, lard and palm oil. But researchers have repeatedly warned that they act as long-term toxins and have no benefit for consumers.  A recent report from the Food Standards Agency (FSA), which will carry out the new inquiry, said: “The trans fats found in food containing hydrogenated vegetable oil are harmful and have no known nutritional benefits. They raise the type of cholesterol in the blood that increases the risk of coronary heart disease. Some evidence suggests that the effects of these trans fats may be worse than saturated fats. —  However, even though such dangers have been known for nearly two decades, there is no obligation for food manufacturers to display the amount of trans fats on product labels(ref).”  Fast foods, notorious for their content of trans and saturated fats, have been linked to childhood obesity.  According to a 2003 AP report : “(AP)  Every day, nearly one-third of U.S. children aged 4 to 19 eat fast food, which likely packs on about six extra pounds per child per year and increases the risk of obesity, a study of 6,212 youngsters found(ref). 

Physical inactivity, a sedentary lifestyle, is clearly another elective factor leading to obesity as well as a host of diseases(ref)(ref).  “Using data from a large prospective cohort study, the Health Professionals’ Follow-up Study, we have demonstrated that increasing TV watching is strongly associated with obesity and weight gain, independent of diet and exercise. Also, prolonged TV watching is associated with a significantly increased risk of type 2 diabetes. Men who watched TV more than 40 h per week had a nearly threefold increase in the risk of type 2 diabetes compared with those who spent less than 1 h per week watching TV(ref).

Inherited genes is clearly a factor that can lead to obesity.  But so can acquired and inheritable epigenetic changes(ref).  That is, early eating and lifestyle habits can permanently change how a person’s genes respond to food leading to obesity later in life. Such changes may possibly also be inheritable.  Metabolic syndrome is a disease of obesity that affects approximately 47 million adults in the US.  It is characterized by obesity combined with a number of other conditions including high triglycerides, abnormal cholesterol, a general inflammatory condition as identified by C-reactive protein testing, insulin resistance and high blood pressure.  “People with the metabolic syndrome are at increased risk of coronary heart disease, other diseases related to plaque buildups in artery walls (e.g., stroke and peripheral vascular disease) and type 2 diabetes(ref).”  The current thinking is that Metabolic syndrome is likely to have an epigenetic origin.  “The idea that epigenetic changes associated with chromatin remodeling and regulation of gene expression underlie the developmental programming of metabolic syndrome is gaining acceptance(ref).” Also, “The preschool years (age 3-6 years) have been regarded as critical for the programming of energy balance, via the concept of early ‘adiposity rebound’. Children who undergo early adiposity rebound are at increased risk of later obesity(ref).”  I bet that the adiposity rebound effect is epigenetic in nature. Epigenetic changes that tend to promote obesity are scary in that  they are permanent unless ways can be found to get rid of them, and in that possibly they can be inherited.  A simple introduction to epigenetics and epigenomics is contained in my February 2009 blog post Epigenetics, Epigenomics and Aging.

The cultural and psychological forces leading to obesity should not be underestimated.  There is the lure of plentitude.  Not only is excess TV viewing a problem in itself but popular TV programs repeatedly show commercials for generous portions of wonderful-looking fast and manufactured foods, ones likely to be contain large amounts of saturated and trans fats.  Many restaurant chains routinely serve portions double in size of what is needed in a meal.  And I still hear the echoes of my grandmother saying to me when I was a thin boy of 7 “Eat, eat Vincy, eat.  It is good for you. Eat!”

What can be done about obesity?  This is a complicated issue, on the personal level, the family level, the national level and all levels in-between.  And of course the list of things that have been suggested for losing weight seems to be endless.  For those of you tending to be overweight by 10-20 pounds but not really obese like I was 10 years ago, you could try what I did to get myself into normal weight range.  It worked for me and is spelled out in my treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY.  In particular, see the combined Lifestyle Regimen and the combined Supplement Regimen.  Besides helping me lose weight, following these regimens helped me feel better, have more energy, have a clearer mind, normalize my lipid scores, and have a better sex life.  And I expect those regiments will also help me live longer, possibly a lot longer.

One view is that stress is the enemy of longevity.  From the Library of Halexandria:  “Stress is an undesirable commodity — if only because it’s not beneficial to wellness.  Thus it stands to reason that a reduction in stress in someone’s life might lead to greater health, and thereby allow one to live longer.”  Some, including myself, tend to disagree, holding instead that animal (including human) longevity is correlated with having and meeting a healthy level of challenge – not too little and not too much stress.  Too little mental, physical or life stress is apt to lead to inaction and then one’s neurons and muscle cells will atrophy and die.  That is why regular exercise and taking on intellectual and life challenges tend to extend longevity.  On the other hand if life challenges are just too overwhelming, an animal may be unable to cope and simply choose to die.  We know about the health-damaging effect of constant mobilization of cortisol in response to stress. 

Imagine that stress is somehow quantified and laid out on the x axis of a graph, and the y axis is probable lifespan in years.  The graph would resemble a normal distribution, e.g. a bell-shaped curve where the largest probable lifespan corresponds to the best amount of stress.  Way too little or too much stress would correlate with shorter life spans.

A recent study done by a team at Rockefeller University seems to indicate that the same principal holds on the cellular level for retinal cells.  When the cell experiences stress in the endoplasmic reticulum (ER), depending on the condition of the cell and the nature of the stress the cell can choose to die or to live longer by mobilizing its defense mechanisms.  The study and its conclusions is explained in a university newswire release that can be found here.  “The team, including Bertrand Mollereau, who is now a professor at the École Normale Supérieure de Lyon in France, believes that a mechanism underlying this protection may involve antioxidant genes that protect retinal neurons from ultraviolet radiation and free radicals. When these neurons are exposed to mild ER stress, the team showed that they upregulate genes that shield them from the substances’ harmful effects. “As in neurodegenerative diseases, when photoreceptor neurons die, they may never be replaced,” explains graduate student Alexis Gambis, who also worked on the project. “The antioxidant upregulation is one way neurons have evolved to protect themselves from exogenous stress and it’s especially important in the eye, which receives damaging UV energy from the sun(ref).”  

Stress is not one thing.  An analysis reviewing the results of 300 independent studies identifies five distinct categories of stress:

1.      “Acute time-limited stressors: lab challenges such as public speaking or mental math.

2.      Brief naturalistic stressors: real-world challenges such as academic tests.

3.      Stressful event sequences: a focal event such as loss of a spouse or major natural disaster gives rise to a series of related challenges that people know at some point will end.

4.      Chronic stressors: pervasive demands that force people to restructure their identity or social roles, without any clear end point – such as injury resulting in permanent disability, caring for a spouse with severe dementia, or being a refugee forced from one’s native country by war.  

5.      Distant stressors: traumatic experiences that occurred in the distant past yet can continue modifying the immune system because of their long-lasting emotional and cognitive consequences, such as child abuse, combat trauma or having been a prisoner of war(ref). “

As far as my personal stress regimen is concerned, thankfully they mostly fall in the first two categories.  Most of the daily stress challenges I face are self-generated: doing at least 47 minutes of mildly cardiovascular exercise, doing many hours of focused longevity research, taking on difficult scientific topics and writing these blog entries.  In addition my challenges include keeping my treatise up to date on a weekly basis, constantly learning more about molecular biology, genetics, genomics, biochemistry and the other expanding areas of science underlying longevity science, handling family finances and taxes, being the handyman in two houses, yard work, commuting back and forth to my New Hampshire lake home in the summer, and leading a balanced all-around family life while doing all that.  I believe the stress of keeping up with these challenges is contributing to keeping me young and fully functional. External stress-generating challenges of the second and third types sometime loom very important for me as they do for other humans, such as sickness on the part of my wife or loved one, concerns about money, concerns about the state of the world.  The key thing is to not let those start to overwhelm me. I am fortunate not to be faced with stress of the fourth type.  And I have done enough psychotherapy and internal re-examination to assure that I am free from stress of the fifth type.

Back in March I posted a short item the substance DHMEQ on this blog, a powerful recently-discovered inhibitor of NF-kappaB.  You might want to check out that post before reading further here.   

DHMEQ was designed and synthesized by Japanese researchers based on the molecular structure of the antibiotic epoxyquinomicin C.  According to a 2002 research report by these researchers shortly after DHMEQ was first developed: “DHMEQ inhibited the TNF-alpha-induced cellular DNA binding of nuclear NF-kappaB, but not the phosphorylation or degradation of I-kappaB. Moreover, DHMEQ inhibited the TNF-alpha-induced nuclear accumulation of p65, a component of NF-kappaB. On the other hand, DHMEQ did not inhibit the nuclear transport of Smad2 and the large T antigen. Also, it did not inhibit the TNF-alpha-induced activation of JNK, but synergistically induced apoptosis with TNF-alpha in human T cell leukemia Jurkat cells.” A 2005 report by some of the same researchers clarified the action of DHMEQ somewhat  “In this cell line (MCF-7 cells), DHMEQ completely inhibited the tumor necrosis factor-alpha-induced activation of NF-kappaB. DHMEQ did not inhibit the degradation of IkappaB but inhibited the nuclear translocation of NF-kappaB by both p65/p50 and RelB/p52 pathways.”  In other words, DHMEQ inhibits NF-kappaB expression by blocking its initial translocation from the cell cytoplasm into the cell nucleus rather than blocking its action on specific genes after it got into the nucleus. Summarizing some recent research:

* DHMEQ shows promise as a therapeutic agent against several forms of cancer, including multiple myeloma(ref),  liver cancer(ref)(ref), human leukemia(ref)(ref), and bladder cancer(ref).  It enhances the effect of taxanes as a therapy for thyroid cancer(ref).  DHMEQ together with another NF-kappaB inhibitor bortezomib sensitises rituximab-resistant AIDS-B-non-Hodgkin lymphoma to apoptosis by various chemotherapeutic drugs(ref).

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