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.

This post is about a relatively older but still-interesting line of research linking the human hormone alpha-melanocyte-stimulating hormone (alpha-MSH) to reduction of inflammation.  Melanocytes are cells which produce the pigment melanin which gives color to the skin, eyes and hair.   In the blog post, More research insight on gray hair and adult stem cell reproduction I discussed how declining numbers of melanocyte stem cells is responsible for the hair of older people turning white or gray.  Melanocytes are found in multiple body tissues in addition to hair follicles, including the skin, meninges, bone and heart.  The role of alpha-MSH in activating  activate melanocytes has been extensively studied for some time(ref)(ref)(ref).  Alpha-MSH is produced in the pituitary gland, in neural cells, monocytes and certain types of skin cells.  For example, consider suntan.  When ultraviolet radiation impacts on keratinocytes, the keratinocytes release alpha-MSH.  Melanocytes have target receptors for alpha-MSH and when alpha-MSH binds to skin melanocytes, they generates the black pigment eumelanin.  The result is suntan. [Actually the situation is a bit more complicated than this since other factors are also involved in producing eumelanin and the melanocytes have other regulatory functions besides producing eumelanin(ref)(ref)(ref)(ref).]

With respect to theories of aging it is interesting that Alpha-MSH inhibits the expression of NF-kappaB and is a powerful anti-inflammatory, affecting what is possibly a key pathway in inflammatory pathologies(ref). “We report that alpha-melanocyte-stimulating hormone(10–9 M) was effective in opposing a tumor necrosis factor- stimulated increase in NF- B DNA binding activity in: (i) normal ocular melanocytes; (ii) cells cultured from ocular melanoma tumors; and (iii) two cutaneous melanoma cell lines(ref).”

  This is quite interesting since runaway expression on NF-kappaB and TNF-alpha seem to be characteristic of melanoma.  Systemic administration of alpha-MSH appears to inhibit inflammation in general.  For example, it has been shown to be capable of inhibiting colonic inflammation in inflammatory bowel disease, at least in rats(ref).  It can inhibit edema in the mouse paw and acute ear inflammation in mice(ref). Another study description indicates “The results suggest that anti-inflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation. In addition to its central influences, alpha-MSH has inhibitory effects on peripheral host cells, in which it reduces release of pro-inflammatory mediators. Alpha-MSH reduces chemotaxis of human neutrophils and production of TNF-alpha, neopterin, and NO by monocytes. In research on septic patients, alpha-MSH inhibited release of TNF-alpha, interleukin-1 beta (IL-1 beta), and interleukin-8 (IL-8) in whole blood samples in vitro(ref).”  In the nervous system, the anti-inflammatory effects of alpha-MSH are communicated via neurogenic signaling.  One report indicates “We recently found that alpha-MSH can act solely within the brain to inhibit inflammation caused by a general irritant applied to the skin. This activity appears to be shared with salicylate drugs and the combined observations suggest the existence of descending neurogenic anti-inflammatory signals capable of modulating inflammation in peripheral tissues(ref).”The way that alpha-MSH works to limit inflammation appears to be through inhibiting expression of NF-kappaB which is essential for the expression of proinflammatory cytokines.  It appears to do this by prevention of degradation of IkappaBalpha, a protein that keeps NF-kappaB locked up in the cell cytoplasm and out of the nucleus(ref). 

NF-kappaB plays a central role in the Programmed Epigenomic Changes theory of aging.  There does not seem to be much current research action on the anti-inflammatory effects alpha-MSH or use of alpha-MSH as an anti-inflammatory therapy but I would not be surprised to see this thread picked up again at some point in an expanded context.

One of the more-traditional theories of aging covered in my anti-aging treatise is Lipofuscin accumulation, a theory that has been around for decades.  According to this theory, aging is caused by or contributed to by lipofuscin, metabolic gunk, oxidized cross-linked proteins, that accumulates in postmitotic cells with age and gums up their workings.  It is found in a variety of cell types in a variety of organs including the heart, kidney, liver, eyes and brain.  Levels of lipofuscin are often used as biomarkers of age.  I recently started to wonder if this theory was too stodgy compared to newer sexier theories like Programmed epigenomic changes.  So, I decided to do a check on lipofuscin-related research.  I came up with several items suggesting that despite all the aging-related research in newer areas of genomics and molecular biology, lipofuscin accumulation continues to be of great importance in aging. 

o    Lipofuscin continues to be studied. A search in pubmed.org on “lipofuscin 2009” reveals 150 citations.  According to a review study, “Lipofuscin formation appears to depend on the rate of oxidative damage to proteins, the functionality of mitochondrial repair systems, the proteasomal system, and the functionality and effectiveness of the lysosomes. This review highlights the current knowledge of the formation, distribution, and effects of lipofuscin in mammalian cells(ref).”

o    Cells have mechanisms for protein repair and a mechanism for getting rid of damaged proteins called proteolysis which happens due to specialized protein complexes in cells called proteasomes.  “Therefore, the accumulation of oxidized protein with age can be due to increased protein damage, decreased oxidized protein degradation and repair, or the combination of both mechanisms. The proteasomal system is the major intracellular proteolytic pathway implicated in the degradation of oxidized protein, –(ref).”  In plain language words, lipofuscin accumulation is due to an imbalance in cell metabolic and waste-degradation functions. 

o    Large accumulations of lipofuscin and lipofuscin-like materials in cells can lead to cell death.  “The results of this study are consistent with the conclusion that accumulation of lipofuscin-like materials results in inhibition of the proteasome, which initiates an apoptotic cascade as a result of dysregulation of several proapoptotic proteins(ref).

·         According to Encylopedia Britannica “The pigment lipofuscin accumulates within heart muscle cells; it is not detectable at ten years of age but rises to almost 3 percent of the cell volume by age 90(ref).”

·        ”This review article covers how lipofuscin and neuromelanin, a related substance, accumulated with age in autophagic vacuoles in neurons and the damage created.  “The most striking morphologic change in neurons during normal aging is the accumulation of autophagic vacuoles filled with lipofuscin or neuromelanin pigments. — The pigments arise from incompletely degraded proteins and lipids principally derived from the breakdown of mitochondria or products of oxidized catecholamines.  Pigmented autophagic vacuoles may eventually occupy a major portion of the neuronal cell body volume because of resistance of the pigments to lysosomal degradation –(ref).” 

·        There is a family of at least eight rare and genetically distinct neurodegenerative diseases associated with accumulation of lipofuscin in cells known as neuronal ceroid lipofuscinoses (NCL)(ref)(ref).  “They (the NCL diseases) are associated with variable yet progressive symptoms including seizures, dementia, visual loss, and/or cerebral atrophy(ref).”

·        The tyrosinase gene is involved in the deposition of cardiac lipofuscin, at least in mice(ref).  This is a relatively older (1993) finding.  “Analysis of spontaneous mutants of the tyrosinase gene, encoded by the albino locus, confirmed that the tyrosinase gene itself controls lipofuscin formation.”  “Tyrosinase is a copper-containing enzyme present in plant and animal tissues that catalyzes the production of melanin and other pigments from tyrosine by oxidation, as in the blackening of a peeled or sliced potato exposed to air(ref).”  So it is a good guess that black lipofuscin skin spots on older people are created by a somewhat similar process to that which turns a sliced potato black.

·        Lipofuscin is often considered in a broader context as one of several forms of undesirable protein aggregations, others sometimes being called ceroids, inclusion bodies, plaques, or aggresomes depending on their source and composition.  While possibly being metabolic products, these aggregations may be biologically active.  They may affect proteasomal activity and protein turnover and are common features of neurodegenerative diseases as well as aging(ref).

·        A diagram of how lipofuscin buildup reduces the effectiveness of cellular lysomes capability to degrade damaged mitochondria can be found here.

·        Acumulation of lipofuscin in the retinal pigment epithelium (RPE) has long thought to be a major factor leading to age-related dry macular degeneration(ref)(ref).  There is a substantial literature on this subject.

These and many other research reports I encountered continue to indicate that lipofuscin accumulation is serious issue in aging.

Lipofuscin accumulation is closely associated with things that happen according to other major theories of aging such as Oxidative Damage and Chronic or Excess Inflammation.   For example, in the case of AMD (adult macular degeneration), “These findings link four factors that have been posited as being associated with: inflammation, oxidative damage, drusen, and RPE lipofuscin(ref).” 

Protection against oxidative damage is one key strategy for minimizing the production of li[pofuscin.  See the firewall for the oxidative damage theory of aging, both lifestyle elements and dietary supplements.  Fortunately, there are several supplements with serve either to reduce levels of lipofuscin accumulation or to help pump lipofuscin out of cells.  They are listed in the firewall for the lipofuscin accumulation theory of aging.

Research in induced pluripotent stem cells (iPSCs) is rapidly moving forward, this being probably the most fast-moving area of stem cell research, a field which itself is proceeding at express speed.  I posted a blog entry Rebooting cells and longevity describing iPSCs way back in March of this year (now a time in ancient history) and have referred to them subsequently in various posts.  Again, an iPSC is a stem cell that is created by resetting a normal somatic cell, say a skin cell, back to the ground-zero state of an embryonic stem cell by introducing four critical proteins that wipe out the accumulated epigenomic information in that cell.  It seems an iPSCs can do most everything an embryonic stem cell (ESC) can do.  So, three months later, what are the currently hot issues with respect to iPSCs?  Here is what I think they are:

·        Creating iPSCs that are genomically stable and free of cancer genes

There is a fair amount of research going on in this area, particularly focused on means for making sure that portions of gene sequences from viral vectors are not integrated into the final iPSCs(ref)(ref)(ref).  This is important since such segments might turn out to be oncogenic.  The proteins used to create iPSCs can be Oct4, Sox2, Nanog, and Lin28 or  Oct4, Sox2, Klf4, and c-Myc.  All of these proteins are traditionally known to be oncogenic and that is also a cause for serious concern. If the proteins are activated by inserting genes for them in order to create the iPSCs, it is important to get rid of those genes before the iPSCs are used for therapeutic purposes.  

The actions of the proteins can be quite complex, for example see the comments here about the multiple actions of Lin28.  This story tells about four current research approaches to getting rid of the cancer genes from iPSCs.  Progress in this area is rapid and the expectation is that in a year or two standardized methods will be available for creating iPSCs that are absolutely genomically stable and free of cancer genes.  In the meanwhile most experimentation with iPSCs has been with cells that may or may not be safe for human use.    

·        Determining similarities and differences between embryonic stem cells (ESCs) and iPSCs

This is a very important issue from several viewpoints.  A lot more is known about ESCs since they have been studied for several years.  If this knowledge can be applied to iPSCs, years of research could be saved.  Apart from the religious objections to using fetus-derived ESCs for human therapeutic purposes, there is a compelling reason to use iPSCs instead if they are truly equivalent and safe.  The reason is that iPSCs are genetically a patient’s own cells and will not be rejected by the immune system when reintroduced into a patient.  Unlike some current stem cell treatments based on using other people’s stem cells, there is no need to wipe out a patient’s immune system before introducing iPSCs.  Current research suggests that there may be some differences between ESCs and iPSCs, but exactly what these are and how they play out is still to be explored.

·        Getting iPSCs to differentiate reliably into somatic cell types and adult somatic stem cells types 

On this front, a recent research report demonstrated that iPSCs can differentiate into functional cardiomyocytes.  The author states “We conclude that human iPS cells can differentiate into functional cardiomyocytes, and thus iPS cells are a viable option as an autologous cell source for cardiac repair and a powerful tool for cardiovascular research.”  There are a number of earlier reports related to ESCs being able to differentiate into cardiomyocytes.  This work on human iPS cells confirms earlier research results with mouse iPS cells(ref).  Other reports confirming the pluripotent differentiation capabilities of  iPS cells keeps rolling in.  For example, scientists at UCLA report creating functional neurons from iPSCs.  As time progresses I expect to see reports on more and more tissue types being created from iPSCs.

As for the critical task of regenerating adult stem cells from iPSCs, my cursory scan of the literature has not picked up anything significant yet.  It is one thing to get iPSCs to differentiate into neurons; it would be something else to get them to replenish a body’s declining stock of neural stem cells.  I believe this is a crucial issue, not only from the viewpoint of designing stem cell therapies but also from the viewpoint of longevity.  The fourteenth theory of aging characterized in my treatise on aging is Decline In Adult Stem Cell Differentiation.  Having a good available supply of adult (somatic) stem cells is critical for organ damage repair and constant tissue regeneration. Examples mentioned or discussed previously in this blog include mesenchymal stem cells, neural stem cells, endothelial stem cells, dental pulp stem cells, and hematopoietic stem cells. With aging the population of adult stem cells declines due to replicative senescence attrition and oxidative damage, and the rates of differentiation into somatic cells also declines.  I would imagine that if iPSCs can be induced to differentiate into nerve or heart cells, they can also be induced to differentiate into the corresponding adult stem cell types which by all logic should be intermediate cell types.

The literature is full of curiosities.  For example a very recent study reports that iPSCs created from Tibetian miniature pigs more resemble human iPSCs than those from any other animals.  A fascinating related area of research involves direct reprogramming of cell types without intermediation of stem cells.  For example, it is possible to transformed human skin cells into mouse muscle cells and vice versa(ref)(ref).  The bottom line is far from in yet, and I will continue to watch and report on news related to iPSCs.

Three of the principal theories of aging articulated in my are treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY are Chronic or Excess Inflammation, Susceptibilities to Cancers, and Decline In Adult Stem Cell Differentiation. Recent research suggests an underlying mechanism that links inflammation, cancer and the role of adult stem cells, at least in the case of autoimmune diseases such as rheumatoid arthritis, Lupus erythematosus, scleroderma and Sjögren’s syndrome.   For some time, it has been noted that these inflammation-promoting autoimmune diseases are associated with elevated probabilities for incidences of cancer, lung cancer in the case of rheumatoid arthritis and lymphoma in the case of lupus for example(ref)(ref)(ref).  However, the reason for this association remained unclear.  Recent research suggests that what might be happening is a) adult stem cells are attracted to the sites of inflammation associated with the disease, basically on a repair mission b) in the abnormal signaling environment of the inflammation  sites, other things are going on possibly leading some of these stem cells to mutate and become cancerous.  “Recent studies have underscored a striking connection between tissue injury, repair and malignancy that may be of significant importance to the pathogenesis of systemic rheumatic diseases.  At the center of this connection lies the stem cell, the effector of tissue repair and regeneration that can arise from the tissue itself or be recruited from immigrant precursors(ref).”

For example, it is well known that lupus can lead to lung inflammation associated with interstitial lung disease and idiopathic pulmonary fibrosis (ref).  Tissue damage ensues which recruits stem cells to the sites of injury, endothelial progenitor cells being among them(ref).  However, the inflammation may also promote the recruitment of circulating tumor cells to the same sites(ref).  What exactly can happens next is unclear, but one theory gaining traction is that the environment is mutantogenic for the stem cells.  The title of one research publication telegraphs the message:

Stem Cells in Inflammatory Disease: Chronic Inflammation and Tissue Damage Recruits Stem Cells, Which Accumulate Mutations and May Become Transformed.

“A recent study by Houghton and colleagues using a mouse model demonstrates a very striking connection between chronic inflammation, hematopoietic stem-cell recruitment and mutation, and cancer formation in the inflamed target tissue. These authors showed that chronic Helicobacter pylori infection stimulates the recruitment of bone marrow derived stem cells (BMDC) into the gastric mucosa, which engraft permanently into the tissue stem-cell niche, assuming functions of the former. In the inflammatory microenvironment generated by H. pylori, the engrafted BMDCs accumulate mutations, and appear to be the cells that give rise to the gastric tumors arising in these animals(ref).”  Another publication reports “Data from emerging studies provide a growing body of evidence that stem cells play critical roles at the injury-repair interface. While performing the function of regeneration so critical for life, they may also be inadvertent partners in pathology, through their ability to self-renew and express various autoantigens also expressed in tumors.”

There is much current research activity in the associated fields of autoimmune diseases, stem cell activities, oncogenesis and inflammation.  So, I expect there will be further clarification of the phenomena described here as time progresses.  Meanwhile, a general message for both healthy people and ones with autoimmune diseases appears to be “keep the inflammation down as much as possible.”  For someone in the midst of a roaring lupus flare, this could require a medical intervention such as prescribing a strong corticosteroid like prednisone.  For healthy people, there is my suggested anti-aging Firewall against Chronic or Excess Inflammation.