30. November 2009 by admin.

I became fascinated with l-carnosine about ten years ago.  Back then, this substance seemed capable of doing more or less what telomerase activators are hoped to be doing now – greatly extending the replicative life spans of certain body cells.  So I started studying l-carnosine intensively and also taking it as a supplement.  And I am still doing that.  The substance clearly has significant anti-aging powers but some of the ways in which it works are still shrouded in mystery. 

L-carnosine does a number of very good things for health and longevity.   I wrote a review of the substance in 2002 and there I said, listing multiple literature citations, “Carnosine can inhibit non-enzymic glycosylation of proteins.  Carnosine blocks the formation of AGEs  protecting against cross-linking of proteins in the eye lense and skin collagen, cross-linking of proteins to DNA molecules, and formation of other abnormal proteins.  Carnosine promotes wound healing, and has numerous anti-oxidant properties including the quenching of  singlet oxygen.  Carnosine traps peroxyl radicals, inhibits damage due to gamma irradiation, binds transition metals rendering them unable to participate in the toxin-producing Fenton’s reaction.  Carnosine may go beyond scavenging ROS to reducing the production of ROS.  It protects against and promotes healing of stomach ulcers and reduction of brain damage due to accumulation of beta amyloid and possibly due to malondialdehyde or hypochlorite anions.  It can very likely be used as an anti-ischemic drug.  Carnosine is an efficient chelating agents for copper and other transition metals, and Carnosine appears to protect neurons from zinc- and copper-mediated neurotoxicity.  Carnosine appears to expand the resistance of rats to various induced stresses.  It can be used in the treatment o severe gingivostomatitis.  Carnosine  is an immunostimulant.  Carnosine is reported to have an ability to up or down-regulate cellular and enzymatic processes to bring them into normal range.  For example, Carnosine can decrease platelet aggregation in patients with low clotting indices.  The list goes on and on.  One study by Egyptian researchers even suggests that Carnosine could be used to correct metabolic disturbances induced by schistosomiasis.”

But the one reported fact about carnosine that really attracted my attention was that it could significantly delay or reverse cellular senescence.  This was long before the days of telomerase activation.  I wrote “Research studies by Mcfarland and all going back to 1994 indicate that Carnosine can delay senescence and promote formation of a more juvenile phenotype in cultured human fibroblasts, extending the Hayflick limit for reproduction of such cells by up to ten doublings.  Late-passage fibroblasts from lung and foreskin tissues were switched back and forth a number of times between Carnosine-enhanced and non-enhanced culture media.   Mcfarland and his colleagues consistently observed that the Carnosine culture medium restored the juvenile cell phenotype within days, whereas immersion in the standard culture medium brought back the senescent cell phenotype(ref).  The life span of cells immersed in the Carnosine medium was also increased, even for old cells. When late-passage lung fibroblasts at 55 PDs (population doublings) were transferred to the Carnosine medium, they lived to 69 to 70 PDs, compared to 57 to 61 PDs for the fibroblasts that were not transferred. Further, the fibroblasts transferred to the Carnosine medium attained a life span of 413 days, compared to 126 to 139 days for the control fibroblasts.  Finally, it appears that when cells in the Carnosine medium eventually enter into cellular senescence, they nevertheless retain a normal or less-senescent morphology.“  

On a cellular level, l-carnosine extended the lifespan of the fibroblasts by a factor of about 3, and this fact really grabbed me. And now that I start to think about it again, it still grabs me.

This led me back then to conjecture that perhaps l-carnosine caused the expression of telomerase or some other telomere-protecting protein and therefore had extraordinary anti-aging power.  But other experts in longevity I consulted at the time, having their own fish to fry, had no patience for that idea. 

A 2004 publication L-carnosine reduces telomere damage and shortening rate in cultured normal fibroblasts  confirmed the earlier Mcfarland observations.  “In this work, we studied the effect of carnosine on the telomeric DNA of cultured human fetal lung fibroblast cells. Cells continuously grown in 20 mM carnosine exhibited a slower telomere shortening rate and extended lifespan in population doublings. When kept in a long-term nonproliferating state, they accumulated much less damages in the telomeric DNA when cultured in the presence of carnosine.  We suggest that the reduction in telomere shortening rate and damages in telomeric DNA made an important contribution to the life-extension effect of carnosine.” 

On the one hand, this capability of carnosine to greatly extend the number of cell doublings excited me greatly at the time and still intrigues me.  Even today, precious few substances seem to have that kind of anti-aging potential.

On the other hand, how carnosine works to extend the number of cell doublings so greatly was then and is still now a mystery.  I further wrote “The mechanism by which Carnosine can extend the Hayflick limit appears to be unknown, though in my mind at least it is possibly the most central issue with respect to Carnosine and longevity research.  Various  possibilities appear to exist, including:  1.  The ROS-scavenging properties of Carnosine significantly reduce damage of telomeric DNA thus extending the maximum number of divisions possible. 2.  As put by Hipkiss “Perhaps the carbonyl binding activity of Carnosine (or the released histidine) might mask any deleterious effects of the aberrant (carbonyl) protein on proteasome function as well as facilitate degradation  to allow the extras cell divisions;” and, 3.  Through some sequence of Carnosine-induced gene transcription and protein release, telomerase is expressed in the cells involved leading to longer telomeres and consequently more extended cell replication cycles.”

As I became more engaged in other areas of anti-aging research around 2003, this unusual capability of l-carnosine slipped to the back of my mind.     However, I just ran across a 2009 publication that brings the enigmatic character of this substance up again.  The publication is appropriately titled On the enigma of carnosine’s anti-ageing actions.  “Carnosine (beta-alanyl-L-histidine) has described as a forgotten and enigmatic dipeptide. Carnosine’s enigma is particularly exemplified by its apparent anti-ageing actions; it suppresses cultured human fibroblast senescence and delays ageing in senescence-accelerated mice and Drosophila, but the mechanisms responsible remain uncertain. In addition to carnosine’s well-documented anti-oxidant, anti-glycating, aldehyde-scavenging and toxic metal-ion chelating properties, its ability to influence the metabolism of altered polypeptides, whose accumulation characterises the senescent phenotype, should also be considered. When added to cultured cells, carnosine was found in a recent study to suppress phosphorylation of the translational initiation factor eIF4E resulting in decreased translation frequency of certain mRNA species. Mutations in the gene coding for eIF4E in nematodes extend organism lifespan, hence carnosine’s anti-ageing effects may be a consequence of decreased error-protein synthesis which in turn lowers formation of protein carbonyls and increases protease availability for degradation of polypeptides altered postsynthetically. Other studies have revealed carnosine-induced upregulation of stress protein expression and nitric oxide synthesis, both of which may stimulate proteasomal elimination of altered proteins. Some anti-convulsants can enhance nematode longevity and suppress the effects of a protein repair defect in mice, and as carnosine exerts anti-convulsant effects in rodents, it is speculated that the dipeptide may participate in the repair of protein isoaspartyl groups. These new observations only add to the enigma of carnosine’s real in vivo functions.”

So the enigma remains unresolved.  In fact the author AR Hipkiss has been an important leader in l-carnosine research all along, having also published some 30 documents having to do with l-carnosine in the last 10 years, including:

Chapter 3 carnosine and its possible roles in nutrition and health. (2009) “Physiologically carnosine may help to suppress some secondary complications of diabetes, and the deleterious consequences of ischemic-reperfusion injury, most likely due to antioxidation and carbonyl-scavenging functions.”

Carnosine, diabetes and Alzheimer’s disease (2009)

Could carnosine or related structures suppress Alzheimer’s disease? (2007) “Protein oxidation and glycation are integral components of the AD pathophysiology. Carnosine can suppress amyloid-beta peptide toxicity, inhibit production of oxygen free-radicals, scavenge hydroxyl radicals and reactive aldehydes, and suppresses protein glycation.” – “Carnosine stimulates proteolysis in cultured myocytes and senescent cultured fibroblasts. These observations suggest that carnosine and related structures should be explored for therapeutic potential towards AD and other neurodegenerative disorders.”

Would carnosine or a carnivorous diet help suppress aging and associated pathologies? (2006) “Carnosine has the potential to suppress many of the biochemical changes (e.g., protein oxidation, glycation, AGE formation, and cross-linking) that accompany aging and associated pathologies. Glycation, generation of advanced glycosylation end-products (AGEs), and formation of protein carbonyl groups play important roles in aging, diabetes, its secondary complications, and neurodegenerative conditions. Due to carnosine’s antiglycating activity, reactivity toward deleterious carbonyls, zinc- and copper-chelating activity and low toxicity, carnosine and related structures could be effective against age-related protein carbonyl stress.”

Does chronic glycolysis accelerate aging? Could this explain how dietary restriction works? (2006) {VG comment: To the extent that chronic glycolysis does accelerate aging, then perhaps l-carnosine’s powerful anti-glycating action could explain some of its anti-aging capability.}

On the mechanisms of ageing suppression by dietary restriction-is persistent glycolysis the problem? (2005) {Same VG comment}

Could carnosine suppress zinc-mediated proteasome inhibition and neurodegeneration?   Therapeutic potential of a non-toxic but non-patentable dipeptide. (2005)

Glycation, ageing and carnosine: are carnivorous diets beneficial? (2005) {VG comment:  Meat-eating has a bad reputation in health circles today.  In this and other articles, Hipkiss points out that meat-eating has some good things going for it too.}

Other researchers have continued to publish about l-carnosine. However the mechanism of how l-carnosine can so greatly extend the replicative life of certain cell cultures and extend the life of lower organism has never been satisfactorily explained as far as I am concerned. In 1999 leading l-carnosine  researchers wrote in the publication Carnosine as a Potential Anti-senescence Drug “Anyway, the question “How could such a small molecule have such profound effects?” remains unanswered, though we hope through increased global scientific collaboration that we shall have the answers sooner rather than later.”  Now, ten years later, the question still remains unanswered.

One thing is for sure though.  L-carnosine will continue to be part of my suggested anti-aging Supplement Regimen and I will continue taking it, currently 500mg twice daily.

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28. November 2009 by admin.

Light metals may not lengthen lives but heavy metals can certainly shorten them.  Toxicity due to heavy metals can inadvertently come about many ways: drinking slightly acid water that has passed through lead pipes, eating too much mercury-containing tuna and swordfish, eating flakes of lead paint that have dropped from the ceiling in an ancient kitchen, breathing fumes from a nearby smelter, oil-painting with cadmium red and yellow, and breathing mercury vapor from smashed fluorescent bulbs.  A man named Orlando used to work in my granddad’s newspaper running a linotype machine back in the 30s in Detroit.  Those machines had pots of boiling lead used to cast type, and Orlando was strange and crazy from breathing the fumes.  Mercury used to be used extensively in shaping the felt used in hats and drove hatters to become mad, thus the phrase ‘mad as a hatter.” A few years back a test showed I had a high level of serum arsenic.  That was probably from handling pressure-treated lumber restoring the deck in my summer home.  

“Symptoms of heavy metal toxicity include mental confusion, pain in muscles and joints, headaches, short-term memory loss, gastrointestinal upsets, food intolerances/allergies, vision problems, chronic fatigue, and others. The symptoms are so vague that it is difficult to diagnose based on symptoms alone(ref).”  Therefore I strongly recommend that any readers who believe they may be suffering from heavy metal poisoning should consult with a medical practitioner to obtain proper testing and treatment.  And, of course, epigenomic deregulation and accelerated aging can result from the presence of heavy metals in the body.  In extreme case, death may soon follow the poisoning.

Dangerous heavy metals include arsenic (found in insect and other pest poisons, in some industrial products and even in some drinking water), lead (found in old-fashioned paints, old plumbing pipes and even new soldered plumbing joints, old lead house paint, old toys and some toys from China, , and fumes from smelters),  mercury (found in large ocean fish and some fish from contaminated waters, fluorescent light bulbs in vapor form, dental fillings, thermometers, fumes from some coal-burning power plants, mining ore processing and foods containing mercury residues from processing), and cadmium (contained in fumes and wastes from various industrial processing, silver soldering, nickel plating, engraving, electroplating, and used in nickel-cadmium batteries as well as cadmium vapor lamps.)  These and other toxic heavy metals (there are about a dozen, all told) are also used in agriculture, in treating parasites in farm animals and often find their way into water and air associated with industrial or agricultural pollution.

Clearing out heavy metals

The sources of heavy metals are so universal that it may be impossible to avoid having some levels of one or more of them in one’s system, but yet the ideal body levels of all such metals is zero.  So, what are the ways of getting rid of heavy metals from one’s body?  I know of three approaches:

-         Intravenous chelation

The standard medical treatment for acute heavy metal poisoning is intravenous chelation, usually with EDTA.  A chelating substance can be thought of as chemical tongs which can grab toxic heavy metal molecules and escort them outside of the body.  “The Chelation process is based upon the use of a water soluble molecule such as EDTA, that can essentially wrap itself around a heavy metal molecule that ISN’T water soluble, and gets trapped inside the body because it cannot pass through the mucous membranes of the kidneys, liver, GI tract, lungs or skin. — The word “CHELE” is Latin for the claw of a crab, and the Chelation process is essentially as if a “Crab claw” wraps itself around a heavy metal molecule, and then gives it free passage out of the body (similar to an illegal alien sneaking across the border in the trunk of a car)(ref). “  The calcium EDTA is dripped into a vein and the chelated metals pass out in the urine. The IV treatments may last 15-30 minutes each and, depending on the degree of toxicity present, a number of treatments may be required.   Other intravenous chelators include DMPS and  DMSA.  The intravenous chelating process also removes desirable nutrients like zink, vitamins C and E which must be replenished.

Intravenous EDTA treatment is FDA-approved for certain indications, generally regarded to be safe and is usually the treatment of choice in case of acute heavy metal poisoning.  However, its widespread use by some practioners of alternative medicine is highly controversial.  These practioners believe that even minor heavy metal toxicity may be responsible for a wide variety of illnesses, including circulatory diseases, and suggest repeated use of intravenous chelation(ref).  They make claims like “EDTA Chelation has been proven effective in the elimination toxins and dangerous arterial plaque in hundreds of medical studies conducted by many of the world’s most highly respected medical institutions over 50 years(ref).”  Twenty, thirty or more sessions of this therapy may be recommended, often to be done in clinics owned by such practioners themselves. 

However, many cardiovascular experts associated with mainline medicine believe that such research claims are vastly exaggerated and question the efficacy of this approach for other than treating acute poisoning(ref).  The paper EDTA chelation therapy for cardiovascular disease: a systematic review concludes “The best available evidence does not support the therapeutic use of EDTA chelation therapy in the treatment of cardiovascular disease. Although not considered to be a highly invasive or harmful therapy, it is possible that the use of EDTA chelation therapy in lieu of proven therapy may result in causing indirect harm to the patient.”

-         Oral supplements that are chelators

As already well-stated in my treatise “While acute poisoning with excessive blood serum levels of PCBs, lead, arsenic, cadmium or mercury requires intravenous chelation and other aggressive treatments, supplements can play a role in ongoing control of serum levels of these substances in healthy individuals and on the biological impacts of the presence of such toxins.  L-carnosine is an important element of my firewall defense against toxic heavy metals like cadmium, lead, and mercury since it has an ability to chelate them (literally, to grab on to and combine with the molecules of these metals so the kidney and liver can excrete them).  Further, according to animal experiments, certain antioxidants already in this firewall, vitamin C, alpha tocopherol, melatonin and alpha-lipoic acid in particular, can play roles in reducing the toxicity of heavy metals and PCBs, in some cases reducing it dramatically.   Other components of the firewall defense against toxic metals are mineral supplements that compete for absorption and compete metabolically with such metals.   For example, copper and selenium antagonize mercury.  Calcium helps reduce lead and zinc helps reduce cadmium.  Magnesium also appears to be very important for protecting cells from heavy metals.”  And, pyridoxamine is also a chelator.

Although I had a few sessions of intravenous chelation many years ago, I now rely on the supplements to do the job.  If I were inadvertently exposed, say, to mercury or arsenic fumes, I would consider a few sessions of IV EDTA treatment.

-         Toxic metal removal by raising body heat and sweating

In a recent blog commentary, reader Jayne pointed out the use of sweating in saunas as a way of getting rid of heavy metals, an approach I had not heard of until then.  There are lots of research citations relating to the role of raising body heat and sweating in elimination of “good” minerals such as calcium, magnesium, potassium and zink(ref)(ref).  In fact, that’s why people who exercise drink Gatoraade to replenish their electrolytes.  There are also mentions in Internet of the use of saunas for “detoxification,” particularly detoxification after exposure to PCBs or solvents(ref)(ref).  I found a couple of casual mentions of the use of saunas for heavy metal removal in the medical literature(ref), and several mentions on commercial sauna sites(ref).  My limited searching has failed, however, to reveal any systematic studies relating sauna use to heavy metal detoxification.  So, I am unable to determine how effective this approach to detoxification may actually be, how hot the sauna has to be, how long to stay in it, safety precautions, etc. 

Beyond saunas, sweat lodges rituals involving intense heat are processes with native-American origins that are supposedly detoxifying.  I went through a few of those a couple years back and the heat stress was so great that I was glad to emerge alive.  A few weeks ago a news report said that three people were killed and nearly two dozen more required hospital treatment due to participating in such a ritual.  So, my fears were not entirely unjustified. Intense sustained heat can be very dangerous.

Any of you readers out there who are members of the sauna or sweat lodge cultures might want to chime in on this.  I have a large sauna at home but family members have gradually filled it with storage boxes.  The same has happened to my sauna at the lake house.    If I were sufficiently motivated I would mobilize efforts to clear them out and start using them again.

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26. November 2009 by admin.

A few hours ago a dear friend of mine asked me to review the supplements he was taking before he flew away to live in Germany.  To provide a context for that review I came up with a simplified explanation of what aging is and what can be done about it.  Given how complex my treatise ANTI-AGING FIREWALLS -  THE SCIENCE AND TECHNOLOGY OF LONGEVITY has become, I thought it might be useful for many of my readers to lay out the same simplified explanation.   

What is aging?

Aging is the lifelong accumulation of changes in the DNA surrounding our genes that result in changing gene expression.  These are called epigenomic changes, and have to do with turning our various genes off and on so to produce the observed phenomena of aging.  These phenomena can include wrinkled skin, balding hair and decreased libido.  More importantly, they include gradual but generalized deregulation of body processes, degeneration of organs and increasing susceptibility to disease processes. This increasing deregulation, degeneration and disease susceptibility may start in subtle ways around age 30 or before and gradually accelerates thereafter.  The curve of impending sickness and death becomes ever more ominous with advancing age.  Nobody dies of old age per-se.  Everybody dies of something, however, like heart failure, diabetes, cancer, stroke, pneumonia or accident, almost all of us by age 110.  We die because the epigenomic changes make the curves of our vulnerability to exactly these causes of death become steeper and steeper  - until the odds of anyone continuing to live go down to zero.  Some people with defective genes may typically die earlier and others with exceptional genes may experience the curve of degeneration slower.  See yesterday’s post paying attention to the item on Centenarian Ashkenazi Jews, but even they die off before 122.  

So, there is a program of aging.  If aging were not programmed there would be an exceptional tiny few of us who lived on to 200, 300 and even 500 and some dogs would live to 150.  Every species has such a program.  Why such a program?  Probably because evolution protects species, not necessarily members of a species.  Evolution operates so as to clear out older members of species who have already raised offspring so they won’t compete for resources with younger ones.   The aging program changes everything in our bodies.  Thousands of genes get switched off and on.  Our hormone levels decrease, our nervous systems become less responsive and so do all the body feedback systems that support us, our immune systems become progressively weaker.  We can gain too much weight; lose our strength, become susceptible to inflammatory processes, and lose eyesight, balance, memory and ability to think.  As we age, one kind of sickness can speed the deteriorative process and lead ever-more quickly to another sickness and then another.  Things that we could fight off quickly in youth become ever-more deadly.  A minor cold can lead to pneumonia and death.  A splinter in a finger can lead to a MRSA infection, hospitalization and death. What are the aspects of the aging program and how do they work?  These are complicated topics treated in my treatise and many earlier blog entries.   

Anti-aging strategies 

The anti-aging strategies available to us are few, including:

o    Avoid causes of accelerated aging

o    Pursue lifestyle habits that are known to slow aging

o    Pursue activities that are known to slow down, reduce the probabilities of or prevent the major diseases and deteriorative processes of aging.

o    Take supplements or pursue activities that might possibly affect the basic program of aging, so as to slow it down or even conceivably stop or reverse it. 

I will comment on these only briefly here since I have discussed each extensively elsewhere. 

o    Avoid causes of accelerated aging 

This includes such things as avoiding excess stress, exposure to radiation and toxic chemicals, smoking, unnecessary exposure to diseases, living in a smog-filled city and eating too much meat. 

o    Pursue lifestyle habits that are known to slow aging 

This includes exercising regularly, getting adequate sleep, eating healthy diets, keeping mentally challenged and also includes having an even temperament, enjoying an active social life, living with a mate and even having an active sex life.    Regarding these first two strategies, for a more complete list please see The Anti-aging lifestyle Regimen section of my treatise which contains numerous “conventional wisdom” suggestions for keeping yourself young.  Also, a great many past blog entries are relevant such as Recent research on the Mediterranean diet, and Mental exercise and dementia in the news again.  Some of the food suggestions are for things I really like.  For example see the blog entries Health and longevity benefits of dark chocolate and Blueberries and health.  These everyday-life suggestions are not just based on folk wisdom.  They are backed up my many large-population studies.  What you do and what you eat constantly reprograms your genes and affects your epigenome.  See my blog post Who is doing gene reprogramming?   

o    Pursue activities that are known to slow down, reduce the probabilities of or prevent the major diseases and deteriorative processes of aging.

An example is taking antioxidant supplements when confronted with a necessity for having an extensive medical radiological exam.  See the blog entry Medical radiation risk - you can do something about it. Many of the lifestyle suggestions mentioned above have a similar effect.  In the blog entry Nrf2 and cancer chemoprevention by phytochemicals, I point to research reports looking at mechanisms through which food substances rich in phytochemicals (e.g. coffee, chocolate, turmeric, olive oil, broccoli, red hot peppers, green tea, garlic, blueberries, rosemary, oregano, and sage) are cancer-preventative. Also, the taking of many dietary supplements such as those found in my anti-aging Supplement regimen falls in this category.  For example, curcumin, resveratrol, lycopene, olive leaf extract and ashwagandha are among the substances found in the Susceptibility to Cancer Firewall.   Omega-3 oils, resveratrol, curcumin, chromium piclonate, L-theanine, quercetin, Vitamin A, and green tea extract are among the supplements in the Susceptibility to Cardiovascular Disease Firewall.   Complete lists of the supplements in the firewalls for each of the 14 theories of aging are contained in the treatise. 

o    Take supplements or pursue activities that might possibly affect the basic program of aging, so as to slow it down or even conceivably stop or reverse parts of it. 

Here we are dealing with the frontiers of science and only a few things are known now that that might work above and beyond normal lifestyle interventions and taking “the usual” supplements.  As already listed in my treatise,  I see the following as possibly able to contribute to extraordinary longevity, listed in order of increasing sophistication: 

-         Use of combinations of green tea, curcumin, chocolate, ashwagandha, and other phyto-substances for their powerful cancer-preventative effects and cardiovascular benefits that operate through genetic mechanisms.

-         Use of r-alpha lipoic acid and acetyl-l-carnitine to address cell mitochondrial longevity and inhibit unwanted cell apoptosis (self-destruction).

-         Use of resveratrol or resveratrol homologs to activate the SIRT1 and FOXO3 “longevity” genetic pathway, the pathway known to confer life extension due to calorie restriction.

-         Use of astragaloside IV or cycloastragenol to activate telomerase expression in stem and progenitor cells as well as regular body cells.  The purpose is to enhance the life spans of these cells, to enhance the ability of somatic stem cells to divide and differentiate to renew regular body cells, to thereby slow epigenomic aging, and to confer longevity to body organs and systems. My readers will find many blog entries related to telomeres and telomerase.

I don’t know how much additional average longevity taking these supplements will confer.  We base our faith in these substances on molecular biology studies, on studies of gene activation pathways, on studies of the life spans and health of small animals, and on studies of disease processes.  It is far too early to see studies of the impacts of taking these substances in large human populations over periods of years.I have a great deal of faith that as time progresses we will see more and more potentially powerful interventions against aging based on emerging discoveries in molecular biology, stem cell biology and genomics.  I write this blog because I want to be there to report them.

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25. November 2009 by admin.

The flow of weekly news items related to telomeres and telomerase has grown from a trickle to a steady stream.  Here is a selection of some recent items. 

• Centenarian Ashkenazi Jews

A recent study of centenarian Ashkenazi Jews found that they and their descendents have a mutant gene which results in higher levels of telomerase, longer telomeres, greater health at old age and – well – and ability to live very long healthy lives.  The study looked at “blood samples from 86 very old, but generally healthy, people with an average age of 97; 175 of their offspring; and 93 other people who were the offspring of parents who had lived a normal lifespan and could therefore make up a control group, with which the results could be compared. — Yousin Suh, associate professor of medicine and genetics at Einstein and a lead author on the paper, said: “Our findings suggest that telomere length and variants of telomerase genes combine to help people live very long lives, perhaps by protecting them from the diseases of old age(ref).”  My own comment is “no kidding, that’s what we’ve been talking about for years now.”  Here is the original November 11 news release from the Albert Einstein College of medicine.  The story was picked up by dozens of publications worldwide.

·         Childhood emotional trauma

Another study reported in the press last Friday indicates that a history of childhood emotional trauma such as having been beaten or sexually abused is strongly correlated with shorter telomere lengths in grown adults(ref).  “– researchers Audrey Tyrka of Brown University in Providence, Rhode Island measured DNA extracted from blood samples of 31 18-to-64 year old adults, including 22 women and nine men. — They found more rapid shortening of telomeres only in those who said they had suffered severe mistreatment as children.”  Again, this tends to confirm what we already know about telomere lengths: they respond negatively to stress, apparently due to repeated over-expression of cortisol.   Again, the story was picked up widely in the press and an interview on the social ramifications of the study with Dr. Audrey R. Tyrka the team leader can be found here.

• The oyster fungus

For those of you who have a passionate interest in the oyster fungus (Pleurotus ostreatus), fungus of the month in October 1998, there is more telomerase news.  A Nov 21 news report describes a study that, interestingly enough, indicates that the ‘telomere sequence of P. ostreatus is identical to that of human telomeres.”  How fascinating that we and some mushrooms could enjoy this same genetic feature, and how indicative this is of how fundamental telomeres are to most life forms!  These oyster mushrooms (so-called because of their appearance), by the way, are good to eat and great for the environment “The oyster fungus, together with the common mushroom, is the fungus with the greatest production and consumption worldwide. Likewise this fungus is of great biotechnological interest for its capacity to produce enzymes and degrade industrial and agricultural waste(ref).”

·         The Arabidopsis weed

There is an October 28 report in ScienceDaily about a common weed (the Arabidopsis plant) and about what studies of its telomeres may mean for us. The story’s headline and lead lines are: “Common Weed Could Provide Clues On Aging And Cancer –— A common weed and human cancer cells could provide some very uncommon details about DNA structure and its relationship with telomeres and how they affect cellular aging and cancer, according to a team led by scientists from Texas A&M University and the University of Cincinnati (UC). — “We found that removal of the plant telomere proteins caused rampant end-to-end joining of chromosomes and dramatic defects in plant development,” explains Shippen.” — “The Cincinnati team then showed that removal of one of the human proteins from human cancer cells caused wide-spread DNA damage and complete loss of some telomeres.”Going back in history a slight bit, I found two recent stories relating to the protein structure and replication of telomeres. 

·         TRF1 and telomere fragility

The first, a July 2009 story deals with the protein makeup of telomeres.  A protein TRF1 that was discovered in 1995 plays a very important role in assuring the structural integrity of telomeres and protecting them from what otherwise would be fragility.  “Using a conditional mouse knockout, de Lange and Sfeir (Titia de Lange  and Agnel Sfeir, researchers at Rockerfeller University)  have now revealed that TRF1, which is part of a six-protein complex called shelterin, enables DNA replication to drive smoothly through telomeres with the aid of two other proteins. — Telomeric DNA has a repetitive sequence that can form unusual DNA structures when the DNA is unwound during DNA replication,” says de Lange. “Our data suggest that TRF1 brings in two proteins that can take out these structures in the telomeric DNA. In other words, TRF1 and its helpers remove the bumps in the road so that the replication fork can drive through. — Sfeir deleted TRF1 and saw that the telomeres resembled common fragile sites, suggesting that TRF1 protects telomeres from becoming fragile. Instead of a continuous string of DNA, the telomeres were broken into fragments of twos and threes. — the researchers observed the dynamics of replication across individual DNA molecules — the first time this technique has been used to study telomeres. In the absence of TRF1, the fork often stalled for a considerable amount of time.”

·         hRAP1 and telomere DNA breaks

The second story relating to the structure of telomeres, September 2009 is entitled “Protein Helps Distinguish Chromosome Ends From DNA Breaks.”  The lead line is “The Stowers Institute’s Baumann Lab has demonstrated how human cells protect chromosome ends from misguided repairs that can lead to cancer. The work, published in The EMBO Journal, a publication of the European Molecular Biology Organization, follows the team’s 2007 in vitro demonstration of the role of the hRAP1 protein in preventing chromosome ends from being fused to new DNA breaks.” – “—in this work, the team demonstrated that the human RAP1 protein plays a key role in preventing chromosome ends from being fused to new DNA breaks. Chromosome end fusions result in genomic instability, which can cause cancer. These findings suggest that RAP1 plays a critical role in cancer prevention in humans.”

There are also several recent stories related to development of anti-cancer drugs that work by inhibiting telomerase, b ut I won’t bother listing those.  It probably won’t be long before telomeres and telomerase – things once known only to a handful of distant researchers and geeky anti-aging aficionados - may be familiar to hundreds of millions.

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24. November 2009 by admin.

If you are an old timer like me you may remember the World War I marching song: 

It’s a long way to Tipperary,

It’s a long way to go.

It’s a long way to Tipperary,

To the sweetest girl I know!

Goodbye Piccadilly, Farewell Leicester Square!

It’s a long long way to Tipperary,

But my heart’s right there.  

Last year at this time, I expected that by now, at least a Phase I clinical trial of Geron’s embryonic stem cell treatment for spinal injury would be well underway.  However, according to a Reuters press release on October 30 2009, “Geron Corporation (Nasdaq: GERN) today announced the company`s plan to advance clinical development of its human embryonic stem cell (hESC)-based product, GRNOPC1, for the treatment of spinal cord injury. The plan is expected to enable Geron to re-initiate the Phase I clinical trial of GRNOPC1 in patients with complete thoracic spinal cord injury and to support future expansion of the trial to patients with cervical injuries.” The company had plans to move the drug into Phase I clinical trials but put these on hold when preclinical trials produced cysts in some animals. “As announced previously, in one preclinical study, a higher frequency of animals developed cysts in the injury site than had been seen in numerous foregoing preclinical studies with clinical grade GRNOPC1.  These cysts are non-proliferative, confined to the injury site, smaller than the injury cavity,and were not associated with adverse effects on the animals. As part of ongoing work to optimize GRNOPC1 manufacturing and product release, the company developed new candidate markers and assays. Data from studies using the new markers were submitted to the FDA. The IND for spinal cord injury was placed on clinical hold pending FDA review of the data.”  In other words, back to the FDA drawing board for the new trial.

The news item goes on:  “Geron will complete a confirmatory preclinical study using GRNOPC1 that has been characterized by the new markers and assays, as agreed upon in discussions with the FDA. As part of the ongoing plan to advance clinical development to cervical patients, Geron had already initiated this preclinical study in an animal model of cervical injury. — In discussions with the company, the FDA has advised that it concurs with Geron that positive data from this study can be used to support both release of the clinical hold and expansion to cervical patients. Geron expects the data from this study to enable re-initiation of the clinical trial in the third quarter of 2010.” 

So the good news is that when, assuming there is a when a year or more from now, GRNOPC1 goes into human clinical trial it can possibly be for both thorasic and cervical spinal cord injuries.  In the meantime, there is yet-another preclinical study.  Learning about this 18 month delay, I composed this version of the Tipperary song:

It’s a long way to stem cell treatment, 

It’s a long way to go! 

It’s a long way to stem cell treatment,

To the sweetest treatment we’ll  ever know!

Goodbye radiation, Farewell scalpel and chemo! 

It’s a long long way to stem cell treatment, 

But my heart’s with the new techno.  

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15. November 2009 by admin.

I am celebrating my 80^th birthday with family and friends today, marking what I hope to be about a third of my way through life.  A good friend from Holland, 3 of my sons and my present and 3 previous wives will be among those showing  up for the birthday dinner tonight.  Also, a dear cousin and his wife are visiting from Italy for the occasion and they will be staying until the 23^rd of November, a first visit to the US.   So, I expect to be taking them around the Boston area, drinking good wine and generally celebrating life for a while. I will be taking a vacation from research and blog writing until then.  I intend to pick this work up again as soon as my relatives leave.  And I will also be working further on my treatise, striving to keep it up to date with the discoveries reported in this blog.

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15. November 2009 by admin.

Maria Blasco heads the Telomeres & Telomerase Group at the Spanish National Cancer Center in Madrid.  She and her group have produced a number of important papers over recent years contributing to our understanding of telomere/telomerase science. A November 2009 publication describes what I believe is a breakthrough result enhancing our understanding of both the Telomere Shortening and Damage and the Programmed Epigenomic Changes theories of aging and showing a way in which they fit together.

The publication, Telomere shortening relaxes X chromosome inactivation and forces global transcriptome alterations describes a new viewpoint on how telomere shortening contributes to aging.  The “classical” viewpoint is that telomere shortening results from cell division and that after a certain number of divisions the telomeres start to become too-short for further cell division to take place reliably.  At that point either apoptosis takes place and the cell dies, or the cell can become senescent, no longer reproducing but sending out noxious signals to neighboring cells.  The new viewpoint suggested in the Blasco paper goes much further.  It says that as telomeres become critically short, the gene expression in the cell changes so as to induce senescence and at the same time to affect the maintenance of epigenomic memory and nuclear organization, thereby contributing to organismal aging on the whole-animal level.  Critically short telomeres deregulate epigenomic control and alter gene expression so as to create the changes we know as “aging.”  Too-short telomeres is not just an issue of affected cells dying off or becoming senescent.  After all, these can be replaced by differentiating stem cells.  It is an issue of screwing up the body’s cellular control mechanisms in a way that creates aging. 

In my mind, this is an important finding and provides all the more reason to pursue telomerase activation as an anti-aging strategy.  I have stated before that telomerase activation may not make telomeres longer because of the complex feedback loops involved in telomere length regulation.  The key point is that telomerase activation might keep telomere lengths from getting critically shorter, and that would be enough to stave off cell senescence and deregulation of the epigenome and, perhaps even, much of what we know as aging.

Going to a further level of detail, the new publication summarizes the results: “Using telomerase-deficient TRF2-overexpressing mice (K5TRF2/Terc_/_) as a model for accelerated aging, we show that telomere shortening is paralleled by a gradual deregulation of the mammalian transcriptome leading to cumulative changes in a defined set of genes, including up-regulation of the mTOR and Akt survival pathways and down-regulation of cell cycle and DNA repair pathways. — Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging.”  We know that mTOR is involved in a number of disease and aging processes and that inhibition of mTOR confirms longevity.  Introductions to mTOR  signaling and its relationship to longevity can be found in my blog entries Longevity genes, mTOR and lifespan, More mTOR links to aging theories, and  Viva mTOR! Caveat mTOR!  As mentioned previously in this blog, the P13/Akt pathway is involved in cancer processes as well as cell survival and stem cell proliferation. 

The paper states “Dysfunctional, critically short telomeres elicit a DNA damage response (DDR) that triggers senescence or apoptosis in mammalian cells, two processes that are associated with organismal aging (1–9).” This has been known for some time.  “Mice with a targeted deletion of the RNA component of telomerase (Terc_/_) display accelerated telomere shortening, premature loss of tissue renewal, and decreased longevity (3, 7–9).”  Again, this is not surprising.    “DNA damage signals originating from critically short telomeres in these mice is in line with current models proposing a causative role for DNA damage in organismal aging (10–13. — Interestingly, epigenetic alterations at heterochromatic regions are proposed to lead to changes in gene expression associated with aging (14–16)..”  Here is where the discussion starts to get interesting.  

Going on, “In S. cerevisiae, induction of DNA double-strand breaks (DSBs) or cellular stress causes a dramatic redistribution of telomeric silentinformation regulator (Sir) proteins and yKU proteins (17–19), thus linking changes in telomere chromatin to global epigenetic alterations. “  This is interesting given the linkages of human Sir proteins to longevity.  Stimulating Sir1 is why people take resveratrol. Disturbing these proteins is likely to contribute to “shortivity.” “Sir complex relocalization is known to alter the expression of stress response genes, survival factors, and ribosomal biogenesis (20, 21). In functional analogy to yeast, mammalian SIRT1 is redistributed upon induction of DNA damage, causing broad alterations in global gene expression (22). Collectively, these findings suggest that aging-related DNA damage drives gene expression alterations that could promote the development of aging pathologies. – The point is restated several times throughout the paper: “These findings suggest that progressive telomere shortening and the accumulation of dysfunctional telomeres with age may constitute a unique source of DNA damage, sufficient to induce global alterations in genome regulation.” – “Using a mouse model system, we provide evidence that progressive telomere shortening in stratified epithelia, such as the skin, is linked to global deregulation of the mammalian transcriptome and loss of maintenance of epigenetic silencing mechanisms, exemplified by the re-expression of an Xi-linked transgene.”  

So, put simply, telomeric shortening at some point induces DNA damage which lets loose signaling which changes the epigenome disrupting epigenetic silencing and resulting in pro-aging global DNA expression.   

From the viewpoint of the Programmed Epigenomic Changes theory of aging, the paper says that telomere shortening is at least one of the drivers of the epigenomic aging program.  The paper goes into significantly more detail.  For those of you who can read such technical material, I suggest you do.  As for me, I popped my daily cycloastragenol telomerase-activator pill just a bit ago.  It is late and I will soon be going to bed.

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13. November 2009 by admin.

An important approach to retarding aging that I have not discussed explicitly so far is hormesis, challenging cells and body systems by mild stress resulting in them becoming stronger and resistant to aging(ref).  The stress can be physical, chemical and even possibly psychological. Regular exercise is a familiar activity that produces hormetic effects.  I can assure you that mild stress is involved because I just got off my treadmill and am still sweating a bit.  And I expect this will help me live longer.  Also, many of the supplements in the combined anti-aging regimen likely exercise some of their positive effects via hormesis.   I review some of the science related to hormesis here, especially the roles of heat shock proteins and chaperones.  And I discuss how the phyto-substances featured in my anti-aging firewalls work through hormesis.
 

The anti-aging effects of hormesis have been observed experimentally.

In the 2004 paper Slowing down aging from within: mechanistic aspects of anti-aging hormetic effects of mild heat stress on human cells, the authors report:  “In a series of experimental studies, we have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These beneficial effects of repeated challenge include the maintenance of stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other stresses, and enhanced levels of cellular antioxidant ability. In order to elucidate the molecular mechanisms of hormetic effects of RMHS, we are now undertaking studies on signal transduction pathways, energy production and utilization kinetics, and the proteomic analysis of patterns of proteins synthesized and their posttranslational modifications in various types of human cells undergoing cellular aging in vitro.”   The Danish authors of this paper also see hormesis as a possible systematic anti-aging intervention.  “Human applications of hormesis include early intervention and modulation of the aging process to prevent or delay the onset of age-related conditions, such as sarcopenia, Alzheimer’s disease, Parkinson’s disease, cataracts and osteoporosis(ref).”

The 2009 paper Heat Stress and Hormetin-Induced Hormesis in Human Cells: Effects on Aging, Wound Healing, Angiogenesis, and Differentiation was generated by some of the same Danish authors and represents their continuing research.  This paper confirms the earlier observations and goes on to say “RMHS (repeated mild heat stress ) given to human cells increased the basal levels of various chaperones, reduced the accumulation of damaged proteins, stimulated proteasomal activities, increased the cellular resistance to other stresses, enhanced the levels of various antioxidant enzymes, enhanced the activity and amounts of sodium-potassium pump, and increased the phosphorylation-mediated activities of various stress kinases. We have now observed novel hormetic effects of mild heat stress on improving the wound healing capacity of skin fibroblasts and on enhancing the angiogenic ability of endothelial cells. We have also tested potential hormetins, such as curcumin and rosmarinic acid in bringing about their beneficial effects in human cells by inducing stress response pathways involving heat shock proteins and hemeoxygenase HO-1. These data further support the view that mild stress-induced hormesis can be applied for the modulation, intervention and prevention of aging and age-related impairments.” 

I have discussed curcumin repeatedly in my treatise and rosmarinic acid in the recent blog post with that name.  The concepts that these substances work by “inducing stress response pathways involving heat shock proteins and hemeoxygenase HO-1” is an interesting one that I have not explored before.

Hormesis can operate through the activation of  heat shock proteins

Heat shock proteins (HSPs) are produced by cells when the cells are exposed to elevated temperature or other stresses.  Their role is to protect cells and tissues which they do by regulating important cellular functions when they are expressed due to stress.  “Hsps are expressed in response to an array of stresses, including hyperthermia, oxygen radicals, heavy metals, ethanol, and amino acid analogues. In addition, the heat shock response is induced during clinically relevant situations such as ischemia/reperfusion and circulatory and hemorrhagic shock. All of the above stresses have in common that they disturb the tertiary structure of proteins and have adverse effects on cellular metabolism. Pretreatment of cells with a mild stress, sufficient to induce the expression of hsps, results in protection to subsequent insults. This phenomenon has been coined “stress tolerance” and is apparently caused by the resolubilization of proteins that were denatured during the stress(ref).”  Discovered in 1974, a large literature has been built up about heat shock proteins which appear to be evolutionary conserved and observed in a wide variety of organisms ranging from bacteria to humans(ref).  Many, but not all chaperone proteins are also HSPs, so in some discussions the terms “heat shock protein” and “chaperone protein” are incorrectly used interchangeably.

Hormesis theory of anti-aging

The hormesis theory of anti-aging is that by systematically introducing mild systematic stresses on body systems , heat shock proteins will be generated and molecular pathways will be activated that exercise protective effects on cells and consequently on entire organisms; the result will be delayed aging. 

Examples on the level of entire organisms are calorie restriction(ref) and exercise.  Hormesis is observed on multiple levels.  For example, confronting mental challenges preserves memory and cognitive capability(ref)(ref)(ref).  A study in Florida of 660 older people, aged aged 63 to 97, showed that people who kept driving were four to six times more likely to still be alive after a three-year period than their counterparts who stopped driving(ref).  Another example may be Polygamy which helps men live 12% longer according to research studies(ref).  One possibility is that polygamy extends life of men because “the challenge multiple wives pose requiring constant physical and mental activity.” I have written several times earlier on hormetic effects without using that name.  See my blog entry Stress and longevity for a further discussion of how moderate stresses confer longevity.

Too much stress, stress that overwhelms the body’s defenses can of course be dangerous or lethal and excess or the wrong kind of stress can further the progress on some diseases like melanoma(ref).  For many substances there is a response curve based on dose where there is a transition point beyond which the effect is no longer beneficial and is deleterious(ref).

Hormesis and dietary phytochemicals

The 2007 publication Dietary Factors, Hormesis and Health states “Some specific dietary components may also exert health benefits by inducing adaptive cellular stress responses. Indeed, recent findings suggest that several heavily studied phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of genes encoding cytoprotective proteins including antioxidant enzymes, protein chaperones, growth factors and mitochondrial proteins. Examples include: activation of the Nrf-2 – ARE pathway by sulforaphane and curcumin; activation of TRP ion channels by allicin and capsaicin; and activation of sirtuin-1 by resveratrol.”

The age-prolonging effects of phytochemicals, as pointed out in the 2008 publication Hormetic dietary phytochemicals.  “One general mechanism of action of phytochemicals that is emerging from recent studies is that they activate adaptive cellular stress response pathways. From an evolutionary perspective, the noxious properties of such phytochemicals play an important role in dissuading insects and other pests from eating the plants. However at the subtoxic doses ingested by humans that consume the plants, the phytochemicals induce mild cellular stress responses. This phenomenon has been widely observed in biology and medicine, and has been described as ‘preconditioning’ or ‘hormesis.’ Hormetic pathways activated by phytochemicals may involve kinases and transcription factors that induce the expression of genes that encode antioxidant enzymes, protein chaperones, phase-2 enzymes, neurotrophic factors, and other cytoprotective proteins. Specific examples of such pathways include the sirtuin-FOXO pathway, the NF-kappaB pathway, and the Nrf-2/ARE pathway.”

Specifically, my blog post Nrf2 and cancer chemoprevention by phytochemicals  discusses the signaling pathways involved in the hormetic process initiated by some phytochemicals , including the roles of the nuclear factor Nrf2 and the MAPK/ERK and PI3K/Akt pathways .  I have discussed these pathways and the sirtuin-FOXO and NF-kappaB pathways  before in this blog and in my treatise.   

Hormesis and the anti-aging firewalls

I have already mentioned how several of the suggestions in my lifestyle firewall regimen, like exercise and keeping mentally and socially active, tend to be life-extending by creating hormetic effects.

Several supplements in my anti-aging firewalls supplement regimen have been shown in-vitro to act via activation of heat shock proteins and hormesis.  The document Curcumin, a medicinal herbal compound capable of inducing the heat shock response, for example, concludes “Curcumin, a widely used medicinal compound, induces the heat shock response in vitro as measured by expression of heat shock protein 70. The mechanism of heat shock protein 70 induction depends on activation of heat shock factor-1. Examining known inhibitors of nuclear factor-KB for their ability to induce heat shock protein 70 may be a valid screening method to discover novel pharmacologic inducers of the heat shock response.” Thirty nine substances in my combined firewall regimen are known inhibitors of NF-kappaB and many if not most of these are likely to activate heat shock proteins. 

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11. November 2009 by admin.

The home run reported this week was in a practice game in a minor league.  But nonetheless the results are impressive and lead to hope for those suffering from certain forms of congenital blindness and vision impairment.  The report leading to this optimism, Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: a phase 1 dose-escalation trial, appeared in the November 7 edition of The Lancet.

The trial involved 12 patients (aged 8—44 years), all having  Leber’s congenital amaurosis (LCA), “a rare inherited eye disease that appears at birth or in the first few months of life, and affects around 1 in 80,000 of the population.”

People with this disease are born with impaired vision and their  vision deteriorates until they are totally blind, usually within 10-15 years. “Typically a baby with LCA will have very reduced vision at birth although the retina may appear normal when first examined. Within months, however, parents will usually notice nystagmus - an involuntary, rhythmical, repeated movement of the eyes. Children with LCA account for 10-18% of all cases of congenital blindness. Vision in individuals with LCA varies greatly from relatively mild acuity problems (20/70) to no light perception(ref).”  Up to this point, the disease has been incurable.

LCA is an autosomal recessive disorder, which means that if both parents are carriers of a defective gene as well as a good gene, there is a 1 in 4 chance the child will end up with two defective genes and manifest the disease.  The 12 patients in the recent trial had a variant of LCA caused a defect in the RPE65 gene(ref)(ref), a gene responsible for encoding the retinal pigment epithelium-specific 65 kDa protein. This protein “is located in the retinal pigment epithelium and is involved in the conversion of all-trans retinol to 11-cis retinal during phototransduction, which is then used in visual pigment regeneration in photoreceptor cells(ref).” 

The  therapy used in “home run” trial  is a simple one.   Each of the 12 patients were given one given one subretinal injection using a thin needle in the worst eye of a “defanged” adeno-associated virus (AAV) into which the RPE65 gene had been inserted.  “The engineered virus then invaded retinal cells and inserted the gene into the cells’ DNA. — Within two weeks, the treated eyes began to become more sensitive to light, and within a few more weeks, vision began to improve. The younger the patients were, the better they responded.  – By both objective and subjective measures, vision improved for all the patients. They were able to navigate obstacle courses, read eye charts and perform most of the tasks of daily living. The children who were treated “are now able to walk and play just like any normally sighted child —  The improvement has now persisted for as long as two years(ref).”  There appeared to be no safety issues or adverse effects involved.   

“The study “holds great promise for the future” and “is appealing because of its simplicity,” wrote researchers from the Nijmegen Medical Center in the Netherlands in an editorial accompanying the report –(ref).” The study had its limits of course.  The patients would like to have their other eye treated and optimum dosage of the adenovirus/RPE65 is not yet determined.  Yet the results lend hope to the other some 130,000 victims of LCA worldwide as well as to victims of other more common hereditary eye diseases such as Retinitis pigmentosa.

After many years of false starts and problematical trials, it appears that gene therapies may finally be getting off the ground.  See also the recent post ALD and lentivirus vectors for gene therapy.

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10. November 2009 by admin.

Senesco is a small research-based company specializing in “genetic technologies designed to regulate cell death.”  A company that started out with focus on commercial agriculture, it has been exploring a proprietary gene, Factor 5A1, that might well also have a role in treating human diseases, particularly cancers.  The story of Senesco is interesting because it illustrates the serendipity that can lead to drug discovery, because it describes a research company that has no research labs, because it points to another gene that could be a key to curing certain cancers, and because after five years the possible cancer therapy is still in a preclinical stage tested only on small animals.

The trade publication Gen featured a story this week, Senesco Attempts to Exploit Cell Death, which tells the early history of the company.  “At the University of Waterloo, Ontario, John Thompson, Ph.D., now Senesco’s CSO, discovered that lipase is regulated by two genes that work together to control senescence in plants. Because the finding held promise for extending the life of plants, Sascha Fedyszyn co-founded Senesco in 1998 to explore agricultural applications. A few years later, company researchers learned that the same senescence cascade in plants operates in humans, too. “That was the start of our life science work,” says Fedyszyn, vp, corporate development. — Senesco scientists found that two genes—eukaryotic translation initiation Factor 5A and deoxyhypusine synthase (DHS)—are powerful regulators of programmed cell death, known as apoptosis in human cells and senescence in plant cells. Although cell death is a normal function, premature apoptosis leads to inflammatory conditions, cancer, and tumor growth.”

The company outsources its research.  “To take greatest advantage of our early stage discoveries, we have formed a highly focused and efficient R&D department headed by John Thompson, Ph.D., the inventor of our technology. This R&D takes place at several highly regarded academic institutions around North America. While most early-stage biotechnology companies spend millions on R&D, we are conducting top-notch research with relatively minimal cash burn by utilizing these institutions(ref).” 

The company maintains relationships with a number of agricultural product firms.  “Agricultural research and development programs continue through licensing and joint ventures with agricultural biotechnology companies such as Monsanto, Bayer Crop Science, and Scotts. Efforts are under way to improve corn, soybeans, rice, cotton, bananas, canola, turf grass, and ornamental plants(ref).”

Relating to the life sciences area, “Senesco’s technology is based on the discovery that Factor 5A1, one of two human genes encoding eucaryotic translation initiation Factor 5A, regulates apoptosis as well as certain execution genes, pro-inflammatory cytokines, receptors and transcription factors and therefore plays a key role in cell death and inflammation. We believe that Factor 5A1 is a novel and potentially powerful therapeutic target for a broad range of apoptotic diseases, including inflammatory/ischemic diseases and cancers(ref).” 

In plain language, the following from the company’s web site says that Factor 5A1 kills cancer cells without affecting normal cells.  “Factor 5A1 functions as a shuttle protein, selectively translocating mRNAs required for apoptosis and cytokine function from the nucleus to cytosolic ribosomes for translation. Our preclinical studies have shown that Factor 5A1 kills cancer cells through both the intrinsic (p53) and the extrinsic (cell death receptor) pathways. We have specifically shown that Factor 5A1 regulates the expression of p53, caspases, TNFR1 (TNFa receptor) and the IFN-gamma receptor, and that it also negatively regulates bcl-2 and telomerase. Our studies to date have shown that Factor 5A1 may be non-toxic to normal cells, presumably because of its function as a shuttle protein. Normal cells are not actively expressing mRNAs of cell death genes, and therefore the Factor 5A1 protein, even if present in normal cells, is non-functional(ref).”

According to the Gen article “The company’s first drug candidate based on this combination therapy, SNS-01, targets multiple myeloma. The cytokines IL-1, IL-6, and NF-kB are known to contribute to the proliferation of this disease. The design of SNS-01 “provides a perfect combination for killing multiple myeloma cells,” says Richard Dondero, Senesco’s vp of R&D. Multiple myeloma is not only a cancer, but also a disease of the immune system with a proinflammatory side. “Our technology lends itself to that,” Dondero says. — Collaborators at the Mayo Clinic tested SNS-01 in in-vitro experiments and on mice. Within two weeks of intravenous delivery of SNS-01, “tumor reduction was visible, and some multiple myeloma tumors were even completely eradicated within six weeks,” says Dondero. Senesco plans to file an IND application for SNS-01 in the treatment of multiple myeloma early in 2010.”

Promotion or inhibition of Factor 5A1 may also serve other therapeutic purposes and Senesco’s experiments with therapies  based on Factor 5A1  go back at least five years.   For example, according to a 2004 report Factor 5A1 may be useful for controlling glaucoma. “By inhibiting Factor 5A1, Senesco blocked TNF-alpha-induced apoptosis by 80% in lamina cribrosa cells of the human optic nerve head. — TNF-alpha is strongly upregulated in the optic nerve head of the glaucomatous eye, and TNF-alpha-induced apoptosis appears to be an important determinant of the progressive neurodegeneration characteristic of glaucoma. Thus, inhibition of TNF-alpha-induced apoptosis may reduce damage to the optic nerve during glaucoma.”  Another 2004 report indicated Proprietary gene Factor 5A1 induces atopsis in lung cancer tumors of mice. 

It will be interesting to see whether Senesco will be successful in moving treatments involving the targeting of Factor 5A1 into clinical trials and, if so, how long it will take for this to happen.

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