My anti-aging firewalls treatise characterizes 14 major theories of aging and 6 additional “candidate” theories of aging.  Up until yesterday and I thought I had come to the end of the line with respect to new aging theories.  However my blog reader jeg3 identified a publication that changed my mind in a comment posted on December 3.  So I will soon be adding a seventh candidate theory of aging to my treatise.  The publication was published in 2008 but somehow escaped by attention until now: Low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage.  It is by Bruce N. Ames, a giant in the field of anti-aging science. 

The new theory is based on two well-documented observations.  The first observation is that most of us do not consume adequate quantities of a number of important micronutrients, these including minerals like zinc, iron, copper, magnesium, calcium, potassium and selenium and vitamins like D, B12, folic acid, pyridoxine, pantothenate, riboflavin, and biotin.   The second observation is that evolution built our bodies so as always to opt for short-term survival over long-term wellbeing whenever there a need to choose between the two.  A familiar example is the “fight or flight” response in case of an emergency. A flood of cortisol is released that speeds up our responses and facilitates us to react quickly.  The price is a weakening of our immune response and a shortening of our telomeres(ref),  events that tend to be life-shortening.  Thus, evolution seems to reason that it is better to live a bit less-longer at the end of our lives than to risk being eaten by a tiger or being killed in an auto crash while younger. 

The Micronutrient triage theory of aging essentially says that the body is very intelligent in its allocation of micronutrients, allocating them according to triage priorities favoring short-term functionality over long-term health.  The topmost priorities are for minute-to-minute and day-to-day body functioning, immediate energy metabolism, keeping up circulation and blood pressure, maintaining digestion and things like that.  The lowest priorities are those that make for longevity: keeping up a strong antioxidant response, DNA damage repair, minimization of glycation and excess inflammation, prevention of senescence, preservation of telomere lengths, and matters like those.  When not enough of a micronutrient is available to handle the low-priority needs, those needs are left unmet.  The consequences may be completely unnoticed in day-to-day experience but are likely to show up late in life as cancers, Alzheimer’s disease, Parkinson’s disease, diabetes, cardiovascular diseases and the other maladies that kill older people.  

Ames summarizes his theory this way “I propose DNA damage and late onset disease are consequences of a triage allocation response to micronutrient scarcity. Episodic shortages of micronutrients were common during evolution. Natural selection favors short-term survival at the expense of long-term health. I hypothesize that short-term survival was achieved by allocating scarce micronutrients by triage, in part through an adjustment of the binding affinity of proteins for required micronutrients. If this hypothesis is correct, micronutrient deficiencies that trigger the triage response would accelerate cancer, aging, and neural decay but would leave critical metabolic functions, such as ATP production, intact.”  

Supporting the theory is the fact that deficiencies in a large number of micronutrients seem to produce the same kinds of DNA damage produced by radiation.  “Approximately 40 micronutrients are required in the human diet. Deficiency of vitamins B12, folic acid, B6, niacin, C, or E, or iron, or zinc, appears to mimic radiation in damaging DNA by causing single- and double-strand breaks, oxidative lesions, or both(ref).’   

Ames cites a formidable collection of research studies to support his theory and builds a strong case for it.  Ames, you may recall, has long been a key researcher in the areas of mitochondrial functioning, DNA damage and the roles of micronutrients(ref).  He was also the lead researcher involved in the discovery of the impact on mitochondrial health of the Acetyl-l-carnitine and alpha-lipoic acid combination back 7 years ago(ref), a supplement combination suggested in my anti-aging firewalls supplement regimen.   If you have never been in Ames’ presence you can get a sense of the man and what he about by viewing his online lecture Understanding Aging.   

A problem of course is that micronutrient needs can vary by age, individual, and individual circumstances, and further studies are needed to nail these down.  “The elderly may need more or less of certain vitamins and metabolites compared with younger people, but this issue has not been thoroughly examined(ref).”  The situation is further complicated in that, for many micronutrients like iron, DNA damage can be produced by either too much or too-little of then.   In general in our society, however, most of us get too little of several critical micronutrients rather than too much. 

Ames points out that seven micronutrients (pyridoxine, pantothenate, zinc, riboflavin, iron, copper, and biotin) are particularly important because they are required for heme synthesis in mitochondria.  “It is likely that a deficiency in any of these seven will cause a deficit of heme and therefore of complex IV, of which heme-a is an essential component  — The normal complement of complex IV keeps oxidants to a minimum; deficits of complex IV result in oxidant leakage, DNA damage, accelerated mitochondrial decay, and cellular aging(ref). “ 

In the publication, Ames strongly advocates micronutrient dietary supplementation.  “Evidence is accumulating that a MVM (multivitamin-mineral) supplement, or smaller combinations of vitamins and minerals, also improve long-term health, reducing heart disease, cancer, and cataracts and improving immune function for those who consume inadequate diets.” 

The good news for followers of my anti-aging firewalls supplement regimen is that that almost all the micronutrients mentioned in the Ames publication are included in ample quantities in the regimen: vitamins B-6, C, D, B-12, A, pyridoxine, riboflavin, pantothenate, folic acid, biotin, zinc, calcium, magnesium,  copper, selenium, omega-3 fatty acids, tocopherol, and  lycopene.  The main micronutrient discussed by Ames but missing from the regimen is iron.  I have not included iron in my supplement regimen because it is included in many foods I normally eat (see this listing) and because it creates damage when in excess.  Also, vitamin C, which I take in generous quantities, facilitates iron absorption.  My regimen contains a B-complex tablet, and I depend on this for riboflavin and biotin.  And there are many additional micronutrients in the regimen that are not mentioned in the Ames paper like Vitamin K and a number of powerfully-acting phytochemicals. 

I will include the The micronutrient triage theory of aging as the 7^th candidate theory of aging in the next update of my treatise.

In the last 2-3 years there is has been a lot of excitement in research circles about brown adipose tissue, in other words, brown fat.  Brown fat, long known to exist plentifully in babies and rodents, is rich in turned-on mitochondria and blood vessels.  Unlike white fat, brown fat burns energy at a ferocious rate.  In adults, however, it tends to be scarce and concentrated around the neck and has been traditionally thought to play a relatively minor role in adult human metabolism.  The newer research suggests a different picture.  Brown fat can be very important for metabolism.  Further, the creation of brown fat can be induced by turning on a certain gene and that induction of brown fat could possibly play a major role in public health by controlling or even eliminating obesity.

About brown fat

Brown fat keeps tiny critters in the wild warm and is important for us too.  “Cold-induced adaptive (or nonshivering) thermogenesis in small mammals is produced primarily in brown adipose tissue (BAT).  BAT has been identified in humans and becomes more active after cold exposure. Heat production from BAT requires sympathetic nervous system stimulation, T3, and uncoupling protein 1 (UCP1) expression(ref).”  When animals are exposed to cold, the expression of the UCP1 gene is upregulated to activate the production of heat.  UCP1, also known as thermogenin, “allows the leak of protons in respiring mitochondria, dissipating the energy as heat; the enzyme has an important role in nonshivering heat production induced by cold exposure or food intake(ref).” 

A little brown fat can go a long way towards burning food energy and total metabolism. “Brown fat cells have been found in adults, in the lower part of the neck just above the collarbone. The region of brown fat cells in the neck was tested by placing five volunteers, in thin clothing, in a chilly room for a couple of hours. The researchers then investigated this region by PET scanning and discovered that metabolism there was on average 15 times higher than in the neighboring white fat tissue. The result suggests that the brown fat may play a significant role in metabolism(ref).” 

So, researchers have reckoned that if they could find a safe and easy way to increase the ratio of brown fat to white fat in adults, that might go a long way towards having a skinnier, healthier less-obese population.  “It has been suggested that manipulating the development of fat cells so that they become brown fat cells rather than white fat cells might be an approach to treat obesity(ref).” 

Recent research related to creating brown fat

A number of important discoveries have been made, one reported today in a news item in Science Daily Brown Fat Cells Make ‘Spare Tires’ Shrink; Promising New Approach to Combat Obesity.  “Scientists at the University of Bonn have found a new signaling pathway which stimulates the production and function of so-called brown fat cells. They propose using these cells that serve as a “natural heating system” in order to just ‘burn’ unwanted excess fat. — The scientists were now able to show which signals prompt the body to produce brown fat cells. A signaling pathway which is controlled by the PKG enzyme takes on a key role in this process. This signaling pathway results in the stem cells of the fatty tissue becoming brown fat cells. For this it switches on the mass production of mitochondria and ensures that UCP is formed — .  — Furthermore, we were able to show that PKG makes brown fat cells susceptible to insulin,” –. “Therefore PKG also controls how much fat is burnt in general.”

This research result follows an important discovery in 2008 that myoblasts, muscle cell progenitor cells, can not only differentiate so as to  produce replacement muscle cells when activated by appropriate signals, but also can differentiate to produce brown fat cells when a gene called  PDRM16 is turned on(ref)(ref). See Making ‘Good’ Fat From Muscle And Vice Versa.

This followed a discovery in 2007 that when PRDM16 genes are inserted into white fat precursors, the precursor cells produce brown fat cells instead of white ones(ref)(ref). “Spiegelman (the lead researcher in this work) said the finding confirms that PRDM16 is the “master regulator” of brown fat development(ref).”  Finding a drug or supplement that activates the PRDM16 gene is therefore a possible strategy for controlling weight and obesity in humans.  Another possibility might involve “transplanting PRDM16-equipped white fat precursors into people who are at high risk of becoming obese, to shift their metabolism slightly into a calorie-burning mode(ref).” 

Are there dietary supplements that differentially promote the creation of brown fat and therefore higher metabolism so as to control weight?  Quite possibly, but my impression is that research in this area is just getting off the ground now.  I have seen several supplement-vending sites that talk about brown fat and vaguely suggest that their supplements may help create it – but they provide no research backup for such claims.  Doing some quick and possibly superficial searching, I found relevant research on only one supplement, the amino acid l-arginine.  Several studies suggest that l-arginine increases lean body mass in obese rats.  And the title of this 2009 publication tells its basic story: Dietary L-arginine supplementation reduces white fat gain and enhances skeletal muscle and brown fat masses in diet-induced obese rats.  L-arginine is sometime advertised as a weight loss substance, as a sexual stimulant, and (combined with other amino acids) as a promoter for the expression of human growth hormone.  Because of a bad experience I had resulting from heavy use of l-arginine several years ago (a bout of arthritis), I have since personally avoided it.  

I expect to see a number of additional research publications on dietary supplements and brown fat in the coming year or two and will report on these as I come across them.   

If you have pet mice suffering from colitis, the probiotic Bacillus Polyfermenticus can help them recover from it according to a 2009 study(ref).  “Mice treated with B. polyfermenticus during the non-inflammatory period of the disease had reduced rectal bleeding, their tissues were less inflamed and they gained more weight than mice that did not receive the treatment.”  This and other probiotics are likely to offer similar and additional benefits to us humans. 

“The study occurred in two phases, one involving live mice with colitis and another that looked at human intestinal cells in a test tube. The mouse study showed that B. polyfermenticus facilitated the recovery of mice from colitis. The mice showed reduced rectal bleeding, less inflamed tissue and they gained more weight than the mice that did not receive B. polyfermenticus. The study also found that the colon tissue of the treated mice had greater angiogenesis, a process that is necessary for wounds to heal. — The test tube study allowed an in-depth look at what happens at the cellular level when human intestinal microvascular endothelial cells are exposed to B. polyfermenticus. This phase found that the probiotic treatment encouraged several steps that are part of the angiogenic process, including the migration of cells and the formation of new blood vessels. — The test tube studies also uncovered how this happens. The researchers found that B. polyfermenticus increases the production of Interleukin-8 (IL-8), a substance that enhances angiogenesis. The study also found that IL-8’s receptor, CXCR2, and a cellular pathway, known as NF-κB, play a critical role in the angiogenic process(ref).”

The 2009 research report Bacillus polyfermenticus ameliorates colonic inflammation by promoting cytoprotective effects in colitic mice concludes “Treating colonic epithelial cells with B. polyfermenticus-conditioned medium (BPCM) enhanced cell proliferation and induced the phosphoinositide 3-kinases/Akt signaling pathway, suggesting that this bacterium can promote epithelial cell proliferation. BPCM also promoted the migration of colonic epithelial cells. These data suggest that B. polyfermenticus ameliorates colonic inflammation by suppressing apoptosis and promoting epithelial cell proliferation and migration.”

Other current research as well as prior research studies also support potential health benefits of bacillus polyfermenticus.  The 2009 report The anti-cancer effect of probiotic Bacillus polyfermenticus on human colon cancer cells is mediated through ErbB2 and ErbB3 inhibition concludes “These results show that B.P. inhibits tumor growth and its anti-cancer activity occurs, at least in part, through suppressing ErbB2 and ErbB3. Taken together, our study suggests that this probiotic may be clinically used as a prophylactic treatment to prevent colon cancer development.”

The 2007 research report A Probiotic Strain of Bacillus polyfermenticus Reduces DMH Induced Precancerous Lesions in F344 Male Rat  states “In this study, we have assessed the effects of B. polyfermenticus on the antioxidant system and the process of colon carcinogenesis in male F344 rats. — These data indicate that B. polyfermenticus exerts a protective effect on the antioxidant system and the process of colon carcinogenesis, thereby suppressing the development of preneoplastic lesions.”

The 2006  report Dietary Supplementation of Probiotic Bacillus polyfermenticus, Bispan Strain, Modulates Natural Killer Cell and T Cell Subset Populations and Immunoglobulin G Levels in Human Subjects concludes “This study suggests that the supplementation of B. polyfermenticus has a potentially positive effect on immune function by enhancing IgG production as well as by modulating the number of immune cell population such as CD4+ and CD8+ T cells and NK cells.”

Other research reports indicating benefits of probiotics include M1198 Lactobacillus Rhamnosus GG Prevents Radiation Induced-Small Intestinal Injury in a MyD88 Independent, But COX2 Dependent Manner, M1199 Counterbalancing Dysbiosis in Crohn’s Disease: Faecalibacterium Prausnitzii, a Major Commensal Bacterium, Exhibits In Vitro and In Vivo Anti-Inflammatory Effects,   and M1200 Probiotic E. coli (Symbioflor®2) Treatment Mediates Antimicrobial β-Defensin (HBD-2) Synthesis and Fecal Excretion in Humans.

Here is where I have to admit a slip-up.  For nearly two years now my personal supplement regimen has included a morning multi-strain probiotic capsule.  However, somehow I have not included that supplement in my anti-aging firewalls Supplement Regimen.  I will add it in when I do my next update of the treatise, probably within 24 hours. Based on the above-cited research I am also looking for probiotic capsules which contain B. polyfermenticus, a microbe that appears not to be included in most mainline commercial US probiotic products. 

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.

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.

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.

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.

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.  

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.

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.