I introduced the PPPPM concept a year ago in a blog post Harnessing the engines of finance and commerce for life-extension.   I wrote that post just after having attended the 2010 version of the 2010 Bio-IT World Conference & Expo.  I speculated that PPPPM will create a basic shift that profoundly affects our health and longevity.  In that blog entry I characterized PPPPM this way: 

“1. The objective of PPPPM is not so much to cure diseases as it is to detect and predict disease susceptibilities before a disease starts or at very early stages of disease progression and initiate personalized interventions to prevent the progression of the disease before it becomes symptomatic or does damage.

 2. PPPPM is participatory in the sense that the collaborative participation of large numbers of health research institutions and care agencies is involved in doing the research and creating the infrastructure to make it workable. It involves a tight and continuing linkup loop of researchers, practitioners, patients and healthy people who want to stay healthy.

Together, these studies suggest that negative health and longevity effects could well result from the prolonged taking of large doses of glucosamine.

Efficacy of glucosamine for averting or treating osteoarthritis is another matter with some studies supporting its capability to address joint diseases and other studies suggesting that the existence of such a capability is questionable. The last study cited above suggests it may be efficacious.   Also in that category is the work reported in the March 2011 publication Effects of glucosamine derivatives and uronic acids on the production of glycosaminoglycans by human synovial cells and chondrocytes. “Glucosamine (GlcN) has been widely used to treat osteoarthritis (OA) in humans. However, its chondroprotective action on the joint is poorly understood. In this study, to elucidate the chondroprotective action of GlcN, we examined the effects of GlcN-derivatives (GlcN and N-acetyl-D-glucosamine) and uronic acids (D-glucuronic acid and D-galacturonic acid) (0.1-1 mM) on the production of glycosaminoglycans (GAG), such as hyaluronic acid (HA), keratan sulfate and sulfated GAG by human synovial cells and chondrocytes. — Together these observations indicate that GlcN may exhibit chondroprotective action on joint diseases such as OA by modulating the expression of HA-synthesizing enzymes and inducing the production of HA (a major component of GAG contained in synovial fluid) especially by synovial cells.”

By Vince Giuliano 

Minor update July 12, 2013

Pyrroloquinoline quinone (PQQ), a redox cofactor available as a dietary supplement, appears to have at least three central biological effects with powerful downstream health and longevity consequences: it stimulates the generation of PGC1-alpha, results in expression of SIRT3, and induces mitochondrial biogenesis.  After brief recapitulation of background, I review some of the key research literature involved.  Of possible practical significance, supplementation with PQQ could possibly offer the benefits of exercise in a pill.

 Background on PGC-1alpha

In a June 2010 blog entry AMPK and longevity, I discussed how exercise activates the AMPK pathway and the role of PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator-1alpha) as a co-transcriptional regulation factor that induces mitochondrial biogenesis by activating transcription factors.

The August 2010 blog entry PGC-1alpha and exercise provides a further and more general introduction to PGC1alpha.  I said “You can probably expect to hear a lot about PGC-1alpha as time goes on because this remarkable substance is turning out to have a lot to do with health and longevity. It appears to be the mediator of the health benefits produced by exercise. This blog post is about PGC-1alpha, about its relationship to exercise, and about efforts to stimulate it with various substances, in essence seeing if it is possible to provide “exercise in a pill.” 

In that blog entry I described how exercise generates PGC1alpha. Expression of PGC-1alpha can also come about as a consequence of cellular stress such as induced by cold.  I also discussed a number of physiological properties of PGC-1alpha affecting health and longevity including:

·        PGC-1alpha regulates energy metabolism involving both white and brown fat.  “PPARgamma coactivator-1alpha (PGC-1alpha), in cooperation with several transcription factors, has emerged as a key regulator of several aspects of mammalian energy metabolism including mitochondrial biogenesis, adaptive thermogenesis in brown adipose tissue, glucose uptake, fiber type-switching in skeletal muscle, gluconeogenesis in liver and insulin secretion from pancreas. Recent studies have shown a reduced expression of PGC-1alpha in skeletal muscle of diabetic and prediabetic humans. Moreover, expression of PGC-1alpha in white fat cells activates a broad program of adaptive thermogenesis characteristic of brown fat cells(ref).”

·         “PGC-1alpha turns on the biogenesis of mitochondria primarily in brown fat, working through NRF1, NRF2 and ERRalpha. It promotes fatty acid oxidation working through the PPARs and RXRs, NRF1 and NRF2, combats ROS and promotes glucose utilization, promotes oxidative phosphorylation working via NRF2 and ERRalpha, promotes angiogenesis working through ERRalpha, and contributes to fiber-type switching.”

·        “PGC-1alpha stimulates mitochondrial biogenesis and promotes the remodeling of muscle tissue to a fiber-type composition that is metabolically more oxidative and less glycolytic in nature, and it participates in the regulation of both carbohydrate and lipid metabolism(ref).”

·        Exercise-induced expression of PGC-1alpha appears to enhance insulin sensitivity.  Thus, it is likely that maintenance of upregulated levels of PGC-1alpha is protective against diabetes.

·        Muscle PGC-1alpha protects against oxidative damage in aging muscle and PGC1alpha prevents age-related loss of endurance running capacity.

·        “It is highly likely that PGC-1alpha is intimately involved in disorders such as obesity, diabetes, and cardiomyopathy. In particular, its regulatory function in lipid metabolism makes it an inviting target for pharmacological intervention in the treatment of obesity and Type 2 diabetes(ref).”

Background on sirt3 mitochondrial biogenesis

Besides the above references to mitochondrial biogenesis, the blog entry SIRT3 research – tying together knowledge of aging points out:

·        Systematic exercise up-regulates PGC-1alpha and increases SIRT3 expression as well as associated CREB phosphorylation. “CREB (cAMP response element-binding) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the downstream genes^[1] (ref).”

·        Cellular stress causes SIRT3 to translocate from the nucleus to the mitochondria and to be highly expressed in brown adipose tissue.  SIRT3 is a mitochondrial sirtuin protein that serves to deacetylate acetyllysine-modified proteins in mitochondria.  

·        “(PGC-1alpha) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1alpha induces several key reactive oxygen species (ROS)-detoxifying enzymes, –Here we show that PGC-1alpha strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. – Furthermore, Sirt3 was essential for PGC-1alpha-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. — Our results indicate that Sirt3 functions as a downstream target gene of PGC-1alpha and mediates the PGC-1alpha effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy metabolism and ROS generation(ref).”

 Background on PQQ

PQQ is a quinone, a bacterial redox co-factor and antioxidant.  It is a natural dietary substance found in common foods, good sources being parsley, green tea, tofu, tomatoes green peppers, kiwi fruit and papaya(ref).The roots of the original discovery of PQQ goes back to 1964(ref) and the substance was first isolated in 1979(ref).  However, the biological significance of the substance has been discovered only through a chain of slowly-developing research.  Much of the original research on PQQ was concerned with its roles in bacteria.  PQQ was not known to be essential to human metabolism until 2003 and research on its central roles in stimulating PGC-1alpha and mitochondrial biogenesis was published until 2010.  The Wikipedia article on PQQ provides an excellent overview with an ample list of research citations. 

The basic relevance of PQQ in terms of the above discussion, put simply, is that it is an upstream activator of CREB which is an activator of PGC-1alpha which in turn activates SIRT3.  Therefore, PQQ is potentially an initiator of the chain of health and longevity benefits that devolve from expression of PGC-1alpha and SIRT3.  The substance could be the long sought-after “exercise in pill form.”

There appear to be some 200 publications on PQQ including a few books.  I will skip over the historical publications and start with a key 2010 publication and work selectively forwards from there.  That 2010 publication is Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression.  “Bioactive compounds reported to stimulate mitochondrial biogenesis are linked to many health benefits such increased longevity, improved energy utilization, and protection from reactive oxygen species. Previously studies have shown that mice and rats fed diets lacking in pyrroloquinoline quinone (PQQ) have reduced mitochondrial content. Therefore, we hypothesized that PQQ can induce mitochondrial biogenesis in mouse hepatocytes. Exposure of mouse Hepa1–6 cells to 10–30 μm PQQ for 24–48 h resulted in increased citrate synthase and cytochrome c oxidase activity, Mitotracker staining, mitochondrial DNA content, and cellular oxygen respiration. The induction of this process occurred through the activation of cAMP response element-binding protein (CREB) and peroxisome proliferator-activated receptor-gamma coactivator-alpha (PGC-1alpha), a pathway known to regulate mitochondrial biogenesis. PQQ exposure stimulated phosphorylation of CREB at serine 133, alpha mRNA and protein expression. PQQ did not stimulate mitochondrial biogenesis after small interfering RNA-mediated reduction in either PGC-1alpha or CREB expression. Consistent with activation of the PGC-1alpha pathway, PQQ increased nuclear respiratory factor activation (NRF-1 and NRF-2) and Tfam, TFB1M, and TFB2M mRNA expression. Moreover, PQQ protected cells from mitochondrial inhibition by rotenone, 3-nitropropionic acid, antimycin A, and sodium azide. The ability of PQQ to stimulate mitochondrial biogenesis accounts in part for action of this compound and suggests that PQQ may be beneficial in diseases associated with mitochondrial dysfunction.”

It is established that cAMP response element-binding protein (CREB) is an important regulator of PGC-1alpha that facilitates PGC-1alpha activation (ref).

NRF-2 is introduced in the blog entry Nrf2 and cancer chemoprevention by phytochemicals and I have mentioned its beneficial effects in a number of other blog postings.  ““Nuclear factor-erythroid-2-related factor 2 (Nrf2) plays a crucial role in the coordinated induction of those genes encoding many stress-responsive and cytoptotective enzymes and related proteins. These include NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, glutamate cysteine ligase, glutathione S-transferase, glutathione peroxidase, thioredoxin, etc.(ref).” (Several additional blog entries written after this one further characterize the health benefits of Nrf2.)

 “The function of PQQ in mammalian physiology remains controversial. PQQ has been proposed as a vitamin (19), but it has not been demonstrated that PQQ serves as an enzyme cofactor in mammalian tissues (20, 21). Upon appreciation that mitochondrial content can be influenced by PQQ nutritional status and that reported beneficial effects of PQQ may be directly related to mitochondrial function, we hypothesized that PQQ may induce mitochondrial biogenesis through a mitochondrial-related cell signaling mechanism. Given that many mitochondrial-related events are regulated by PGC-1alpha and nuclear respiratory factors (15), we hypothesized that PQQ may interact with a PGC-1alpha-related pathway. We used the mouse Hepa1–6 hepatocyte cell line as a model to investigate these hypotheses. We also explored whether PQQ may protect against the toxic effects of mitochondrial electron transport chain inhibition(ref).”

The aforementioned article goes on to describe experimental procedures that establish:

·        PQQ induces mitochondrial biogenesis.

·        PQQ induces nuclear respiratory factor (NRF) activation, both NRF-1 and NRF-2.  

·        PQQ induces PGC-1alpha promoter activation and increases PGC-1alpha mRNA and protein expression.  Further, PGC-1alpha binding can directly regulate NRF-1 and NRF-2 activity.

·        PGC-1alpha is required for the induction of mitochondrial biogenesis by PQQ.

·        PQQ stimulates the phosphorylation of CREB at serine 133 and CREB is required for PQQ-induced mitochondrial biogenesis.

·        PQQ-mediated mitochondrial biogenesis is not due to auto-oxidation or IPQ addition.  That is, “PQQ-induced mitochondrial biogenesis and nuclear respiratory factor activation is not caused by generation of either hydrogen peroxide, superoxide, or IPQ in the media by PQQ(ref).” 

·        PQQ improves cell viability and preserves mitochondrial function due to mitochondrial inhibitors.

·        The exact role of CREB in  PQQ stimulation of  PGC-1alpha is not clear. “CREB has been shown to regulate PGC-1alpha, and data shown here suggest that PQQ acts through CREB to regulate PGC-1alpha, but regulation of the PGC-1alpha and PGC-1-related co-activator by CREB has not yet been demonstrated. Also, it is recognized that the PGC-1 family of co-activators likely act and respond to differing physiological stimuli and processes (ref).”

PQQ and neuroprotectivity

 The 2011 publication The neuroprotective action of pyrroloquinoline quinone against glutamate-induced apoptosis in hippocampal neurons is mediated through the activation of PI3K/Akt pathwayreports “In this study, we investigated the effects of PQQ on glutamate-induced cell death in primary cultured hippocampal neurons and the possible underlying mechanisms. We found that glutamate-induced apoptosis in cultured hippocampal neurons was significantly attenuated by the ensuing PQQ treatment, which also inhibited the glutamate-induced increase in Ca2+ influx, caspase-3 activity, and ROS production, and reversed the glutamate-induced decrease in Bcl-2/Bax ratio. The examination of signaling pathways revealed that PQQ treatment activated the phosphorylation of Akt and suppressed the glutamate-induced phosphorylation of c-Jun N-terminal protein kinase (JNK). — Taken together, our results indicated that PQQ could protect primary cultured hippocampal neurons against glutamate-induced cell damage by scavenging ROS, reducing Ca2+ influx, and caspase-3 activity, and suggested that PQQ-activated PI3K/Akt signaling might be responsible for its neuroprotective action through modulation of glutamate-induced imbalance between Bcl-2 and Bax.”

PQQ and uranium toxicity

The 2011 publication Uranium exerts acute toxicity by binding to pyrroloquinoline quinone cofactor provides at least one explanation of why uranium is so toxic – it binds to PQQ and prevents its biological actions.  “Uranium as an environmental contaminant has been shown to be toxic to eukaryotes and prokaryotes; however, no specific mechanisms of uranium toxicity have been proposed so far. Here a combination of in vivo, in vitro, and in silico studies are presented describing direct inhibition of pyrroloquinoline quinone (PQQ)-dependent growth and metabolism by uranyl cations. Electrospray-ionization mass spectroscopy, UV-vis optical spectroscopy, competitive Ca(2+)/uranyl binding studies, relevant crystal structures, and molecular modeling unequivocally indicate the preferred binding of uranyl simultaneously to the carboxyl oxygen, pyridine nitrogen, and quinone oxygen of the PQQ molecule. The observed toxicity patterns are consistent with the biotic ligand model of acute metal toxicity. In addition to the environmental implications, this work represents the first proposed molecular mechanism of uranium toxicity in bacteria, and has relevance for uranium toxicity in many living systems.”

Other health benefits of PPQ

Here is a sample of recent publications outlining other health benefits of PPQ, particularly as related to cancers and Alzheimer’s disease:

·        Pyrroloquinoline quinone inhibits the fibrillation of amyloid proteins. (2010)

·        Role of glutathione in augmenting the anticancer activity of pyrroloquinoline quinone (PQQ)  (2010)

·        Protective effect of pyrroloquinoline quinone against Abeta-induced neurotoxicity in human neuroblastoma SH-SY5Y cells  (2009)

·        Identification of transcriptional networks responding to pyrroloquinoline quinone dietary supplementation and their influence on thioredoxin expression, and the JAK/STAT and MAPK pathways  (2010)

·        The inhibitory effect of pyrroloquinoline quinone on the amyloid formation and cytotoxicity of truncated alpha-synuclein (2010)

In addition, there have been many recent studies concerned with the chemistry and biochemistry of PQQ and its behavior in a number of bacteria.

The case for PQQ as a dietary supplement

 The first-mentioned publication goes on in its discussion to make what seems to be a possible case for PQQ supplementation: “The induction of mitochondrial biogenesis by PQQ has a number of health implications. PGC-1α elevation, particularly in muscle and adipose tissue, may also be helpful in that PGC-1alpha expression is decreased in obesity (56, 57). CREB null and PGC-1alpha null mice have hepatic steatosis and impaired gluconeogenesis and β-oxidation (38, 58, 59). PQQ-deficient mice have elevated serum triglycerides, which is reversed upon PQQ repletion (1). In addition, mice with deletion of all CREB isoforms have reduced commissural structure formation and impaired fetal T cell development (60), and other mouse models of CREB-targeted deletion show impaired memory and neurodegeneration (61, 62). Likewise, dietary PQQ deprivation results in immune dysfunction (63). PQQ is also neuroprotective when administered by intraperitoneal injection (64, 65) or diet supplementation (66).”

PQQ is not the only dietary supplement that can activate PGC-1alpha and therefore unleash its chain of beneficial results including enhanced SIRT3 expression and mitochondrial biogenesis.  Resveratrol and and other substances in my anti-aging firewalls dietary supplement regimen, can also do this.  And the drug rapamycin can also enhance PGC-1alpha expression(ref).

The basic arguments for PQQ supplementation relate to solubility and bioavailability.  Going on to quote additionally from the 2010 publication: “Although other phytochemicals are associated with the activation of cell signaling pathways important to mitochondrial function, PQQ has properties that set it apart from other compounds. As an example, resveratrol and genisten have been demonstrated to affect cell-signaling pathways, including those important for mitochondrial biogenesis. Resveratrol can induce deacetylation of PGC-1alpha (ref) and AMP-activated protein kinase activation (ref), which are potential mechanisms for PGC-1α activation. Both resveratrol and genistein are relatively insoluble in water, and increasing its water solubility does not increase resveratrol absorption (ref), although genistein bioavailability can be increased by complexing genistein with cyclodextrins (ref). In contrast, PQQ is relatively water-soluble (>1 g of PQQ/liter of water) and is easily absorbed at low dietary concentrations intakes (ref). Although genistein can induce PGC-1alpha protein expression and mitochondrial biogenesis (3), genistein may also have phytoestrogenic properties because of its ability to activate the estrogen receptor (ref).”

Going on: “The observed effects of PQQ are also observed at concentrations lower than those for resveratrol and genistein, particularly in vivo. In cell cultures in vitro, PQQ causes changes in mitochondriogenesis and function at concentrations similar to those reported recently for small molecule activators of SIRT1 (ref), which are being explored for their therapeutic potential (ref). These observations suggest that further study related to PQQ is warranted. One important note is that PQQ can increase PGC-11alpha mRNA transcription, which is different from the post-translation regulation of PGC-1alpha by resveratrol and raises the likelihood that a combination of various compounds, such as are often present in fruits and vegetables, can stimulate mitochondrial biogenesis through different modes of action. Because mitochondria function as the principal energy source of the cell, compromised function of this key organelle is linked to numerous diseases and metabolic disorders (ref)(ref). In this regard, PQQ would appear to have therapeutic potential similar to resveratrol, genistein, hydroxytyrosol, quercetin, or other compounds that can induce mitochondrial biogenesis(ref).”

Does PGG supplementation make sense?

My impression is that the PQQ supplementation phenomenon is new and just taking off. A few of the supplement companies have picked up on the 2010 findings outlined above and are starting to offer PQQ supplements, Life Extension Foundation having been a leader in this regard.  Most supplement vendors offer PQQ only in proprietary combinations with other substances.   I have found this discussion of PPG supplementation dosage on a site providing practical Pyrroloquinoline Quinone & Methoxatin information. My impression is that the information on that site is responsible and informative although not completely documented.  For example, that site contains an  interesting table for the PQQ  content that researchers have found in food.  That discussion points out that there are many imponderable factors that could affect what is the optimum amount for a healthy adult to take as a daily PQQ supplement. “This question has not been fully resolved and is complicated by the inability to measure all forms of PQQ (pyrroloquinoline quinone | methoxatin). However, it is possible to make several good inferences from current animal studies and data–.”  The discussion argues that, all things considered, 10-20mg of PQQ a day is probably a reasonable dose.  The supplement-makers apparently concur and the PQQ supplement products I have seen range from having 5 to 20 mg of PQQ per pill. 

In considering PQQ supplementation, I hasten to point out that a number of other dietary supplements offer positive benefits for mitochondrial health including r-alpha-lipoic acid, acetyl-l-carnitine, resveratrol, quercetin and co-enzyme Q10.  For a discussion of the supplements I have been  taking related to mitochondrial health, you can have a look at the Mitochondrial Damage Firewall in my treatise.

Some supplement marketers are representing PQQ as being a new vitamin, although whether it satisfies the criteria for being a vitamin has been disputed(ref).

Given that I exercise at least 45 minutes a day, eat a reasonable diet, and take all the supplements in my anti-aging firewalls dietary supplement regimen, do I think additional enhancement of PGC-1alpha and all of the associated health benefits would come about for me if I added PQQ as a supplement?  Or would adding PQQ to my dietary regimen be simply redundant?  Or could I increase the effectiveness or reduce the cost of the regimen by substituting PQQ for other supplements?  I simply did not know when I first drafted this blog in April 2011.  Because of the importance of SIRT3 expression, however, in 2012 I started regular supplementation with PQQ and have continued that pattern since (July 2013).

Since drafting the above over two years ago,  another 50 research publications relating to PQQ have appeared in pubmed.org, further elucidating its mechanisms of action and health benefits. In the interim I have developed an increased appreciation of the importance of SIRT3 expression for controlling mitochondrial ROS and general health maintenance during aging.  At some point I will generate a new blog entry covering the new research and updating this one.

The situation at the Fukushima nuclear plant in Japan is giving great urgency to the issue of personal protection against ionizing radiation.  This blog entry is about how a degree of personal protection against radiation damage can be achieved by taking antioxidants.  I do not think it is an exaggeration to say that what I will be discussing could in the long term save the lives of millions of people. 

The Fukushima nuclear disaster

As of this writing the situation at the Fukushima Daiichi reactors remains uncontrolled.   It is a slowly-unfolding disaster, appearing to get worse and worse.   Smoke or metallic vapor from overheated or melted fuel rods contain large quantities of radioactive fission byproducts.   And very little can be done to stop fuel rod overheating without pumping in large quantities of water which releases radioactive pollution into the environment via steam and water runoff.  An immense amount of radioactive material has already been released into the atmosphere affecting a vast area of Japan as well as the ocean.   Many workers at the plant are expected to die quickly due to radiation exposure.  We don’t know how and when the continuing release of radiation can be contained.  Much of Japan including Tokyo could be contaminated semi-permanently by fallout resulting in radiation levels orders of magnitude higher than are normally acceptable.  Tens of millions of people are likely to be effected. 

An excellent source of information on the situation in Japan is the blog All Things Nuclear.  The March 30 entry relates: “Today the IAEA has finally confirmed what some analysts have suspected for days: that the concentration per area of long-lived cesium-137 (Cs-137) is extremely high as far as tens of kilometers from the release site at Fukushima Dai-Ichi, and in fact would trigger compulsory evacuation under IAEA guidelines. — The IAEA is reporting that measured soil concentrations of Cs-137 as far away as Iitate Village, 40 kilometers northwest of Fukushima-Dai-Ichi, correspond to deposition levels of up to 3.7 megabecquerels per square meter (MBq/sq. m). This is far higher than previous IAEA reports of values of Cs-137 deposition, and comparable to the total beta-gamma measurements reported previously by IAEA and mentioned on this blog. — This should be compared with the deposition level that triggered compulsory relocation in the aftermath of the Chernobyl accident: the level set in 1990 by the Soviet Union was 1.48 MBq/sq. m.  — Thus, it is now abundantly clear that Japanese authorities were negligent in restricting the emergency evacuation zone to only 20 kilometers from the release site.”  Other blog entries refer to the release of substantial quantities of radioactive iodine-131 and to how plutonium is being found in soil samples.

Background on nuclear radiation

For the general Japanese public, the biggest concern is not direct radiation from the Fukushima plant but rather radioactive substances which are released into the environment either via the atmosphere or via runoff into the ocean.  Radioactive substances can enter the body via the air, groundwater, tap water or foods or vegetables consumed. Three radioactive substances of primary concern are:

Radio iodine-131:  Although having a half life of only 8 days, iodine-131 can be dangerous if ingested by someone with a thyroid iodine deficiency.  It is a beta radiation emitter, which means the radiation is not a threat unless the emitting substance is inside the body. “Due to its mode of beta decay, iodine-131 is notable for causing mutation and death in cells which it penetrates, and other cells up to several millimeters away. For this reason, high doses of the isotope are sometimes paradoxically less dangerous than low doses, since they tend to kill thyroid tissues which would otherwise become cancerous as a result of the radiation. For example, children treated with moderate dose of I-131 for thyroid adenomas had a detectable increase in thyroid cancer, but children treated with a much higher dose did not(ref).”  As long as the damaged Fukushima plant continues to release iodine-131 into the environment, it will be a threat. 

Caesium-137: Has a half life of about 30 years and emits beta and gamma radiation.  Because it is chemically similar to potassium, it is readily absorbed in vegetables and human bodies.  “Caesium-137 is water-soluble, and the biological behavior of caesium is similar to that of potassium and rubidium. After entering the body, caesium gets more or less uniformly distributed throughout the body, with higher concentration in muscle tissues and lower in bones. The biological half-life of caesium is rather short at about 70 days.^[6] Experiments with dogs showed that a single dose of 3800 μCi/kg (approx. 44 μg/kg of caesium-137) is lethal within three weeks^[7](ref).”

Plutonium:  Plutonium is a byproduct of nuclear reactions, is the heaviest stable element and has been called ‘the most toxic substance known to man,” emitting alpha, beta and gamma radiation.  The most important isotope of plutonium is plutonium-239, with a half-life of 24,100 years..  Plutonium-238 has a half-life of 88 years and emits alpha particles. plutonium-244 has a half-life of about 80 million years. “Isotopes and compounds of plutonium are radioactive poisons that accumulate in bone marrow. Contamination by plutonium oxide (spontaneously oxidized plutonium) has resulted from a number of nuclear disasters and radioactive incidents including military nuclear accidents where nuclear weapons have burned.^[86] Studies of the effects of these smaller releases, as well as of the widespread radiation poisoning sickness and death following the Atomic bombings of Hiroshima and Nagasaki, have provided considerable information regarding the dangers, symptoms and prognosis of radioactive poisoning. PMID 19454804(ref).”

As reported in the news, higher than normal levels of both iodine-131 and caesium-137 have been noted not only in Japan but worldwide due to the Fukushima incident.  And plutonium has been found in soil samples near the reactor sites.

According to the International Atomic Energy Agency Briefing on Fukushima Nuclear Accident, 31 March 2011 (14:00 UTC), On 30 March, deposition of iodine-131 was detected in 8 prefectures, and deposition of cesium-137 in 12 prefectures. On 30 March in the prefectures where deposition of iodine-131 was reported, the range was from 2.5 to 240 becquerel per square metre. For caesium-137, the range was from 3 to 57 becquerel per square metre. In the Shinjyuku district of Tokyo, the daily deposition of both iodine-131 and cesium-137 on 30 March was below 30 becquerel per square metre. — Since our briefing of yesterday, significant data related to food contamination has been submitted by the Japanese Ministry of Health, Labour and Welfare. Seventy-six samples were taken from 28-30 March, and reported on 30 March. Analytical results for 51 of the 76 samples for various vegetables, fruit (strawberry), seafood (sardines), and unprocessed raw milk in eight prefectures (Chiba, Fukushima, Gunma, Ibaraki, Kanagawa, Niigata, Saitama, and Yamagata), indicated that iodine-131, caesium-134 and caesium-137 were either not detected or were below the regulation values set by the Japanese authorities. However, it was reported that analytical results in Fukushima prefecture for the remaining 25 of the 76 samples for broccoli, cabbage, rapeseed, spinach and other leafy vegetables, indicated that iodine-131 and/or caesium-134 and caesium-137 exceeded the regulation values set by the Japanese authorities.”

Right now, as reported in the news, the biggest dangers from iodine-131 and caesium-137 due to the Fukushima situation are within a 100 kilometer distance of the power plant site, although levels significantly higher than normal have been reported elsewhere in Japan. Higher levels of these substances due to the Fukushima situation have also been observed in the US, both on the West and East coasts.  These US levels are so-far significantly below those considered to offer health risks.  As the damaged reactors and stored fuel rods continue to release large quantities of the radioactive substances, and because major new releases due to possible meltdowns could occur, however, the danger exists that the relatively comfortable situation in the US could change. And there is the danger of consuming contaminated vegetables or seafood anywhere it may be shipped to.   

Biological impact from radiation damage due to ingested substances is different than radiation from sources outside the body in several important respects including:  1.  Alpha and beta radiation is very short range so is of no threat when coming from substances outside the body unless those substances are touched, inhaled, eaten or otherwise penetrate the body and 2.  Radiation from a substance like iodine-131 or caesium-137 that is absorbed in body tissues continues to create damage as long as that substance is within the body.

Consequences of radiation damage

Radiation damage can be short term or long term and is measured by exposure.  Radiation dosages are measured in sieverts.  “The sievert (symbol: Sv) is the SI derived unit of dose equivalent radiation. It attempts to quantitatively evaluate the biological effects of ionizing radiation as opposed to the physical aspects, which are characterised by the absorbed dose, measured in gray. It is named after Rolf Sievert, a Swedish medical physicist renowned for work on radiation dosage measurement and research into the biological effects of radiation(ref).”

This link contains a table relating exposure in sieverts to biological impacts.  “Annual limit on intake (ALI) is the derived limit for the amount of radioactive material taken into the body of an adult worker by inhalation or ingestion in a year. ALI is the intake of a given radionuclide in a year that would result in:

• a committed effective dose equivalent of 0.05 Sv (5 rems) for a “reference human body”, or
• a committed dose equivalent of 0.5 Sv (50 rems) to any individual organ or tissue,

whatever dose is the smaller^[8](ref).”  The average natural radiation dose is 2.4 mSv per year, with a “typical range” reaching up to 10 mSv.  As the table shows, a short-term dose of as little as 2 sieverts can lead to severe medical problems and a 5-50% chance of death even with medical care.  And any dose of over 8 sieverts is sure to lead to rapid death.

The CDC has prepared a fact sheet Acute Radiation Syndrome (ARS): A Fact Sheet for the Public. 

Longer-term exposure to even low intensities of radiation can lead to mutations of cell-cycle genes and cancers

Protective measures

Known protective measures can be taken when ingestion of one of the mentioned substances is unavoidable or has already happened.  These are time-honored approaches known for decades.  Specifically:

Potassium iodide for iodine-131

Absorption of iodine-131 can be significantly reduced or avoided by taking potassium iodide, though taking such pills after exposure to iodine-131 may be useless.  A recent article in Pharmacy Practice News reports “As alarmed residents visit various Internet sites to purchase what is touted as a panacea for radiation sickness, costs of KI have skyrocketed. According to some reports, a package of 14 tablets that normally costs about $10 has soared to $540 in some ebay.com listings—a shocking 5,300% increase. Although some manufacturers are struggling to meet demands for KI in this suddenly lucrative market, others have simply given up, temporarily ceasing production.^1-4”  And this increase is in the US, not Japan.  Further, the article reports “In situations where internal radiation contamination is suspected, the initial concern is inhalation of radioactive iodine, which is readily absorbed by the thyroid gland, leading to thyroid injury/cancer, particularly in infants/fetus, children and patients with low iodine stores. KI is known to flood the thyroid gland with stable iodine, preventing the organ from absorbing radioactive iodine—but it can only go so far. Consumers should be told that KI only protects the thyroid (not other parts of the body) from radioactive iodine—it cannot reverse effects of radioactive iodine once damage to the thyroid has occurred—and it cannot protect the body from radioactive elements other than radioactive iodine.5 — A dose of KI is recommended before or immediately following radiation exposure in all children and adults under the age of 40 years who are not allergic to iodine or shellfish, and if radiation still poses a threat 24 hours later, a repeat dose is administered (unless the patient is pregnant or breastfeeding, or a newborn infant).”  Use of potassium iodide in other than emergency situations is definitely not recommended.  You can see the document Prophylactic Use of Potassium Iodide (KI) in Radiological Emergencies – Information for Physicians. 

Chelating Plutonium via DPTA

The 2005 publication Chelating agents used for plutonium and uranium removal in radiation emergency medicine points to an approach for removal of ingested plutonium.  A chelating agent is one that chemically grabs molecules of an offending substance for transportation outside of the body.  DPTA is a chelating agent that is approved by the FDA for removal of plutonium as well as americium, and curium which are also radioactive.  The CDC document Facts About DTPA provides some basic information about the substance including: “DTPA is a kind of medicine called a chelating agent. Chelating agents work by binding and holding on to radioactive materials or poisons that get into the body. Once bound to a radioactive material or poison, the chelating agent is then passed from the body in the urine. Chelating agents help decrease the amount of time it takes to get a poison out of the body. — What does DTPA do?  When radioactive materials get into the body through breathing, eating, drinking, or through open wounds, we say that “internal contamination” has occurred. Over the past 50 years, almost all cases of internal contamination have happened in people who use radioactive materials in their work. Since the 1960s, doctors have used DTPA as a chelating agent to treat internal contamination from radioactive materials such as americium, plutonium, californium, curium, and berkelium. Currently, DTPA is approved by the U.S. Food and Drug Administration (FDA) for chelation of only three radioactive materials: plutonium, americium, and curium. — What DTPA cannot do: Knowing what DTPA cannot do is also important. DTPA cannot bind all of the radioactive materials that might get into a person’s body after a radiological or nuclear event, such as a terrorist attack with a “dirty bomb.” This medicine cannot prevent radioactive materials from entering the body. DTPA cannot reverse the health effects caused by radioactive materials once these materials have entered the body. — How does DTPA work?  DTPA comes in two forms: calcium (Ca-DTPA) and zinc (Zn-DTPA). Both forms work by tightly chelating (holding on to) plutonium, americium, and curium. These radioactive materials (bound to DTPA) are then passed from the body in the urine. When given within the first day after internal contamination has occurred, Ca-DTPA is about 10 times more effective than Zn-DTPA at chelating plutonium, americium, and curium. After 24 hours have passed, Ca-DTPA and Zn-DTPA are equally effective in chelating these radioactive materials. — How well does DTPA work?  Chelating agents work best when given shortly after radioactive materials or poisons have entered the body. The more quickly a radioactive material or poison is removed from the body, the fewer and less serious the health effects will be. After 24 hours, plutonium, americium, and curium are harder to chelate. However, DTPA can still work to remove these radioactive materials from the body several days or even weeks after a person has been internally contaminated. — Who should get DTPA? Many people could be internally contaminated after a radiological or nuclear terrorist event. People contaminated with small amounts of radioactive materials might not need treatment with DTPA. Doctors and public health authorities will work together to decide who will likely benefit from DTPA treatment.”  The literature related to plutonium chelation tends to be old with some articles going back 50 years or more(ref).

Clearing Caesium-137 with Prussian Blue

The CDC fact sheet Prussian blue tells the story: “Prussian blue can remove certain radioactive materials from people’s bodies, but must be taken under the guidance of a doctor. — People may become internally contaminated (inside their bodies) with radioactive materials by accidentally ingesting (eating or drinking) or inhaling (breathing) them, or through direct contact (open wounds). The sooner these materials are removed from the body, the fewer and less severe the health effects of the contamination will be. Prussian blue is a substance that can help remove certain radioactive materials from people’s bodies. However, small amounts of contamination may not require treatment. Doctors can prescribe Prussian blue if they determine that a person who is internally contaminated would benefit from treatment. — What Prussian blue is:  Prussian blue was first produced as a blue dye in 1704 and has been used by artists and manufacturers ever since. It got its name from its use as a dye for Prussian military uniforms. Prussian blue dye and paint are still available today from art supply stores. — People SHOULD NOT take Prussian blue artist’s dye in an attempt to treat themselves. This type of Prussian blue is not designed to treat radioactive contamination and is not made for that purpose. People who are concerned about the possibility of being contaminated with radioactive materials should go to their doctors for advice and treatment.  — Use of Prussian blue to treat radioactive contamination: Since the 1960s, Prussian blue has been used to treat people who have been internally contaminated with radioactive cesium (mainly Cs-137) and nonradioactive thallium (once an ingredient in rat poisons). Doctors can prescribe Prussian blue at any point after they have determined that a person who is internally contaminated would benefit from treatment. Prussian blue will help speed up the removal of cesium and thallium from the body. —How Prussian blue works: Prussian blue traps radioactive cesium and thallium (mainly Tl-201) in the intestines and keeps them from being re-absorbed by the body. The radioactive materials then move through the intestines and are excreted (passed) in bowel movements. Prussian blue reduces the biological half-life1 of cesium from about 110 days to about 30 days. Prussian blue reduces the biological half-life of thallium from about 8 days to about 3 days. Because Prussian blue reduces the time that radioactive cesium and thallium stay in the body, it helps limit the amount of time the body is exposed to radiation. — Who can take Prussian blue/ The drug is safe for most adults, including pregnant women, and children (2 ─12 years). Dosing for infants (ages 0 ─2 years) has not been determined yet. Women who are breast feeding their babies should stop breast feeding if they think they are contaminated with radioactive materials and consult with their doctors. People who have had constipation, blockages in the intestines, or certain stomach problems should be sure to tell their doctors before taking Prussian blue. Before taking Prussian blue, people also should be sure to tell their doctors about any other medicine they are taking. — How Prussian blue is given:  Prussian blue is given in 500-milligram capsules that can be swallowed whole. People who cannot swallow pills can take Prussian blue by breaking the capsules and mixing the contents in food or liquid. Breaking open the capsules will cause people’s mouths and teeth to be blue during the time of treatment. — The dose of Prussian blue depends on the person’s age and the amount of contamination in the body. Prussian blue usually is given 3 times a day for a minimum of 30 days, depending on the extent of the contamination. – Warning:  People SHOULD NOT take Prussian blue artist’s dye in an attempt to treat themselves. This type of Prussian blue is not designed to treat radioactive contamination and is not made for that purpose. People who are concerned about the possibility of being contaminated with radioactive materials should go to their doctors for advice and treatment.”

Taking antioxidants to minimize radiation damage

The above treatments are directed to elimination of dangerous radioactive substances from the body and may constitute a first level of defense in case of ingestion of radioactive substances through breathing, eating, drinking or exposure of open wounds.  As recommended by the CDC they should be undertaken only under the guidance of a physician.  Even using these approaches, however, the various radioactive substances will be resident in the body for a certain period and can possibly create serious damage depending on exposure dose and how quickly the removal action is initiated.  There is a second level and complimentary of defense possible, and that is to minimize the damaging biological impact of radiation through taking a regimen of antioxidants.

I have written about the use of antioxidants to protect against the negative effects of medical imaging radiation first in a 2008 position paper Protection Against Radiation – The Second Line of Defense, and also briefly in an August 2009 blog entry Medical radiation risk – you can do something about it.  Medical imaging radiation usually originates from outside the body and is electromagnetic in nature making it akin to gamma radiation such as is generated by an X-ray machine or as exists in outer space.  Many studies have shown that antioxidants can be protective against biological damage caused by such exterior-originated radiation.  Many such studies are cited in my position paper and a few new ones are cited here below.  Much of this work has been sponsored by NASA and has been concerned with safety in space of astronauts. 

Would antioxidants also provide protection from in-body radiation sources such as iodine-131 or caesium-137?  The mechanisms of radiation damage are the same.  Ionizing radiation, whatever the source may be, knocks electrons loose from molecules producing free radicals.  These free radicals can propagate producing secondary showers of free radicals, particularly when generated by high-energy photons from gamma radiation.  Free radicals can generate multiple forms of damage including to tissue structures, body cell DNA, germ-line DNA and mitochondrial DNA.  From my treatise on radiation and antioxidants: “Ionizing x-radiation in any quantities is potentially deleterious to health. Radiation ionizes oxygen to produce Reactive Oxygen Species (ROS) like OH which steal electrons from lipids in cell membranes, a process called lipid peroxidation. A chain of damaging events can be let loose from a single high-energy electron event as unstable fatty acid radicals propagating in tissues produce other unstable radicals. The result can be damage to DNA or mitochondrial DNA, mangled chromosomes, protein cross-linking, cell apoptosis, genetic mutations, mutated germ cells and other forms of cell havoc. Radiation damage can show up in many ways including skin erythema, hair loss, vascular damage, internal bleeding, cataracts, cancers, weakened immune systems, sterility, mutations in offspring, premature ageing and death. Cell DNA repair mechanisms are effective in correcting some radiation-induced damage but may themselves be compromised by radiation.”

Newer literature references re antioxidants for radiation protection

My treatise PROTECTION AGAINST RADIATION – – THE SECOND LINE OF DEFENSE, last updated in 2008, provides a thorough discussion of how antioxidants are radioprotective and cites 30 of some 110 applicable literature citations I came across up to that point. Also you can check on the 2008 publication Antioxidants Reduce Consequences of Radiation Exposure.  The following are selected updates on relevant research as reported in Science Daily articles.

A March 2011 Science Daily story Antioxidant Formula Prior to Radiation Exposure May Prevent DNA Injury, Trial Suggests reports: “A unique formulation of antioxidants taken orally before imaging with ionizing radiation minimizes cell damage, noted researchers at the Society of Interventional Radiology’s 36th Annual Scientific Meeting in Chicago, Ill. In what the researchers say is the first clinical trial of its kind, as much as a 50 percent reduction in DNA injury was observed after administering the formula prior to CT scans. — People are 70 percent water, and X-rays collide with water molecules to produce free radicals (groups of atoms with an unpaired number of electrons that are dangerous when they react with cellular components, causing damage and even cell death) that can go on to do damage by direct ionization of DNA and other cellular targets, noted Murphy. The research team evaluated whether a special combination of antioxidants have an ability to neutralize these free radicals before they can do damage. — “Our intent was to develop an effective proprietary formula of antioxidants to be taken orally prior to exposure that can protect a patient’s DNA against free radical mediated radiation injury, and we have applied to patent this formulation and a specific dose strategy,” said Murphy. — The experiments measured DNA damage as a surrogate marker for DNA injury.”

A September 2008 Science Daily story Plant Antioxidant May Protect Against Radiation Exposure reports on research specifically concerned with identifying protective measures in case of a nuclear emergency: “Resveratrol, the natural antioxidant commonly found in red wine and many plants, may offer protection against radiation exposure, according to a study by the University of Pittsburgh School of Medicine. When altered with acetyl, resveratrol administered before radiation exposure proved to protect cells from radiation in mouse models.”  — The study, led by Joel Greenberger, M.D., professor and chairman of the Department of Radiation Oncology at the University of Pittsburgh School of Medicine, is overseen by Pitt’s Center for Medical Countermeasures Against Radiation. The center is dedicated to identifying and developing small molecule radiation protectors and mitigators that easily can be accessed and administered in the event of a large-scale radiological or nuclear emergency. — “New, small molecules with radioprotective capacity will be required for treatment in case of radiation spills or even as countermeasures against radiological terrorism,” said Dr. Greenberger. “Small molecules which can be easily stored, transported and administered are optimal for this, and so far acetylated resveratrol fits these requirements well.” — “Currently there are no drugs on the market that protect against or counteract radiation exposure,” he added. “Our goal is to develop treatments for the general population that are effective and non-toxic. — Dr. Greenberger and his team are conducting further studies to determine whether acetylated resveratrol eventually can be translated into clinical use as a radioprotective agent. In 2004, this same team of researchers identified the drug JP4-039, which can be delivered directly to the mitochondria, the energy producing areas of cells. When this occurs, the drug assists the mitochondria in combating radiation-induced cell death. — The results of the research were presented during the American Society for Therapeutic Radiology and Oncology’s (ASTRO) 50th Annual Meeting in Boston.”

An October 2008 2009 story Herbal Tonic For Radiotherapy? Gingko Biloba Tree May Protect Cells From Radiation Damage reports on radioprotection provided by Gingko biloba against gamma radiation from caesium-137: ” Antioxidant extracts of the leaves of the Gingko biloba tree may protect cells from radiation damage, according to a study published in the International Journal of Low Radiation. — Chang-Mo Kang of the Korea Institute of Radiological and Medical Sciences in Taegu and colleagues are interested in the protective effects of well-known herbal remedies of which Gingko biloba is one. G. biloba is a unique tree species with no close living relatives and extracts of its leaves contain antioxidant compounds including glycosides and terpenoids known as ginkgolides and bilobalides. — These compounds are thought to protect cells from damage by free radicals and other reactive oxidizing species found in the body. These are generated continuously by the body’s normal metabolism, and in excess in some diseases or after exposure to pollution or radiation. They damage proteins, DNA and other biomolecules and left unchecked can kill cells. — As such, extracts of certain plants that contain antioxidants, including G. biloba, have attracted interest for their pharmacological activity. G. biloba is currently sold as a herbal supplement and there are numerous claims for health benefits, including the possibility of preventing the onset of dementia or Alzheimer’s disease. — Kang and colleagues have now collected human white blood cells, lymphocytes, from healthy donors aged 18 to 50 years. They treated half of these cells with commercially available G. biloba extract in the laboratory and doused the other half with salt solution as an experimental control. They then compared the effects of gamma radiation from radioactive cesium on the white blood cells compared to the untreated control samples. — The team uses a light microscope to look for lymphocytes undergoing programmed cell death, or apoptosis, as a result of radiation exposure. They found that there was a significant increase in apoptosis in the untreated cells compared with those treated with G. biloba extract. Almost a third of the untreated cells underwent apoptosis compared with approximately one in twenty of the treated cells. Parallel studies with laboratory mice also demonstrated a similar protective effect against radiation poisoning. — The results suggest that the extracts can neutralize the free-radicals and oxidizing agents produced in the cells by the radiation and so prevent them from undergoing apoptosis.”

The July 2009 Science Daily story New Pill May Prevent Injury After Radiation Exposure reports “Researchers from Boston University School of Medicine (BUSM) and collaborators have discovered and analyzed several new compounds, collectively called the ”EUK-400 series,” which could someday be used to prevent radiation-induced injuries to kidneys, lungs, skin, intestinal tract and brains of radiological terrorism victims. The findings, which appear in the June issue of the Journal of Biological Inorganic Chemistry, describe new agents which can be given orally in pill form, which would more expedient in an emergency situation. — These agents are novel synthetic “antioxidants” that protect tissues against the kind of damage caused by agents such as “free radicals.” Free radicals, and similar toxic byproducts formed in the body, are implicated in many different types of tissue injury, including those caused by radiation exposure. Often, this kind of injury occurs months to years after radiation exposure. The BUSM researchers and their colleagues are developing agents that prevent injury even when given after the radiation exposure. — This paper describes a newer class of compounds, the ”EUK-400 series,” that are designed to be given as a pill. According to the researchers, experiments described in their paper prove that these agents are orally active. They also show that the new agents have several desirable “antioxidant” activities, and protect cells in a “cell death” model. — These same BUSM researchers and collaborators had previously discovered novel synthetic antioxidants that effectively mitigate radiation injuries, but had to be given by injection. “We have developed some of these agents and have studied them for over 15 years beginning with our work at the local biotechnology company Eukarion,” said senior author Susan Doctrow, PhD, a research associate professor of medicine at BUSM’s Pulmonary Center. “These injectible antioxidants are very effective, but there has also been a desire to have agents that can be given orally. A pill would be more feasible than an injection to treat large numbers of people in an emergency scenario,” she adds.”

The 2007 article Antioxidants Could Provide All-Purpose Radiation Protection reports “Two common dietary molecules found in legumes and bran could protect DNA from the harmful effects of radiation, researchers from the University of Maryland report. Inositol and inositol hexaphosphate (IP6) protected both human skin cells and a skin cancer-prone mouse from exposure to ultraviolet B (UVB) radiation, the damaging radiation found in sunlight, the team reported November 5 at the American Association for Cancer Research Centennial Conference on Translational Cancer Medicine. — According to the researchers, inositol and IP6 could decrease the severity of side effects from radiation therapy, saving healthy cells while simultaneously increasing the potency of the treatment against cancer cells. Both molecules are potent antioxidants, the Maryland researchers say, capable of preventing reactive molecules from injuring DNA and turning cells cancerous. — “Both of these potent antioxidants have been shown to have broad-spectrum anti-tumor capabilities, and now our studies confirm the degree to which these molecules protect against the DNA-damaging effects of ionizing radiation,” said Abulkalam M. Shamsuddin, M.D., professor of pathology at the University of Maryland School of Medicine. “Radiation damage is radiation damage, regardless of the source, so there could also be a protective role for IP6 in any form of radiation exposure, whether it is from a therapeutic dose or from solar, cosmic or nuclear sources.” – Normally, cells permanently damaged by radiation undergo a genetically programmed process of cell suicide, called apoptosis. Shamsuddin reports that UVB-irradiated human keratinocytes, when treated with IP6, were more likely to survive. Untreated skin cells were more likely to undergo apoptosis, indicating that the DNA in those cells was damaged irreparably and fatally. According to Shamsuddin, the treated cells take an extended pause at the point in the cellular life cycle where innate mechanisms repair DNA before the cell divides. — “IP6 certainly has some interactivity with DNA, but how exactly it works to repair DNA is still something of a mystery. There are reports that IP6 binds with DNA repair molecule Ku to bring about the repair process,” Shamsuddin said. — According to Shamsuddin, IP6 could also offer protection against accidents or purposeful incidents involving nuclear material. “It could also be advisable to use IP6 plus inositol as a cautionary treatment following a nuclear disaster or dirty bomb,” Shamsuddin said.”

Drugs under development that mitigate radiation damage

The April 2009 story Developmental Drug Helps Protect Against Radiation Damage reports “The study, led by Joel Greenberger, M.D., professor and chairman of the Department of Radiation Oncology at Pitt, is overseen by Pitt’s Center for Medical Countermeasures Against Radiation. The center is dedicated to identifying and developing small molecule radiation protectors and mitigators that can be easily accessed and administered in the event of a large-scale radiological or nuclear emergency. — JP4-039 assists the mitochondria, the energy generator of all cells, in combating irradiation-induced cell death. For this study, cells treated immediately after irradiation with JP4-039 demonstrated significant radioprotection, suggesting a potential role for the drug as a mitigator of radiation damage. — “Currently, no drugs on the market counteract the effects of radiation exposure,” said Dr. Greenberger. “We know this drug can counteract the damage caused by irradiation, and now we want to develop the ideal dosage, one that is effective for the general population while remaining non-toxic. Our goal is to take this drug through a phase I clinical trial and, once the dosage is established, develop the drug for late-stage clinical trials and market licensing.” —  The study, led by Joel Greenberger, M.D., professor and chairman of the Department of Radiation Oncology at Pitt, is overseen by Pitt’s Center for Medical Countermeasures Against Radiation. The center is dedicated to identifying and developing small molecule radiation protectors and mitigators that can be easily accessed and administered in the event of a large-scale radiological or nuclear emergency. — JP4-039 assists the mitochondria, the energy generator of all cells, in combating irradiation-induced cell death. For this study, cells treated immediately after irradiation with JP4-039 demonstrated significant radioprotection, suggesting a potential role for the drug as a mitigator of radiation damage. — “Currently, no drugs on the market counteract the effects of radiation exposure,” said Dr. Greenberger. “We know this drug can counteract the damage caused by irradiation, and now we want to develop the ideal dosage, one that is effective for the general population while remaining non-toxic. Our goal is to take this drug through a phase I clinical trial and, once the dosage is established, develop the drug for late-stage clinical trials and market licensing.”

The 2008 story Could a Nanotube-Based Drug Prevent Radiation Injury? reports “The Department of Defense has commissioned a nine-month study from Rice University chemists and scientists in the Texas Medical Center to determine whether a new drug based on carbon nanotubes can help prevent people from dying of acute radiation injury following radiation exposure. The new study was commissioned after preliminary tests found the drug was greater than 5,000 times more effective at reducing the effects of acute radiation injury than the most effective drugs currently available. — “More than half of those who suffer acute radiation injury die within 30 days, not from the initial radioactive particles themselves but from the devastation they cause in the immune system, the gastrointestinal tract and other parts of the body,” said James Tour, Rice’s Chao Professor of Chemistry, director of Rice’s Carbon Nanotechnology Laboratory (CNL) and principal investigator on the grant. “Ideally, we’d like to develop a drug that can be administered within 12 hours of exposure and prevent deaths from what are currently fatal exposure doses of ionizing radiation.” — The drug is based on single-walled carbon nanotubes, hollow cylinders of pure carbon that are about as wide as a strand of DNA. To form NTH, Rice scientists coat nanotubes with two common food preservatives — the antioxidant compounds butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) — and derivatives of those compounds. — “The same properties that make BHA and BHT good food preservatives, namely their ability to scavenge free radicals, also make them good candidates for mitigating the biological affects that are induced through the initial ionizing radiation event,” Tour said. — In preliminary tests at M.D. Anderson in July 2007, mice showed enhanced protection when exposed to lethal doses of ionizing radiation when they were given first-generation NTH drugs prior to exposure.”

Wrapping it up

1.     By far, the best protection against nuclear radiation is avoiding it.

2.     We do not know when the release of radioactive substances into the environment from the earthquake and tsunami-struck Fukushima Daiichi nuclear power plant in Japan will stop.  So far, efforts to bring the situation under control have not succeeded.

3.     Two radioactive substances of particular concern are iodine-131 and caesium-137.  These have already been released into the environment in large quantities due to the Fukushima disaster.  These substances are both highly radioactive and highly bioactive, being readily absorbed into human bodies.  Also of serious concern is plutonium, an extremely toxic byproduct of nuclear fission that has been found in the ground near the reactor sites. 

4.     Consequences from internal exposure to these substances can be most serious both in the short and long term.  Each of these substances in critical doses can cause death if left lodged in the body.

5.     Radiation from ingested radioactive substances originating from a nuclear accident is in some respects similar to radiation received from external sources, in some respects different.  The big dangers from of iodine-131, caesium-137 or plutonium come into play if they are absorbed into the body via breathing, eating or drinking them.  Caesium-137, for example, is readily absorbed from soil into certain vegetables and can enter the body effectively by eating such contaminated vegetables.

6.     Traditional means exist for removing these substances from bodies or preventing their absorption including use of potassium iodide, Prussian blue, and  DPTA.  These approaches should be pursued only under medical supervision.

7.     Effectively removing or preventing adsorption of iodine-131, caesium-137 or plutonium using these approaches takes time, may be only partially effective, and may still leave the result of substantial radiation injury under the best of circumstances.

8.     Antioxidants have been shown to be at least partially effective in reducing the damaging effects of radiation from external sources.  The known mechanisms of radiation damage suggests that the same should be the case for radiation from ingested sources.

9.     Research studies have established that a number of conventional antioxidants are protective against internal radiation damage including but not limited to resveratrol, alpha-lipoic acid, ginko biloba, beta carotene, curcumin, inositol, selenium, melatonin, vitamin C, vitamin E, N-acetylcysteine and ginseng(ref)(ref)(ref).

10.                        A number of new antioxidant and antioxidant combinations as well as other substances are being investigated for their superior abilities to protect against radiation.  How their effectiveness compares against that of conventional antioxidants is unknown. 

Everyone knows that old age can lead to many diseases and problems.  And sooner or later one of those diseases or problems will kill everybody.    But, what exactly is the relationship of aging to diseases?  The question leads to surprisingly interesting answers.

First, please have a look at this video for opinions of some prominent scientists:

Here, I address the points in the video and expand on several key related points. 

Aging increases the probability of multiple diseases and conditions which enhance the probability of death, and the rate of increase accelerates with age. 

Nobody dies of old age per-se but most everybody will die from a disease or problem of old age.  In the video Dr Guarante mentioned several disease susceptibilities that increase radically with aging including the biggies of cancer, heart disease, dementia and diabetes.  And there are many other conditions of aging that also lead to disability and death. For example, loss of eyesight and hearing can lead to automobile accidents.  Age related neurological and muscular changes can affect balance and body control leading to falls that create serious damage, disabilities and more imminent death.  Among trauma patients “Increasing age was associated with higher mortality, an increased proportion of falls and fatal head or spine injuries(ref).”

Increasing lifespans implies increasing healthspans.

Animal experiments with multiple species ranging from roundworms to fruit flys to mice indicate that interventions that radically increase lifespans have a similar effect on healthspans.  See, for example, the blog entry New extraordinary longevity lessons from the nematode which chronicles how researchers over 20 years have managed to discover interventions that multiply both the lifespans and healthspans of nematode worms (C-elegans) by a factor of over seven. 

In humans the ratio of healthspans to lifespans has been historically increasing, not decreasing.     

We are not only evolving to live longer(ref)(ref) but also the proportion of our life spent in a healthy state is increasing.  This is the gist of the message in the 2004 publication CHANGES IN THE DISPARITIES IN CHRONIC DISEASE DURING THE COURSE OF THE TWENTIETH CENTURY by the Nobel-Prize winning economist Robert W. Fogel.  This fact is contrary to the fear that extending lives will lead to longer and longer periods of disability and skyrocketing medical costs. If this tendency were to continue long enough we could approach the state of the “One hoss shay” where most of us live full healthy active lives until one day we simply drop dead.  Personally, I intend to be one of those. 

Interventions that increase our lifespans might be the most direct approach to addressing most diseases of old age

The major diseases of aging occur in the biomolecular architecture or “remodeling” that occurs with advancing age in individuals on the organ, cellular, proteomic and epigenetic levels.  An age-related disease like Alzheimer’s Disease (AD) is not due to a bacterial bug that could be cured with any conceivable antibiotic.  Rather, the disease is associated with multiple and complex changes in gene expression, cells and tissues that go with aging.  So far, despite billions of dollars spent on research on AD, there is still nothing approaching being a cure.  See my May 2010 blog entry Alzheimer’s Disease research update.  (I am, by the way, currently working on an update reflecting the vast recent research efforts being devoted to AD.)

In animal models, an intervention that increases lifespan tends to postpone all of the disease susceptibilities and problems that occur with aging.  They still happen, but happen later.  This has led to a simple but powerful hypothesis:

The best way to get at most intractable diseases of aging is to go first after aging itself.    

Along with some highly respected researchers I very strongly suspect that if in fact a cure for AD is found, it will turn out also to be an anti-aging treatment.  Supportive of this point is the July 2010 publication SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10.  On the one hand “Our findings indicate SIRT1 activation is a viable strategy to combat AD and perhaps other neurodegenerative diseases.”  On the other hand SIRT1 activation is activation of the calorie restriction pathway known to be life-extending for a wide variety of species.  I will say more about this particular research when I write next about AD research.  This research, incidentally, originated in Dr Guarante’s lab at MIT, the Glenn Laboratory for the Science of Aging.

Finding a cure to a single disease of old age may or may not by itself have a big effect on average lifespans. 

If such a cure addresses epigenetic factors related to aging, such a cure might indeed increase average lifespans(ref).  And I believe that for aging-related diseases, any approach to a cure that does not address the epigenetic factors is doomed to fail.  That is why I am optimistic that a good chunk of the $31.2 billion currently being spent by the NIH on medical research may turn out to be research on aging – even if it is now labeled as cancer, dementia or other research(ref). 

Many of the current anti-aging interventions like use of Rapamycin were discovered accidentally, and I expect that pattern to continue.  Rapamycin was discovered from a random soil sample on Easter Island, an island known by locals as “Rapa Nui.”  That is how the drug got its name.  Later the mTOR gene was discovered because it was the gene that most reacted to rapamycin.  mTOR stands for “mammalian target of rapamycin.  And a little later yet it was discovered that inhibiting mTOR via rapamycin was life-extending across many species.  And now, rapamycin and the mTOR pathway are the subjects of intense research mainly addressed at curing diseases(ref).”   

My colleague filmmaker Robert Kane Pappas and I spoke about the longevity sciences and their implications on The Power Hour Wednesday March 9.  The Power Hour with Joyce Riley is a syndicated radio program available nationally and internationally.   Advertising-free audio files for the conversation can be downloaded and heard by clicking

https://files.me.com/dotcalm9/75tthn.mp3  (Part 1)  https://files.me.com/dotcalm9/21d6o2.mp3 (Part2)

Robert was the scheduled guest.  However, after I called in about 15 minutes into the show, the hostess Joyce Riley invited me to stay on the line.  I did that participating with Robert in the discussion until the end of the show.  The Power Hour program is commercially-supported and our on-radio conversation was interspersed with advertising commercials including ones for health products.  I emphasize that I appeared as a call-in guest on the show, have no commercial links to or interests in any of the products advertised, and do not necessarily endorse their use.  I believe the same holds for Robert.  Also, to clear another matter up, Joyce referred to me as a “prominent geneticist,” which I am not.  I did point that out later in the show, indicating that my field is interpretation of advanced research in all fields of science relating to longevity.  Beyond that, Joyce asked a lot of provocative questions leading to a lively discussion. The Power Hour program is directed at a general audience of radio listeners, and Joyce repeatedly mentioned that there were large numbers of people calling in, “the switchboard is overloaded.”  Many of the call-in questions and remarks were interesting because they illustrate the lack of public information about aging.  Also evident in the caller remarks was the low esteem in which science is held by many people, assuming  for example that any products of scientific research are not “natural” and therefore against God’s will or the natural order of things.  Also evident was failure to distinguish between the activities of basic research scientists on the one hand and exploitative drug company practices on the other hand.  Nonetheless, some of the discussion relating to our health care system and the role of the pharmaceutical industry was interesting. 

Also interesting was the repeated raising of the question:  “If and as interventions for significantly extending human lifespans become available, will they be available to the general public or only to the very-rich?”

Robert has spent the last 4 years producing the film To Age or Not to Age and in the process has conducted extensive interviews as well as informal discussions with many prominent researchers in the longevity sciences.  And he and I have enjoyed many long and sometimes-heated discussions.  This has given Robert a unique perspective of the aging research area – that of a sensitive interviewer and a  filmmaker.

Shortly before the film To Age or Not to Age was due to be shown for the first time on national TV late last Fall, Robert came across this blog and decided he had somehow to shoehorn me into his film.   We met that weekend in Bridgeport Connecticut for an improvised filming session in a public park.  I appear in three short segments towards the end of the final film, briefly presenting my theory of how closing the loop in the stem cell supply chain could lead to very long lives.  Since then Robert and I have established a close collaborative relationship.  We find ourselves aligned on the need to better inform the public on a variety of issues connected with aging research and the personal and social implications of ever-longer lifespans.  Besides jointly bringing you the video entries in this blog and joining in events like this radio show, we have been planning other movies covering many aspects of the longevity sciences and the profound implications of us living longer lives.

A non-scientific but fun trailer for To Age or Not to Age is:

As a belated second-birthday present, I am giving this blog a new name – Aging Sciences, as you can see in the header.   Starting now the latest blog entry will be available online at www.agingsciences.com.  Nothing is lost and all existing links to past articles will continue to work because they will retain their old addresses.  Users can continue to use the old blog address of www.anti-agingfirewalls.com if they prefer.   The old blog name basically references current anti-aging interventions, only one of many aspects of the aging puzzle.  The new name more-accurately reflects what the blog has grown up to be about – all the key sciences involved in the ongoing study of aging and possible interventions that can combat aging.  The new web address should also be a lot easier to remember.

Besides rapamycin itself, a number of other substances to varying degrees also inhibit mTOR signaling. Some of the newer substances are reported in publications such as (2008) A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis, (2008) Palomid 529, a novel small-molecule drug, is a TORC1/TORC2 inhibitor that reduces tumor growth, tumor angiogenesis, and vascular permeability, (2009) Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTO and (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. Some of these alternative substances are selective in whether they affect mTORC1 or mTORC2. And they may vary also in toxicity and secondary effects.