By Alan Cocchetto, NCF Medical Director

From Summer 2018 Forum

While NCF receives emails and phone calls from patients and researchers alike regarding the CFIDS connection to radiation we have continued to move ahead to refine our scientific model.

Many of our readers are probably not aware of the current findings from other CFIDS researchers may fit into our medical picture. As such, I would like to discuss some of the newest noteworthy findings.

Metabolomics, CFIDS and Radiation

One of the more interesting papers that we hear from patients about is that from Dr. Robert Naviaux. His paper, titled “Metabolic features of Chronic Fatigue Syndrome” has garnered much attention among the CFIDS community [1]. Naviaux and colleagues performed targeted, broad-spectrum metabolomics to gain insight into the biology of CFS. According to their paper, “metabolomics showed that CFS is a highly concerted hypo metabolic response to metabolic stress that traces to mitochondria and was similar to the classically studied developmental state of dauer. . .

Dauer, which means persistence or long-lived in German, is an example of one well-studied system. The developmental stage of dauer is a hyper metabolic state capable of living efficiently by altering a number of basic mitochondrial functions, fuel preferences, behavior, and physical adverse environmental conditions. Entry into dauer confers a survival advantage in harsh conditions. Entry into dauer confers a survival advantage in harsh conditions. When the dauer response is blocked by certain‘ mutations (dauer defectives), animals are short-lived when exposed to environmental stress. These mutations show that the latent ability to enter into a hypo metabolic state during times of environmental threat is adaptive, even though it comes at the cost of decreasing the optimal functional capacity. Similar to dauer, CFS appears to represent a hypo metabolic survival state that is triggered by environmental stress.”

In our subsequent literature search, two papers jumped out at us at the NCF. The ?rst was titled, “Deep hypo metabolic state mitigates radiation-induced lethality in zebrafish” and the second was titled, “Pharmacologically induced reversible hypo metabolic state mitigates radiation induced lethality in mice [2,3].”

As you can imagine, radiation exposure would certainly qualify as an urgent environmental stress or threat. From the above radiation papers, we found the following description, “Free radical-mediated damage to macromolecules, altered cell signaling, perturbed cellular and tissue homeostasis leading to cell death are predominant mechanisms through which low linear energy transfer (LET) radiation inflicts damage in biological systems. The extent of management manifestation and its consequences during the post-irradiation [post-IR] period depends upon the absorbed dose and elapsed time, and damage manifestation becomes irreversible with time. It can be expected that if the rate of cellular metabolism is reduced, it would lead to slowing down of molecular and biochemical activities and ultimately damage manifestation in irradiated organisms. Reduction in the rate of metabolism, by lowering temperature, is well studied and is known to reduce radiation-mediated damage. Oxygen, available in the cell and tissue milieu, further complexes radiation by increasing the quality and quantity of free radicals and the decreasing oxygen availability is known to reduce the flux of oxygen centered free radicals and subsequent damage induction. In nature, a number of vertebrates and invertebrates undergo metabolically suppressed state known by a variety of terms like hibernation, torpor, aestivation and brumation. During this state, oxygen requirement as well as metabolic rate decreases to a minimum level where the organism operates cellular function, which is just sufficient for survival.

Experimental studies have clearly suggested that naturally non-hibernating species like laboratory mice can also be made to enter the hibernation-like state by a variety of approaches like low temperature, hypoxia, hydrogen sulfide, carbon monoxide, etc. One of the hallmarks of the hypo metabolic state is to render the organism resistant to a variety of stresses. These studies have raised significant interest in the phenomenon of hypo metabolism and its possible biomedical implications. The controlled and reversible slowing down of the metabolism and the subsequent molecular functions has interesting implications for radiation exposure scenarios. Young and Taylor have suggested that in humans a wakeful hypo metabolic state is possible through parasympathetic dominance during meditation, while the cardiac activity and other bio-chemical data supported biological aestivation. It can be anticipated that a reversible hypo metabolic state, if induced in radiation exposure victims, will reduce the radiation effects that Would be invaluable for management of radiation exposed victims.

Thus, the radiation literature and Naviaux’s findings in patients certainly overlap. Could CFIDS pa- tients be in a hypo metabolic state due to enviromnental radiation exposure‘? You bet! Our own research indicates that this is the case. Furthennore, since the Chemobyl liquidators have been found to develop CFIDS, this adds credence to one argument regarding the radiation-CFIDS exposure! Should you have any doubts, I would encourage the reader to examine the literature on radiation sickness for the medical details including quality-of-life issues associated with this type of exposure.

Telomeres, CFIDS and Radiation:

Another recent paper that was of interest to the NCF Was titled, “Association of Chronic Fatigue Syndrome with the premature telomere attrition” by scientists at the CDC [4]. According to the paper, “This study found a significant association of ME/CFS with premature tellomere attrition that is largely moderated by female subjects < 45 years old. Our results indicate that ME/CFS could be included in the list of conditions associated with accelerated aging.” There you have it, the CDC is chalking up their findings for telomere attrition in patients merely as accelerated againg! Hey, CDC, what is causing this to occur and is there more to this story?

Well the NCF has another take on ths as you might expeet. Since We have the hypometabolism issues and now, alterations to telomeres, what have we concluded?

First, let us examine what the function of a telomere is. Telomere is from the Greek telos (end) and meros (part). Telomeres are an essential part of human cells that affect how our cells age. Telomeres are the caps at the end of each strand of DNA that protect‘ our chromosomes, like the plastic tips (aglets)at the end of shoelaces. Without the coating, shoelaces become frayed until they can no longer do their job, just as without telomeres, DNA strands become damaged and our cells can’t do their job [5]. Thus, telomeres protect the vital information in our DNA. DNA makes up all of the cells in our body as it is the genetic material that makes us who we are. Every organ in our body (skin, liver, heart, etc.) is made up of cells so telomeres are vital to our health. Our cells replenish by copying themselves and this happens constantly throughout our lives. Telomeres get shorter each time a cell copies itself, but the important DNA stays intact. Eventually, telomeres get too short to do their job, causing our cells to age and stop functioning properly. Therefore, telomeres act as the aging clock in every cell and their shortenting is involved in all aspects of the aging process on a cellular level. Thus, telomere length represents our biological age as opposed to our chronological age. As you would perhaps expect, radiation adversely telomere function as well as length [6,7]. Loss of either telomere function or telomere length maintenance has been associated with genomic instability, something the NCF has already identified and had published on in their CFIDS patient cohort, These references provide evidence that dysfunctional telomeres contribute to both ionizing radiation induced frequencies and to genome instability but also to increased carcinogenic potential following low dose exposures as well. In addition to evidence supporting the crucial role of telomores in the formation of chromosome and chromatid aberrations induced by ionizing radiation, shorter leukocyte telomere length has been demonstrated to predict cardiovascular disease and mortality. This is something that has been reported upon previously in CFIDS patients as the three most prevalent causes of death were heart failure, suicide and cancer [8]. These findings are certainly in line with the CFIDS epidemiology done previously by the National Cancer Institute [9].

Glycolysis, CFIDS and radiation:

Another paper that We had found to be important to our on-going research was titled “Elevated Energy production in Chronic Fatigue Syndrome patients [10]. Here the authors concluded that the “results present an unorthodox view on CFS pathology: the fatigue is not caused by lack of ATP, and instead might be caused by a pathological process linked to non-mitochondrial ATP production such as glycolysis.” Glycolysis is the ?rst step in the breakdown of glucose to extract energy for cellular metabolism. Glycolysis is important due to the fact that it is well established to be affective by ionizing radiation [11]. In fact, substantial data has suggested that glycolysis under aerobic condutions, also known as the Warburg effect, privides a growth advantage for tumor cells and can lead to malignant progression. More recent reports have identified the Warburg effect to be implicated in resistance to cytotoxic stress, including ionizing radiation as well as chemotherapy. Lastly, glycolysis is important from a cell standpoint as it is implicated in cancer formation and malignancy. This isn’t too far fetched when you consider all of the CFIDS medical evidence to date!

References:

l. Metabo1ic features of Chronic Fatigue Syndrome; Naviaux RK, Naviaux JC, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, Gordon E, Proc Natl Acad Sci USA, 2016 Sep 13;113(37):E5472-80, doi: 10.1073/pnas.1607571113. Epub 2016 Aug 29.

2. Deep hypometabolic state mitigates radiation-induced lethally in zebrafish; Ghosh S, Indracanti N, Kay J, PremKumar I, Biomed Res Clin Proc, 2(2): 1-9

3. Pharmacologically induced reversable hypometabolic state mitigates radiation induced lethality in mice; Gsosh S, Indracanti N, Joshi J. Indracanti N, Joshi J, Ray J, Indracanti PK, Sci Rep, 2017 Nov 2,7(1):14900

4. Association of Chronic Fatigue Syndrome with premature telomere attrition, Rageevan MS, Murray J , Oakley I, Unger ER, J T ransl Med, 2018 Feb 27, 16(1);44.

5. www.tasciences,com/what-is-a-telomere

6. Telomeres and Telomerasse in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis, Sishc BJ, Nelson CB, McKenna MJ, Battaglia CI, Herndon A, Idate R, Liber HL, Baily SM, Front Oncol. 2015 Nov 24,5;257

7. Telomere shortening and ionizing radiation: a possible role in vascular dysfunction; Sabatino L, Picano E, Andreassi MG, Int JRadt Biol. 2012 Nov; 88(l1):830-9

8. Causes of death among patients with Chronic Fatigue Syndrome, Jason LA, Corradi K, Gress S, Williams S, Torres-Harding S, Health Care Women Int. 2006 Aug.27(7).615-26

9. Chronic Fatigue Syndrome and subsequent risk of cancer among elderly US adults, Chang CM, Warren JI, Engels EA, Cancer. 2012 Dec 1:118(23):5929-36

10. Elevated energy production in Chronic Fatigue Syndrome patients; Lawson N, Hsich CH, March D, Wang X, J Nat Sci. 20l6;2(10)

11. Radiation induces aerobic glycolysis through reactive oxygen species; Zhang J, Rajaram N, Brizel DM, Frees AE, Ramanujam N, Batinic-Haberle I, Dewhurst MW. Radi0thner Oncol. 2013 Mar;106(3);390-6