Friday, 22 April 2016

Promoting autophagy with the aid of periodic, habitual therapeutic fasting for brain cancer management

I am inclined to conclude that the studies presented here in relation to fasting and autophagy provide sufficient evidence to support a key aspect of my metabolic strategy to manage brain cancer.... and no, its not just because I am biased. ;-)

I have been experimenting with personalised fasting protocols lately, allowing for what I feel could be a theoretically viable symbiotic relationship of periodic, habitual therapeutic fasting + complimentary dose specific supplementation of fish oils + salt preparations + magnesium chloride supplementation as a specific, targeted, individualistic approach. I base this approach on my exhaustive research undertaken over the years following my diagnosis, scrutinising decades of evidence based, peer reviewed research to falsify or validate my hypotheses. I will attempt to explain why and how I believe implementation of such an approach could yield positive results for my n=1 experiment:

Numerous individuals have queried my dietary protocol, however it could reasonably be postulated, based on the evidence and underlying physiological mechanisms of this type of dietary manipulation, that the most significant benefits would likely come from calorie restriction and fasting. The metabolic state prior to commencement of a fast and personal dietary choices upon completion of such endeavours are undoubtedly of vital importance of course so as to not raise IGF-1 and upregulate mTOR during the re-feeding phase. 
The gut microbiota before, during, and after fasting is another subject of great interest to me but I won't go into that because it is fairly complicated territory to cross over and I don't have time to talk about the trillions of bacteria involved despite it being critical to all aspects of health and all life on this planet as we know it... primordial poop and all that jazz.

Back to autophagy, fasting, and re-feeding....

Growth factors must be regulated via continued calorie restriction and considered selection of macro and micronutrients. In the fasted state these undesirable growth factors that act in a cascading domino fashion on reactant signalling pathways are metabolically inhibited or 'dulled' for want of a better expression (at least I tried eh? could have just said 'regulated'), so we want to continue to take advantage of this rather than cause an upsurge of insulin and contributory growth factors during the re-feeding stage. The same thing happens (the inhibition of stated growth factors) with hyperbaric oxygen therapy so it makes sense how all this fits together in powerful synergy to increase metabolic stress on tumour cells. In preparation for re-feeding I consume exogenous ketones (Ketoforce or KetoCaNa, available here!prettyPhoto to blunt the response of growth factors and to prevent over-consumption of food once I start eating again. This is to ensure that the whole practice of the fast is not counterproductive.

The benefits of fasting: mTor in the spotlight- IMG-
I believe that my restricted, dairy free ketogenic diet may effectively be mimicking (or at least I hope!) some of the favourable metabolic adaptations that come with a prolonged fasted state, with the benefit of continuous daily nourishment to maintain my current satisfactory weight. I have little stored body fat to tap in to so it would be nice to keep some functional strength and adequate bone density. On the plus side, due to the stringent approach I have adopted, my metabolic flexibility is comparable to that of a small (healthy) child.
Fasting helps to regulate cascading signalling pathways like mTor and IGF-1.
Turbulence must ideally be steadied in the midst of the re-feeding phase,
maintaining consistent, therapeutic blood glucose readings.

Fasting on a ketogenic diet is something I do habitually and it can be incredibly beneficial for cancer management as I will attempt to explain. If I were a food guru I would advise against fasting because it is remarkably effective under the right circumstances and I wouldn't be able to make much money off of you with my magical foods (diminished returns you see, I can't live in a box). I may even throw the 'starvation mode' myth at you if I was feeling particularly nasty. Yes I do love 'magic mushrooms', but I also like to think I have a moral compass that guides me in the right direction when exploring these investigations and going over all the information with a fine toothed comb.

I typically aim for at least 1 day a week of no food with a controlled water intake. The benefits of intermittent fasting have been well documented both in the academic literature and to the general public over the past few years (Michael Mosley's blood sugar diet anyone?, 5:2 diet?). 
For my personalised approach to periodic fasting, keeping the containment of seizure activity in mind, salts are added to my water and fluid intake is closely monitored to prevent 'breakthrough' seizures (by maintaining homeostasis of electrolytes in the brain as I expel urine throughout the fasting period). Some may also benefit from this if they ever feel light-headed during a fast but this may simply be the case if they are not metabolically adapted to utilising fats as a predominant fuel source. On a well structured ketogenic diet for cancer management this should be a seamless transition because the diet itself mimics a fasted state as mentioned previously in this post. In this state fatty acids are already an obligitory source of cellular energy production by peripheral tissues and also the brain of course. 
I can have 'breakthrough' seizures if I fail to maintain desirable therapeutic ratios of electrolytes in the brain.
Can we query current rationalities and approaches to nutrigenomics?

The pre-eminent curiosity that I retain regarding health practitioners is that specialists in nutrition on occasion appear to not possess the adequate level of biochemical grounding to explain the vital processes happening at the cellular level during fasting and through manipulation of eicosanoids (fatty acids), conversely from my personal experiences, experts in biochemistry don't apply their vast knowledge of these complex physiological systems to basic fundamentals of nutrition in a sensible, practical sense. In other words, the nutrition experts sometimes oversimplify very complicated metabolic processes and the biochemist could be overcomplicating his or her work that could be applied practically via simple means. This is purely based on observational, subjective personal extrapolations of course. Disclaimer, don't shoot me. ;-)
The alimentary canal- human digestive tract.
I suggest a more balanced approach where these complicated mechanisms are explained in sufficient detail and with careful cogitation, along with their appropriate practical applications. In other words why go around the moon to get to the sun even though space travel in itself is complicated. A rocket scientist has a complicated job but we have sent monkeys into space. The monkey just needs to know how to practically apply this information with enough detail. You can probably tell by now that I like my appreciably contrived analogies. With a new dawn of 'personalised medicine' approaching on the horizon however, I am encouraged by the direction in which we are heading.

Eicosanoids and cancer- could nutrition professionals benefit from a greater understanding of the numerous underlying processes of physiological processes to improve complimentary treatment protocols? IMG-
Autophagy- essentially the process of 'self-eating'!... in a good way (clearing out the rubbish)

    As demonstrated aptly by Pac-Man, lysosomes are organelles that contain digestive enzymes. They digest excess or worn out organelles, food particles, and engulfed viruses or bacteria. Lysosomes are like the stomach of the cell.
As we begin to think about autophagy in general, and the specific mechanisms of mitophagy, the genius of the human body's innate natural survival adaptations reveal themselves in quite remarkable ways. Its all very clever when we delve just a little deeper into it. If we don't feed the body it will be more efficient at doing some essential housekeeping! I feel it is appropriate to give the analogy of someone who has a messy house, cleaned once per week (typically Sunday because there are less time constraints and other responsibilities to deal with). The house can be cleaner if all resources can be employed to the task at hand with no alternative concurrent responsibilities. With respect to our physiological requirements in a fasted state, the digestive system is able to take a much needed rest from metabolising nutrients from food, focusing all of its energies on cleansing organs, doing some dusting, and clearing out the rubbish!
Because I want to break free- a significant role of mitophagy involves the removal of damaged,
depolarised mitochondria. Nutrient deprivation is the key activator of autophagy.   
I enjoy the process because it allows time for contemplative introspection. I'm so glad that I push myself to the limit even though it can be quite challenging at times. Fasting teaches you a lot about what your body and mind are capable of, and the sense of well-being I experience is very satisfying. I do often feel as though I could be doing more but that may simply be my natural personality and state of mind, mentally flawed in certain situations perhaps, but a useful mental state to make the most out of trials and tribulations that life throws at me. I enjoy fasting and I am practicing this today and tomorrow (a 2 day fast), it provides me with a time to slow down and reflect on life. I use this time to listen to my body and clear my mind of what should be trivial concerns and negative thoughts.
Scientists understand that controlling the lysosomal-autophagic pathway
allows for effective approaches to modulate cellular clearance.
Complex processes clearly, but simple applications.
I found this great explanation of autophagy via Dr. Jason Fung's article on fasting and autophagy which details everything better than I can! I really admire his work. You can follow the link on the picture below to learn more.

I mentioned all of this in my Youtube video. I have added it here to act as a sort of appendix:

What is clear to me is that there are several benefits to these physiological responses to fasting and calorie restriction. I wanted to show that this can be explained through the basic fundamentals of cell biology.

In my Youtube video I mentioned expression of FGF21 and PARa during fasting in humans and other animals. Its complicated but there are numerous benefits to this in relation to fasting. The diagram may help to detail the biochemical mechanisms better than I can. Clear as mud?

'There are multiple interactive pathways and molecular mechanisms by which CR (calorie restriction) and IF (intermittent fasting) benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease. A better understanding of the impact of CR and IF on the aging nervous system will likely lead to novel approaches for preventing and treating neurodegenerative disorders.'

This study shows that circulating levels of FGF21 are markedly increased by fasting in humans and are part of the late stages of the body's adaptive response to starvation — a protective mechanism that evolved to aid survival in periods of famine.

The Peroxisome Proliferator Activated Receptor alpha (PPARα) is a transcription factor that plays a major role in metabolic regulation. The map puts PPARα at the center of a regulatory hub impacting fatty acid uptake, fatty acid activation, intracellular fatty acid binding, mitochondrial and peroxisomal fatty acid oxidation, ketogenesis, triglyceride turnover, lipid droplet biology, gluconeogenesis, and bile synthesis/secretion. In addition, PPARα governs the expression of several secreted proteins that exert local and endocrine

It all actually started for me with the Valter Longo studies for cancer management as soon as I received my diagnosis and read 'Cancer as a Metabolic Disease'. Here are some of those studies that sparked my initial enthusiasm for this approach:

Dietary restriction and cancer management

Fasting and IGF-1

Fasting cycles retard growth of tumours and sensitise a range of cancer cell types to chemotherapy

Sunday, 10 April 2016

More thoughts, experiments and investigations on curcumin in vivo

Following on from my last post, I have been questioning myself more about optimal dosages for supplementation of curcumin, particularly in light of such studies whereby 'high' amounts of the compound are tolerated with minimal to zero toxicity reported. One particular study caught my eye.

'A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complex™, Sabinsa Corporation). Healthy volunteers were administered escalating doses from 500 to 12,000 mg.'

12,000 mg is a lot considering I take 1,500 mg per day which I deem to be the optimal therapeutic dose for me as an individual. There may be situations by which higher doses may be more beneficial though I believe the dosages I maintain at the moment should be adequate for my current aims. 

The results of the study revealed some thought provoking findings though I dd wonder about the 17 participants that did experience issues:

'Seven of twenty-four subjects (30%) experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg.'

The study goes on to say that 'no toxicity appeared to be dose related', indicating that of those 17 participants there may have been extraneous factors or sensitivities to the curcuminoid formulation regardless of the dose ingested. I also believe that because the trial was looking at a single, oral dose of this formulation, it may have been enough to explain some of these mild, adverse effects. Nevertheless, they concluded that ,'The tolerance of curcumin in high single oral doses appears to be excellent.' 

Given the relatively very high doses used in the study on the whole and the fact that only mild toxicity was reported, I would say that this conclusion appears to be valid but I would like to see more studies using high such high doses for comparison in order to truly validate these findings. 

Another aspect of curcumin I have been looking into is a hypothesis I had about curcumin being beneficial to combat neurodegenerative disease, in part by acting as a chelating agent.

It is of upmost importance to consider this as we see that in neurodenerative diseases we typically see elevated levels of copper and iron in the brain 


Iron (Fe) and copper (Cu) are essential to neuronal function; excess or deficiency of either is known to underlie the pathoetiology of several commonly known neurodegenerative disorders. This delicate balance of Fe and Cu in the central milieu is maintained by the brain barrier systems, i.e., the blood–brain barrier (BBB) between the blood and brain interstitial fluid and the blood–cerebrospinal fluid barrier (BCB) between the blood and cerebrospinal fluid (CSF).

It is worth noting, as I referenced in my magnesium and epilepsy report, that a hallmark of many neurodenerative diseases is an impaired blood brain barrier (a so-called 'leaky brain'), which would make these homeostatic interventions more necessary. A suitable analogy may be that it is like keeping an open wound clean to avoid infection. We don't want an accumulation of metals in the brain as it would allow the disease to progress.

...and with conditions like epilepsy we know excess (or insufficient levels of) copper acts as a seizure trigger.

Keeping all this in mind I then began to wonder if the same benefits of curcumin as a chelating agent could apply to mercury toxicity. I eat a lot of fish so I have been contemplating this benefit/risk conundrum for some time. Interestingly I then found this rodent study-;jsessionid=0447181CD798D7026E04D05B1B9A485F.f03t01?userIsAuthenticated=false&deniedAccessCustomisedMessage

The results indicated that- 'Curcumin treatment (80 mg kg−1 b.w. daily for 3 days, orally) was found to have a protective effect on mercury-induced oxidative stress parameters, namely, lipid peroxidation and glutathione levels and superoxide dismutase, glutathione peroxidase and catalase activities in the liver, kidney and brain.'
There is no requirement for mercury of course (its all bad!) so this would be welcome news if humans can benefit in a similar fashion. Effective doses would need to be established of course. The European Laboratory of Nutrients (ELN), do Toxic Elements tests that would enable me to see what is going on in my body and could enable me to be more thorough with my own experiments. They can be found here and it would probably be a great idea to have these tests for those who experience brain fog or have a history of neurodegenerative disease in their family.

It is a difficult balance at times however the problem is typically too much rather than too little. 

This may be a useful supplement to take for patients who have a gadolinium based contrast agent when having MRI scans in light of recent evidence. 

'Newer reports have emerged regarding the accumulation of gadolinium in various tissues of patients who do not have renal impairment, including bone, brain, and kidneys.'

It would be interesting to see if patients who have fewer MRIs with the contrast for the same stage of disease live longer than those who have the imaging procedure more frequently. I suspect we would never see a study like that due to reasons of efficacy (ironic perhaps in light of this study), however it would be interesting to see if there is any correlation. I know correlation does not always equal causation but there are probably ways you could qualitatively measure this alongside subjective observational findings.

Thursday, 7 April 2016

Curcumin: Problems and promises

I take curcumin regularly. This is a nice visual representation of how it potentially acts as an anti-cancer agent providing all conditions requiring therapeutic efficacy are met.

Bioavailability is key here to make the most of the therapeutic benefits of curcumin. If you take it as a supplement make sure it is paired with piperine and is taken in therapeutic doses. We need more in vivo studies in brain tumour patients to elucidate what would act as an optimal dose, crossing the blood brain barrier so I will continue to research this medicinal compound. 

'Major reasons contributing to the low plasma and tissue levels of curcumin appear to be due to poor absorption, rapid metabolism, and rapid systemic elimination. To improve the bioavailability of curcumin, numerous approaches have been undertaken. These approaches involve, first, the use of adjuvant like piperine that interferes with glucuronidation; second, the use of liposomal curcumin; third, curcumin nanoparticles; fourth, the use of curcumin phospholipid complex; and fifth, the use of structural analogues of curcumin (e.g., EF-24). The latter has been reported to have a rapid absorption with a peak plasma half-life. Despite the lower bioavailability, therapeutic efficacy of curcumin against various human diseases, including cancer, cardiovascular diseases, diabetes, arthritis, neurological diseases and Crohnʼs disease, has been documented. Enhanced bioavailability of curcumin in the near future is likely to bring this promising natural product to the forefront of therapeutic agents for treatment of human disease.' 

As the acclaimed philosopher Karl Popper explained, a good scientist should constantly be trying to prove themselves wrong in order to have a truly unbiased opinion. This forms the basis of pure, valid, reliable scientific research.

If I am trying to prove myself right all the time without a healthy degree of skepticism I may ignore the challenges and barriers that appear to be appropriate considerations when undertaking my own research. Preconceived notions must be forgotten to avoid so called 'pseudo-science', this is always my approach.

It is only by seeking to disprove my theories and scrutinising the methods and conclusions of these studies that I can come to a valid conclusion once I have all the evidence and all questions have been answered. Knowledge is about probability and contingency, we are justified in believing whatever seems most probable given our current data and we should always be willing to revise our beliefs in light of new data. My metabolic approach to my specific situation will progressively evolve as I continue to question myself and learn more.

Monday, 4 April 2016

Current ketogenic diet proposals for cancer management are questionable

I've been saying for a while now that these ketogenic diet proposals for cancer management have been deeply flawed- the inclusion of dairy and the lack of consideration for the role particular amino acids play in proliferation of these defective cells.