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Fasting and Cancer part 2

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Below is a link to more information on research conducted by Dr. Longo regarding fasting and the immune system

https://news.usc.edu/63669/fasting-triggers-stem-cell-regeneration-of-da...

" “PKA is the key gene that needs to shut down in order for these stem cells to switch into regenerative mode. It gives the OK for stem cells to go ahead and begin proliferating and rebuild the entire system,” explained Longo, noting the potential of clinical applications that mimic the effects of prolonged fasting to rejuvenate the immune system. “And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting. Now, if you start with a system heavily damaged by chemotherapy or aging, fasting cycles can generate, literally, a new immune system.”

Prolonged fasting also protected against toxicity in a pilot clinical trial in which a small group of patients fasted for a 72-hour period prior to chemotherapy, extending Longo’s influential past research."

The key part for CML patients is the idea that fasting for 72 hours can cause leukemic stem cells to divide. And it is that division which enables a TKI to kill it. I have a question on this hypothesis sent to Dr. Cortes and also to Dr. Longo. I hope they respond.

In the mean time, I only made the fast for two days. I have to try again before Lent ends.

Scuba, thanks for the information. Very curious how Dr Cortes responds to your question. 

 

Hi Scuba,

I am very curious about how Dr. Cortez responds to your ideas on how to coax LSC's out of quiescence. Regarding getting your body into ketosis by fasting (short periods of starvation) being crucial to this? 

Would a very low carbohydrate diet - i.e paleo or Atkins etc. - have the same effect as a fast? Lowering or removing carbs from the diet does produce 'ketosis' in most people who do not eat carbs at all, or at least reduce them to < 20g per day. Ketosis when starving produces unpleasant effects, where as getting your body into ketosis by carb restriction (but keeping a good level of healthy forms of fat like natural cold pressed oils, natural butter and full fat cream etc) seems to have benefits. Weight loss being one, higher energy levels another. 

My question is if getting into ketosis via strict carb restriction is the key to coaxing the stem cell populations our of hiding (normal and Leukaemic) then would you need to fast?

Sandy 

PS thanks for starting a new related thread on this... the original is at risk of becoming too long.

 

I heard back from Dr. Cortes regarding Pioglitazone. He said he is well aware of the research and  studies are under way. Regarding fasting, he had no comment.

Regarding fasting effects on cancer:

https://keck.usc.edu/fasting-like-diet-turns-the-immune-system-against-c...

There is discussion whether a multi-day fast 2 or 3 day (3 day emerging as more effective) vs a low carb (<20g) low calorie "fasting mimicking diet" is more effective. Both seem to be necessary to maximize benefit.

What is clear is that dramatic reduction in calories and elimination of carbs as a fuel source causes enzymatic changes in the body which re-direct the bodies resources. Older cells, primarily immune system cells, are canabalized to provide building blocks for ongoing systems. Most importantly - cancer protecting T-cells (Tregs) are discharged away from cancer tumor sites (and this includes the bone marrow where LSC's congregate).

To be clear - it's not the diet alone that coaxes LSC's to divide thereby making them vulnerable to TKI attack. It's the combination of fasting to first rid LSC's of their protective Treg cells (which then allows the immune system to attack them via autophagy) and then when the fast is broken, gene activation occurs which signals the bone marrow stem cells to get busy diving to replenish the scavenged older blood cells. It is this replenishment signal coupled with Treg removal that, in theory, opens LSC's to dramatic destruction by our rejuvenated immune system AND TKI attack.

Although I did make it two days (water only fast) and I remain in ketosis (little to zero carbs) for more than a week now, I will try going for a full 3 days water only fast to more fully test this idea. In my case, as I am already PCRU, I won't know if this is working. Only by stopping Sprycel and test for treatment free remission (and succeed) will I suspect  this approach has worked.

It will take years of clinical trial study to prove that fasting plus TKI eliminates LSC's. Since fasting is probably good to do anyway from time to time, and the current science is promising - I feel it's worth trying now and not wait for clinical proof. The only thing Iwe have to lose are a few pounds. And that's a benefit in its own right.

For those of us who are not PCRU and are struggling to lower PCR levels, adding a fasting program (3 days no food - followed by low carb Ketosis diet), to test this idea, they might be able to let us know if it works for them. It would be a remarkable finding among ourselves to see a small group of CML Support group members who have been unable to lower their PCR's (i.e. plateaued) and then after trying this approach, experienced  a sudden drop in their PCR. Although not scientific - it would be prroof enough for me. No one should attempt this fasting program without consulting a doctor. Electrolyte balance is important and TKI's do stress the heart.

One caveat for women -

http://www.drhardick.com/intermittent-fasting-men-vs-women

https://draxe.com/intermittent-fasting-women/

There does seem to be a gender difference in how the sexes react to "starvation". Women are more prone to negative reaction to fasting than men. Something to consider.

Dr. Longo summarized his findings this way:

“It may be that by always being exposed to so much food, we are no longer taking advantage of natural protective systems which allow the body to kill cancer cells,” Longo said. “But by undergoing a fasting-mimicking diet, you are able to let the body use sophisticated mechanisms able to identify and destroy the bad but not good cells in a natural way.”

In answer to your question - a fasting mimicking diet may be all that is necessary to trigger this important cancer killing process.

 

Scuba,

Did you hear from Dr Cortes or Dr Longo on your question?

also, earlier I saw a more recent thread of yours on this topic but I can’t seem to find it now.

Gleevec stopped working for me after 6 years, so in between that and my next TKI ,  I took the opportunity to water fast for four days. What a fabulous feeling!! 

Now I’m on Sprycel for just 2 weeks and super excited about your thread which discussed fasting while on Sprycel (Dasatinib).  

I’m ready to do that!  I’m looking for that thread. Where did it go??  Lol 

 

sarah63

I found the answer to my earlier question. Very interested in this discussion, and still looking for the longer thread. 

Fortunately there is a medically supervised fasting program just an hours’ drive from my home.  (USA, California).  I accomplished a 4 day fast at home but was not on any meds.  I may decide to do a longer fast at True North in  Santa Rosa, California. I spoke with Dr Goldhamer by phone who hopes my doc will permit a med vacation during fast. But after the great info (though theoretical) on your post, I’m inclined to do the fast on Dasatinib

Any feedback?  Is anyone else trying fasting on TKI?  I’m sure I could not have done it on Gleevec cause I neede food to take it. But Dasatinib is good on an empty stomach (for me).  I’m getting stoked about this. 

 

Sarah63

Hi Sarah,

I have done two water only fasts now (3 days). I never stopped taking sprycel during these fasts, but then again I only take 20 mg (1/5th normal dose).

I do recommend people consider adding sole water (Himalayan salt) during and fast to keep salt balance in the body as well as magnesium supplement.

I do admit that fasting for me has become an overall health approach and not just to eliminate CML - although for all I know my CML is gone by now (I was PCRU when I started this).

The theory I have is simple:

1. During a water only fast especially after day 3, the body will have consumed many older blood cells especially white cells (including leukemic ones) (Dr. Longo research).

2. WBC count during this time will fall as the body uses these cells for protein spare parts.

3. Upon re-feeding - triggers are released to ramp up blood production especially white blood cells causing stem cells including leukemic ones to come out of quiescence and divide in larger than normal numbers.

4. It is the stem cell division trigger triggered by re-feeding which exposes a leukemic stem cell to TKI's  and is killed. And killed in larger than normal numbers.

5. This reduces CML stem cell population faster than what would otherwise occur (if occur at all).

6. My theory is that if the CML population is reduced enough below a threshold number, normal body immune function will take over and a TKI is no longer needed. One is functionally cured. That's the iidea.

Many unknowns - lots of guessing (educated guessing) - no clinical trials (no money to be made) - just a hunch given the simple idea that prolonged fasting triggers WBC cannibalization (fact) that is then re-populated quickly upon re-feeding which triggers Leukemic stem cell division that is prime for destruction by lurking TKI. My idea could certainly be incorrect. But the harm in trying is low. Fasting has been around a long time.

I have found that apart from the CML part of my experiment, I find fasting and low carb to be a better lifestyle . Good for the heart, and other organs of the body. One bad thing - no dessert. I'm o.k. with that now.

How many people try?

Result?

Imtinib and fast possible?

(Lemon water)

Any side effects....?

I don't think it's possible with Imatinib - you need food with Imatinib to avoid nausea.

However - it may be possible to try a keto diet (fasting mimicking) very low in calories (take Imatinib with 1/2 avocado for example). Unfortunately the only science I am aware is zero calories triggering blood celll harvesting and stem cell division initiation following re-feeding (after day 3).

Scuba I've always eaten with my Imatinib, have no idea if I would have nausea.  I had surgery a year ago and was off Imatinib for a month.  I would like to do the fast.  Does everyone suffer nausea if Imatinib is taken without food? Do you still take your supplements while on the fast?  Vitamin D tested  3 Jan 2019 and is at 16.4   Started taking D and K (per your advice 25 Dec 2018)  New Dr suggested 20k per day vitamin D, started that Jan 15 2019. If I suffer nausea, I'm thinking stopping the Imatinib for 3 days.  What are your thoughts?  

Your vitamin D level is indeed very low. In my research I know of no one who had high vitamin D levels prior to CML diagnosis. In other words, it seems that low vitamin D may very well be a requirement for CML to gain a foothold. My vitamin D level prior to diagnosis was 17 ng/ml - same as yours. I use to get colds and flu all of the time more than once a year (colds). I haven't had a cold or flu since 2013 - since starting my vitamin D protocol.

I would not recommend taking 20k vitamin D per day. It is too much at one time for the body. You can safely raise your vitamin D level (as vitamin D3) by taking 10,000 IU's per day every day for three weeks not to exceed 50,000 per week. (I took 10,000 for five days followed by 5,000 the next two days). After that I took 5,000 one day followed by 10,000 the next day during winter and then only 5,000 per day during summer.* My vitamin D blood level rose steadily to where it is now (60-70 ng/ml). I test twice per year. We're all different so you need to test to verify your levels and dose. Vitamin D is fat soluble so needs to be taken with food that has fat in it. Do not take vitamin D3 on an empty stomach, it won't get absorbed. I do take 200mcg vitamin K2 (aka MK-7, menanquinone) per day and it is also fat soluble.

I do not take vitamin supplements during a fast. But I do take minerals in the form of Sole water (himalayan salt 1/4 teaspoon in a glass of water), magnesium, vitamin C.

(* The medical experts caution against vitamin D doses higher than 1,000-2,000 per day. I do know many people who follow the same dosing schedule I follow and have been following for years now in order to maintain vitamin D levels above 50 ng/ml but less than 100 ng/ml. I have a feeling that over time, the medical literature will start to reflect the need for higher vitamin D intake for immune health. Keep in mind, our bodies will make 10,000 IU's of vitamin D in 30 minutes when our skin is exposed to summer noon time sun - no shirt -shorts

https://www.vitamindcouncil.org/about-vitamin-d/how-do-i-get-the-vitamin...).

Average vitamin D3 level?

Range?

The medical experts caution against vitamin D doses higher than 1,000-2,000 per day. Why 60,000 tablet available? (1 per week)

Any side effects.........

I would never take a 60,000 once per week dose. Too much at one time.

 

Hey Scuba  I just did they 3 day fast.  I did have coffee in am to prevent headache, as I drink coffee every day.  At 22 hrs I kind of struggled with hunger.  Changed what I was doing, had some water and was good.  It actually got easier and could have gone past 72 hrs with no problem.  I followed the protocol for coming off fast but did end up with diarrea.   I lost 5 pounds. For me I've learned that eating is a habit.  I'm going to intermittent fast every week now.  Also every month will include a 3 day fast.  At least that's the plan.  I'm grain free now.  Eat mostly organic and no canned foods.  I still have huge bread cravings.   For that I make Paleo bread (coconut flour, flaxseed meal, and tapioca flour)  Any suggestions to end the bread cravings.  I'm grain free for 2 months. Thank you Ray

 

Hi, I've been following the fasting discussion, its very intriguing. I got approval from my onc to do a doctor supervised fast, provided I continued to take my Dasatinib, which seems to be the whole point of the exercise as laid out by Scuba. 

Coincidentally, I spoke with Dr. Goldhamer at True North and he said that based on my need to continue taking the TKI he would put on a 600 calorie green juice fast. He said doing a water only fast while taking the TKI was not advised / possible. He recommended a two week stay, with 60% of the time fasting and 40% to get back on food. I've decided to ponder this whole thing a while longer before taking action. Any notes from the field much appreciated. 

 

 

   

Hi Riggered.  I followed Scuba's water only.  The coffee was to prevent caffeine headache.  The worst for me was the fast exit.  Internet recommended lemon water first, or apple cider vinegar, then half hr later some fruit, then half an hr later bone broth.  I did apple cider vinegar water, then a kiwi fruit, then 1/2 an avocado was about an hr then I had soup I made, mostly bone broth.  Not sure what happened.  Hope Scuba will have insight on this. After reading this from Scuba I did some research to find disadvantages of a fast, and couldn't find any.  Some people are even advocating longer fasts.  At 72 hrs, I could have gone further. Really hope more people that have tried water only, and others who have done juice fasts chime in here. 

 

 

 

 

Key to a fast is to think like an animal. Our ancestors and the animals don't fast out of choice. They were force to 'fast' because there was no food. This is why fasting is a useful tool because we are evolved to go without food for extended periods of time and still have energy to go hunt.

So I ask you - if an animal was 'starving' for a few days, do you think it slowly decides to eat gradually with varying food types when it finds food? Think about that. It's hungry.

The cheetah after catching its first meal in days will lay into it and eat all it can. But it will eat just what it caught until full which actually won't require much because it's stomach is smaller. And what it eats is mostly protein with a little bit of fat. It eats until it is not hungry.

'Eating' lemon water then vinegar then fruit (i.e. SUGAR) then avocado (i.e. FAT) within a short time is why your system rebelled. Re-feeding after a fast should be normal - as if you discovered food following a hunt. You were mixing sugars and fats together - suddenly. Along with vinegar. Not good. You can do that because you can shop for it in the store. But that is not how our ancestors ate. A good way to "break a fast" is to eat a bit of protein - just protein, all by itself. A piece of chicken , some lean meat, etc. And water. An hour or so later, some veggies (the way animals nibble on grasses after a eating a catch) for roughage. Then back to normal eating later in the day. Fast over.

The craving for 'bread' is caused by carb adaptation. Your body craves carbs - so do animals. But they only get carbs "in season". Humans can get carbs any time. The key is to keep carb intake below 20 grams a day and your cravings will go away. I no longer have any craving for bread. But I routinely enter ketosis to make sure I have a balance of hormones and enzymes (carb burning/ fat burning). Most people only have carb burning hormones and enzymes (insulin is the big one).

(One final note. It's important during a fast to make sure you are getting 'salt' in the form of minerals - K, Ca, Na, Mg .... I drink one - two glasses of Sole water (1/4 teaspoon Himalayan salt in glass of water) every day during a fast. I drink plain water the rest of the time. It helps prevent headaches and it makes sure you get electrolytes so heart rhythm is steady and normal. No headaches as well.)

 

 

Thank you Scuba.  Wish I would have asked instead of internet research on breaking fast.  Do you recommend no caffeine during fast?  Are you easy into ketosis? What process do you use to enter ketosis?  Do you try to enter ketosis before 3 day fast? What are your feelings on a juice fast?  I used to juice frequently and it really seemed to help a swollen prostrate.  

Taking a moment to thank you and everyone on this site.  My education level on CML and alternatives has been incredible.   The expertise on this site is amazing.  Wish my oncologist would read this forum.  When I asked him if imatinib interfered with vitamin D levels, his answer was yours was probably already low.  My vitamin D level in my 70 years was tested for the first time Jan 2, 2019 and my level was 16.4  Testing for vitamin D was turned down by my oncologist and approved through another Dr. I was diagnosed with CML Aug 22, 2016.   Thus my frustrations.  Sorry to vent. Thanks again to all of you and I'll never stop learning about CML and alternatives to it's destruction. 

I drink coffee every day - several cups in the morning. Sometimes an espresso or two after dinner with friends. Fasting is the cessation of calorie intake. Coffee has no calories - so no problem. Juice fasting is not a fast. In fact, juices are loaded with sugar. I would never juice fast if my goal is to get into ketosis.

Ketosis occurs when the body's sugar is depleted - usually after a day or so. Once sugar is burned up through metabolism, the body switches over to ketone body making as an alternative energy supply. So fasting and ketosis are linked. By fasting one will enter ketosis. You will know you are in ketosis by testing with ketone test strips which you can buy at a pharmacy (chemist). When I fast, ketones usually show up a couple of days later if I am not exercising. If you are exercising you will enter ketosis within a day.

Once 'in' ketosis, you can stay there for an extended period by eating food with high fat (avacado, cheese, nuts) and moderate protein (not a lot of protein, just some). You will no longer be hungry and you have nutrition, but no carbs/sugar, so you stay in ketosis. Ketosis only occurs in healthy people when sugar is depleted and carb intake is less than ~20 grams (which is very little). I go in and out of ketosis regularly. But once I am in ketosis I do not get hungry and forget about food which is good.

Ketones are great for the brain and not so good for cancer. Another reason I modified my diet to be more Keto-friendly. I eat carbs for fun once in a while - they are no longer part of my diet. So - no bread, ice cream or pasta for me - EXCEPT when there is a celebration to be had. I do eat lots of veggies which do not seem to affect my ketosis status much.

(diabetics can not enter ketosis lightly. Ketosis can be dangerous for a type - 1 diabetic (i.e. no insulin response) as ketones can build up to dangerous levels. A normal metabolism (non-diabetic) will keep ketones at a safe healthy level)

I really don’t understand they fasting story. How can one fast without stoping  daily medication intake ? 

Medication for CML does not have any significant calories (close to or actually zero). You take your medication throughout a fast on an empty stomach - but only if the medication does not require food.

Fasting is not practical for some people taking Gleevec that require food. Nilotinib (Tasigna), however, is the opposite - you can't take it with food. Food has to be avoided a few hours before or after eating. So Tasigna users can fast easily.

It is possible to achieve a 'fasting like' state by reducing calories and eliminating most if not all carbs:

https://drmowll.com/what-is-the-fasting-mimicking-diet/

In this way, a person can take gleevec with some food that has fat in it (i.e. avocado, cheese, etc.), but a small portion so calories for the day are low and they may get the benefits of fasting (autophagy, metabolic reset). I don't know how much food has to be eaten with gleevec in order to avoid nausea. When I was taking gleevec, I was taking it with oatmeal and oatmeal is loaded with carbs.

(For me - if I eat during a fast - all bets are off, I'm back to eating, so I prefer to just not eat for a day at a time during the month and then a longer fast a few times a year when I go without food for 3 or so days. I'm used to it - even look forward to it. Once you kick the carb addiction, your body functions more smoothly through the day with no hunger (no energy lows around 2:00 p.m.!). Carb eating causes hunger. Ketones provide a steady energy supply so there is no sudden hunger or sudden crash. Our bodies were not evolved to be eating all of the time. Feast or famine was the way. So when food is plentiful (i.e. carbs), the body is designed to store all it can as fat and keep eating. Then when food goes away (including carbs), the body uses the fat for energy maintenance and bits/pieces of protein (i.e. autophagy) to make a little bit of maintenance sugar (protein + glycerol = glucose). It's amazing how little sugar the body needs when ketones are around. My lifestyle is now low carb. I am in mild ketosis most of the time)

 

I tried ( pre-CML ) to remove sugars and Carbs from my diet but headache was a big problem for me, was that ever an issue for you? And how you coped with it?

Absolutely headaches are a problem when cutting carbs - but only once.

You have to get over the sugar/carb to Ketosis hurdle. Chances are you have never been a day without carbs or food. So your "fat" burning machinery is shutdown with not enough fat enzymes available when carbs go low. It's just like exercising for the first time after being idle for a few weeks - it takes a bit of time to adapt.

Fortunately, adapting to low or zero carb intake takes only 24-72 hours. Your body will ramp up fat mobilization enzymes so your liver can produce ketones. Ketones are a substitute for carbs and when they are getting produced in sufficient quantity, your fatigue, headache and hunger goes away. This is a one time occurrence. When you eat carbs again ketones go away. Getting back into ketosis is much easier the second time around because ketone biochemistry is up and running.

I just returned from a trip to the Bahamas with friends and I indulged in every carb invented. It was fantastic. When I returned home, I reverted to my Keto-diet. It took a couple of days for ketones to return, I immediately lost the vacation weight (mostly water) and I felt no carb to keto headache transition - none. That's because I was in keto before the trip and returned to keto within a week coming back. As carbs went low, my body already had ketones replacing the lost energy.

Now to answer your question on what to do during the transition:

1. Drink lots of water including one glass or two per day that has 1/4 teaspoon of himalayan sea salt. The salt will help balance the cation chemistry in your blood (produces headaches when out of whack) as your body transitions to keto.

2. Take magnesium supplements (citrate or taurate based) - 200-400 mg which will also help with the headaches.

3. See Number one above.

Completely avoiding headache is tough because there will always be a gap between lost sugar and ketone ramp up the first time. That gap has to be bridged - it can be as short as only a few hours to a day or so. Once bridged, it won't happen again.

https://www.myketokitchen.com/keto-resources/keto-flu/

Thank you for taking the time, and sharing your own experience, i will start right away, i am having my BCR Abl check again soon and i need to see an improvement from 11% and i hope all these techniques help with that.

 Thank you 

Recently I discovered my platelets has been increasing . From March last year till date it has gone up from 125,000-558,000 and my BCR-ABL is also increasing. I have been on glivec for 5 years now . I was on remission 0.0001 but now it’s gradually going up 6.5.  Am worried . I did another Bcr abl test 2 days ago waiting for the result to see the difference. Please I want to if it’s possible that I will get back to remission . 

 

Scuba, thanks for taking the time to post all the information about the benefits of fasting.  I’ve been reading of the various benefits of ketosis but was not aware of the benefits it may cause to leukaemia cells.  

Hello Mr. Scuba, I am on Imanatib would fasting prevent Imanatib from working. I have reached a plateau. I have been at .01% for almost a year. My doctor had informed me that he may switch or increase meds. I would definitely like to try fast but am not sure if it would prevent Imanatib from being absorbed properly. Thank you for this theead.

Unfortunately, imatinib often causes nausea and upset stomach. Fasting would not prevent imatinib from working (or any other TKI), but keeping imatinib "down" would likely be a problem.

Switching to a low dose dasatnib (20 - 40 mg) in your case should be considered. Then you can try fasting without any issue. I always take my dasatnib on an empty stomach before retiring for the night.

I've taken imatanib while fasting in a meditation centre. Its not that pleasant but its doable and my nausea passed in about 30 mins, it was helpful to be lying down and ready to sleep after taking the dose.

Hey Scuba!

I'm relatively new to this forum but already I've learned so much from your experiences! Thank you in advance!! I was diagnosed last year and immediately started exploring different diet/fasting options to combat the disease. 

What would be your recommendations for me for a fasting routine? What kind of fasting should I be "working up" to (e.g. 3-day, 5-day?)?

I've been doing intermittent fasting almost daily with OMAD's (one meal a day) about twice a week. Recently I did a 42hr fast but that has been my maximum so far. I'm on Dasatinib

I really hope I tap on your extensive knowledge and experience to come up with a fasting protocol I can follow long-term to fight my CML. Would highly appreciate any help whatsoever!!

 

Cheers, Deon

I typically fast one day a week.

If you have never fasted before - best to try one day first and then work up to two days and then 3 days. Maximum stem cell regeneration benefit is seen after 3 days according to Dr. Longo (USC).

To avoid fasting side effects - make sure to drink plenty of water (including added Himalayan salt at 1/4 teaspoon per glass) and be patient. You will feel fatigue and hunger the first day or so. After that, it gets much easier.

Hey Suba,

 

Driving down to Houston next Monday for my bloodwork at MD Anderson.  Not wanting to fast this close to my bloodwork.  I am interested in trying a 3 day fasting but the stress on a female body is suppose to be a bit rougher.    Do you only do water and how did you do your first try?  Is there something I can eat/take that might pull me through a rough patch?  I am planning on continuing my vitamins during this.  

 

Steff

No need to answer.  I saw after I posted your responses to others.  Ty

No need to answer.  I saw after I posted your responses to others.  Ty

No need to answer.  I saw after I posted your responses to others.  Ty

In your opinion, is there an "optimal" fast that one would try to achieve? I'm quite comfortable with 24hr fasts but I'm wondering is this enough to induce effective autophagy and stem cell regeneration for long-term. My ultimate goal is also to lower the level of LSC's such that I can be taken off the medication

 

Thanks! Deon

24 hour fasts are not sufficient. You must be in ketosis in order for stem cell based autophagy to kick in. According to Dr. Longo, it takes 3 days of fasting for stem cell based immune system regeneration to occur. And multiple cycle are required.