Designing an E4 Fasting trial...

[Julie G]

I'd like to get researchers interested in studying how fasting affects the ε4 variant of apolipoprotein in humans. Help me design a trial. Obviously, there are an infinite number of directions this could take.

I'll throw out one idea that skips over the obvious; fasting vs. non-fasting, which probably should be our starting point. I strongly suspect that E4s who fast will yield superior results so I'm more interested in the specifics of HOW to best fast. Drs. Longo and Mattson (i think!) have both proposed that fasting is best done in the context of a LFHC diet based on their work with animal models and epidemiological longevity observations; Okinawnan's etc. It's worth noting that E4 carriers are dramatically under-represented in centenarians using this dietary approach. In other words, it seems to work well for other APOE genotypes, but not our population. I suspect that a LF approach will make BHB production (to offset our reduced cerebral glucose utilization) less efficient. I also suspect that it will be more difficult for subjects to adhere to long fasts on a LF diet.

I'd like to have a dataset of all healthy ε4's (equal number of men, women, heterozygotes & homozygotes) half on LF (<30% of calories) half on HF (>70% of calories) using a 16 hour fast, eating ad libitum during their 8 hour feeding window. The endpoints could be glycemic markers, standard & advanced lipids, IGF1, inflammatory markers, BHB levels, BMI, BP, cognitive testing. Both would receive optimal nutrition, eating plentiful vegetables/adequate protein, and participate in daily exercise. Just one idea . Share yours.

[KatieS]

When you state LF, most of us only strive to keep low saturated fat, less than 10% of calories., but the rest of the diet is higher than 30 % fat.

[apod]

Are you thinking more in terms of looking at IF via 16-20h/d between dinner & breakfast, or something more like a weekly 36h fast or multi-day fast / FMD? It seems like you would need to control for energy balance, as the fasting group would likely experience some level of CR as compared with the control group. A non-CR'd fasting group vs a CR'd non-fasting group vs a control would be an interesting 3 groups.

http://wefa.st has an interesting "Monk Fast" protocol

http://www.dailymail.co.uk/news/article ... mance.html

This was an interesting recent study on IF via breakfast-skipping vs dinner skipping:
Impact of breakfast skipping compared with dinner skipping on regulation of energy balance and metabolic risk (2017):
https://www.ncbi.nlm.nih.gov/pubmed/28490511

"When compared with the 3-meal control, 24-h energy expenditure was higher on both skipping days, whereas fat oxidation increased on the breakfast skipping day only. The postprandial homeostasis model assessment index and glucose concentrations after lunch were, however, higher on the breakfast skipping day. Concomitantly, a longer fasting period with breakfast skipping also increased the inflammatory potential of peripheral blood cells after lunch. Conclusions: Compared with 3 meals/d, meal skipping increased energy expenditure. In contrast, higher postprandial insulin concentrations and increased fat oxidation with breakfast skipping suggest the development of metabolic inflexibility in response to prolonged fasting that may in the long term lead to low-grade inflammation and impaired glucose homeostasis."

(Although, I would wager if you compared the sleep differences between the guys eating dinner vs. those skipping dinner, you would see worse sleep in the dinner skippers.)

[Julie G]

Good point, Katie. My understanding, and I can't find the specific paper where I read it , is that they propose IF within the context of overall low dietary fat based on animal and observational human longevity studies. I think it'd be interesting to examine that within an all E4 dataset given our reduced cerebral glucose utilization issues.

[Julie G]

Definitely endless possibilities, apod! I was thinking of a 16 hour (or even longer) fasting period least 3 hours before bed till sometime after lunch. I struggle with controlling for energy balance, but on retrospect think it would be necessary to validate the effects of either approach and control for a caloric restriction effect.

[SusanJ]

Julie, I like your outline. I'd add a hormone panel, before and after. Lower BMI seems to come with some hormonal hits for me and I'd guess others, too.

[Gilgamesh]

Great initiative, Julie! I have little to add beyond the already noted excellent ideas. Just a quick thumbs up to apod's point here:

(Although, I would wager if you compared the sleep differences between the guys eating dinner vs. those skipping dinner, you would see worse sleep in the dinner skippers.)

Some may not experience sleep difficulties, of course, but I do, when going to bed on a non-fullish stomach. So I'm stuck between Scylla and Charybdis on this matter: the disadvantages of a full belly at bedtime (less problematic when low-carb, I'd venture) vs. the disadvantages of bad sleep.

Very cool study, by the way. Previous data I'd seen on breakfast-skipping was not based on actual studies, so couldn't control well for confounding factors such as unhealthier, stressed-out people having a higher tendency to skip breakfast.

G

[Greenie]

Several of Dr. Longo's studies involved 3 day fasting to promote autophagy and the clean-up of cellular debris. It seems that this metabolic waste is what is especially dangerous in Apoe4. The longer fast is particularly important in triggering the body to destroy inefficient white blood cells and reset the immune system. It might be easier to show quicker results using a longer fasting period.


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[Tincup]

Hi Julie,

I've been playing with Longo's research.

From what I can see their "Ah Ha" moment was fasting (3-4 day) & refeeding (till they regained their weight) cancer model mice while giving them chemo. After the 6th or 7th cycle, they noticed the white blood cell count and quality was like that of a young mouse. So the idea that fasting upregulates autophagy, apoptosis & mitosis. Many of the body organs & immune systems shrink. When refeeding occurs stem cells activate and rebuild the shrunken organs and immune system - like new. So that some of the parts of the immune system that were autoimmune get destroyed and recreated without the autoimmune component. I think this is amazing.

I've been playing with this, not knowing what results I'd see. Since I eat 1x/day (22:2 IF), if I skip eating for four days, it turns into a 120 hour (5 day fast). I then chose a 10 day refeeding period. On my refeed, I'm eating somewhat more protein and animal protein than Gundry recommends - trying to trigger the TOR & IGF-1 pathways into their rebuild mode, also more of the carby resistant starches. Otherwise I'm eating our normal Gundry program, which is high fat, but low sat fat (and even lower now as I traded out olive oil for perilla, macadamia nut & avocado oil for the time being for chylomicron & LPS reasons). These pathways are obviously downregulated during the 120 hour fast. Longo calls these modes different "programs." Program A (fasting, protecting cells, upregulating apoptosis & etc), Program B - growth & reproduction.

So far I've had two fasting cycles and am 10 meals into the second refeed (start the 3rd fasting cycle tomorrow). I plan on continuing for at least 8 cycles. I winged it picking the length of fasts & refeeds. In his MS study on humans, they used a 7 day fast and are talking about one fast every two months. What I've noticed is my lifelong nasal congestion has improved dramatically. Going Matrix helped, but this is much better. Not sure how I'll test other things.

As to activity, I found I could ski my normal 34k' vertical off piste on day two (starting 40 hours fasted) of a fast. Day 5 I was not as spiffy. I could still do it, but my volume was less and I could tell I lacked energy. On the other hand, skiing was normal the day after one meal of refeed. Of course I'm well keto-adapted. On day five of my first fasting cycle, my serum ketones were at 6.7 mmol/L, breath ketones were about 70 and urine ketones at 80 mg/dL. Also blood sugar drops into the 50's.

Longo TEDx - good intro.
Longo - Rhonda Patrick - more details
Longo patents a lot of the data from studies behind paywalls are in the patents
More of his papers from the Prolon FMD food site

Longo decided to do the fasting mimicking diet (FMD) because it took years to get 18 subjects to fast with doctor's approval in the fasting/cancer chemo study. Thought this would be easier. All the details of the FMD are in the patents.

Gundry has a FMD diet plan that approximates Longo's, from real food, in his second book. As usual, I want a stronger signal so am just water fasting.

As to how these pathways play out in lower creatures. These Rhonda Patrick interviews with two scientists from the Buck are interesting Judith Campisi, Gordon Lithgow

While I think IF is powerful. I think that multiple cycles of many day fasting/refeeding with regeneration of systems from stem cells is much more powerful.

Can provide more links or PM papers to those who are interested.

[Julie G]

George, I'm beyond impressed with your experimentation. I'm s-l-o-w-l-y moving in a similar direction. I'm convinced that longer fasts have tremendous healing properties. You're helping me to understand the importance of the re-feeding period.

Otherwise I'm eating our normal Gundry program, which is high fat, but low sat fat (and even lower now as I traded out olive oil for perilla, macadamia nut & avocado oil for the time being for chylomicron & LPS reasons).

You suspect that the saturated fat in EVOO has lead to elevated LPS and chylomicrons? Interesting. Out of curiosity, how are your thyroid markers?

FWIW, I slightly mischaracterized Dr. Mattson's preferred macronutrient ratios in my first post above. He uses the term LPHC (low protein high carb.) You can read more in this paper:

Nutritional strategies to optimise cognitive function in the aging brain
https://www.ncbi.nlm.nih.gov/pubmed/27355990