Seasonal Variability - Hadza Example

[Russ]

Brief but fascinating Facebook post by Nassim Taleb (Anti-Fragile) today re the math behind the importance of variability in reversing diabetes...

Mechanisms that are First-In/First-Out (FIFO) (path independent) do not like variability and volatility (i.e., Jensen's Inequality/Antifragility) as much as ones that are Last-In/First-Out (LIFO) (hence path dependent).
Take diabetes. We are discovering that diabetes is not (as we thought) the result of being overweight, rather the effect of absence of variation, not losing weight, not having periods of starvation (that among other things, clean up the fat deposit in the pancreas that is LIFO). So someone overweight who loses weight can be much better-off than the same person a bit thinner at stable weight.
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There is plenty of research in diabetes hinting at this from many sides but nobody tried to put a systematic mathematical apparatus on it. Though the math is not trivial (because of path dependence), I was able to play with it with Monte Carlo analyses.
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Note that the Russians have known that for over a century.
http://www.ncl.ac.uk/magres/research/di ... versal.htm
See also (easier read)
http://www.dailymail.co.uk/health/artic ... -diet.html
Reversing Type 2 Diabetes - Newcastle Magnetic Resonance Centre - Newcastle University
Our work has shown that type 2 diabetes is not inevitably progressive and life-long. We have demonstrated that in people who have had type 2 diabetes for 4 years or less, major weight loss returns insulin secretion to normal.
NCL.AC.UK
http://www.ncl.ac.uk/magres/research/di ... versal.htm

Seems like an even stronger argument for 'mix it up from time to time' for everyone, and wholly conjecture, but I wonder if this is doubly true for us E4's?

[ApropoE4]

Had we been on speaking terms, I would ask Taleb to produce the code, or at least the model and assumptions underlying his monte-carlo analysis of diabetes prevention, but we haven't been on speaking terms for over 10 years now.

[Russ]

Another hat-tip to Taleb for referencing this new paper on variability/fasting....

http://www.sciencerecorder.com/news/201 ... ast-month/

From the referenced USC release story, a potentially important twist for us...?

In a new study, Longo and his colleagues show that cycles of a four-day low-calorie diet that mimics fasting (FMD) cut visceral belly fat and elevated the number of progenitor and stem cells in several organs of old mice — including the brain, where it boosted neural regeneration and improved learning and memory.

Note that a they documented the benefits were NOT due to caloric restriction.

More evidence that mixing things up may be good for everyone, but especially for us where our 'thrifty' allele may actually be an advantage?

[Russ]

Here is a link to the full paper and Summary...

Summary
Prolonged fasting (PF) promotes stress resis- tance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regenera- tion. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/bio- markers for aging, diabetes, cardiovascular dis- ease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.

http://www.cell.com/cell-metabolism/pdf ... 0224-7.pdf

...and this section on adult neurogenesis...

Adult neurogenesis plays an important role in learning and memory (Clelland et al., 2009; Deng et al., 2010; Mattson, 2012). To determine whether the diet affected neurogenesis, we measured BrdU incorporation in the subgranular layer of control mice at the age of 8 weeks, 12 weeks, 6 months, and 24 months (Figure 4B). Similarly to previously reported data, we observed an age-dependent decline in BrdU incorporation in the dentate gyrus (Lee et al., 2012c) (Figure 4B). To assess whether the cognitive improvements in the FMD group are asso- ciated with neural regeneration, we measured the proliferative index of DCX+ immature neurons in the sub-granular cell layer of the dentate gy- rus. BrdU+ or BrdU+ DCX+ double-label- ing indicated an increased proliferation of immature neurons in the FMD group compared to that in controls (Figures 4C–4E). To investigate mechanisms of FMD-induced neurogenesis, we fed 6-month-old mice, in which cellular prolif-
eration in the dentate gyrus is reduced by more than 50% compared to that in 8-week-old mice (Figure 4B), with a single cycle of the FMD. After 72 hr on the FMD, we observed a reduc- tion in circulating (Figure S1E) and hippocampal IGF-1 (Figure 4F) but increased IGF-1 receptor mRNA expression in the dentate gyrus region of the hippocampal formation (Figure 4G). Micro- dissected dentate gyrus-enriched samples from FMD mice displayed a major reduction in PKA activity (Figure 4H) and a 2-fold induction in the expression of NeuroD1 (Figure 4I), a tran- scription factor important for neuronal protection and differenti- ation (Gao et al., 2009). Similarly, a single cycle of the FMD increased radial glia-like cells (type I) and non-radial precursor (type II) neural stem cells (Figures S4B, S4C, S4F, and S4G), immature neurons (Figures S4D and S4I–S4Q), and the dendrite-covered area (Figures S4E and S4H) in CD-1 mice.

These results in two genetic backgrounds indicate that the FMD promotes neurogenesis in adult mice. Notably, the brain did not undergo a measurable weight reduction during the FMD, indicating that regeneration can also occur independently of the organ size increase after refeeding. Thus, we hypothesize that alterations in circulating factors, such as the reduction in IGF-1 levels and PKA signaling, can induce pro-regenerative changes that are both dependent and independent of the major cell proliferation that occurs during re-feeding, in agreement with our previous finding in bone marrow and blood cells (Cheng et al., 2014). Most likely, the increase in IGF-1 and PKA after re- feeding also contributes to the proliferative and regenerative process, raising the possibility that both low and high levels of these proteins can promote regeneration depending on the timing of their expression. Alternatively, the FMD may increase survival of newly differentiated neurons, as observed in the den- tate gyrus of alternate day-fed rodents (Lee et al., 2002; Mattson et al., 2001). The observed improvements in cognitive perfor- mance in the FMD cohort might be affected by a PKA/CREB- dependent regulation of NeuroD1 (Cho et al., 2012; Sharma et al., 1999), which is known to increase neuronal survival and differentiation of hippocampal progenitors (Roybon et al., 2009), enhance functional integration of new neurons, and alle- viate memory deficits in a mouse model of Alzheimer’s disease (Richetin et al., 2015).

Note that the fasting phase diet was pretty low protein, high fat, and moderate carbs....and also "plant-based"...

The develop- ment of the human diet took into account feasibility (e.g., high adherence to the dietary protocol) and therefore was designed to last 5 days every month and to provide between 34% and 54% of the normal caloric intake with a composition of at least 9%–10% proteins, 34%–47% carbohydrates, and 44%–56% fat.

Human Diet
The human fasting mimicking diet (FMD) program is a plant-based diet program designed to attain fasting-like effects while providing micronutrient nourishment (vitamins, minerals, etc.) and minimize the burden of fasting. It comprises proprietary vegetable-based soups, energy bars, energy drinks, chip snacks, chamomile flower tea, and a vegetable supplement formula tablet (Table S4). The human FMD diet consists of a 5 day regimen: day 1 of the diet supplies $1,090 kcal (10% protein, 56% fat, 34% carbohydrate), days 2–5 are identical in formulation and provide 725 kcal (9% protein, 44% fat, 47% carbohydrate).

Direct link to Supplementary Materials...
http://www.cell.com/cms/attachment/2033 ... 4/mmc1.pdf

[Stavia]

Very interesting. Does anyone do this?

Oy - my baseline cals is 1200. What would my FMD be....
And chip snacks??? Energy bars? I'm sure we could do better.

[RichardS]

Just a reminder about potential conflicts from the two of the authors studying diets including "medical food"...

"CONFLICT OF INTEREST
V.D.L. and T.E.M. have equity interest in L-Nutra, a company that develops
medical food. 100% of the L-Nutra equity belonging to V.D.L. will be donated
to non-profit organizations. Neither author had any role in data analysis."

Also, the description of the human diet in the study is skimpy. I don't see a viable way to replicate it based on the what little information was provided.

[Julie G]

Interesting to note that the diet many of us have settled on is similarly heavily plant-based, HYPOcaloric, low protein, high fat, and moderate carbs BUT this human FMD diet is a five day protocol practiced intermittently. That variability might be key- props to Russ

[circular]

Stavia I dream of a whole food "energy" or "snack" bar that meets our requirements, and my food restrictions, that I can have on the go (Not to be eaten for every meal of course.) In the explosion of meal bars at the stores I haven't found one for me but I keep looking …

[Tincup]

Very interesting. Does anyone do this?

At the end of our Cali trip (which extended for a week after the Meetup), my fasting blood sugar had crept up. Additionally, I had some bloods done and my fasting insulin had increased to 8. Following the Newcastle approach which Russ linked https://www.apoe4.info/forums/posting.p ... 22#pr14798 I went to eating once a day eating about 1,000 calories/day 60 g carbs of which 30 are fiber (still a big Walhs/Gundry salad), 50 g of protein from eggs & shrimp and the rest from EVOO & avocados. Took a few days, but my fasting sugars dropped into the 70's and my ketones are around 3 mmol/L. This is a very low calorie diet for me. I still paying a lot of attention to feeding my mitochondria and microbiome.

In this newsletter, the author talks about the Newcastle approach and tries it himself. However the only thing in common is the 800 calories/day. He does not use their 600 calorie meal replacement shake plus 200 calories of non-starchy veggies. I designed my diet to be as nutritious as possible (see Cronometer screenshots below) & continued my supplements. http://www.yourhealthbase.com/archives/ihn252.pdf http://www.yourhealthbase.com/archives/ihn251.pdf http://www.yourhealthbase.com/archives/ihn250.pdf

From what I can see, the key is reducing liver fat, which is the issue with IR and T2 diabetes.

In my case, my first day was 750 calories, then went to 1000, as I thought the 750 was a bit light for me and my activity level. Did that for a week. I likely started out fully glycogen saturated as started the day after my birthday. In 7 days, went from 175# (I'm 6'0") to 163.5#. I'm guessing 5#s was water weight from the glycogen depletion. Anyway after 8 days, continued eating once a day, but added in some more calories, primarily from nuts - macadamia and hazelnut. Didn't want to drop too much more weight, at least quickly. Those who've met me in person know I don't need to loose a lot of weight.

I should also note that in California, I was on the up side of the caloric intake variability. Primarily through buckets of nuts.

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[Russ]

Richard, Thanks for pointing out the potential conflict. Indeed looks exactly like the guy is trying to develop a business for a 5 Days per Month shake-based diet. I also agree it brings things further into question as there isn't enough info to replicate in the paper.

Of course, if the experiments do hold up, I assume it should be easy to achieve the same or better effects with real food, and am guessing that ideal implementation of same principles wouldn't follow such a rigorous schedule. Given all we think we know, I do find it quite plausible that a episodic lower-calorie, higher-fat plants only diet could actually make sense for several days to a week several times per year?