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Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Alzheimer's, cardiovascular, and other chronic diseases; biomarkers, lifestyle, supplements, drugs, and health care.
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TheresaB
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Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby TheresaB » Sat Feb 04, 2017 10:25 am

Dr Dale Bredesen emphasizes exercise in his protocol to reduce, even reverse, hippocampal atrophy in the brain; to increase BDNF (Brain Derived Neurotrophic Factor); and to work hand in hand with diet and fasting to create ketones to fuel the brain.

Now I’m just an ApoE4/4 layperson (no medical or scientific background) trying to make sense of EVERYTHING to live a healthful life in both mind and body. I’ve often wondered what is the best exercise “formula.” I’ve specifically pondered the role, if any, of strength training. I’ve heard that body builders have a high IGF-1 which is contrary to longevity. What I was unsure about was if the high IGF-1 was the result of gym time, or if body builders induce a high IGF-1 through diet to develop muscle growth. Adding to my confusion was Dr Steven Gundry’s comment during his Ancestral Health Symposium presentation (August 2016) in addressing the lab results of a particular patient by saying, “that the last thing ApoE4s should be doing is Cross Fit.”

Dr Gundry prides himself in aiding the longevity of his patients, particularly his ApoE4s. When we consulted with him, he made a point of telling us of two 4/4s, one 85, the other 86, and three 3/4s at 90, 91 and 93, all of whom are thriving, active, and “bright eyed and bushy tailed.” Toward the goal of longevity, one of the things Dr Gundry emphasizes is a low IGF-1 (insulin like growth factor). He’s told us IGF-1 is a marker for how well a person is aging, saying that super old people who are aging well in their late 90s/early 100s usually run an Insulin Like Growth Factor around 70. He also stresses keeping mTOR turned off. There is no way to measure mTOR directly, but IGF-1 seems to be a good proxy.

I now feel the culprit is the diet that the body builders follow to induce muscle growth that results in high IGF-1. Dr Gundry had previously told us IGF-1 is raised through sugars and animal protein. It can be also lowered to a certain extent with calorie restriction and intermittent fasting, but Dr Gundry mostly emphasizes lowering animal protein to bring IGF-1 down.

In my first consult with Dr Gundry, May ’15, my IGF-1 was 129, and I was following a vegan diet (no animal protein) at the time! After incorporating intermittent fasting and following his diet which reduced my carbs/sugars, added good fats, and is nearly vegan with some, albeit low and only certain kinds of animal protein, my IGF-1 went down to 75 in Jun ’16. :D But then I started a strength training program and my IGF-1 went “up” to 79 in Jan ’17. What I didn’t know was this the result of adding strength training? the “holiday cheats?” or merely a reflection of everyday “noise?” :?

Dr Gundry had also previously told us that the all the literature is very, very clear, that the amino acids in animal protein absolutely turn on mTOR and you want to keep it turned off. There’s a direct association of mTOR to cancer. According to Wikipedia, “Over-activation of mTOR signaling significantly contributes to the initiation and development of tumors and mTOR activity was found to be deregulated in many types of cancer including breast, prostate, lung, melanoma, bladder, brain, and renal carcinomas.”

Of additional interest to us ApoE4s, Wikipedia also says, “mTOR signaling intersects with Alzheimer’s disease (AD) pathology in several aspects, suggesting its potential role as a contributor to disease progression.”

So during our recent consult, concerned about my recently adopted strength training program, I asked Dr Gundry about his comment that the last thing ApoE4s should be doing is cross-fit. He confirmed the indictment is on cross-fit, not on strength exercise in general. He told us that as ApoE4s, we have to be mindful that we have the potential to develop small vessel disease because our cholesterol is more “active” and small blood vessels occur in the brain, and in the heart, and elsewhere. He doesn’t view cross-fit as a strength training program, he views it as trying to damage your heart as much as you can. :lol: He told us almost every patient of his who is a big time cross-fitter has positive Cardiac Troponin-I elevation which is a test that is hundred times more sensitive than the test used in an emergency room looking for heart attacks. When his cross-fit patients back off, their Cardiac Triponons go back to normal. Not just cross-fit, he says he also sees this in marathoners and in a patient of his who is an avid hiker.

I’d been going to a coach-supervised class (meaning I couldn’t wimp out) following progressively harder strength work-out routines for four months prior to my last lab test, yet my Cardiac Troponin-I was the lowest it’s ever been at a very good level of <.4. The range is listed from 0.0 to 2.7. So exercise is good, just not too much/too hard, especially for ApoE4s. I now attribute my bump in IGF-1 to my holiday “cheats.” (Rats! Those blood tests won't let you get away with anything!) :oops:

Although it is aimed at cancer, this article, “Muscles Fight Cancer – The Science behind Outmuscling Cancer” http://colinchamp.com/muscles-fight-cancer/ has helped me put some of the pieces together. I now understand some of the science behind why strength training is good for us ApoE4s. It specifically discusses how muscles fight cancer and addresses the relationship between exercise and IGF-1/mTOR. As suggested above by Wikipedia, mTOR also contributes to AD progression, so I felt it relevant to present here.

To highlight from the article:

    Resistance training increases IGFBP-3, which binds to insulin-like growth factor (IGF), decreasing its ability to promote cancer (growth factors are normal within the human body, but too many can lead to excessive cellular growth, including cancer growth)

    The body holds a balance between TNF (tumor necrosis factor) and IL-6. Fat tissue secretes the pro-inflammatory cytokine TNF-alpha. Muscles secrete IL-6 which fights inflammation. The article says “inflammation is the fertilizer of cancer cells.”

Having heard Dr Bredesen speak many times, my non-scientific mind says inflammation is also an AD “fertilizer.”

    AMPK (AMP-activated protein kinase) is an enzyme extensively expressed in our muscles, liver and brain. (my emphasis) It serves as an energy sensor and regulator. AMPK signals to our body and cells that it is not a time for building, but rather for breaking down. AMPK is the antithesis of cancer.

    Muscle-derived IL-6 helps regulate AMPK (while muscle contraction directly activates AMPK), which stimulates the breakdown of fat and cholesterol, stimulates our mitochondria,and potentially fights cancer.
I’ve also heard Dr Bredesen emphasize optimizing mitochondrial function. Mitochondria are the small subunits within cells that manage the energy supply for that cell— if they stop working well, this leads to early death of brain cells, causing shrinking of the brain, so stimulating mitochondria sounds like a good thing to me.

    AMPK blocks mTOR. mTOR is the same pathway that is blocked with targeted cancer drugs.

    The article also introduces the Warburg hypothesis. Warburg showed that regardless of the presence of oxygen, cancer cells prefer to use glucose for energy. In normal cells, preference is given to the mitochondria for energy production. Newer data shows that AMPK blocks the Warburg Effect by blocking the ability of cancer cells to use sugar for energy.

    AMPK is upregulated via several mechanisms (in no apparent order):
    • Muscle contraction during exercise with the more intense exercise resulting in increased expression of AMPK
    • Carbohydrate restriction (with or without fasting and even in the face of an increase in calories)
    • Intermittent fasting

I hope I haven’t rambled too much.
-Theresa
ApoE 4/4

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Stavia
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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby Stavia » Sat Feb 04, 2017 10:49 am

Theresa this is brilliant. Thank you so much. I am referencing it in the primer.

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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby TheresaB » Sat Feb 04, 2017 11:13 am

Thank you Stavia, I'm honored. :oops:
-Theresa
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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby MarcR » Sat Feb 04, 2017 12:02 pm

Love this post, Theresa - thank you!

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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby Julie G » Sat Feb 04, 2017 12:35 pm

+1

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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby Jafa » Sat Feb 04, 2017 2:40 pm

Thank you Theresa, I really appreciate you taking the time to share this informative article and your experience of participating in Dr Gundry's programme.

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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby Lucy5 » Sat Feb 04, 2017 3:53 pm

This is an amazing resource, Theresa. Thank you!!

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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby Starfish77 » Sat Feb 04, 2017 4:41 pm

TheresaB,
Thank you for making such an excellent explanation of some things I couldn't understand too well before.
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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby apod » Sat Feb 04, 2017 5:43 pm

In a recent Bulletproof interview with Oz Garcia, Dave Asprey mentioned Coffee as an interesting MTOR suppressant.
https://www.youtube.com/watch?v=n8K7M9fCWjg#t=27m30s

Apparently, you can stack all of these things together for a pretty awesome spring loaded MTOR spike.
Image
Suppversity has had some good articles on it:
http://suppversity.blogspot.com/search?q=AMPK

"Exercise, contrary to dieting or overeating, appears to have the unique quality of driving both at the same time - fat loss and protein synthesis, AMPK and mTOR. This works, and this is going to be the main message of this concise piece of the Intermittent Thoughts series, because the exercise induced muscular(!) AMPK-response differs from the one your brain and many other organs will exhibit, when you starve yourself during a diet. Actually we have been knowing for quite some time that the predominant isoform of AMPK that is expressed during exercise is AMPK-alpha2. Back in 2000, already, Wojtaszewski et al. found that "high" (in this case >70% of the individual VO2max) intensity exercise for 60min selectively increased AMPK-alpha2 activity almost threefold (Wojtaszewski 2011). Similar to the results of previously discussed studies, the increased AMPK levels returned to baseline within 3h after exercise-cessation.

Only the increased expression of the alpha1 isoform of AMPK, but not AMPK-alpha2 does impair mTOR signalling. Against that background, the systemic antagonism of AMPK-alpha1 (expressed in liver, brain, and other organs) and mTORc1 mediated protein synthesis stands in stark contrast to the metabolically highly beneficial synergism of concomittant exercise-induced AMPK-alpha2 and mTORc1 expression.

To make a long story short: Exercise is unique in its ability to help you shed fat and build muscle "at the same time", because it activates a specific isoform of the "starvation sensor" AMPK, which does not block the concomitant increase in protein synthesis subsequent to the (likewise) exercise-induced increase in mTOR phosphorylation."


http://suppversity.blogspot.com/2011/09 ... nt_25.html

"What's good for the obese is rarely good for athletes."
"A chronic overexpression of AMPK and consequent catabolism of metabolically active tissue (muscle and organ tissue) is unquestionable as undesirable as the fattening, cancer-promoting and life-shortening effects of chronic activation of the mammalian target of rapamycin (mTOR)."

I can never quite make up my mind whether to optimize my diet more for strength, body composition, and athletic performance (none of which I really "need" in my day to day life) via more BCAAs & Protein, Carbs, and Calories, or to optimize more for theoretical gains in ideal gene expression via less BCAAs & Protein, less Carbs, and fewer Calories, or to cycle between the two (on a weekly or seasonal basis), or stay at a moderate level in the middle. There's also the slight optimization between cardiovascular / cognitive health via more dietary cholesterol and saturated fat & MCTs or less. Right now, I'm back on the Low-BCAA, lower-animal protein, low-SFA, low-carb, Gundry-protocol. Tricky! :geek:

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Re: Exercise, muscles, mTOR, IGF-1, brain health, and cancer

Postby SusanJ » Sat Feb 04, 2017 6:02 pm

Teresa, thanks for pulling these pieces together.

Just a quick note on IL-6 being anti-inflammatory. Looking at the article and some quick references, it's produced by working muscles and involved in local signaling to rebuild muscle.

So, IL-6 is pleiotropic but it is principally defined as pro-inflammatory. You definitely don't want high systemic IL-6 levels. Bredesen tests for IL-6 along with TNF-alpha for systemic inflammation. Just don't want folks to think if their IL-6 tests are high, it's a good thing.

High systemic IL-6 amounts are not good:
Early after stimulation by antigen and APC, the Th cells begin to produce IL-2 and are designated Th0. As the Th cells continue to respond to the activating signal, they progress towards polar extremes of differentiation designated Th1, Th2, and Th17 depending on the nature of the cytokines present at the site of activation.54 IL-12 produced by macrophages or NK cells induces differentiation towards Th1, IL-4 produced by NK1.1+ T cells, basophils, or mast cells induces differentiation towards Th2 and TGFβ and IL-6 produced by yet to be defined cells induce differentiation towards Th17...
Th17 cells are induced early in the adaptive response to extracellular bacteria and help to recruit the neutrophil response that eliminates these pathogens. They also direct the destructive inflammatory responses that are part of many autoimmune diseases.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923430/

After adjustment for potential confounders, having a high interleukin-6 level (> 2.0 ng/L) twice over the 5-year exposure period nearly halved the odds of successful aging at the 10-year follow-up (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.38–0.74) and increased the risk of future cardiovascular events (OR 1.64, 95% CI 1.15–2.33) and noncardiovascular death (OR 2.43, 95% CI 1.58–3.80).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826354/


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