Early impressions, initial reactions

[Stavia]

Okies about to walk to the gate.
<waves>

[Stavia]

20160501_150425.jpg

This is the size meal Im talking about. Its my dinner for the plane trip.

[Julie G]

I appreciate your feedback, Dan. You're smart and have a good handle on the science. I had a few additional thoughts... Our reduced cerebral glucose utilization occurs in a dose dependent manner with homozygotes being more severely affected. Insulin resistance (IR) worsens this phenomenon as does menopause, and to a lesser degree, andropause. For women, estrogen helps to shuttle glucose to the brain. When levels drop off precipitously, some women experience very severe symptoms including cognitive decline. Men experience a similar phenomenon that (hasn't been as well teased out) and may have to do with the fact that IR tends to set in around this same time.

As a heterozygote, who's avoided IR, and may be supplementing with testosterone; you might have inadvertently avoided some of these risk factors- lucky you . Others, like Stavia (and myself,) who are both post-menopausal, homozygotes, and healing from various degrees of IR may need to apply different strategies or different levels of strategies than you need. We are all snowflakes with different risk levels for different diseases (primarily dementias and heart disease) and will subsequently need different strategies.

FWIW, many here have challenged the assumption that a higher fat diet (ketone production!) automatically leads to higher lipids. We have many members who eat a mildly ketogenic diet and regularly yield excellent LDL-Ps. My macros are around 65%-F, 15%-P, 20%-C and my last LDL-P was 889. Minimizing SFA, eating heaps of veggies, exercising, and practicing either IF and/or CR have been helpful to many and have lead to both excellent glycemic control and decent lipids.

[DanH44]

As a heterozygote, who's avoided IR, and may be supplementing with testosterone; you might have inadvertently avoided some of these risk factors- lucky you . Others, like Stavia (and myself,) who are both post-menopausal, homozygotes, and healing from various degrees of IR may need to apply different strategies or different levels of strategies than you need. We are all snowflakes with different risk levels for different diseases (primarily dementias and heart disease) and will subsequently need different strategies.

I wish that were the case. Sadly, I did go thru full-on, no-HRT, menopause before I started taking male hormones. However, as it turns out, I don't have insulin resistance; I have insulin insufficiency. I don't know if this is a signalling problem or a b-cell problem. So, not sure where this leaves me w res to the estrogen shuttle. But, I was just pubmed-ing today re exercise, e4, and cerebral glucose utilization and came across lotsa interesting stuff, some of which I know you've seen, e.g. the 2014, "Exercise, APOE genotype, and the evolution of the human lifespan". I've been a lifelong jock; just to give you an idea, in my early teens I discovered playing football or running for a half mile was a total cure for menstrual cramps. In the 2014 paper, they ask at the end, "How does physical activity exert its beneficial effects in the context of APOE ε4 status to reduce the risk of CAD and AD?". My guess for the latter is it's due to the known exercise-induced increased blood flow to the brain. Not only that, I was reading today that the BBB transporter, MCT1, can and does import lactate, and at increased levels during and after exercise. So this could tend to supplement a diminished glucose utilization capacity and gives me reason to hope that maybe I did get lucky.

FWIW, many here have challenged the assumption that a higher fat diet (ketone production!) automatically leads to higher lipids. We have many members who eat a mildly ketogenic diet and regularly yield excellent LDL-Ps. My macros are around 65%-F, 15%-P, 20%-C and my last LDL-P was 889. Minimizing SFA, eating heaps of veggies, exercising, and practicing either IF and/or CR have been helpful to many and have lead to both excellent glycemic control and decent lipids.

WOW. That's an amazing LDLp for 65%fat e4/e4!!! Well, you show me it can be done. To be honest, I haven't measured my particle numbers since medicating my hypothyroid. I'm definitely going to experiment more with my diet and see if I too can get a few ketones up there.

[Stavia]

12 midnight here, 5pm my body clock, can't sleep mfffhhhhh, so here's some more chatting....
Dan so you are male gender but karyotype XX? If I'm correct, then for you I guess it's uncharted territory and you gonna have to write your own manual in terms of e4-ness. Would you now on your androgen therapy have the risks of a 3/4 woman (AD>CVD) or a 3/4 man (the converse)? Are androgens possibility protective in e4s in the same way as oestrogens? On a brain previously working on oestrogen... hmmm....dunno. Any ideas? Mebbe a coronary calcium scan would give some clues? You may have clean arteries

Now your markers of glycaemic control are good and you certainly don't have hyperinsulinaemia so I wouldn't worry there. Even though you don't produce a lot of insulin. I guess if you match it with low insulin triggering foods its not a major issue. So the oxidative stress on your mitochondria from that source should be low.

Do you ever get brain foggy? Mebbe not. Mebbe your exercise coupled with your low GI diet is actually producing sufficient low levels of ketones and lactate. A blood test would be interesting.

Going back to exercise, I always thought it was the BNDF it produced that was directly brain protective. And growth of coronary artery collaterals that was CVD protective amongst many other good metabolic effects. As well as the effects on lowering IR by increasing muscle insulin sensitivity. Which leads to the reduced inflammation...... And other reasons which the zopiclone has erased from my brain.

Bottom line is do you feel well?
If you think there is room for improvement then tinker away.

[Julie G]

Thanks for setting me straight, Dan. I liked my version of things better . How old were you when you went through menopause? Were you very symptomatic? I ask because some researchers are linking "hot flushes" to reduced cerebral glucose metabolism. Any brain fog/cognitive decline during that period? FWIW, you seem to have navigated that intact and your current metabolic markers looks great.

Perhaps creating some ketones will help protect your brain moving forward? Stephan Cunnane, a Canadian researcher, has found that even BHB levels as low as .04 -.05 mml/L will help offset our reduced glucose metabolism in healthy young E4 carriers. Some of us, who are older and have additional risk factors, shoot for higher numbers.

When you check your advanced lipids, please share with the group. We learn so much from lipid/diet interactions.

[DanH44]

Dan so you are male gender but karyotype XX?

yes

If I'm correct, then for you I guess it's uncharted territory and you gonna have to write your own manual in terms of e4-ness. Would you now on your androgen therapy have the risks of a 3/4 woman (AD>CVD) or a 3/4 man (the converse)? Are androgens possibility protective in e4s in the same way as oestrogens? On a brain previously working on oestrogen... hmmm....dunno. Any ideas? Mebbe a coronary calcium scan would give some clues? You may have clean arteries

Is there a different AD progression path for men and women?

As to the CHD, I started experiencing angina in my early 40s after heavy, fatty meals, but somehow this wasn't sufficient to change my behavior. A few yrs after that, I got together with a vegetarian woman who did convince me to change and the angina abated. Ten yrs later we broke up and meat + angina returned. This current very high fiber, low SFA diet that I segued into 2 yrs ago has me angina free and able to run further than a few hundred feet again.

I don't think my calcium scan would give me good news. My LDL-P was 1796 in Nov 2010 right after I discovered low carb eating and began to be able to lose weight. My other LDL-P was 1432 in Aug 2011 right after low-carb had returned me to my high school weight. I think I've always had endogenous high testosterone for XX. PCOS associates w high androgens, T2D and FtM transsexuals. I don't know what an ovarian tissue examination would have shown, but my breasts were very cystic. At any rate, I was hugely surprised when I got pregnant the 1st time. I really thought I was more intersexed than that.

Now your markers of glycaemic control are good and you certainly don't have hyperinsulinaemia so I wouldn't worry there. Even though you don't produce a lot of insulin. I guess if you match it with low insulin triggering foods its not a major issue. So the oxidative stress on your mitochondria from that source should be low.

That makes me wonder, which triggers oxidative stress, hyperglycemia or insulin resistance? I've been thinking the disease driver was hyperglycemia (->high insulin -> ROS, IR), which I'm sure I've experienced plenty of. I think I would be a Kraft type V. Are you saying my mitochondria might have been spared because the high glucose never got into my cells?

Do you ever get brain foggy? Mebbe not. Mebbe your exercise coupled with your low GI diet is actually producing sufficient low levels of ketones and lactate. A blood test would be interesting.

Yes on the fog. In my early 40s I had the 1st incidence of losing memory of where I was and not recognizing familiar surroundings. That was a hugely stressful period and like the angina, did not return over the next many years. Ten yrs later, during menopause, I lost the ability to read novels because I couldn't remember what I had read the prev day. Currently, my pattern is I wake up really sharp and clear. This will give me generally around 8 good hours, although it varies. I think I should pay more attention to whether it correlates with what I eat. Losing immediate recognition of my surroundings while driving is a relatively frequent experience, although less so lately (perhaps as I get better with glycemic control? or more from the extra butyrate from the fiber?)

I'm also having problem with executive function lately. One of my huge strengths mentally had been always being in touch with the larger picture and always driven to stay on purpose. This function is no longer automatic - sigh. Now I have to constantly check in and often forget - BLEH!

Are there blood tests for these? Would you have to do them fasting, PP and after exercise (for the lactate)?

Going back to exercise, I always thought it was the BNDF it produced that was directly brain protective. And growth of coronary artery collaterals that was CVD protective amongst many other good metabolic effects. As well as the effects on lowering IR by increasing muscle insulin sensitivity. Which leads to the reduced inflammation...... And other reasons which the zopiclone has erased from my brain.

Lotsa reasons why exercise is vital. But particularly so for e4 in as it addresses our particular glucose deficit.

Bottom line is do you feel well?

Lest I give the wrong impression, I feel amazing compared to how I felt 10, 5, 2, or even 1 year ago. Biggest recent improvements were pain abatement coinciding with dropping o-6 to under 6g / day, no more insomnia correlating to higher carb / fiber, more energy with getting thyroid meds, as well as no more angina, AND I can run again. FAST. Fast, as in 20% under world record time for 100m for my age group. But, I want to see if I can reduce my brain fog and improve exec function.

How old were you when you went through menopause? Were you very symptomatic? I ask because some researchers are linking "hot flushes" to reduced cerebral glucose metabolism. Any brain fog/cognitive decline during that period? FWIW, you seem to have navigated that intact and your current metabolic markers looks great.

Very late, I seem to remember 54.
Hot flashes and migraines. My hot flashes seemed to be triggered with strong emotion.
See my reply to Stavia on the menopausal MCI.
It took a lot of effort and experimentation to get those markers good, with the exception of trigs. They were always the 1st to come down.

Perhaps creating some ketones will help protect your brain moving forward? Stephan Cunnane, a Canadian researcher, has found that even BHB levels as low as .04 -.05 mml/L will help offset our reduced glucose metabolism in healthy young E4 carriers. Some of us, who are older and have additional risk factors, shoot for higher numbers.

When you check your advanced lipids, please share with the group. We learn so much from lipid/diet interactions.

I'm hoping extra ketones might make a diff; worth a try. Will keep the group posted!

[Julie G]

(((Dan))) Angina is pretty scary. I'd be very leery about changing what is working for you now until you get to the bottom of that... Did you ever work with a cardio? How do you know it really was angina? Have you ever had an EBT or CT scan to check your calcium score or soft plaque? I might suggest investigating further before you begin thinking about trying to creates ketones... although you probably already are with your exercise, CR, and even when you sleep

Men and women have VERY different AD risks. It is much higher for women. Late menopause is good- actually neuroprotective. Interestingly, PCOS also reduces cerebral glucose metabolism. The worst triple whammy is E4, IR, and PCOS. You may have hit a home run which could have accounted for your cognitive symptoms. Transitioning genders puts you in a very unique risk category.

[Stavia]

Good questions Dan. I can't answer the question if your mitochondria have previously been spared cos the cells were insulin resistant. My biochemistry isn't detailed enough. I do hear you tho that you are worried about your previous lifestyle which brings me to my question - are you sure it was angina? Unless it was Prinzmetals ie vasospasm, angina means there is significant atherosclerosis with a host of significant implications. There are also many non cardiac causes of chest pain....for a 40 year old lifelong hormonally female heart ( in the absence of decades of poorly controlled frank diabetes and morbid obesity) to have coronary atherosclerosis to the extent of angina would be extremely rare.

[Stavia]

Then you asked men vs women risks for apoe4. Obviously I am now talking in terms of epigenetic effects of whatever sex hormone is around each cell, and not about gender. Generally e4 women have a higher risk then e4 men for Alzheimers. I think the converse is true for CVD. But this latter pattern is changing for all genotypes and as women get older and further out from the menopause, their risk of CVD approaches that of men. It used to be in the 80s that men outnumbered women in coronary care units 10 to 1 and nowdays over the age of 70ish its 1 to 1.
In you it is likely to be more complex and there ain't going to be any published evidence. But from first principles I'd say your endogenous oestrogen until your 50s protected your heart more than if you were XY until that age. What is the exogenous testosterone doing now? Possibly good for your brain. I don't have a clue about your heart which is why I'm asking if you are intending to investigate it further.
But I still think the important part is that you feel well.