Confusing statement in Brinton paper about ketogenesis being harmful?

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circular
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Confusing statement in Brinton paper about ketogenesis being harmful?

Postby circular » Wed Jun 17, 2020 1:38 pm

A 2012 paper by Roberta Brinton (Estrogen Regulation of Mitochondrial Bioenergetics: Implications for Prevention of Alzheimer's Disease) states:
Abstract

Alzheimer's disease (AD) is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. Increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. Compromised aerobic glycolysis pathway coupled with oxidative stress is first accompanied by a shift toward a ketogenic pathway that eventually progresses into fatty acid oxidation (FAO) pathways and leads to white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid [ :shock: ]. Estrogen-induced signaling pathways converge upon the mitochondria to enhance mitochondrial function and to sustain aerobic glycolysis coupled with citric acid cycle-driven oxidative phosphorylation to potentiate ATP (Adenosine triphosphate) generation. In addition to potentiated mitochondrial bioenergetics, estrogen also enhances neural survival and health through maintenance of calcium homeostasis, promotion of antioxidant defense against free radicals, efficient cholesterol trafficking, and beta amyloid clearance. Significantly, the convergence of E2 mechanisms of action onto mitochondria is also a potential point of vulnerability when activated in diseased neurons that exacerbates degeneration through increased load on dysregulated calcium homeostasis. The "healthy cell bias of estrogen action" hypothesis examines the role that regulating mitochondrial function and bioenergetics play in promoting neural health and the mechanistic crossroads that lead to divergent outcomes following estrogen exposure. As the continuum of neurological health progresses from healthy to unhealthy, so too do the benefits of estrogen or hormone therapy.

It sounds like if women continue with menopausal HRT they don't need to worry about being fat adapted, and if they don't continue with HRT and are fat adapted it could cause harm.

Have any studies looked at whether being fat adapted as a lifestyle leads to "white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid"? Many feel mentally sharper when fat adapted, which would symptomatically argue against this. How do we resolve the statement?

Regrettably I don't have time to dig, so I'm just throwing this out here to hear others' thoughts :D
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Confusing statement in Brinton paper about ketogenesis being harmful?

Postby Julie G » Thu Jun 18, 2020 7:51 am

It sounds like if women continue with menopausal HRT they don't need to worry about being fat adapted, and if they don't continue with HRT and are fat adapted it could cause harm.

Have any studies looked at whether being fat adapted as a lifestyle leads to "white matter degeneration and overproduction and mitochondrial accumulation of β-amyloid"? Many feel mentally sharper when fat adapted, which would symptomatically argue against this. How do we resolve the statement?

Regrettably I don't have time to dig, so I'm just throwing this out here to hear others' thoughts :D

My guess is that Dr. Brinton's thoughts have evolved since this 2012 paper. She's since come out with White Matter Lipids as a Ketogenic Fuel Supply in Aging Female Brain: Implications for Alzheimer's Disease where she describes the brain's need for ketone bodies as being so strong that in a self-preservation twist, it will catabolize myelin lipids from the brain blood barrier when peripheral ketones aren't present. :shock:
Under conditions of diminished glucose availability, the brain will progressively utilize circulating fatty acids as a ketogenic energy source (Morris, 2005, Guzman and Blazquez, 2004). Utilization of liver-derived ketone bodies by brain is well established under two conditions: during breast feeding of high lipid diet and during periods of starvation (Morris, 2005). During these states, the ketone bodies acetoacetate and β-hydroxybutyrate supply up to 60% of the human brain's energy requirements (Veech et al., 2001, Cahill, 2006). Ketone bodies derived from liver metabolism of lipids cross the blood brain barrier (BBB) through the monocarboxylic acid transporter (MCT1) (Ding et al., 2013, Morris, 2005). However, as with glucose transporters, MCT1 expression can decline with age and AD (Ding et al., 2013). A potential compensatory response to decline in peripherally derived ketone bodies is the utilization of brain-derived sources of fatty acids to generate ketone bodies (Yao et al., 2011b). Herein, we provide evidence from the aging female brain indicating that endogenous brain lipids can serve as a source of ketone bodies. Specifically, we provide a mechanistic pathway for myelin catabolism initiated by mitochondrial H2O2 activation of the cPLA2-acid sphingomyelinase pathway that leads to loss of myelin integrity, lipid droplet accumulation, fatty acid metabolism, and ketone body generation.

I don't see this being an either/or situation. As a 4/4, with diminished cerebral fuel as one of my greatest obstacles, I'm doing all I can to upregulate both the glucose (maintaining insulin sensitivity, supplementing E2 and B1) and the ketone (diet + fasting + exercise) pathways. After all, our brains were designed to be metabolically flexible. As long as we're insulin sensitive, our brains have the ability to chose between fuel sources.

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Re: Confusing statement in Brinton paper about ketogenesis being harmful?

Postby circular » Thu Jun 18, 2020 8:46 am

Julie G wrote:My guess is that Dr. Brinton's thoughts have evolved since this 2012 paper ... I don't see this being an either/or situation. As a 4/4, with diminished cerebral fuel as one of my greatest obstacles, I'm doing all I can to upregulate both the glucose (maintaining insulin sensitivity, supplementing E2 and B1) and the ketone (diet + fasting + exercise) pathways. After all, our brains were designed to be metabolically flexible. As long as we're insulin sensitive, our brains have the ability to chose between fuel sources.

Thanks Julie! Wow re: Dr. Brinton's progress, and you provide, as usual, a helpful and succinct summary. I do the same, and I recall discovering I had very low "normal" B1 (on the floor of the range) and then supplementing leading to an immediate increase in energy on all levels. It was one of the "big ones" on my trajectory out of the "chronic fatigue" related issues, along with HRT and leaving a very moldy environmental ecosystem.
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Confusing statement in Brinton paper about ketogenesis being harmful?

Postby Ljflynn47 » Thu Jun 18, 2020 6:30 pm

Hi.
New to this forum and journey. 53 y/o female 4/4. Just starting keto. Should I be supplementing vitamins B1 and E2, and should I be on HRT?
Thanks for the advice.
LJ

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Re: Confusing statement in Brinton paper about ketogenesis being harmful?

Postby summer0088 » Fri Jun 19, 2020 12:41 pm

Ljflynn47 wrote:Hi.
New to this forum and journey. 53 y/o female 4/4. Just starting keto. Should I be supplementing vitamins B1 and E2, and should I be on HRT?
Thanks for the advice.
LJ


Hi Ljflynn47! Welcome to the ApoE4 forum! We're so glad to have you here.

I know you will find many here who share your 4/4 status as well as your interest in the keto diet. Supplementation is a well chartered territory on our site as well so I hope you will be able to find useful information on everything.

If you haven't already explored the forum, here are some areas that you may find helpful. The "How-to" guide in the wiki link is great and helps to get the most out of the Apoe4 website. You may also want to view the Primer, written by one of our physician members and is a great introduction. Also, feel free to introduce yourself to the community in the Our Stories section.

Also, searching our forums for the specific topics (eg, B1 or HRT) you mentioned may be enlightening

So happy to have you here, Ljflynn47!

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Re: Confusing statement in Brinton paper about ketogenesis being harmful?

Postby floramaria » Fri Jun 19, 2020 3:26 pm

Ljflynn47 wrote:Hi.
New to this forum and journey. 53 y/o female 4/4. Just starting keto. Should I be supplementing vitamins B1 and E2, and should I be on HRT?
Thanks for the advice.
LJ

Welcome, Ljflynn47! Ah, if only there were answers that applied equally to everyone this would be so much easier! Looking back at posts above yours, I see that circular notes that her B1 was at the bottom of the range, and that for her, supplementation was helpful.
Without knowing what your levels are, it would be difficult to know whether you would want to supplement . It would actually just be a guess, unless you happen to know that with your current food and supplement intake, you are really not getting much B1. One thing you could do, if you want to track how much of any nutrient you are getting in your diet would be to enter your food for a few days at least into Cron-o-meter, and see how close you are to your desired intake. Cron-o-meter is free and gives you a full breakdown of all components of food; it might prove to be a useful tool for you as you are working with your ketogenic diet. When I changed to a ketogenic diet and was just getting the hang of it, I used Cron-o-meter off and on for the few months and found it very helpful to see how I was doing on hitting the levels of fats/proteins and carbs I was aiming for. You could also get a blood test to see what your levels
of B1 are.

The thread on HRT is one of the longest on this site. It is one of the more controversial parts of the program recommended by Dr Bredesen and other cognitive health specialists. There are a lot of opinions. As a 53 year old female, you'd want to know your current levels of hormones as a baseline. Then to decide whether bioidentical HRT (BHRT) is right for you, a good place to start would be with the excellent section that Stavia wrote on the topic in the Primer . If you go to the Primer and then look at supplements, you will find not only what Stavia has written herself, but also links to a lot of relevant resources. Ultimately, the decision about BHRT is one you would want to make in consultation with your health care provider.
As Stavia writes in the Primer, the topic is "a biggie"!

Best wishes to you as you are beginning your journey. You have found a community here with many
fellow travelers, and a wealth of information and support.

~floramaria
Functional Medicine Certified Health Coach
IFM/ Bredesen Training in Reversing Cognitive Decline (March 2017)

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Re: Confusing statement in Brinton paper about ketogenesis being harmful?

Postby circular » Sat Jun 20, 2020 5:42 pm

Julie G wrote:
Roberta Brinton paper wrote:Ketone bodies derived from liver metabolism of lipids cross the blood brain barrier (BBB) through the monocarboxylic acid transporter (MCT1) (Ding et al., 2013, Morris, 2005). However, as with glucose transporters, MCT1 expression can decline with age and AD (Ding et al., 2013). A potential compensatory response to decline in peripherally derived ketone bodies is the utilization of brain-derived sources of fatty acids to generate ketone bodies (Yao et al., 2011b).

I'm stuck on this point now. Wish there were a way to check our MCT1 transporter capacity. We make a good assumption that our glucose transporters at least need help, but it appears we should also assume -- at least as we age -- that the MCT1 transporters might also be losing efficiency.

If estrogen and B1 assist our glucose transporters, what can we do to support our MCT1 transporters, so our peripheral ketone bodies are sure to get in and spare our myelin sheaths?
ApoE 3/4 > Thanks in advance for any responses made to my posts.

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Re: Confusing statement in Brinton paper about ketogenesis being harmful?

Postby Ljflynn47 » Mon Jun 22, 2020 7:52 pm

Floramaria and Summer0088–
Thank you for your responses and the advice. I’ll do some digging and read the sections you recommend. And speak with my doc. Thanks for being welcoming. This is scary so friendly ‘faces’ are helpful.
-LJ


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