Associations of protein and fiber with Amyloid-β

[Searcher]

I thought about situations where one could overly restrict protein and impair one's health and came up with strength training, those with high muscle mass, intercurrent illness, post surgery, wound healing, pregnancy, leaky gut (?). Can anyone think of others?

Age.

Anorexia nervosa & other eating disorders.

[apod]

@apod Thank you for the links. One difficulty here is determining how much protein is optimal for one’s health. I eat vegan (non-processed foods) with lots of pulses (fairly high in protein) with some fish (2-3 times/wk: sardines, salmon) & solo road cycle (~18-21mph avg) for about 7-10h/wk (135mi-200mi/wk). A quick calculation shows me that my protein use is ~1.2g/kg, 85g/d (I weigh 160#), but I know many people taking large amounts of whey protein who are encouraged by supplement manufacturers & their surrogates (magazines, web, etc.) to increase their protein with no downside stated. But there is a downside of up regulating IGF-1, see https://source.wustl.edu/2006/12/does-t ... ncer-risk/.

This stuff is really tricky since the original paper I quoted is a meta study & does not have much granularity, but I am surprised that this associating wasn’t mentioned in Dale Bredesen’s, End of Alzheimer’s, book, which i’ve Been following the recode protocol since 11/17. And besides individual characteristics, my exercise goals are longer term, not individual performances. This study makes me question if I shouldn’t increase my protein to 1.5g/kg. I am APOE3/4.

Interestingly, here's where my IGF1 last measured while supplementing Whey Protein Isolate + leucine-rich BCAAs and eating ~100-125g protein/d:

male-hormone-2017-05-18.png

Reference range by age (at least, in southern China...):

Screen Shot 2018-02-23 at 10.58.53 PM.png

I believe this puts me within the lower reference range for a senior citizen (I'm active and in my 30's.) Looking at some charts, it appears as though my levels are lower than women in their 80's . In this study, going any lower than this lower 70-80 range where I sit was associated with increased mortality: https://www.ncbi.nlm.nih.gov/pubmed/21795450 -- All-cause mortality was increased in subjects with low as well as high IGF-I, with a hazard ratio (HR) of 1.27 (95% CI = 1.08-1.49) and HR of 1.18 (95% CI = 1.04-1.34), respectively, so it appears that low-IGF1 could be more of a health risk than high IGF1. I should probably measure hormones again sometime.

Thinking more about my diet / lifestyle, this makes me wonder if IGF1 might be more closely associated with caloric intake / carbohydrate intake / nutrient timing / other hormones rather than protein intake. Or, perhaps I have some other genetic / epigenetic factors at play. It would be interesting to look at IGF1 and Leptin (I generally run minimal, near-undetectable levels of leptin while eating low-carb with low body fat.) I think I was also supplementing TMG at the time, which raises IGF1 in theory.

From what I've read, higher levels of IGF1 is associated with greater telomere length, lower incidences of cognitive decline & higher neurotrophic factor levels, lower levels of inflammation, higher antioxidant status, improved blood sugar control, greater amounts of functional muscle tissue & strength, faster recovery, etc. On paper, IGF1 looks fairly cardioprotective and supportive to mitochondrial health & function. Whey provides cysteine in a form that boosts glutathione (which is in large part stimulated by insulin) -- this is an interesting article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569588/

That said, I do subscribe to the idea that lower intakes of protein generally makes more sense to me than higher intakes for overall health & longevity. Right now, I sort of hedge my protein intake with 1-2tbs/d of marine collagen peptides (rich in Glycine) while supplementing creatine / methyl donors in an attempt to balance out the methionine.

[cdamaden]

How about using BUN results to drive protein consumption levels? I think a BUN of 8-10 is good based on all cause mortality studies.


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[Julie G]

How about using BUN results to drive protein consumption levels? I think a BUN of 8-10 is good based on all cause mortality studies.

I like the way you're thinking, Chris. I suspect that there would be indications in blood work if protein intake is too low. For instance, I'm always at the bottom of the reference range or slightly below for total protein. This article indicates that a low protein diet can be the cause. I also have low IgG (hypogammaglobulinemia) likely secondary to an ongoing Babesiosis infection. I wonder if I'm in the population that could benefit from consuming more? I'd appreciate hearing from some of our practitioners on other blood work indications that protein intake may be too low.

[apod]

Looking further into BCAAs, I dug these up (Yikes):

Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease (2014):
https://www.sciencedirect.com/science/a ... 6114000047

Amino Acid Catabolism in Alzheimer’s Disease Brain: Friend or Foe? (2017):
https://www.hindawi.com/journals/omcl/2017/5472792/

Effects of specific nutrients on cognition and alzheimer's disease neuropathology: The case of BCAAs (2017):
http://www.alzheimersanddementia.com/article/S1552-5260(17)32468-8/fulltext

Branched-chain amino acids and Alzheimer’s disease: a Mendelian randomization analysis (2017):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648806/

"Branched chain amino acids, in synergy with a high-fat diet, induce systemic toxicity and worsen Alzheimer's disease-like pathology. Increasing BCAA levels through dietary supplementation in rats led to a decrease in neural growth factor (NGF) in the hippocampus, a part of the brain involved in memory formation and known to undergo extensive neuronal loss in AD patients. Administration of the leucine metabolite α-ketoisocaproic acid also decreased NGF as well as brain-derived neurotrophic factor (BDNF). Wild-type lean mice fed a high leucine diet also developed hippocampal-selective retromer deficiency. High BCAA intake aggravated cortical tau pathology. Higher plasma isoleucine (BCAA) levels was positively associated with AD, suggesting that lifelong raised isoleucine levels may increase the risk of Alzheimer's disease.

High levels of circulating BCAA are associated with metabolic risk factors of AD. A study using AD mice found that a high protein/low carbohydrate diet resulted in a 5% reduction in the brain weight in AD mice, including decreased neuronal density and volume in the CA3 region of the hippocampus that is important for memory. A high protein/low carbohydrate diet has also been associated with increased excitotoxicity in the aged brain. These data suggest that high levels of amino acids or products of their catabolism may contribute to neurodegeneration. Consistent with this assessment, catabolism of branched chain ketoacids by branched chain ketoacid dehydrogenase (BCKDH) in mitochondria results in substantial production of damaging superoxide radical. Mice on the low BCAA diets performed better at the novel object recognition task than mice on other diets. These data suggest that diets containing low protein levels or low levels of the potent mTOR activators leucine and arginine may prove beneficial for AD patients, although decreasing the levels of all three BCAAs together was more potent than decreasing only leucine levels on enhancing peripheral metabolism in mice. Some of the beneficial health effects conferred by the low protein diet in young and middle aged mice may be mediated by decreased plasma branched chain amino acid levels."

(EAAs > BCAAs?)

This part was particularly relevant, thinking about the energy homeostasis / T3D model of AD:

"A healthy individual is able to process the excess amino acids consumed into other useful metabolites or oxidize them for energy production. To use them as fuel, the carbon skeletons are oxidized in the citric acid cycle to produce carbon dioxide, and the excess nitrogen is disposed of as the relatively nontoxic nitrogenous waste product urea. However, when neurons cannot catabolize glucose efficiently, such as during AD, they may become reliant upon amino acid oxidation for energy production. If neuronal amino acids become depleted or if the machinery used to metabolize amino acids becomes dysregulated, the neurons may die, contributing to disease progression. However, even if amino acid oxidation is able to maintain neuronal energy levels, the increased amounts of ammonia released during amino acid catabolism could lead to neuronal cell death because all of the enzymes of the urea cycle needed to detoxify ammonia are not present in neurons or glia. Instead, astrocytes express high levels of the glutamine synthetase enzyme to sequester ammonia into glutamine, which is then released from the brain. Due to the 40-fold lower expression of glutamine synthetase in neurons, they are not equipped to detoxify the excess ammonia. "

[Orangeblossom]

I wonder about the nutrients and vitamins in a higher protein diet such as perhaps B12, maybe that influences the results. Some meats can be much higher in those vitamins.

[RJones]

apod wrote:

" In this study, going any lower than this lower 70-80 range where I sit was associated with increased mortality: https://www.ncbi.nlm.nih.gov/pubmed/21795450 -- All-cause mortality was increased in subjects with low as well as high IGF-I, with a hazard ratio (HR) of 1.27 (95% CI = 1.08-1.49) and HR of 1.18 (95% CI = 1.04-1.34), respectively, so it appears that low-IGF1 could be more of a health risk than high IGF1."

Thank you apod for an informative post. Trying to catch up here.

I was under the impression that lowering IGF1 was desirable and "anti-aging", and that was the motivation for fasting. I think Valter Longo advocates that one monitor IGF1 and keep it low via fasting.

But if the optimal level in terms of all-cause mortality is in the middle, then maybe my impression is not correct? Or maybe "it's complicated"?

[Searcher]

Older people are more prone to a change in mitochondrial protein content which leads to loss of mitochondrial respiratory capacity with age. This can be remedied with physical activity, notably high intensity interval training. Unfortunately, excessive restriction of protein intake in older age groups can lead to sarcopenia or weakness, which limits the opportunity for high intensity physical activity. Genes upregulated by high intensity physical activity include those involved in angiogenesis (new blood vessels). Genes involved in protein catabolism (breakdown) are downregulated by such activity.

It could well be that older people who unduly restrict their protein intake grow weaker and less active, setting off a downward spiral of such unhelpful effects.

One way to develop as well as measure muscle strength is to count how many times you can squat. If you're strong, do this with small weights that you raise from shoulder level to above your head (squat press). Maintaining this number would suggest that your protein intake is not limiting your muscle mass or strength.

[edit: Decreased mitochondrial respiratory chain efficiency and insulin resistance in neurons are associated with the APOE4 allele, at least in mice. Age exacerbates this association.

https://www.ncbi.nlm.nih.gov/pubmed/28957663

Mitochondrial hydrogen peroxide emission and cellular redox state link excess fat intake to insulin resistance even in humans, at least in skeletal muscle.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2648700/

Inadequate protein and excess saturated fat intake in older people probably amount to a double whammy for mitochondrial respiration. Adequate protein intake in older people, together with high intensity interval training - short bouts of activity at near maximal intensity - seem sensible as ways of supporting mitochondrial respiration and angiogenesis.]

[Julie G]

I like your theory, Searcher, and believe it is entirely plausible, but likely far from complete. Dr. Gundry would propose an alternative hypothesis that accumulated damage from lectins as we age prevents adequate absorption of protein. His recommendation would be to heal the underlying issue (gut) rather than increase protein intake... although transitionally that may make good sense. FWIW, Dr. Bredesen generally agrees with this nuanced approach.

I suspect that there are many layers of complexity to the adequate protein issue that make it highly individualized. I'll use myself as an example. Researchers are noticing a correlation between Lyme disease and gluten sensitivity. I've recently learned that I'm dealing with a Lyme disease co-infection, Babesiosis. Because I've had severe and chronic GI issues, I had the Cyrex labs #3 Wheat/Gluten Proteome Reactivity & Autoimmunity testing performed. Sure enough, I was overwhelmingly positive to 11 of the 12 proteins tested. Eliminating gluten (and all grains) has yielded amazing health benefits for me. I'm still a work in progress and am working on further healing my gut from years of damage.

A diet low in protein and inadequate strength training is clearly one obvious pathway towards hypoproteinemia and the subsequent sarcopenia, but I suspect that there are likely many pathways to the same condition.

[Searcher]

Julie,

Sorry, just saw this.

Malabsorption would lessen the impact of protein intake on amyloid-b in the brain. For example, if there were 100% malabsorption (zero absorption of protein), then the level of protein consumed would make no difference to Aβ in the brain.

However, the report was that the more protein consumed by older adults, the less likelihood of ‘high’ Aβ burden in the brain.

Of course, it's always worth excluding or correcting malabsorption.