Possible risks of high-fat diets: compromised autophagy

[Brian4]

I eat a very high-fat (75–78% fat by calories), low-carb diet. It's always bugged me a bit that no long-lived population eats this way. In fact, most very long-lived populations eat low-fat diets.

I recently came across the work of Ana Maria Cuervo, who focuses on autophagy. The following are four papers by her and her team on the deleterious effects of dietary lipids on autophagy. Worth reading.

https://www.ncbi.nlm.nih.gov/pubmed/206 ... t=Abstract

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909278/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429556/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3311383/

It appears that both chaperone-mediated autophagy as well as macroautophagy are affected.

Brian

[Julie G]

I've wondered about this as well. I've gotten to the point where I typically eat once a day. Is that still considered "chronic" exposure to lipid overload if the one meal has 70% fat? Not to confuse the issue, but we have these studies suggesting ketosis promotes autophagy:

https://www.ncbi.nlm.nih.gov/pubmed/27050461

https://www.ncbi.nlm.nih.gov/pubmed/27050461

https://www.ncbi.nlm.nih.gov/pubmed/15883160

[Kenny4/4]

I eat a very high-fat (75–78% fat by calories), low-carb diet. It's always bugged me a bit that no long-lived population eats this way. In fact, most very long-lived populations eat low-fat diets.


Brian

I agree Brian.
All of the Blue Zones of Longevity tend to be higher carb, lower protein and low -moderate fat that is plant derived. I do notice an overlap of inverse APOE 4 frequency as well. Mediterraneans in Sardinia and -Ikara as well as Spanish descendants in Nicoya Costa Rica and ethnic Chinesee in Okinawa would have very low APOE4 frequencies. The exceptions might be the First Day Adventists of Loma Linda who would in my best guess have quite a few Northern Europeans included who would increase the frequency of APOE4. Iceland however seems to be a unique long lived high fat and high animal protein consuming society that has a moderately high frequency of APOE 4. Perhaps research can tease out the difference if there is one. Maybe it’s exercise (Iceland is exercise obsessed)and or total calories consumed?


The other question is how large a role does autophagy play in actually preventing Alzheimer’s ? I think we have this simplified vision of biological vacuum cleaners clearing amyloid and Tau out of brain and bloodstream as we fast or eat the right foods. Maybe it is that simple?Somehow I think it is more targeted and specific with Amyloid and Tau than the all encompassing term- Autophagy. I agree it helps to not eat too much and eat high quality foods but there has to be a specific more concentrated way to clear amyloid or prevent hyperphosphorlation of Tau. My guess is eat less, eat less carbs but eat enough that you don’t starve your brain.

I go back to APOE4 =40% less IDE(Insulin Degrading Protein) -IDE clears amyloid. Therefore eat less insulin creating foods such as carbs and excess protein we will allow IDE to clear more Amyloid???

Reduce phosphorylation of Tau by reducing glucose, other sugars such as fructose and keep protein at a maintenance level. Phosphorylation of glucose is a key reaction in sugar metabolism because many sugars are first converted to glucose before they are metabolized further and phosphorylation is used to do this and in converting carbs and some amino acids to energy.
My best guess? True ? False ?

[aphorist]

This issue I have argued ad nauseam with proponents of a high fat, ketogenic diet. Individuals who wake up in the morning and consume this garbage butter fat coffee or just avoid carbohydrates in any form to gorge themselves on a ketogenic, high fat diet.

Deprivation of cytosolic acetyl-CoA is triggers autophagy. If one consumes a high fat diet, that won't occur. Acetyl-CoA will be there.

[Brian4]

I've wondered about this as well. I've gotten to the point where I typically eat once a day. Is that still considered "chronic" exposure to lipid overload if the one meal has 70% fat? Not to confuse the issue, but we have these studies suggesting ketosis promotes autophagy […].

Another post eaten. Arg.

Summary of my post that I don't have the fortitude to recreate: I think, following Cuervo, the best thing to do would be to eat within a narrow window, perhaps, yes, but eat low fat foods in that window. Looking at all the evidence, I'm convinced low-fat eating is a safer bet as a long-term strategy (I say "bet" because we obviously need tons more research) than low-carb eating, probably for almost everyone. The only reason I eat a high-fat diet is because it's all my gut tolerates.

[Kenny4/4]

This issue I have argued ad nauseam with proponents of a high fat, ketogenic diet. Individuals who wake up in the morning and consume this garbage butter fat coffee or just avoid carbohydrates in any form to gorge themselves on a ketogenic, high fat diet.

Deprivation of cytosolic acetyl-CoA is triggers autophagy. If one consumes a high fat diet, that won't occur. Acetyl-CoA will be there.

If one consumes carbohydrates Acetyl-CoA will be there as well.Keotone bodies will also produce some Acetyl-CoA. Are you saying only deprivation of cytotoxic acetyl-CoA triggers autophagy? The other Carb and Keotone body types don’t? How significant a role percentage wise is it in total aitophagy? How important is enhancing autophagy? Is it or Tau and Amyloid pathology more important? Does autophagy actually help with Tau and Amyloid pathology?

[aphorist]

If one consumes carbohydrates Acetyl-CoA will be there as well. Keotone bodies will also produce some Acetyl-CoA. Are you saying only deprivation of cytotoxic acetyl-CoA triggers autophagy? The other Carb and Keotone body types don’t?

My point is that fasting involves the deprivation of cytosolic acetyl-CoA, which functions as a signaling pathway for autophagy. I doubt there is a ultimately a difference between excess consumption of carbs or high fat diet, such that individuals who elect for a HFD and claim they are in ketosis are not getting the benefits of autophagy (in the traditional sense).

How significant a role percentage wise is it in total aitophagy? How important is enhancing autophagy? Is it or Tau and Amyloid pathology more important? Does autophagy actually help with Tau and Amyloid pathology?

Above my paygrade. But I would point to the role of acetylation in tau and its purported prevention in the turnover of tau.

Min, S., Cho, S., Zhou, Y., Schroeder, S., Haroutunian, V., & Seeley, W. et al. (2010). Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy. Neuron, 67(6), 953-966. doi:10.1016/j.neuron.2010.08.044

Carlomagno, Y., Chung, D., Yue, M., Castanedes-Casey, M., Madden, B., & Dunmore, J. et al. (2017). An acetylation–phosphorylation switch that regulates tau aggregation propensity and function. Journal Of Biological Chemistry, 292(37), 15277-15286. doi:10.1074/jbc.m117.794602

The thought is that autophagy inducing processes that inhibit acetylation may help clear p-tau.