@pmiguel You’re mixing up LDL-P and LDL-C. this review is disputing the proposed causal link between LDL-C (amount of cholesterol contained in LDL particles) and CVD. Ron Krauss as you correctly said was talking about the proposed causal relationship between LDL-P (number of LDL particles) and CVD which is widely supported among experts.
While much is made of cases where someone has borderline hign LDL-C but a low LDL-P, cases where someone has sky-high LDL-C will almost always have high LDL-P.
And, whether expert or not, there are plenty of people out there who would dismiss LDL-P as a risk factor for CVD.
@pmiguel Actually LDL-C and LDL-P are discordant quite often and increasingly so as people get closer to a profile of metabolic disease.
You can also see from this scatter plot that you are incorrect. The amount of people with high LDL-C and low LDL-P is small but not clinically insignificant. It should be considered.
Name a serious lipidologist/cardiologist who disputes the link between LDL-P and CVD…
I’d also like to point out that in your original comment you said
“At this point my main reason for believing the cholesterol (or apoB) hypothesis”
This is incorrect. They are not the same hypothesis. The cholesterol hypothesis is the hypothesis that cholesterol is causative in atherosclerotic disease. The apoB hypothesis is that apoB proteins (which are structural features of lipoproteins) are the causative agent. This paper is trying to show that the cholesterol hypothesis is incorrect. Everything you mentioned in your original comment is evidence against the cholesterol hypothesis but supports the apoB hypothesis.
Also, again. This study is disputing that there is a CAUSAL link between LDL-C and CVD. There is certainly an ASSOCIATION between LDL-C and CVD but that is not the same thing. All the people you are referencing (Peter Attia, Tom Dayspring, Ron Krauss) would AGREE with this paper.
@ManyLives I’ll just cede the point to you.
@rhonda this is a really poor study. Or at least the conclusions drawn from it and trumpeted through the media are poorly supported by the study.
Take a look here:
Basically the ability to do some number of push-up stratifies the firefighters into age groups. When age is accounted for there is significant differences between only two groups. This presumably disappears when smoking is taken into account since the authors didn’t do that test. (Although they did collect the smoking status of the participants.)
Yeah as I looked closer at the study I see some of the analysis did not account for all confounding factors. It is always difficult to establish causation with these types of studies and statistical adjustment for age and BMI suggested that some of the risk reduction seen with higher push-up categories was accounted for by these characteristics. Also, the study assessed the association between push-ups and cardiovascular disease events. These results do not support push-up capacity as an independent predictor of cardiovascular disease risk. However, a higher level of muscular strength has been associated with lower cardiometabolic risk independent of cardiorespiratory fitness in other studies. Muscular strength has also been shown to have an independent protective effect for all-cause mortality and hypertension in healthy men.
I think the bottom line is it doesn’t hurt to do your best to stay fit and try to crush it with your push-ups!
Okay, I just tried it. No metronome, so I don’t know if I was keeping pace. (80 beats per minute). I got 33 with my back flat, touching the floor each rep. I’m 56, non-smoker. No history of firefighting…
Wow FP, this is even more bizarre than the Ginger Exosome-like Nanoparticles paper I posted:
The Ginger ELNs protect mice from DSS-induced colitis through interactions with Lactobacillus rhamnosus. Ginger is a root and so it would be expected that it would communicate with bacteria. But Grape ELNs do this directly?
…we show that the cells targeted by grape exosome-like nanoparticles (GELNs) are intestinal stem cells whose responses underlie the GELN-mediated intestinal tissue remodeling and protection against dextran sulfate sodium (DSS)-induced colitis.
Why does a plant do this?!?
This paper is covered in a This Week in Microbiology episode:
which is easier to understand than the paper…
Dosage of ginger was 0.5mg of ginger/25g of body weight (low) or 10mg of ginger/25g of body weight. Subjects were mice. Presuming linear dose response by body weight that would be about 1g of ginger (low) or 1 ounce of ginger (high).
This is one of those mysterious ones – why would ginger produce microRNAs that impact gene expression in gut bacteria? Ginger root would need to interact with its soil microbiome. Maybe that is the source of these activities?
Discussion of this review by hard-core virologists in the most recent episode of the podcast This Week in Virology:
Here is a good article:
Although only tangentially related to your question, it can give you some useful background.
My advice is that you probably should get some more information. I think there is reasonable consensus that it is the LDL particles themselves – that is, the number of them – that confers risk. Not the amount of cholesterol they carry. So getting an actual LDL-P number assay done (NMR) would be helpful.
Past this, if your LDL-C is very high, then your LDL-P will almost certainly be high also. Whether you choose to use statins or not should be a discussion between you and your doctor. Otherwise what is the point of having a doctor?
Thank you, I’ll take a look. My doctor was unfamiliar with FH, and I had to request the lipoprotein(a) test which showed my low density lipoprotein(a) was around the 300 range. Triglycerides 41, HDL 87. TC 249. I did request the Lp(a) test on the advice of my mother, who does see a cardiologist, and diagnosed her with FH by specifically requesting lipoprotien (a) testing. The problem with FH is that diet has no positive effect on Lp(a), although I’m sure I could make my LDL worse. It’s a genetic defect. Now, my lifestyle makes it much more likely I would survive the heart attack… bonus I guess. The issue is that statins seem to lower numbers overall, to include HDL, and might have negligible improvements. So much of this research I have been able to find deals with people with high triglycerides and poor HDL, when really, the only marker I have that would indicate I’m not incredibly healthy is the 400+ lipoprotien. I’m military insurance, so my doctor is whoever I happen to have at the time at the military treatment facility, and I don’t exactly have a valid reason to request a referral to a cardiologist. I mean, I’m a marathoner and my resting heart rate is 55 BPM (female).
You could listen to the Dayspring lipid podcasts that Peter Attia posted last week on his site:
It touches on many of the topics you mention here. Recent evidence is that high HDL isn’t actually protective–all drugs that increase it appear to have failed to produce lower levels of CVD. So at best, it is a marker for some other process that may be protective.
Also, don’t confuse Lp(a) with LDL-P. LDL-P comes from an assay (usually NMR) that counts/calculates the LDL particles per liter of blood. Lots of small LDL particles are thought to be much more atherogenic than lower numbers of large LDL particles – even if the amount of cholesterol they carry (LDL-C) is the same. If your LDL-C is what is 300, it is still within the realm of possibility that your LDL-P is okay. But you would need to get the NMR test to tell you that.
Lp(A) is an LDL particle with an additional lipoprotein – apolipoprotein A – added to it. Peter Attia had an earlier podcast that went into some detail on Lp(a):
If you did have your Lp(a) tested and it is high, then you should listen to this. It is currently much more difficult to treat than high LDL and many doctors know nothing about it. Just treating it with a statin is unlikely to be sufficient.
Also, keep in mind that FH is not a single genetic condition, but rather a host of genetic predispositions to high blood cholesterol levels. Some probably do respond to changes in diet.
Best summary of Attia/Dayspring current lipidology knowledge I’ve seen! A keeper. Thanks!
Yes, I definitely had my Lp(a) tested, and last one was 333 (I pulled my last labs just to double check my numbers.) Looking for info on this topic that few know very much about was one of the things that led me here. I have been listening to some of Peter Attia’s stuff over the past couple of days to include the Lp(a) podcast you referenced, and it’s been interesting. I’ll take a look at the ones you posted, as well. Thanks!
I’m glad you’re investigating your options. Ask your doctor for a referral to a FH / lipoprotein specialist.
Also check out the Valter Longo interviews with Rhonda.
Beg Peter Attia to review your case.
Link is to a news release. Here is a link to the full paper:
@rhonda, I would have concerns that the residual TiO2 might be worse than the BPA. Report:
on a paper:
Previous studies showed TiO2 inhale or ingested ended up in the blood stream where it was phagocytosed. From the paper:
“By binding to and activating the NLRP3(NALP3) inflammasome,(12,31−33) a macromolecular complex found in macrophages, neutrophils, platelets, and microglia, the TiO2 crystals cause inflammatory cascades leading to death of proximal cells.”
Furthermore, the paper itself reported an association of TiO2 crystals in the pancreases of type 2 diabetics, but not in non-diabetics. Small study – but all 8 T2D pancreases examined had the crystals whereas none of the 5 non-T2D pancreases did.
Trying to wrap my head around the research paper. Here if you can get through the paywall:
From the abstract:
We investigated the role of nuclear factor erythroid 2–related factor 2 (Nrf2) in renin-angiotensin system (RAS) gene expression in renal proximal tubule cells (RPTCs) and in the development of systemic hypertension and kidney injury in diabetic Akita mice. We used adult male Akita Nrf2 knockout mice and Akita mice treated with trigonelline (an Nrf2 inhibitor) or oltipraz (an Nrf2 activator).
So, if I understand correctly, these are type 1 diabetic mice. Directly activating Nrf2 using oltipraz in these diabetic mice resulted in hypertension and kidney damage.
I’m not sure how generally we want to interpret these results. Although if you are a type I diabetic with uncontrolled hyperglycemia you would probably want to keep an eye on your blood pressure in the unlikely event you were taking oltipraz.
What about sulfurophane? No idea. Not covered in this paper.
Well, okay, since we are basically stumbling around in a dark room trying to figure out what is happening, let’s take the worst possibility – that sulfurophane acts as a Nrf2 activator in exactly the same mode as oltipraz. In that case don’t use either if you are hyperglycemic. Get your hyperglycemia under control before inducing Nrf2 in your kidneys.
Although, chances are that oltipraz and sulfurophane are doing 10 other things beside dis-inhibiting Nrf2 and some of these 10 other things mitigate or aggravate damage-causing processes in some kidney cells in the presence of hyperglycemia.
If you are doing Time Restricted Eating, you are already spacing out the sulfurophane. I’m not sure what sulfurophane’s half-life is, though.
A news report about this paper was posted to Steve Gibson’s grc.health news group. Although it has this undercurrent of “auto-immunity”, it doesn’t really seem to be about that. Or at least not in the typical sense one sees the immune system invoked.
This appears actually to be a metabolic hack that involves triggering a set of immune cells in the blood of T1D patients given the vaccine to use glycolysis non-aerobically in non-hypoxic conditions. That is, “aerobic glycolysis”. These cells then apparently become a sink for sugar, fermenting it to lactic acid or otherwise shunting it off into other pathways. As a result the T1D patents given these vaccinations dropped their A1C’s from 7 to 6.
A few oddities about this process. (1) the drop in A1C occurs 2-3 years after the vaccinations but then seems durable – still in effect 5 years later and (2) it doesn’t impact the production of insulin by the pancreases of the patients. The patients are still diabetic, they just have better blood sugar control.
If you go into the paper understanding that it really is a metabolic hack that causes the drop in A1C’s it is much easier to understand. That said, BCG vaccination has also been used to treat a type of bladder cancer and multiple sclerosis. The latter presumably must be through actual immuno-modulation, right?
Super interesting. Thanks for posting this.
Yes, you are welcome.
Actually I haven’t been able to find any other person who found this interesting. No one I’ve told at work (largely research biology professors) nor anywhere else.
Just more indication to me of how weird biology is. Always something coming out of left field to surprise you.
Also the fact that these guys did an 8 year study when the end point they were looking for (restoration of pancreatic islet function) never happens. But they doggedly must have persevered tracking down the source of the 1 point drop in A1C that they did see.
Is there any indication what minimum level of beta-hydroxybutyrate would be necessary for this protection. That is could this be achieved by just taking a couple of grams of an exongenous beta-hydroxybutyrate salt.
@woody42, not really. My take was >2nM might reach the therapeutic range. But that is pure speculation on my part.
I’m doubting most people can get to >2nM just taking a couple of grams of exogenous BHB-salt. But it would depend on what your diet, etc. were like otherwise.
From the paper:
“Cellular quiescence is a crucial process for maintaining the stemness of embryonic stem cells (ESCs) through inducing autophagy. We did not show sufficient results to prove β-HB induces autophagy and autophagy-dependent cellular quiescence (An et al., 2014, García-Prat et al., 2016). However, we predict that β-HB can induce autophagy in vascular cells, as well as ESCs, based on our observations of AMPK activation and mTOR inhibition by Oct4 upregulation after treating with β-HB in vascular cells. ”
@rhonda – is this enough to make you consider a ketogenic diet? Since I started ~8 hour TRE, I have no difficulty maintaining >2mM BHB fasted most mornings of the week.
I’m considering experimenting a modified ketogenic-ish diet with an emphasis on salmon, avocado, olive oil, nuts…as long as I can eat a lot of leafy greens and some blueberries.
I also seem to have no problem getting high levels of BHB with a 16-hour fast.
What concentration of blood BHB do you get after a 16-hour fast?
Leafy greens don’t seem to be an issue for me. I’m eating 2 large salads a day sometimes. I put lots of a salad dressing I make myself on them–just “O-live” olive oil (~80%), Braggs ACV (~20%), sweetened with some raspberry stevia.
BTW, @RadioheadKush Peter Attia recommended this critique of the study:
It would be good to see Rhonda’s view on this, I’ve noticed a number of studies on mice with ketogenic diets that come to the same conclusion as this study. The key failure point for me is that fat is not a natural diet for mice, does the study have any relevance for humans or is it designed for failure?
@Magonrag @pmiguel There is a really interesting phenomenon that occurs in rodent studies given a ketogenic diet. Many of them tend to overeat unless they are given a calorie cap. In the literature, mice given a ketogenic diet that are allowed to eat ad libitum will develop obesity and metabolic problems. Mice that are fed a ketogenic diet that has a restricted calorie cap actually have improved healthspan and lifespan. I discuss this with Dr. Eric Verdin. I do not understand why rodents are not satiated on a ketogenic diet.
Thanks for the link Rhonda, I really appreciate your work.
@rhonda @Magonrag Yes and if the “KD causes T2D” meme was based on this phenomenon I would have some sympathy for it. But it is typically based only on the fact that a perfectly healthy animal in ketosis will be insulin resistant and eventually undergo some atrophy of its Pancreatic islet beta cells. But this atrophy and the insulin resistance is easily reversed by eating carbs for a few days as demonstrated here:
So Magonrag’s initial link was just someone click-baiting the internet.
The paper referenced by the medicalxpress.com article doesn’t come to the conclusion that the click-bait title suggests.
I have seen another rat experiment that did:
However it was based on the mice failing oral glucose tolerance tests and showing atrophy of pancreatic beta cells after being on a KD. It’s conclusions generated a rebuttal:
Irritatingly, the rat paper did not cite a previous study in mice showing the same effect. Perhaps because the study in mice showed that all the “T2D-like” symptoms were reversed when carbs were added back to the mice diets:
So the T2D diabetes that one gets from a KD can be reversed by eating carbs for a few days. Not really an issue, is it? The only real danger there is that you might fail an OGT test if you had been in sustained ketosis for a sufficient period of time–an issue frequently mentioned on ketogenic diet sites.
Meh. Hazard ratios below 2 – probably just looking at statistical noise. Although extremely high or low carbohydrate consumption might have been a marker for lower overall interest in ones personal health.
Pmiguel. Excellent content. Thankyou. I on the have followed a ketogenic diet for the past 3 years. I test ketones regularly out of interest, I do not aim at raising ketones, I find following a real food diet, limiting white carbs keeps me in the low nutritional ketosis range approx 0.5 to 0.8mmol quite easily.
Sleep effects it, type of exercise effects it. High intensity resistance training or metabolic conditioning circuits knock me out of ketosis, to drop back in later in the day, steady state endurance for an hour will drop me back in if I am out after a cheat meal.
Eating a sugary cake will make me lie down and be lazy for a couple of hours after, however if I have new potatoes in a meal it has no effect.
I started the diet 3 years ago, lost 30lbs in 2 months. Whilst reducing exercise incidently.
I still eat the same way (I am a monotonous creature of habit with meals) and in the following years my weight has regained 20lbs. However my fat percentage has not increased. It is currently 9.7% via dexa. Interestingly my muscle mass has been increasing from when my bodyweight hit its lowest %.
I practice bodyweight callisthenics each day as the stimulus. For me, a ketogenic diet has been excellent.
Magonrag you are welcome.
I’ve followed a ketogenic diet for about 5.5 years. Yes, I’ve noticed that my BHB levels drop after a powerlifting workout. I used to jog, but haven’t for many years. So its interesting to me that it might have a positive effect on ketones.
I hadn’t really intended to stay on a KD this long, but it suits me.
Here you go: this is a much better study. Clearly not “pro-KD” by any means. (This is 2010, the pro-KD camp would be a very tiny minority at this point.) The authors still seem to believe there is something bad about the effects of the KD, but at least they looked into and found that these “negative” effects were “rapidly reversed upon cessation of the diet”.
Again, Virta Health’s success reversing T2D using KD as well as studies showing increased average lifespan of mice fed a KD – as long as they were not allowed to become obese eating it – indicate the effect described are not ultimately harmful.
Discussed in another thread, but this letter to the editor politely (but completely) refutes “Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets” link: https://doi.org/10.1152/ajpendo.00208.2013
which, I think, is often the source of the “KD leads to T2D” meme. The meme seems absurd given Virta Health’s success in reversing T2D. But absurdity is no bar to meme propagation…
Hi pmiguel, many thanks for taking the time to review the study and article, and also for your insight.after reading the study at source thanks to your link I totally agree with you, I should be less naive when reading press releases in future, it’s interesting that a number of UK newspapers published similar articles denouncing a ketogenic diet on the back of this study yesterday, after reading the study it’s evident the articles are disingenuous. I wonder what is the agenda for someone to feed a flawed analysis to multiple national press outlets to discredit a diet that has immediate weight loss benefits when the lay person tries it.
Yes, I remember some years back reports in a ketogenic diet site of a British expose on the Ketogenic Diet. The reporters took one pair of twin brothers and put one of them on a ketogenic diet. Not sure if the manage to get the KD twin to fail an OGT, but to the extent they were just trying to smear KDs, they were remiss if they did not.
I think the medicalxpress.com coverage of this paper:
is poor. Actually it is probably just click-bait.
The paper itself doesn’t promote the perennial canard “KD makes you T2D!” After a cursory look at it, I think it is looking at the metabolic differences between a KD and the so-called HFD.
Of course mice aren’t just tiny humans and this isn’t their natural diet. But neither is mice chow. And very few human eat anything approximating a natural diet.
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