The Arrow #274

Greetings all.

Today’s Arrow, like the last one, is going to be a bit eclectic.

I’m going to start off with a sort of rant, photos included. It shows once more how shittification has become the norm.

A couple of weeks ago, I played golf with a friend, whom I’ve played with many times. I usually outdrive him by ten yards or so. This time, he was outdriving me by the same distance. He was using an older driver he hadn’t used in a while, and it was working well for him. I asked if I could give it a try.

When I did, I ended up outdriving him again. I used it a few more times with the same result, so I knew I had to get one.

I never, ever purchase new golf clubs. They are a rip…at least as far as I’m concerned. New drivers these days can cost $700-$800, which is insane. A metal head and a graphite shaft for hundreds of dollars?!?! It’s crazy. The parts probably don’t cost a hundred bucks total.

So I go through my favorite online purveyor of used golf equipment and end up finding the exact driver I’m looking for. For those interested, it’s a Ping 400Max 9 degree with the same shaft my friend has on his. It cost a couple of hundred bucks (free shipping included) and was on it’s way to me the next day.

A few days later, I get an email telling me the club has arrived and showing a photo of where it was delivered.

Notice the unreadable sign in the lower left of the gate.

Problem is, this isn’t the gate to our house – we don’t have a gate. We have a driveway and a mailbox. And I have no clue where this house is.

I go online to see if I can get someone to help me figure it out. It was delivered by FedEx, so I had to go through their bot to try to get it resolved. Which got me nowhere. I ended up recruiting MD to drive around the neighborhood with me to see if we could find it. It was a nightmare. It was rush hour, and many houses in Montecito have long driveways. Pulling in, then backing out onto the main street going through town was treacherous. So we abandoned that, drove back home, then walked around the area to see if we could find it.

We live off a small street (clearly marked with the address in big numbers) off the main street going through our part of town. We walked up and down the street, and I finally saw the box left against a gate. We couldn’t see it when we drove by, because the driveway curved 40 feet before it got to the gate.

I grab the box and notice the sign on the gate behind it, which I couldn’t read because it was blurred in the picture from the driver sent to me by email. Here it is.

I’m thankful no one had gone in or out of the gate before I got there, or the club may have been crushed and bent. Maybe the delivery driver couldn’t read English. Or just didn’t care.

A couple of days later I happened to get a phone call from one of our best friends. She and her husband own and operate an enormous fulfillment house in the mid-west. They ship stuff all over the world every day. I told her about what had happened, and she replied that FedEx was the worst of all the shipping companies. I always thought the company (which was started in Little Rock, Arkansas, a fact most people don’t know) was the best. It was the ‘when it absolutely positively has to be there overnight’ company! She said they were terrible and that they never used them. And recommended their clients not to use them. They used to be great, but no longer apparently.

So, shippers beware.

Parkinson’s Disease and Low-Carb

I received this email a week or so ago from a gentleman.

His email got me to puzzling on it. I asked MD, and oddly neither of us has ever directly treated a person with Parkinson’s Disease, nutritionally. So I dove in to see what, if anything, diet (or something else) could do.

I knew the basics about Parkinson’s from my medical education. But that was a long time ago.

I wanted to learn if there was anything in my domain (diet, nutrition, and metabolic health) that could be useful to treat the disorder.

So, I turned to my trusty sidekick Perplexity dot ai to see what I could find. I’ve discovered Perplexity is a vastly better search tool for medical issues than anything else I’ve tried. It far surpasses Google Scholar or anything else I’ve used to suss out papers.

Here’s what I found.

The progressive loss of dopaminergic neurons in one particular part of the brain (the substantia nigra) is the main issue with PD and to date there’s nothing on the horizon that I’m aware of that will bring them back online and producing adequate dopamine, but there is some research that the low-carb/ketogenic diet may be neuroprotective—i.e., that it may slow their loss and keep the remaining pool of nigral neurons working. 

But Parkinson’s disease is not only a dopaminergic motor disorder; it also involves mitochondrial dysfunction, oxidative stress, neuroinflammation, and prominent non-motor symptoms such as fatigue, sleepiness, urinary dysfunction, pain, anxiety, and cognitive impairment.  

If mitochondrial dysfunction, neuroinflammation, and oxidative stress are among the other mechanistic underpinnings of Parkinson’s Disease (PD), it would stand to reason that a low-carb/ketogenic diet might offer a means to address those issues and also provide ketones to fuel a brain struggling from impaired glucose metabolism.

I found an 8-week 2018 randomized pilot trial testing low-fat and ketogenic diets; both improved Unified Parkinson’s Disease Rating Scale (UPDRS) scores, but the ketogenic arm produced a much larger improvement in the portion of the score that measures non-motor experiences of daily living, with the biggest between-group gains in fatigue, sleepiness, pain, urinary problems, and cognitive impairment, symptoms that drive disability perhaps more than tremor or rigidity. 

The most persuasive mechanistic rationale for the improvement seen is that ketone bodies may provide an alternative fuel when glucose handling is impaired, while at the same time improving mitochondrial efficiency and reducing oxidative stress and inflammatory signaling. So it makes biochemical/metabolic sense that the diet should help. And it’s probably why researchers keep coming back to test ketogenic regimens in PD, despite the limited scope of the human literature so far.

To date while there’s not enough data to say that the ketogenic diet is a proven PD therapy, I think we can say that there is at least a biologically plausible mechanism for why it would be beneficial; it is generally feasible for most people to follow, and it may help some patients, especially with non-motor symptoms and quality of life. And since there’s essentially no downside to trying it as an adjunct while we wait for larger, better-controlled trials, why not? 

But there’s also another diet angle I found intriguing. And it’s decidedly not ‘low carb’. 

Particularly in the realm of autoimmune and inflammatory diseases, research attention of late has turned toward the microbiome and whether the disruption of it might weaken the gut’s protective barriers and allow for toxic insults to access the brain and nervous system. 

In my search down the dysbiosis rabbit hole I ran across this paper titled “Resistant starch improves Parkinson’s disease symptoms through restructuring of the gut microbiome and modulating inflammation” that piqued my curiosity even more. (And it didn’t even come from Perplexity. I found it while looking for another paper.)

This study looked at whether resistant starch, found in foods such as cooked and cooled potatoes, rice, beans, some whole grains, and unripe bananas could help people with Parkinson’s disease.

Arrow and PP readers are well aware of what a starch is – a long chain of glucose molecules hooked together by bonds that the human intestinal enzymatic machinery can easily break apart to liberate the sugar. But resistant starch is a little different. 

In it the links between the molecules have been altered to make them less readily broken by these starch-cleaving amylases in the gut. It develops when a starchy food has been first heated (cooked) and then chilled. Reheating will restore some but not all of the starch granules to digestibility, so even if later reheated a portion of them will remain resistant to digestion into glucose, essentially becoming analogous to ‘fiber’.

When eaten, these resistant starches travel on down the GI tract to become food for lower intestinal bacteria, which turn them into short chain fatty acids (SCFA) such as butyrate, propionate, and acetate. These fats nourish the colonocytes, and their presence alters the make-up of the microbiome.

So in this study, the researchers gave resistant starch to people with Parkinson’s and then tracked changes in their gut bacteria, inflammatory markers in blood and stool, and Parkinson’s symptoms over time. They found that resistant starch changed the gut microbiome in a helpful direction, increasing bacteria linked to gut health and raising short-chain fatty acid production. 

All signs of a healthier gut. 

Mechanistically, this is compelling because dysbiosis in PD is linked to lower SCFA production, impaired gut barrier integrity, endotoxin translocation, and downstream immune activation. Resistant starch can restore SCFA production, improve epithelial barrier function, and reduce inflammatory signaling, which may indirectly lessen neuroinflammation and support neuronal resilience.

And in the study above these changes were linked clinically to lower inflammation and improvements both in motor symptoms, such as movement and rigidity, and in non-motor symptoms, such as improved mood and overall quality of life as assessed on PD symptom rating scales.

What makes the study intriguing is that it supports the idea that PD is not just a brain disease; it’s a gut disease, too. So by feeding beneficial bacteria and improving gut health, it may reduce inflammatory signals that worsen Parkinson’s symptoms. 

Does the study prove that resistant starch is a cure or a replacement for standard treatment? 

No. But it does suggest that adding resistant starch to the diet could be a useful strategy for helping people with Parkinson’s feel and function better.

But what I felt was really exciting is there could be some synergy between ketogenic/low-carb diets and resistant starch through complementary mechanisms.

Ketogenic diets mainly address brain cell energetics, inflammatory tone, and oxidative stress by shifting fuel toward ketones, whereas resistant starch improves microbiome composition, SCFA production, gut permeability, and immune signaling. Together, they target two major PD-relevant vulnerabilities: impaired brain energy metabolism and gut-derived inflammatory stress.

That also explains why the symptom improvements in the study seemed strongest in non-motor domains. If the gut-brain axis contributes to constipation, fatigue, sleep disturbance, mood symptoms, and perhaps cognitive complaints, then resistant starch could improve those burdens from below; if the brain is under energetic and oxidative stress, ketone availability could turn the lights back on above. This dual-pathway logic is stronger to me than either intervention alone.

At the very least low-carb/ketogenic diets and resistant starch are rational, mechanistically plausible therapies worth studying more deeply.

What does that mean in food terms?

In Jason Fung’s really excellent book The Hunger Code, he describes how various starches respond to heating and cooling. Cooking, refrigerating, and reheating rice, for example he says, increases the resistant starch by two-and-a-half times. And the more times you heat and chill it the more resistant starch develops. (Great news for left over Chinese food, I guess.)

Potatoes develop resistant starch when cooked and refrigerated, but the starch behaves differently upon reheating and the resistance is reversed. Meaning of course that potatoes cooked and eaten cold, as in potato salad, would retain the resistant starch they developed. Dr. Fung says they have over 50% more resistant starch in them, which will, of course, lower the effective carbohydrate load of a serving and thus the effect on blood sugar and insulin. Baby potatoes are naturally higher in resistant starch than big Idaho bakers. 

I’d add a word of caution you may want to heed before going face first in the potato salad or the leftover fried rice.

Get yourself a continuous glucose monitor (CGM) and try some of these resistant starches out first to see what effect they have on your blood sugar. In Dr. Fung’s same discussion on resistant starches he mentions the lower glycemic index and the glucose and insulin curbing effect of eating steel cut oats over more processed versions (instant or rolled). I can say without hesitation that in our n=2 experiment with CGMs, MD and I both saw our blood sugar climb high and stay up for hours after eating steel cut oats. More so than any other food we experimented with. So, caveat emptor.

More on Perplexity

When I wrote about ApoB in the last Arrow, I wanted to find a particular paper. One by Ebbeling et al, as it turned out.

When I discovered the benefits of a low-carb diet forty-some years ago, there were so few papers available describing them that I could count them on one hand. I remembered both the titles, the years, and the authors of them all. Now the number of papers is in the hundreds, if not thousands, so even though I can sort of remember specific papers by what they say, I usually can’t remember the authors and the exact title. Which is where Perplexity is most helpful.

I simply ask it to find me a paper published between this year and that year (I can generally remember the time period in which the paper I’m searching for was published). I provide the gist of what the paper is about, and, Bingo, Perplexity usually serves it up. As a bonus, it occasionally produces another paper or two I didn’t even know existed on the same subject. (It’s almost like the old days when I went to the stacks and pulled journals and made copies. Well … almost.)

I went through this process in Perplexity when I was working on the ApoB section in the last Arrow, and it came up with the exact paper I was looking for: the paper by Ebbeling et al. And not only that, it came up with a link to the paper, so I didn’t even have to search my own database for it.

I clicked on the link provided and was taken to this paper in PubMed, which was not the Ebbeling paper.

Clearly, this is not the Ebbeling paper. I wrote the following to Perplexity:

I immediately received this response:

It’s sometimes difficult to imagine you’re not dealing with a real person, but an LLM instead. But because it is an LLM, one has to be mindful not to assume everything is correct. It can be correct, or sort of correct, or completely off the mark as was the citation above. Despite my love affair with Perplexity, I always keep a careful eye on her to make sure she hasn’t succumbed to infidelity.

LDL, ApoB, and PCSK9 Inhibitors

Since the great selling point of PCSK9 inhibitors is that they reduce ApoB better than statins, I’m going to take a minute to review ApoB, which is really just a marker of metabolic dysfunction.

Think of ApoB as a readout of how well your liver is managing the daily flood of fat and sugar coming in from your bloodstream. Under normal, insulin-sensitive conditions, the liver efficiently packages and exports only as many lipoprotein particles as the body needs. But when insulin resistance develops — whether from excess visceral adipose tissue, chronic high carbohydrate intake, or both — the liver loses its sensitivity to insulin's normal "slow down" signal. In a healthy metabolic state, insulin drives the degradation of newly formed ApoB before it can be assembled into a VLDL particle. But in an insulin-resistant liver, that degradation pathway is blunted, so more ApoB survives and gets packaged into circulating particles. The result is a higher output of VLDL particles, which ultimately become LDL particles and cascade downstream into elevated triglycerides, lower HDL, a shift toward small dense LDL, and, critically, a higher total ApoB particle count: which is the very definition of the classic atherogenic dyslipidemia of metabolic syndrome.

So, to repeat myself, ApoB is simply a marker of metabolic dysfunction. Reducing ApoB levels with a drug while leaving the underlying metabolic mess unfixed isn’t the optimal strategy for enjoying better health. Or even marginally improving your health. If you heard an ominous clanking noise coming from your car engine, you wouldn’t just crank up the radio so you could no longer hear it. You would instead head to a mechanic. But turning up the volume on the radio is sort of the same thing as treating a marker of disease rather than the disorder itself.

Okay, enough review, on to the PCKS9 inhibitors.

The liver cells are lined with tiny proteins called LDL receptors. These LDL receptors can kind of be thought of as little magnets that attract LDL particles floating around in the blood, grab them, and pull them into the liver to be broken down and eliminated. Once these receptors do their job and drop the LDL off to be destroyed, they recycle back to the cell surface to do the job again.

Each one of these receptors can make this round trip roughly 150 times. They could make the trip more times than that, but the liver also produces a protein called PCSK9 (proprotein convertase subtilisin/kexin type 9), whose job it is to sabotage those receptors.

When PCSK9 latches onto a receptor and gets dragged inside the cell along with it, the receptor can't detach and return back to the surface to grab another LDL. Instead, it gets sent to a cellular "shredder" (called a lysosome) to be destroyed. Fewer working receptors means more LDL stays stuck in your bloodstream. And, of course, more LDL in the bloodstream triggers cardiologists, who want it down, down, down. Usually without a thought as to why the level might be elevated in the first place.

Enter the PCSK9 inhibitors. 

PCSK9 inhibitors are monoclonal antibodies made in the lab that target the protein PCSK9 before it can grab onto an LDL receptor. The LDL receptor that might otherwise have been dragged off to the lysosome (the shredder) and been destroyed now can escape that grisly fate and head back to the cell surface and grab another LDL. As long as the PCSK9 protein is inhibited by the drug (the PCSK9 inhibitor), the LDL receptors work away feverishly and reduce LDL levels in the blood.

And the cardiologists are very happy. And so is Big Pharma, because PCSK9 inhibitors cost anywhere from $5,000 to $6,000 per year. They lost their big cash cow when statins all went generic. Statins, too, cost a fortune before they went generic.

Here is an interesting fact most people, including most doctors, don’t know about statins.

Statins actually increase PCSK9 production as a side effect, which partially undermines their own effectiveness. Combining a statin with a PCSK9 inhibitor counters that rebound, and together the two drugs can cut LDL by more than half compared to a statin alone.

(Betcha never heard that before statins went generic and PCSK9 inhibitors came on the market. The seminal paper showing statins increase PCSK9 came out in 2004, when statins were really just getting kicked off.)

Many cardiologists now put people on both drugs. (Because two drugs is always better than one. Right? Jesus wept!)

But I’m not sure they’ve thought it through.

LDL is the main lipoprotein that floats through the bloodstream carrying cholesterol to the tissues that need it. Almost every cell can make cholesterol if push comes to shove, but most of it is shipped out via the LDL particles from the liver. 

The liver also makes PCSK9, the protein that disables the LDL receptor. Why would the liver want to disable the LDL receptors? Do you suppose there is a reason? Might it be that the tissues are calling for more cholesterol? If the receptors on the liver cells are grabbing it out of the blood, that means less is going out. It’s kind of like blocking the Strait of Hormuz.

Since the liver is the main organ regulating most of what goes on metabolically, it sounds reasonable that a signal from the tissues for more cholesterol might stir the liver into action to provide more. The means it has of providing more is to make the PCSK9 protein, which disables the LDL receptors, which, in turn, means more LDL particles circulating to the tissues instead of getting jerked back into the liver.

Sounds like a finely tuned machine to me.

When metabolism goes south, the system obviously isn’t as finely tuned as it should be. 

As discussed above in the review of ApoB, the issue is caused not by random elevations of LDL and/or ApoB. It is driven by a disordered metabolism – typically insulin resistance.

Treating the blood markers LDL and ApoB doesn’t really solve the underlying problem. It just solves the lab results. But that’s apparently what makes cardiologists happy.

The problem with these drugs is that though they do a great job (in most cases) of lowering LDL and ApoB, they don’t do a particularly great job at keeping those who take them from dying. Which, to my mind, anyway, is the most important factor to be considered.

There have been a ton of studies done on statins. Below is a graphic I pulled from PubMed of all the studies on statins published over the past few decades. I ran my cursor over the line representing 2014, when the number of studies reached an all-time high of 3,880 studies on statins done in that year alone. Most of the other years are not that far off. What can be gleaned from this little chart are that there have been a sh#tload of studies done on statins.

I have not read them all. I have not read anywhere close to the total number. 

But I have read the first studies on statins done early on at a cost of millions of dollars, vastly more than the rest of the studies on the list. Those studies showed that statins did indeed minimally decrease the number of heart attacks in those who took them. But they did not decrease all-cause mortality. In other words, they didn’t make people who took them live longer. Which should be the sine qua non of what a decent drug should do.

If the drug prevents a number of heart attacks and makes those who take it live longer, then you’ve got a valuable drug. But if it just shifts the cause of death to something else, what’s the point?

If you go on X/Twitter and post that statins don’t improve all-cause mortality, some nimrod will immediately reply with a study showing they do. You can’t possibly contradict them with another study showing they don’t, because you’ll immediately be hit with another post from the same nimrod contradicting you. (For all I know, said nimrod may well be a bot operated by a drug company.) In any case, it’s a mug’s game, so I try not to play it.

I’m sure a handful or more of the many thousands of studies may show a decrease in all-cause mortality, but there are just as many – or more – that don’t. Plus the early hugely expensive ones don’t.

But just for argument’s sake, let’s say they do modestly at best improve all-cause mortality.

This increase comes at a price. And I’m not just talking about the price of the drug (which can be huge), I’m talking about the side effects.

I asked Perplexity to review the package inserts on statins, on PCSK9 inhibitors, and the two-drug combo and list the side effects. It came up with the following chart:

So, in taking these drugs together or separately one is risking a number of side effects that can severely compromise one’s quality of life for very little, if any, guarantee of an extension of life.

To me, that seems like a bad trade off.

Changing from a see food diet (I see food; I eat it), i.e., the typical American diet to a low-carb/ketogenic diet that provides an abundance of quality foods seems like a much better choice to me than taking shots a couple of times per month and/or downing a statin, which can cause diabetes (especially in women).

But that’s just me. Others may differ.

Speaking of X/Twitter…

A reader emailed me a link to a great X/Twitter post.

I have a few very minor quibbles, but for the most part the tweet is right on. One quibble is that in 1953 and 1954 major studies were published showing the relationship between smoking and lung cancer. So not all the studies were funded by tobacco companies. These two studies — the Doll, Hill studies — were taken seriously by the medical community, and many doctors stopped smoking and encouraged their patients to do so as well. Obviously, the tobacco industry fought back, but these two studies were the beginning of the end for Big Tobacco.

Odds and Ends

• Cargo of a Roman merchant ship dated from between 14 and 37CE found at the bottom of a Swiss lake. Some people have all the diving luck!

• World's oldest gorilla celebrates her 69th birthday with a veggie feast.

• Cursive writing--that most human and artful communication device--and why it's still important.

• Greatest song lyrics? Maybe. Where is 'To dance beneath the diamond sky with one hand waving free... silhouetted by the sea... circled by the circus sands... with all memory and fate driven deep beneath the waves... let me forget about today until tomorrow?' Oh, well. Can't please everybody. 

• Return of the Cloud Jaguar. Spotted creature spotted for the first time in a decade.

• Eavesdropping on sperm whale communications, researchers find that their vocalizations are surprisingly like human languages. Take a listen.

• A simple little rule of 3-3-3 that may make it easier to stick to your workout routine. MD and I double up the strength and cardio doing a workout involving both three times a week. Then 2-3 ARDs and at least one full rest day.

• New Chinese technology creates humanoid robots that can outrun humans in a half marathon. What could go wrong here?

• The amazing prehistoric finds under Pembroke Castle, birthplace of Henry VII. I am always intrigued by the layers of civilization that once excavated illuminate our past.

• Apparently this is a real thing. Who knew?

• What an amazing find!! Incredible. A fragment of Homer's Iliad, which almost makes the 1,600 year old mummy itself seem mundane.

• On April 23, 1985 Coca Cola launched one of the biggest marketing flops in history. Why was it such a dismal failure?
  

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Video of the Week

When I was a kid, there were all these shows on TV that were made for movie shorts in the 1930s and 1940s. They were all black and white, of course, but I didn’t know the difference as our TV was black and white. My family didn’t have a color TV until I was a junior in high school.

My favorites of these short films were The Three Stooges. I can still make all the noises that Curly made and do all the hand gestures, which, believe it or not, were difficult to perfect.

The films I hated were any of the ones involving the Marx brothers. I especially loathed Harpo Marx, who, I thought, was an idiot. He didn’t talk and did nothing but run around chasing women and sounding that stupid horn that he squeezed the bulb to make it honk.

I had no idea why he was called Harpo. I figured it was just a stupid name to go along with his stupid antics. Little did I know that he could actually play the harp. And play it well. Thus his stage name.

Since I have quirky music tastes, I get fed all kinds of different music via YouTube. Imagine my surprise when I got the video below of Harpo Marx playing the harp.

It inspired me to read a little more about him. Strangely enough, he was apparently a helluva croquet player. He was inducted to the Croquet Hall of Fame. Not only was he not mute, he had a deep, stentorian voice. Who knew?

Enjoy!

Oh, and BTW, this is not the complete Hungarian Rhapsody #2 by Liszt. Marks starts out with it, then mixes in a bunch of other stuff before he finishes off. But it’s genius.

Time for the poll, so you can grade my performance this week.

That’s about it for this week. Keep in good cheer, and I’ll be back soon.

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This newsletter is for informational and educational purposes only. It is not, nor is it intended to be, a substitute for professional medical advice, diagnosis, or treatment and should never be relied upon for specific medical advice.

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