Now that I’ve dug into supplements that target the mitochondria I can get to my original tangent into clinical mitochondrial medicine. Here, researchers are using genetic tools and/or prescription-grade drugs targeted to correct genetic errors or metabolic defects in the mitochondria.

As an aside, keep in mind that the supplements I discussed in the last post are short on clinical studies and long on extrapolation from early-stage animal and biochemical (i.e. test tube) data.

You may recall that our mitochondria have a bacterial-like ‘chromosome’ that carries genes for 13 of the proteins in their inner membrane (you can see the membranes in the picture at the top) that carry electrons (to transfer energy to our energy currency molecule – ATP), as well as genes that produce 24 RNA molecules involved in the production of those key proteins. There are many other mitochondrial genes that, once upon a time, were part of the original prokaryotic genome, but have been moved to the nucleus of the host cell. (If this last sentence didn’t make sense, I burrowed into the evolutionary history of these organelles in the previous 2 posts on their origin story.)

The first disease found to be caused by mutation in the mitochondrial genome was identified in 1988: Leber hereditary optic neuropathy, which results in a loss of vision. Mutations in nuclear genes can also cause diseases that affect mitochondrial function. Over the last three decades, mutations causing these disorders have been identified in almost 300 genes, but the underlying causal mechanism is not known in most of them. A recent review listed 12 of these, for which mechanisms producing the disease symptoms, and potential therapies, are available.

These are pretty rare diseases: an estimated 1 in 5000 adults affected. They can start up at any time in life, with a range of symptoms. Not surprisingly, these diseases mainly affect organs with a high energy demand, particularly the heart, muscle, and brain.

One such that piqued my interest is thiamine pyrophosphokinase (TPK) deficiency – not exactly a household name but read on, you’ll recognize some of the players. In this disease, an enzyme (TPK) is not made due to a mutation in its gene. The lack means that vitamin B1 (thiamine) which we get from food or supplements, is not converted into its active form, called thiamine pyrophosphate (TPP). TPP is used in many basic cellular processes involved in energy production such as the Krebs cycle. This fundamental metabolic pathway, which occurs in the mitochondria, removes electrons from our foodstuffs. Remarkably, simply supplementing with vitamin B1 can reverse the symptoms in over 50% of people with this mutation; adding biotin, another B vitamin, improved outcomes even further.

But that’s old school medicine. What’s really intriguing is the application of new, cutting edge technologies to diseases caused by errors in mitochondrial genes. This new approach is shifting the field from managing symptoms to addressing underlying genetic and metabolic defects using techniques like precision gene editing, mitochondrial transplantation, and small molecules (i.e. synthetic drugs) that target mitochondria.

Let’s start with a simple (!) example, of a small molecule. Idebenone is a drug designed to look and act like CoQ10. CoQ10 is a small molecule that interacts with the large electron-transporting protein portions, called complexes, of the electron-transport chains. Idebenone is used to treat disorders due to mutant genes that disable complex I – the first of three such protein machines. The drug works by transferring electrons directly to complex III, bypassing complex I. Idebenone has been shown to improve conditions like Leber hereditary optic neuropathy, and been approved for its use in Europe.

We can’t get too excited about the small molecules however, because of several problems. These include poor bioavailability - those two membranes limit access; difficulty in making them tissue specific (as many mitochondrial diseases are expressed only in certain tissues or organs); and heterogeneity in patient outcomes - due to differences in their mtDNA mutations. Many labs are exploring nanoparticle‐mediated delivery to selectively target mitochondria and thus enhance drug uptake.

So let’s jump to some of the more science fiction-y approaches to treating diseases caused by faulty mitochondria. About 20 years ago a Japanese scientist observed mitochondria moving between different types of cells in petri dishes. Since then, researchers have extracted, concentrated, and modified mitochondria and then transplanted them into affected cells.

Here is one cool example. We know that in type 2 diabetes, the beta-cells in the so-called islet regions of the pancreas, which produce insulin, are in a state of constant metabolic activity to produce and package the hormone. This means high demand on the mitochondria to make the ATP which fuels the production line. This constant demand on the mitochondria generates lots of damaging reactive oxygen species (explained in more detail in the previous two posts). Inevitably the insulin production declines and the diabetic condition results.

Enter the transplanted mitochondria. In petri dishes, stem cells from fat tissue can transfer mitochondria to the insulin-producing beta cells. But moving cells into the pancreas is tricky, so the stem cells are grown together with isolated human donor islets. The mitochondria essentially transfer themselves, thus “recharging” the islets’ batteries and giving them a survival edge before they are transplanted into diabetic patients. In the past 5 years, there have been over 20 small clinical trials using this method resulting in significant improvements in diabetic individuals.

So far we’ve seen that drugs can either (1) get into mitochondria and correct internal faults – sort of like changing your oil after 20,000 miles, or (2) be given as supplements to provide a missing compound essential to mitochondrial function – a bit like adding detergents or octane boosters to your gas tank. On a finer level, (3) ineffective or damaged mitochondria can even be replaced.

But what about targeting the genetic causes themselves? This idea is pretty futuristic, and many gene-editing approaches have been tried. Currently, the most powerful of these is the CRISPR system, and to date has been approved to repair mutant genes in sickle cell disease, another anemia called beta-cell thalassemia, a rare liver disease called transthyretin amyloidosis, and to modify patient T-cells outside the body for re-infusion to treat cancers.

If you’d like a visual overview of CRISPR technology (and the precursor gene editing methods):

This is clearly an amazing and powerful technology (that was developed first by bacteria!) but applying it to the mitochondrial genome is still beyond our reach. If you look at the pretty picture at the top of this post, you can see why. Mitochondrial genomes are protected by two membranes which are very picky about what they let through. To date, no one has figured out how to get the bulky CRISPR molecular machine in! That said, its potential for treating and curing other human diseases is almost untapped. Gemini tells me there are over 200 startups currently using this gene-editing method to treat more common disorders such as cancer and heart disease. The big question is when will the price come down? The list price for the first FDA-approved CRISPR gene therapy - for sickle cell disease, brand name Casgevy - is $2.2 million per patient. This is just chapter one in what some clinicians are calling Medicine 2.0 – an exciting time in biomedical research.

Now that you know about the vital role of the mitochondria, you no doubt appreciate the potential impact of maintaining and even optimizing the health of these cellular powerhouses.

I want to emphasize several points before getting to the possible role of supplements. First, our mitochondria inevitably accumulate damage as we age. Remember that mitochondria contain their own circular DNA – a very reduced remnant of their origin as free-living single celled organisms. This genetic material is highly vulnerable to damage because it lacks the robust repair mechanisms found in the cell’s nucleus.

You doubtless also recall that at the end of the electron transport chain, where ATP is produced, oxygen takes the spent electron away. This step can produce ‘reactive oxygen species’ as a toxic byproduct. These are so-called free radicals that can compromise the mtDNA, causing small mutations and large-scale deletions.

Damaged or deleted mtDNA strands are often smaller. Because they are smaller, they can replicate faster than healthy mtDNA. The cell inadvertently clones the mutated versions, causing them to take over the mitochondrial pool, with suboptimal replacements.

Second, as our cells age, the sensors that tag a mitochondrion as “damaged” don’t work as well. The cell fails to recognize the garbage, allowing mutated mitochondria to linger. And, the signals that tell the cell to manufacture new, ‘original part’ mitochondria become less effective. As a result, the replacement rate drops off.

In this post, I will discuss the supplements that get the most press as maintaining and bettering mitochondria function. Keep in mind that I’m pretty skeptical about claims based on small sample sizes or animal data alone.

1.NAD+ is a really important molecule in the cell. Its best-known function is as the delivery truck for those electrons from the cell’s interior (called the cytoplasm) to the mitochondria. Once NAD+ docks on the mito-membrane, the electrons are shuttled into the electron transport chain (ETC) and a now-vacant NAD+ is recycled to repeat its task. Without enough NAD+ mitochondria can’t produce enough ATP to power a cell. This is not usually a problem (well, not until we get older, see below) as cells can build NAD+.

A lot of data shows that NAD+ levels - in a variety of tissues - drop as we age. This correlation suggests, but does not confirm, that low NAD+ contributes to age-related declines. Correlations can be dangerous, seducing us with their likely explanatory power, but experimental confirmation is required. There are a lot of examples of spurious correlations. One of my favorites: Murder rates in Detroit go up in the summer; ice cream consumption also goes up. Conclusion: Eating ice cream causes homicidal rages. (Well maybe but probably not enough to explain the observed increase.)

Some of the observed decline over time happens because certain enzymes (including sirtuins for those of you familiar with this story) that protect DNA and counter inflammation are used more and more as we age, to counter age-related damage. These reactions consume and don’t recycle NAD+ thus using it up faster than the body can produce it.

When NAD+ levels drop, the efficiency of the electron transport chain drops too, so ATP production falls off and toxic reactive oxygen starts accumulating. Remember that oxygen is required to pick up the spent electrons at the end of the electron transport chain (ETC). If you think of the ETC as a bucket, with a spigot at the bottom, the tap is open when oxygen is present. Electrons can keep entering the bucket only because the tap drains them off once they’ve transferred their energy to the enzyme that makes ATP. If the tap is closed i.e. no oxygen around, then the whole process backs up and no ATP is made – with very unfortunate consequences. Alternatively, if there are a lot of electrons available (i.e. lots of food) but you don’t need the energy, ATP production slows and unused oxygen can generate ‘oxidative stress’, another term for the damage that can be caused by uncontrolled oxygen atoms.

So, assuming that NAD+ levels need supplementing (remember the data are inconclusive), how do you do that? The first thing you have to know is that you can’t just take a pill because NAD+ is broken down in the gut. (Intravenous injection does bypass the gut but aside from being pricey, has many unpleasant side effects and the effect on intracellular NAD+ level is extremely variable.)

You can mimic the way your cells naturally do it. The most efficient way is to take the pieces (NMN and NR) from the breakdown of NAD+ and put them back together. Or you can start with a B vitamin (B3 aka NA), that the body also uses. Finally, you can build it from scratch, starting with an amino acid, tryptophan. De novo synthesis is a pretty inefficient, costly pathway in terms of energy. Let’s look at the first two possibilities. I will stick with acronyms for most of these compounds because their full names are mouthfuls.

A side note on taking high doses of B3. As an important B vitamin, our bodies have proteins that pick B3 up from the gut and carry it across cell membranes. However, at the high doses required to boost NAD+ it causes an unpleasant side effect called the niacin flush. Blood rushes to the surface of the skin, causing intense redness, a hot prickling sensation, and severe itching—usually starting on the face and spreading to the neck, chest, and arms. Although it’s not dangerous, longterm use can have some more serious effects.

We can get the building blocks for NAD+ in our food – all living organisms have mitochondria, and thus contain NAD+. This NAD+ in the gut is first broken into NMN, which is then converted to NR, which is then converted to a third precursor, NAM. All of these building blocks can be used to build NAD+ but while NR can get out of the gut and then into cells, in most tissues, NMN cannot cross a cell membrane.

A recent study springboarded off animal work that suggested in rodents, gut bacteria may convert NR or NMN into the more potent NA, thus supporting the use of oral formulations of both precursors. If our gut bacteria convert oral NR and NMN into nicotinic acid (NA) this would be gradual in the digestive tract; slow, sustained microbial release would avoid the massive, sudden spike in free NA in the bloodstream that normally triggers skin-flushing receptors following oral NA.

This randomized, placebo-controlled study gave oral NR, NAM, and NMN to 65 healthy participants for 14 days. At this time, the level of NAD⁺ was measured in blood. I like the study design, half males and females, but the sample size in each supplement group was quite small – about 15, and the average age was 37, so the results are difficult to interpret for an aging cohort. NAM increased blood NAD+ after 4 hours, but the level did not stay up for the final test at 14 days; whereas both NR and NMN roughly doubled blood NAD+ at the later endpoint.

NR metabolism was very consistent in the 16 individuals who received it, supporting its potential for wide use. But what about NAM? Nicotinamide (NAM) is widely used as an oral supplement and is one of the most common, affordable forms of vitamin B, and doesn’t cause the flushing reaction. There is a downside to NAM: high doses of oral NAM can inhibit the anti-aging enzymes (sirtuins) I mentioned earlier; NR and NMN don’t do this.

To evaluate the role of gut microbes, the researchers took gut microbes from fecal samples of 6 people not tested for NAD+ metabolism, and gave the bugs NR for 48 hours. The bacteria rapidly converted NR to Nam, which was converted to NA. In other words, gut bacteria do not produce more NMN or NR; rather, they convert them into NA. Our blood is good at converting NA into NAD+, but it cannot directly utilize NMN or NR.

This study suggests that NR is the best bet for upping NAD+; at least in the blood. It seems pretty safe at standard dosages: 250 mg to 1,000 mg per day. Clinical trials—including high-dose safety studies up to 3,000 mg daily—also report positive outcomes. But before you jump into NR, remember a few caveats. First, the one small human study referenced here, used relatively young subjects. No guarantees for us older folks. The Petri dish studies of metabolic activity of microbial bacteria are suggestive, not proof positive that the oral NR you take will actually convert to NAD+. Finally, no studies look at the final tissue destinies of NAD+ in the blood. Presumably, as it can cross cell membranes, it goes where needed, but we don’t know that.

Next, when your cells process NR to build NAD+, the excess byproduct is converted into nicotinamide (NAM) and ultimately joined to a compound called a methyl group to be excreted in urine. Taking chronic high doses of NR could theoretically deplete your body’s pool of methyl sources which are vital for DNA activity, liver health, and neurotransmitter synthesis. For this reason, some people taking NR also take a methyl supplement—such as trimethylglycine (TMG) or methyl-B12— especially if they have a genetic condition that affects their ability to produce methyl groups.

One final caveat: This nicely designed study was carried out by a team at the Nestle Research Headquarters in Switzerland. Nestlé owns and manufactures several cellular health and healthy-aging product lines. For example, their Celltrient Cellular Energy brand includes Tru Niagen (NR) to target NAD+ boosting. They also own brands like Solgar and Pure Encapsulations, which also sell NR. Confict of interest?

(If you’d like an en easier to digest summary, but note it’s put out by the company.)

Full disclosure: 6 or 7 years ago when I first became aware of the decline in NAD+ with age, I tried several brands of NR/NMN – my n of 1 analysis – no effect!

2. COQ10. Like NAD+, CoQ10 levels decline with aging as well as statin use. Given that there may be as many as 40 million Americans on these LDL-lowering drugs, the effect could be significant! CoQ10 contributes to mitochondrial health in two ways. First, this compound is an essential electron carrier in the mitochondrion. Remember that the electron transport chain (ETC) is a group of proteins (actually several distinct groups but we don’t need to worry about that) embedded in the inner membrane that extract the energy from electrons to build ATP. CoQ10 is an electron shuttle in each of the groups.

Although oral CoQ10 can successfully cross cell membranes and penetrate the highly selective inner mitochondrial membrane to enter the ETC, most of what you take in a pill doesn’t get that far. You can hedge your bets by taking oil-based softgels and taking your supplement with a fat-containing meal. Supplementing with ubiquinol (the active antioxidant form of CoQ10) improves its bioavailability. Finally, it’s alleged that synthetically modified compounds (such as a pricey supplement called MitoQ) attach a positively charged molecule to the CoQ10 core. Because the inside of a mitochondrion is negatively charged, these compounds are actively pulled directly into the inner mitochondrial membrane at a higher rate. As was the case with NAD+ supplements, the few human studies are small, and sometimes carried out by the manufacturers. I have taken CoQ10 for years, and can’t say it does anything, but I haven’t figured out how to clone myself to do the experiment. That snide remark aside, I think there is enough evidence to take it but I won’t spend the money on MitoQ.

3. Urolithin A (UA). This compound has been used by body builders for over a decade to stimulate muscle growth. It has been reported to have diverse positive effects including anti-inflammatory, antioxidant and anti-tumor action. In terms of muscle, some evidence suggests that Urolithin A may promote muscle protein synthesis and muscle growth. Our gut bacteria naturally make small amounts of UA from compounds in pomegranates, berries and nuts. Because diet, age, genetics and disease affect the composition and activity of the gut microbiome, people produce differing amounts of UA; here the supplement industry steps in.

Urolithin A turns up a series of biochemical reactions that are triggered by low energy levels in cells, ultimately increasing the number of mitochondria – which will counter the low energy. Of course, this will increase ATP available for muscle action thereby facilitating muscle growth.

In addition, Urolithin A may enhance the breakdown of old, damaged mitochondria, a process known as mitophagy. Mitochondrial autophagy is especially important as we age as it facilitates the turnover of mitochondria and prevents the accumulation of dysfunctional ones, which could result in a cell being unable to provide sufficient energy to survive. Mitophagy also adjusts mitochondrial numbers and organization to meet changing cellular energy demands.

I should note that both of these findings about the role of UA in mitochondrial health have been validated primarily in test tubes, and in a few studies of mice, using biomarkers that may or may not reflect mitophagy. There are a few small human studies in which small groups, usually of older men, were given UA, and showed improvement in exercise-based tasks. I have experimented with UA, couldn’t notice any effect after 3 months so quit – a few years ago the price tag was high enough to dissuade me from further use.

4. Pyrroloquinoline Quinone (PQQ) is the last supplement, and much less well-known than the previous three. It triggers a metabolic path that has numerous beneficial effects in cells: activating mitochondrial biogenesis; assisting enzymes in the mitochondrial respiratory chain, helping optimize ATP (energy) production, neutralizing harmful free radicals directly inside the mitochondria, and lowering reactive oxygen species (ROS) that can damage cell structures.

While these effects have been verified in animal models and Petri dishes, human studies struggle with oral bioavailability—meaning much of the ingested supplement is metabolized before it ever reaches target tissues to stimulate actual mitogenesis. Based on the available information, I think there is no support for taking this.

There are a few other supplements that may or may not provide key elements important to mitochondrial function, but evidence for this specific action is lacking. If you want a top ten of these, and brief descriptions go here.

Concluding thoughts: Our mitochondria definitely decline with age. It would be wonderful to have a magic bullet to fix them. I don’t see anything matching that description in the available supplements. NR is the best of the lot, and may be coming down in price with increased demand. But of course, like all supplements, there is no federal agency regulating and overseeing its composition and claims. So, like all over the counter formulations, unless you pay for high quality analysis, buyer beware!

Mitochondria have been front and center in a lot of longevity and anti-aging news for a long time. A lot of (often pricey) supplements claim to optimize the health of your mitochondria, get rid of damaged ones and even promote propagation of young, healthy organelles. The animal research for some of these is intriguing, and some scientists have preliminary human trials that appear to support some claims. I like to look closely at these anti-aging claims and get at the science. I can’t claim to have the ultimate answer, but as always, looking at the basic science can help us evaluate the claims and possible utility of trying to age-proof these critical cellular components.

There is so much to cover here that I’m going to break it into three posts. First, exactly, what are these little things that are so critical to life. Once you’re on board with what the mitochondria do, we can talk about how supplements might be able to support them. Finally, I’ll get into some of the less controversial, but really game-changing advances in treating diseases that are caused by dysfunctional mitochondria.

The story of our mitochondria is truly amazing. If you know it feel free to skip ahead, but I love it because it is such a one-off, and if it hadn’t (improbably) happened, none of us multicellular creatures would be around. Aside: the ‘endosymbiont theory’ that I describe here is a classic example of how science works; more and more data were put together into a coherent story that was at first rejected, then gradually accepted until now it is the official model.

Way, way back in the history of life on Earth, when bacteria ruled, pre-mitochondrial cells took up residence in other slightly more complex cells (known as eukaryotes, i.e. cells that had already developed a nucleus; from ‘karyon’ -Greek for kernel – what the cell nucleus looked like to early microscopists). Those early, proto-mitochondria retained many traits inherited from their free-living ancestors, which were a diverse group of prokaryotes (aka and affectionately known as proks, which is the more correct term for the single cells we often call bacteria). But in the process of transforming from proks into mitochondria, they banished almost all of their genes to the nucleus of the host cell.

Scientists can force this engulfment in a lab setting but what typically happens is that the intruder cell dies; either eaten of killed by the host. But on one happy occasion, some 1.5 billion years ago, instead of being digested, the prok provided an efficient process, that utilized oxygen, for storing energy in ATP. What did the prok get in return? Protection and nutrients. Of course, this didn’t happen overnight and over countless years, the resident prok became a true organelle, or little cellular organ, one of many that contribute to the maintenance and life cycle of every cell in the body of eukaryotic creatures (critters whose cells have a nucleus and other organelles) like ourselves.

If you want to explore this endosymbiont theory in more depth, here’s a good video:

Mitochondria still retain their own circular DNA (mtDNA), a characteristic of proks, as opposed to our linear chromosomes. This tiny chromosome carries only 37 genes. Of these, 13 encode key proteins in the electron transport chain, the functional part of the organelle, of which you will hear more below; the remaining 24 code for RNA molecules that are used to regulate or facilitate protein synthesis in the mitochondria.

This organelle is inherited exclusively from mom, packaged in the egg that gave rise to each of us. This maternal origin lets scientists study so-called mtDNA (because it’s the DNA in the. Mitochondrion), that can explain ancient human migrations and ancestry. In addition, because mtDNA determines how cells generate energy, mutations in this DNA can cause inherited metabolic and neuromuscular diseases that are always passed from a mother to all her children. We’ll come back to these in the last post.

Let’s take a look at the key functions of mitochondria so you can understand why they are so important to health and longevity. First, and best known, they are the main drivers of ATP production. Embedded in the inner of its two membranes is a string of proteins known as the Electron Transport Chain (ETC). I think of this group of proteins like a bucket brigade that takes electrons from foods (glucose, fatty acids) and in a series of small steps transfers their energy from food to a ubiquitous energy storage molecule called Adenosine Triphosphate (ATP). This series of steps ends when the used-up electron is dropped off with an oxygen atom, then immediately combines with H+ into a water molecule. The whole process is called oxidative phosphorylation and is the reason we have fancy organ systems to breathe and move blood around the body – to get oxygen into cells to pick up electrons.

For a nice graphic overview, you can watch this YouTube; but beware, the AI voice mispronounces almost every jargon term!

The mitochondria are also involved in some other important processes that I’ll come back to when I tell you about some new advances in treating diseases caused (mainly) by genetic defects in the mitochondrial genome. We will get to some of the claims in the supplement field, which include these 4 silos: NAD+ Precursors (NA, NR, NMN); Coenzyme Q10 (CoQ10 / Ubiquinol); Urolithin A and Pyrroloquinoline Quinone (PQQ).

But first, you guessed it, a little more background. In our first few days of life, all our mitochondria are the ones we got from mom in the egg, which has roughly half a million! During the first few divisions of the fertilized egg, these just get divvied up but eventually, and for the rest of our lives, we replenish the supply.

This process, called mitogenesis, or sometimes biogenesis, is obviously important, and is a primary target for supplement claims. Because mitochondria are always active – your cells constantly require energy in the form of ATP to stay alive – they can be damaged by exposure to oxygen (think of how metals rust), or just wear out. As they accumulate damage, they release compounds that tell the cell they need replacement. Different tissues have different turnover rates of their mitochondria i.e. time required to completely replace ALL these organelles. For example, a liver cell does this about every 10 days, and the heart, which is arguably your busiest muscle, approximately every two weeks.

Our cells also use environmental cues like exercise, cold exposure, and low ATP levels (such as induced by fasting) to ramp up more mitochondrial production. We don’t make mitochondria from scratch; new ones can be built by either fission (dividing an existing one into two) or fusion (combining two smaller ones into one larger one).

One final note on mitochondria in muscles. Since this tissue is a big energy consumer, the supplement industry targets a lot of its claims to enhanced muscle function via mitochondrial improvement. Of course, I want you to be able to evaluate these claims.

Our skeletal, or voluntary, muscle is a weird tissue. It starts out as cells (stem cells to be exact), then as it grows, these fuse to form long fibers that are designed to contract against the bones to which they are anchored, thus moving us. Inside the muscle fibers, individual mitochondria connect to each other to form a continuous grid that transmits energy rapidlythroughout the fiber. This network is constantly remodeling through cycles of joining (fusion) and splitting (fission), giving muscle a unique ability to adapt rapidly in response to changing metabolic demands.

The next post in the series will look in detail at the role of the most common supplements: NAD+ precursors (i.e. building blocks) - as this compound is critical to mitochondrial function; COQ10, which is a component of the electron transport chain; Urolithin A, which targets a master switch in cellular metabolism that, among other things, ramps up production of new mitochondria; and Pyrroloquinoline Quinone, which, similarly, targets another cellular master switch. Stay tuned - coming soon!

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, after Alzheimer’s disease. Alzheimer’s robs us of our memory, cognitive abilites, and eventually our lives. Parkinson’s starts by taking away our coordination and fine motor control, and eventually leads to death as the respiratory muscles fail. Like AD, PD is caused by damage and ultimately death of specific groups of nerve cells in the brain. The neurons involved in PD are located in a brain region called the substantia nigra. These cells produce dopamine; the fall in dopamine levels causes the symptoms of the disease.

Although we typically link dopamine with the brain’s reward system, it is also an important chemical messenger that facilitates smooth, coordinated movements of our muscles.

While the exact trigger is unknown, scientists believe it results from a combination of genetic changes and environmental factors like toxin exposure. Symptoms develop slowly and include tremors, rigid muscles, slowness, and balance issues

Like so many other degenerative conditions, as we get older, our risk for PD increases. Less than 4% of people with PD develop an unfortunate early-onset form of the disease before age 50. Prevalence rates grow from roughly 3.8% in adults in their 40s to over 25% in individuals older than 89

Currently about 1.1 million people in the U.S. are living with Parkinson’s disease, and this number is expected to rise to 1.2 million by 2030. Nearly 90,000 people in the U.S. are diagnosed with PD each year, with an average onset age of 60, and the incidence rate increases sharply with each advancing decade of life.

Although men are 1.5 times more likely to have Parkinson’s disease than women, over time the ratio equalizes as women live longer, and as we have seen, risk continues to increase with age.

We’ve known about PD for over a century, and a combination of medications that boost dopamine, novel surgical options like deep brain stimulation (DBS), and targeted physical or speech therapies can be quite effective, especially when started early during the disease.

My intent here is not to give you an exhaustive peek into PD but to tell you about a fascinating hypothesis as to its cause. This idea surfaced about 20 years ago but recently has gotten more press due to increased information and awareness of the microbiome. In many people with PD, it may have gotten its start when misfolded α-synuclein proteins form in the gut and travel to the brain via the vagus nerve.

Ok, these terms need a little explanation. You may have heard of the vagus nerve. Its name means wanderer in Latin. It perfectly describes this nerve (cranial nerve 10), which is the longest and most complex nerve in the body. It wanders all the way from the brainstem down to your chest and abdomen, connecting to almost every major organ, including your heart, lungs, and gut along the way.

A misfolded protein doesn’t work as it should because much of a protein’s ability to function depends on its specific shape, as these compounds have to interact with others in very deliberate ways. Think of putting together a 1000-piece puzzle: some pieces are just a little different than others but only the one right one fits into a given spot.

Now the specific protein that is implicated in PD, α-synuclein, is found in the brain at presynaptic terminals – the starting point of communication between two nerve cells. In a healthy brain, it regulates communication between neurons by assisting in neurotransmitter release (such as dopamine), and stabilizing the cell membranes involved in this process.

When the shape of certain proteins, such as α-synuclein, changes, not only do they not work, but they can act like an infection, and instigate a shape change in other proteins. A domino effect.

Here’s why more and more neurologists and clinical scientists are looking closely at a gut origin for PD. The identifying characteristic of Parkinson’s is the buildup of misfolded α-synuclein, called Lewy bodies in the brain. Autopsy and biopsy studies show these identical misfolded proteins can be found in the nerve network of the gut, often up to two decades before a formal diagnosis of PD.

These, and other proteins, can move from the gut to the brain. Studies in animals show that if the vagus nerve—which physically connects the stomach and brain—is cut, the spread of the disease is stopped.

Studies in both large populations and clinical work have shown that individuals with gastrointestinal damage, such as irritable bowel disease (IBD) or ulcers, have a substantially increased risk of developing Parkinson’s disease. Severe constipation frequently precedes motor symptoms like tremors or rigidity by 10 to 20 years. Individuals with chronic constipation face a 2.5 to 3 times higher risk of developing PD. Patients with ulcers, acid reflux, or esophageal and stomach lining damage have a 76% higher risk of later developing PD.

People with Parkinson’s often have a gut microbiome that is out of whack compared to healthy members of the same household Specifically, they tend to lack the bacteria that produce short-chain fatty acids (SCFAs), which keep the gut lining healthy. (If you have followed the ketogenic diet, these are the compounds that a high fat diet will break down into, and are thought have positive effects in both gut and brain.)

This microbial imbalance breaks down the integrity of the mucus membranes lining the gut, causing so-called leaky gut. Toxins and inflammatory compounds from the intestines can then pass into the bloodstream, eventually crossing the blood-brain barrier to trigger neuroinflammation and accelerate dopamine cell death (among other issues they cause).

These findings raise the possibility of preventing and/or limiting the progression of PD. Here are some of the things researchers are trying by targeting the gut-brain axis.

Phase 2 clinical trials (small scale testing in people with the disease) are looking at the use of oral small-molecule therapies. In pharmaceutical lingo, a small molecule is a low-molecular-weight chemical compound that can easily enter cells. In other words, they don’t have many building blocks at the level of an individual molecule. Because of their small size, they can be taken in pill form and can cross cell membranes to alter biological processes inside cells. These compounds appear to prevent protein misfolding directly inside cells, stopping the whole process in the gut before the infectious proteins can move up the vagus nerve to affect the brain.

Other clinical trials are using engineered antibodies to clear out the mis-folded protein outside of cells. Antibodies are compounds produced naturally by our immune system that are tailor made to find, inactivate, or kill disease-causing organisms or toxins. They can also be produced in a lab, which is the process described here; many such antibodies are already in use to treat a wide variety of other diseases. Antibodies are too big to enter the cells where the mis-folding happens, but as the proteins tries to move from the gut into the vagus nerve, they can ‘stand guard’ and grab them before they can get into the central nervous system.

You may have wondered about the feasibility of fecal transplants. If not, read on. Several human trials are assessing these transplants (yes, they are just what you think they are) from healthy donors into early-stage PD patients to completely remodel a pro-inflammatory gut environment into an anti-inflammatory state which may reduce or prevent misfolded proteins from entering the nervous system.

And if we are really going to address prevention we should go to the root of it and talk about diet. We know that what you eat affects the gut microbiome. Following a diet known to support anti-inflammatory bacteria (those bugs that produce short chain fatty acids), like the Mediterranean Diet or the closely related MIND diet (specifically developed to address neurodegenerative disorders like PD), can reduce the risk and slow the progression of Parkinson’s.

It seems like every day I come across something new in the aging field. All too often, my response is WTF?? I usually don’t write about these phenomena because, well, what can you do? But I have to make an exception because this one is just so fascinating, with lots of implications that maybe, can be addressed.

To start, you have to know that in us humans, like other mammals, sex is determined by a pair of chromosomes. (Note: I’m NOT talking gender, which is determined by a whole lot of different factors.) These two are called (prosaically) the sex chromosomes. Females have two X, while males have one X and one Y. Also somewhat prosaic is the source of the names. The X was first observed in the late 19^th century when biologists were first able to see the chromosomes in their ‘condensed’ forms i.e. when they were drastically shortened and coiled so as to allow their movement into daughter cells during the process of cell division. The X didn’t pair like the other so-called autosomes, or non-sex chromosomes, so was dubbed ‘X’ as a ‘mystery’ or ‘to-be determined’ chromosome. Subsequently, it was found to pair with the Y, which was so-named because Y follows X in the alphabet.

That’s old hat. What is new is the finding that as males age, they lose Y chromosomes. Weird right? Probably not. For background, you have to know two things. First, the Y is the smallest chromosome by far. Second, when cells go to divide, they first make a copy of each chromosome (although the copies are supposed to be exact, there are always copying errors), and then one of each copy goes to the two new ‘daughter’ cells. The copied pair sticks together until the actual divvy-up process takes place then one of each goes to each daughter cell. You can see a graphic of this here:

But back to males losing the Y. Because it’s so tiny, sometimes it gets lost in that process of divvying up the chromosomes. So one new daughter may end up with two, or none. If the cell lacking a Y goes on to divide for additional rounds, a whole new line of Y-less cells emerges. And, by the way, this happens in females too, it’s just much less common because the X chromosome is so much larger, and there are two of them in each cell.

Now, much of the research showing that this loss occurs, is based on blood cell surveys - so it’s not clear how common this is in other tissues. The cells producing blood divide a lot so I am not surprised to see that errors occur and accumulate over time.

How common is this in men as they age? Well, it depends on how it’s measured, and remember my caveat that it hasn’t been measured in all tissues, but it seems to be quite uncommon before age 40, and begins rising after age 60, with loss seen in about 10-20% of men in their 60s, and it keeps going up, increasing with age until 85, after which it plateaus at roughly 40% of men. But keep in mind, this does not mean 40% of all cells lose Y—it means many older men have some blood cells that have lost it.

As I said above, normal cell division will result in some cells without a Y, and if these go on to proliferate, then whole clusters of cells without the chromosome will be generated. Of course, as cell division continues throughout life I would expect to see more Y-less cells in older men.

But one other risk factor is smoking. Smoking is well known to produce a lot of potentially harmful chemicals that can cause DNA damage, hence the contribution to lung cancer. But DNA damage in the Y chromosome can interfere with the normal process of copying the chromosome, and as you saw earlier, this can ultimately result in whole populations of cells without a Y. Some studies suggest this risk is reduced by quitting, but I’d like to see this replicated. Other environmental factors such as exposure to toxic compounds like arsenic, glyphosate (Roundup), air pollutants or polycyclic aromatic hydrocarbons, are also correlated with loss of Y.

Smoking isn’t the only thing that can cause damage to the DNA in our chromosomes. Sorry to say, but just getting older will result in DNA damage. Think of aging like the stashing process that relegates junk into in your garage; over time there’s more and more of it. Every time the DNA in a chromosome is copied during cell division, which takes place continually through life in most tissues, errors occur. Some of these get caught and fixed, but the fixers themselves wear out over a lifetime. So, inevitably, more DNA damage, and more Y chromosome loss, as we age.

For years, researchers thought that the Y chromosome was mainly involved in sex determination and male fertility, so losing it in blood cells probably didn’t matter. However, some recent studies link higher loss of Ys with several important causes of mortality. One such is cardiovascular disease, and especially fatal heart attacks. This conclusion is based on a study of about 1000 Danish men. In the older individuals, there was a strong genetic basis for loss of the chromosome, which was associated with higher all-cause mortality, particularly in men below 80 years.

Intriguingly, in contrast to younger age groups, loss of Y was associated with better survival in centenarians, probably because if you make it to 100 you have a lot of good genes that are protective against deleterious effects such as loss of Y, bad diet, smoking, etc.

Given all that I’ve said above, it’s probably not surprising that higher rates of certain cancers have repeatedly been associated with loss of Y. And there are suggestions of increased risk of kidney disease and neurodegenerative diseases. My take on here is the studies are few and small, and we already know that aging alone contributes to higher risk for cancers, neurodegenerative, and kidney diseases. The link between Y loss and all of these needs to be firmed up. But, read on for a mechanistic explanation; a causal path between the loss of the smallest chromosome and a host of disease will become clear.

The most likely explanation for the multitude of ill effects pursuant to losing one’s Y is the surprising -to me- effect this can have on the immune system. However, the loss of the chromosome also has big effects on the expression of certain genes in leukocytes (aka white blood cells), which directly affect their activity in the immune system. Another – again surprising to me- effect of loss of Y is across-the-board removal of methyl groups (these are epigenetic tags on genes that act as volume controls in the activity of the gene) from genes involved in white blood cell specialization.

Taken together, my take on the genetic effects is a decline in immune system functions. This conclusion is based on the connection between white cell activity and important immune system functions such as surveillance (i.e. patrolling for foreign pathogens) and regulating inflammation.

The genetic effects on the immune system can explain the links to cancer, heart disease and neurodegeneration that have been reported.

Keep in mind, these possible effects of losing the Y chromosome don’t mean guaranteed disease, or that every man is likely to suffer its loss, or even that men will become women. (You may see this proclaimed on the internet!)

The evidence I’ve summarized is pretty preliminary and the mechanisms are definitely speculative. But researchers continuing to follow this lead, though in the current political climate, I have to wonder about funding.

Just a quick update on the emerging idea that vaccines can be protective against problems other that the diseases they were designed to target. Last year there were a number of studies corroborating the protection offered by the shingles vaccine against dementia (I recently wrote about this).

Recently, a preliminary study has been published showing that the Covid mRNA vaccine can protect against cancer. Now, before you get too excited, let me tell you the details. The study was done retrospectively, meaning that the analysis was done on an existing group of patients who were being treated for their (different) cancers.

The study looked at patients with one of two pre-existing types of cancer. In each of these subsets, they were further divided based on whether or not they had received an mRNA vaccine within 100 days of starting immunotherapy treatment.

In the first group, of almost 900 people with advanced non-small cell lung cancer, the180 patients who received a mRNA vaccine had an average survival of just over 3 years, compared to 20.6 months in 704 patients who did not receive a vaccine. In the 2^nd group of patients, these with metastatic melanoma, average survival was 26.67 months in the 167 patients who did not receive a vaccine, but the 43 patients who had been vaccinated were still around at the 3 year end point of the study.

These results sound promising, but you have to remember that these are relatively small sample sizes, and the study was not set up to look specifically for protection against cancer that had not yet been diagnosed. Nonetheless, these are striking results, especially considering that survival was most improved in patients with tumors that don’t respond well to immunotherapy. (Side note: the current standard of care for many tumors is so-called checkpoint therapy. This treatment relies on blocking a molecule that many tumors have that tricks your immune system into thinking the tumor is normal healthy tissue. But not all tumors have this molecule; these don’t respond well to the checkpoint treatments.) Average survival in the patients (i.e. with non-responsive tumors), if they got the Covid vaccine, was almost five times greater than those who didn’t take the vaccine.

When the scientists who did the retrospective analysis saw these striking differences in survival, they naturally wanted to try to understand how a vaccine against a viral respiratory disease could provide a significant increase in survival to serious cancers. So they turned to mice.

In brief, they found that the mRNA vaccines work like an fire alarm, activating the body’s immune system. This activated immune system is better able to recognize and attack cancer cells.

If you want more detail: Cancer cells are very responsive to their environments. What they do when they detect higher immune activity is to make more of the molecule I described above as the basis for checkpoint therapy. Remember, that when this molecule is present at higher levels, checkpoint therapy blocks it and the immune system can then better recognize and attack tumors. Importantly, the retrospective study was done on cancer patients already receiving said therapy. It will be critical to determine if mRNA vaccines are equally protective in people not already being treated for cancer.

Back to the researchers who published these findings, they looked at the patients in the ongoing cancer treatment and saw the same immune system activation following Covid vaccination as observed in the animals. Ditto in healthy controls without cancer who received COVID mRNA vaccines.

Next is a larger, multi-center, randomized clinical trial to replicate these findings and determine whether COVID mRNA vaccines should be part of the standard of care for patients receiving immune checkpoint inhibition.

These results, while very preliminary, leave me wondering if there is an almost universal benefit to vaccination, in that it is an immune system boost. Funny, isn’t this what MAHAs are trying to get through various supplements, nutriceuticals, and assorted chicanery?

I’ve been waiting to write this post, as I wanted to speak to one of the study authors, but no luck yet, so, without further ado, some remarkable news on the dementia front.

A new analysis of a vaccination program in Wales found that the shingles vaccine not only appeared to lower new dementia diagnoses by 20%, it also helped those who already have the disease.

Since my posts usually involve some aspect of aging, and dementia has been front and center on a number of occasions, you may find this number quite amazing. Yes, you read it correctly, a 20% decrease in dementia diagnoses in the vaccinated folks. If a new drug came out with that kind of effect, there would be big bold headlines - but I haven’t seen many ripples about this (and there are several similar studies with similar results).

This study, from a group of Stanford researchers, analyzed the health records of a large group of older adults who were vaccinated in Wales. One of the scientists recognized a fortuitous “natural experiment” in the rollout of an early version of a shingles vaccine in Wales, way back in the 70s. The vaccine used at that time contained a live-attenuated, or weakened, form of the virus.

The vaccination program, which began Sept. 1, 2013, limited the (free) vaccine to those who were born on or after September 2, 1933, making them 79 years old. These people were eligible for the vaccine for one year. (People who were 78 would become eligible the next year for one year, and so on.) About half of the people who were eligible actually chose to be vaccinated. (Before this vaccination program, essentially no one was getting a shingles vaccine.) People who were born before September 2, 1933, were out of luck — they would never become eligible for the vaccine.

The age limits were designed to ration the limited supply of the vaccine, but they also created a beautiful natural experiment as to the longterm effect of the vaccine. By comparing people who turned 80 just before Sept. 1, 2013, with people who turned 80 just after, the researchers could isolate the effect of the vaccine.

And comparisons between the vaccinated and unvaccinated were readily available because Wales, like many other developed nations, maintains a national database of health records. The researchers looked at the health records of more than 280,000 older adults who were 71 to 88 years old and did not have dementia at the start of the vaccination program. They focused their analysis on those closest to either side of the eligibility threshold — initially comparing people who turned 80 in the week before to those who turned 80 in the week after.

The research group compared the health outcomes of those people - of similar age - who got vaccinated to those who did not, for 7 years after the initial vaccination. This distribution of people in identical ages and presumably life styles is about as close to a randomized controlled trial as you could get without actually conducting one.

Remember a randomized control trial (RCT) is an experimental study that randomly assigns participants into two or more groups—an intervention group(s) receiving a treatment (here the vaccine) and a control group receiving a placebo or no drug. The RCT is considered the “gold standard” for evaluating the effectiveness of interventions because it minimizes bias by balancing the uncontrollable factors we see in people like lifestyle choices, education level, socioeconomic status, etc. Here, the same proportion of both groups likely would have wanted to get the vaccine, but only half, those not yet 80, were allowed to by the eligibility rules. In other words, overall the vaccinated 79 year olds were as similar as you can get to the unvaccinated 80-year olds, except for this tiny difference in age.

As expected, over that seven-year period, the vaccine reduced the occurrence of shingles by about 37% for people who received the vaccine, similar to what had been found in clinical trials of the vaccine.

The shingles vaccine used in this study, available in 1973, is what is called a live-attenuated vaccine, i.e. it contains the actual virus, but weakened so as not to be able to cause disease. The current best option is called Shingrix, which is a highly effective (>90%), ‘non-live, recombinant subunit’ vaccine. This means it contains just a piece of the virus, not enough for it to cause the disease. The older, now-discontinued live-attenuated vaccine (Zostavax) was only about 51% effective and its effectiveness waned over time. Shingrix gives better, longer-lasting protection without the risk of transmitting the virus. (An analysis of the effect of Shingrix on dementia has found similar protection, but as the vaccine only became available in 2017, the population sizes and outcome data are more limited; more on this below.)

Let’s look at the analysis path that the researchers used, because it is extraordinarily detailed so as to provide the fullest support for the conclusion that the vaccine is the causal element in the reduction in dementia seen in vaccinated individuals.

They started by replicating the finding from earlier clinical trials that the Zostavax vaccine reduced cases of shingles. Then, they extended this approach to the outcome of interest: dementia, which for the purpose of this study was any diagnosis thereof - not limited to any specific type. This had never been assessed in clinical trials of the shingles vaccine. They found that the vaccine reduced the probability of a new dementia diagnosis over the seven-year follow-up period by approximately one-fifth or 20% fewer cases of dementia!

But they didn’t stop there. They went on to show that the shingles vaccine did not affect the occurrence of any other common diseases such as cancer or heart disease, which might conceivably affect dementia risk. Similarly, they showed that getting the vaccine did not lead to a healthier lifestyle, e.g. characterized by preventive health measures or more frequent vaccinations. Finally, they showed that the reduction in dementia did not emerge until a year or more after the vaccination, supporting the role of the vaccination’s protective effect as causal.

Now, let’s get back to the differential effect in women. After the first year, new diagnoses of dementia in women had fallen by about 6%, whereas the decline in men was about 1%. To try to understand a mechanism, the researchers point out that for many other live-attenuated vaccines (remember this was the only type available in the 70s) the response (i.e. protection from the disease being vaccinated against) differed strongly by sex, with beneficial effects often seen only in females but not male.

These remarkable findings, published last year in Nature, support an emerging theory that viruses that affect the nervous system can increase the risk of dementia. Additional confirmation of this effect has been reported in Australia, in England with the newer, more effective Shingrix vaccine, and the Stanford group has followed up on their initial analysis with a report that even in people already diagnosed with dementia the progression and severity of the disease are less.

These findings also lend support to a growing body of evidence that vaccines can elicit a broad immune response (i.e. not specific to only the disease targeted by the vaccine) with off-target effects such as the dementia reduction presented here. It’s not yet clear if these protective effects are stronger with live-attenuated vaccines, but ongoing studies with Shingrex may help answer this question.

As you now know, the commercial peptides we’re talking about are synthetic amino acid chains that can mimic the body’s natural signals to target recovery, muscle growth, skin repair and possibly overall wellness. Cosmetic peptides are more or less regulated by the Food and Drug Administation (FDA) but there’s another universe of these substances that are out in the wild west of online sites.

Unless you’ve been living in the Gobi Desert, you’ve heard of drugs like Ozempic or Semaglutide that are used for weight loss, and possibly for a variety of other aspects of metabolic health. These drugs mimic a naturally occurring peptide called GLP-1. Other peptides have been developed as drugs, including insulin. Insulin was the first naturally occurring peptide to be used as a drug, but the human form is what is used, not a synthetic, modified version. The weight loss drugs are by far the biggest success story in the synthetic arena; shown to be clinically effective; originally in diabetes treatment, and later in weight loss. (Other uses, e.g. reducing smoking and other addictive behaviors are tantalizing possibilities.) But, the development and fine tuning of the peptide into an effective drug that is tolerated reasonably well (though there are many people who can’t take the side effects) took over 20 years!

There are probably dozens if not more new peptides in the wellness, performance, and anti-aging areas. None of these are anywhere near the developmental timeline of the GLP-1 drugs. One such is BPC-157. Body protection compound-157 (BPC-157) occurs naturally in the gut where it helps to heal tears or other injuries to the intestinal lining. Because of its demonstrated role in healing injured tissue and promoting the maintenance of healthy tissue it was investigated in animals for these effects outside of the gut. A meta-analysis (I’ve written about these in earlier posts – basically it combines a lot of different studies, and I take them with a few grains of salt) of almost 40 animal studies supported its potential for promoting healing in musculoskeletal injuries such as fractures, tendon ruptures, ligament tears, and muscle injuries. Despite lacking US Food and Drug Administration approval and its use being banned in professional sports, it is increasingly used by clinicians and athletes.

In 2023, the FDA named BPC-157 a Category 2 bulk drug substance, meaning it can’t be compounded by commercial pharmacies and lacks safety date in people. Despite this, BPC-157 products can legally be sold as “dietary supplements” or “research chemicals,” as these classifications are not regulated by the FDA. In addition, BPC-157, along with many peptide hormones, are not classed as illegal drugs. This means that their possession is not illegal (unlike substances such as anabolic steroids) and you can go online and buy anything marketed as BPC-157. Just be aware that these are not regulated for quality and safety.

Full disclosure: A few years ago, I read up on BPC-157, was intrigued by the animal studies, found a supplier that seemed to do safety and quality testing, and tried it. My n of 1 report is that it did nothing for a mild case of osteoarthritis in my knee. I did not inject it directly into the knee and maybe the compound didn’t reach the affected area or maybe it just didn’t work. After a month of injecting a small volume of ice-cold fluid into my leg I gave up on it.

Before going on with this meander through the biohacking world, I have to digress to explain the difference between two categories of drugs: biologics and small molecules. This may at first seem pretty esoteric but it has a significant bearing on the peptides I’m introducing here.

Small molecule drugs, like aspirin, ibuprofen, penicillin and statins, as the name suggests, are not large molecules – unlike biologics which are. Recall the discussion from my last post on the difficulty of getting any but very small molecules across the skin. This means that bigger things, like biologics (i.e. the peptides we are discussing here) must be injected.

A further difference is that small molecule drugs are relatively easy to design and build, whereas most biologics are extracted from living organisms, often bacteria which can be grown in large quantity. Currently, most drugs on the market are small molecule compounds manufactured through chemical synthesis, and usually can be taken orally. But, the use of biologics, e.g. antibodies, other immune system agents, and vaccines, is growing fast. Because they are more difficult to grow or synthesize, they are more expensive and the purification and quality control aspects more difficult.

Which brings me back to injecting something that is not regulated as a drug. The quality controls on unregulated compounds are essentially non-existent. You take the seller’s word on purity, and concentration. These little vials can contain manufacturing impurities (solvents, heavy metals, synthesis byproducts), microbial contamination (bacteria, endotoxins) from non-sterile handling, and breakdown products (aggregates, oxidized forms) due to poor storage. A related concern is mislabeling and/or addition of supposed inert substances, which expand the possibility of infections or adverse immune reactions.

A lot of people are injecting these compounds at home (I know I did it myself – though I did use sterile technique and investigated the company). There are also a lot of ‘clinics’ that have sprung up to recommend and inject them for you. So, onward to more of these ‘miracle’ drugs.

A good discussion of possible dangers: https://theconversation.com/peptides-performance-boosting-anti-ageing-drugs-or-dangerous-snake-oil-259531

Next there’s TB-500. This peptide is a small piece of a naturally-occurring protein called thymosin beta-4. It is found in a lot of our organs (brain, kidneys, heart, skin, eyes) as well as in some immune system cells and tumors. It has also been reported to be present in ‘wound fluids’ (whatever they are) and this may be one basis for its supposed role in regeneration.

A lot of studies that look at where proteins occur in the body (and in various developmental stages) have shown that the larger protein (thymosin β4), is widely distributed in embryonic tissue. More recent studies that try to determine its function suggest it acts as a growth promoter because it sped up the development of organs and tissues in newborn mice. Findings like these can give rise to the idea that because the protein plays a role in tissue development in embryos and infant mice, it could do the same in adults. I want to stress that not only is this a leap of faith, but the findings themselves are controversial. And of course, anything that speeds up growth, means more cell division, which means that it can also initiate or promote cancer.

If you want to more info on how TB-500 works, here is a starter. In adult rodents, thymosin β4 is released by immune system cells after injury. Then, it prevents further damage by reducing inflammation, bacterial growth, and cell death. It works by binding to the protein actin (which underlies muscle contraction, and also movement of substances within cells). This binding stimulates certain types of cell to migrate to the wound site, including the mobilization of the stem cells that form new blood vessels and regenerate tissue. In other words, in grown up rats, TB-500 does show regenerative and healing activity. Having worked with mice and rats for over 25 years, I feel confident in saying that rodents are not small people. Not to be dismissive, but results based on rodent studies absolutely need to be confirmed for safety and efficacy in people.

Next up is ipamorelin, another naturally occurring peptide that stimulates release of growth hormone (GH). It is often combined with yet another peptide, CJC-1295 which also stimulates GH release. You probably know that GH is widely believed to have magical anabolic qualities, i.e. promoting muscle growth, fat loss, improved strength, and faster recovery from injuries. The reality is that in many clinical trials GH had only small effects at best. Way back in the 1990s, drug companies were investigating developing ipamorelin and other similar compounds as drugs to boost GH production to treat various metabolic deficiencies. They gave up when clinical trials showed no effects.

People often combine peptides, a trick called ‘stacking’ to boost the individual effects on recovery, body composition, or for anti-aging. And of course, if individual applications have not been validated or passed regulatory approval, combinations certainly won’t have this vetting.

If you want to know more about this particular combination, read on. CJC-1295 and Ipamorelin are often combined to potentially stimulate growth hormone release. Specifically, CJC-1295 is a look-alike of the hormone produced in the hypothalamus (in the brain) that tells the pituitary gland to release GH. Ipamorelin is what’s called a GH secretagogue, meaning it acts on the hypothalamus to tell it to produce more of the hormone that acts on the pituitary. The combination then is hypothesized to create a sustained GH pulse for potential benefits like muscle gain, fat loss, improved sleep, and faster recovery. Of course, as I said earlier, there are no clinical data (i.e. in people) supporting this idea. Which is not to say it is not possible.

One final biohack deserving mention is melanotan. This is another synthetic peptide that mimics the action of a hormone called melanocyte-stimulating hormone (MCH). MCH stimulates skin cells, called melanocytes, to produce the skin-darkening pigment melanin. This means darker tan with less sun.

Melanotan is also sold as a libido-enhancing hack because it can bind to receptors in the brain, activating pathways involved in sexual arousal. This effect can treat erectile dysfunction (ED) and low libido by increasing arousal and causing erections. One reported side effect is priapism, or spontaneous, prolonged (possibly over 4 hours) erections, requiring medical intervention to prevent permanent damage.

I was surprised at the popularity and online presence of many of these compounds. Celebrity endorsements, sometimes coupled with partnerships in treatment clinics, are all over the internet. If you don’t want to inject yourself, you can easily find a practitioner who will. Never mind that their qualifications, like those of the peptides themselves, may be suspect.

To end on a note of tested medical achievement in the peptide field, a recent report from Northwestern University described a treatment that can significantly reduce long-term brain damage after stroke. Most of us have family or friends who have suffered the sometimes devastating consequences of strokes; for these people, this peptide could be a real game changer. The therapy, like all of these discussed here, has to be injected, but was shown to cross the blood-brain barrier, meaning no need for surgery or other invasive procedures.

Bottom line, peptides have a lot of potential but at the moment, their promise is unrealized and their use is on a caveat emptor basis.

We are all familiar with the term ‘protein’: likely in terms of how much to eat each day (which I’ve obsessed about myself). You may be less familiar with its chemical structure: each protein is composed of a string of hundreds to thousands of building blocks called amino acids. The sequence of any protein in the human body is determined by the corresponding DNA sequence of one or more genes. Proteins are essential to life because they perform a variety of crucial functions: structural support (e.g. collagen), enzyme activity (e.g. pepsin – the enzyme in the stomach that starts breaking down the protein in the food you eat), hormone (e.g. insulin – regulates blood sugar levels), antibodies (whose production is induced by vaccination or prior disease), as well as other, less well-known classes.

I’m NOT going to tell you more about proteins here. My current interest is in peptides, a mixed bag of compounds made up of shorter strings of amino acids whose functions are widespread in the body. In fact, scientists are just scratching the surface of what these things can do. One example that is pretty well-known these days is GLP-1, a peptide - that acts as a hormone - of about 30 amino acids (i.e. much shorter than most proteins). Several modifications of this peptide (known as GLP-1 agonists, meaning they have similar action) are making a lot of money for some drug companies under the brand names of Ozempic, Wegovy and Muonjaro, because of the effect of the peptide – appetite supporession - and consequently weight loss. At this moment, most of these drugs have to be injected to avoid unpleasant GI (gut) side effects, but an oral form has just been approved.

There is a whole universe of peptides being explored for other applications. Two intriguing areas are in skin care/rejuvenation and repair of soft tissue (muscle, tendon) injuries.

In this post, I’ll talk about the cosmetic potential, as this seems to be the ‘face’ of peptide science at the moment. These peptides are applied topically, mainly to the face. Claims include wrinkle repair, increased production of collagen and elastin (proteins in the skin that provide support and firmness), reduced redness and irritation, and in general, anti-aging effects.

Topical (i.e. on the skin) application offers a more direct route to the area of interest, particularly the face, if enough of the peptide can get in. And, by limiting the area where it’s applied and active, you need less of the peptide than if it were spread through your entire body.

You usually don’t want a given peptide circulating through your whole body. There are a lot of reasons for this, including the possibility that as your liver breaks it down some problem-causing by-products could be created, or the risk of an immune (e.g. allergic) response.

The problem with any lasting treatment for the skin is getting it through the surface layer of the skin. Small molecules like glycerin (aka glycerol, a common moisturizer) can get through the stratum corneum, the outermost, waterproof layer of the skin (skin layers are nicely illustrated in the first couple minutes of this video):

Some other substances can sneak through the pores (shown in the video as the channel between the surface and the gland deep in the skin), or even get into the cells of the skin and sneak in that way. Retinol, for example, because it is somewhat fatty, can transit the layers of dead cells of the outer skin by inserting itself into the thin fatty layers between those dead cells (imagine the fatty layers as the mortar between ‘bricks’). Derived from vitamin A, retinol and related compounds, when applied topically, can increase cell growth and collagen production in the skin and thus act as a mild anti-aging treatment. But, these aren’t peptides, so let’s get back to those.

Shorter peptides (fewer than about 5 amino acids) can also penetrate more easily due to their smaller size. One example is a short peptide (3-5 amino acids depending on the modifications done to it), carrying a copper atom. Both entities can stimulate wound healing and skin regeneration in animals and the modified peptide (called GHK-Cu) was first developed for dressings and creams that speed tissue repair.

In the past decade, a slew of facial applications of this compound have become popular (see video below). A few ‘clinical trials’ claim that its use as a facial treatment can reverse aging. It’s important to note that many so-called clinical trials can be quite small, of short duration and run by the company making the product; making the results somewhat suspect in my opinion.

It’s also possible to get peptides through the skin barrier by chemical modifications, like attaching a small tail of fat. Then, like retinol, these peptides can squeeze through the layers of dead cells of the outer skin. One example is Palmitoyl-KTTKS. The palmitoyl portion - sounds like oil and it is – chaperones the string of letters which are the 5 amino acids, to get through the skin. This peptide (the 5 ‘letters’) is actually a small piece of the much larger collagen protein which is the main structural protein in our skin. When Pal-KTTKS arrives in the lower layer of the skin (these are live cells), that fragment essentially tricks them into ‘thinking’ that collagen is breaking down; the cells respond by making more collagen which firms the skin.

Many peptides are larger, meaning even with a fat friend, they can’t squeeze in. But, if they can be packaged in fatty wrappers called liposomes, their movement through the outer skin layer is easier. Formulation of both the preceding peptides in liposomes has been made and tested in small trials (with the same caveat) and shown to be more effective than other delivery methods.

You can see some nice graphics and explanations for these transport pathways across the skin in the first section of the following video. The narrator (an influencer, not a scientist) then segues into a thinly-disguised advertisement which I would skip but if you’re interested in specific products, by all means listen. There are literally dozens of products of the two methods of transport I discussed above, as well as other possible approaches I’ll touch on later.

At this point, I need to digress briefly to discuss the difference between a cosmetic substance and a drug. This may seem like a semantic distinction, but not to the FDA (US Food and Drug Administration, which regulates both). From the FDA website:

Cosmetics are “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body...for cleansing, beautifying, promoting attractiveness, or altering the appearance” e.g reducing the look of wrinkles, moisturizing, or helping to fight bacteria. These typically do not require premarket approval by the FDA (except for color additives).

Drugs, on the other hand, are “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals” e.g treating wrinkles, preventing hair loss, or providing antiseptic properties. Drugs must prove safety and efficacy with FDA approval, whereas cosmetics don’t, but manufacturers are still responsible for safety. A product can be both (like an anti-dandruff shampoo), requiring adherence to both regulations.

Seems to me that peptides are a gray area. Injectible forms are classed as drugs, but my hunch is that for topical application, because of the overlaps in the preceding definitions, they can be classed as cosmetics despite the fact that some drugs (e.g. fentanyl, estrogen) can be applied as skin patches.

One final way of getting peptides into the lower levels of the skin where they can modify cellular activity is by damaging the surface layer slightly by microneedling, laser, ultrasound or electroporesis. This damage creates openings through the barrier layer to the living cells below and is extensively used by estheticians to deliver peptides and other compounds.

Many topical peptides and even proteins have been successfully and widely used in the past. These include delivery of a protein/peptide mix from the tuberculosis bacteria used to diagnose tuberculosis. Cyclosporin, a peptide used to treat skin conditions like psoriasis, can also penetrate skin (with a little help from microneedling).

This last paragraph was going to be the end of the story but then I came across yet another peptide touted for wrinkle reduction. This hexapeptide (i.e. 6 amino acids long) is called Argireline. This peptide was designed to mimic the action of Botox, the injectible anti-wrinkle agent derived from the toxic protein of a bacteria that causes muscle paralysis (and often death due to paralysis of respiratory muscles). The clever idea behind botox was that in smaller (i.e. non-lethal) doses, injected directly into areas with wrinkles, the muscles whose contractions cause the wrinkles are inactivated. Now you know that injected compounds are classed as drugs, thus you need a physician’s order to get Botox.

Argireline is a much smaller compound, but still needs help to get through the skin barrier. Although it is sold in a variety of formulations (e.g. in water, a water-oil mix, in liposomes – those fatty ‘wrappers’) only those using a fat-based formula showed much effect.

Because Argireline was designed to look like part of the Botox protein, it can have a similar effect, namely reducing wrinkles caused by contracted muscles (e.g. frown lines). That said, the it disperses much more rapidly in the skin; meaning the effect is not as noticeable or long-lasting as the drug.

One final note on the way out: this past Sunday’s (1/4/2026) New York Times Business section published a long article on the prevalence of biohacking with peptides. These are not cosmetic creams that, while of questionable effect, have at least been safety tested. The peptides profiled in the NYT, with engaging names like Body Protective Compound 157, have had little safety testing in humans, and are the topic of my next post.

I’ve been obsessed with protein for years– and it turns out that now the rest of the world is too. I draw the line at buying ‘high protein’ labels in the grocery; it reminds me of the ‘low cholesterol’ days of the 1990s when everything (including foods that, being derived from plants could not possibly contain the stuff) were labeled ‘low cholesterol’. There is plenty of protein in foods from many sources, as all creatures, whether animal, plant, or otherwise, rely on proteins for vital structural and functional components. That said, not all protein is created equal. Differences between plant and animal sources, for example, fall under the rubric of protein quality, which I wrote about in previous posts on the importance of muscle tissue.

There are a couple problems with getting enough protein – and this amount (you’ll see it as grams/kg or per pound) has been evolving in the past decade as well – as we age. One important issue is called anabolic resistance. Time for a deep dive.

Technically, anabolic resistance just means the body becomes less responsive to anabolic stimuli. What does this mean? To understand this, I have to introduce the notion of metabolism: All of the countless chemical processes taking place continuously in the body that support normal function and life itself. Here is an abbreviated example of just a few of these pathways (don’t try to read it, just appreciate the sheer volume and complexity):

There are two sides to this beast. People mainly think of catabolism when discussing metabolic pathways: what happens to food when it is broken down to release energy (some of which you can see in the diagram above).

Anabolism, the opposite of catabolism, is the process of building UP body components e.g. muscle, bone, organs, etc. Think of anabolic steroids - well known drugs for building big muscles in body builders. In this post, I’ll focus on anabolic resistance. The definition is simple: anything that reduces, or resists, the building (anabolic) process. In the context of protein intake, this leads to reduced ‘muscle protein synthesis’ (MPS, or the process of building muscle).

For a brief refresher on the structure of proteins and their formation from amino acids:

In a nutshell, anabolic resistance is important because we want to maintain the muscle we have as we age. In order to do that, we have to continually ‘remodel’ the muscle tissue. Amazingly, all of the muscle you have is re-built every few months. Imagine having a construction crew at your house, constantly taking walls, floors, fixtures, etc. apart and rebuilding everything to keep it running as smoothly as possible. This is what our bodies do in the ongoing process of keeping entropy at bay.

Of course, the body can recycle many of the amino acid building blocks of protein from the tissue that is dismantled. But inevitably, a small percentage is lost, or needs replacement, due to damage. And of course, if you are building new muscle (MPS), you will need more of these building blocks, which you get from eating protein.

Anabolic resistance in this picture can take two forms. First, as we get older, all of our systems become less efficient, including our digestive systems, which dismantle the protein we eat into individual amino acids (less often into short chains of 2-3 aminos). For the same amount of protein you ate as a 20 something, as a 60+something, you may only be pulling out 80-90% of the same amino acids. Clearly, this gives you fewer building blocks and the result is less muscle protein synthesis. The fix is easy, up your dietary protein intake.

If you are interested in a deeper dive into the process of muscle turnover and remodeling, read on. This occurs in several stages:

First, the muscle stem cells, called satellite cells, are stimulated to turn on and divide (which of course uses amino acids to build the proteins of the new cells), and we get a bunch of unspecialized (i.e. early stage in development) muscle cells, called myoblasts.

These ‘baby’ myocytes (the jargon term for a mature muscle cell) continue to differentiate (i.e. mature into the specialized shape, structure and function of active muscle). At this point, they do what muscle cells do as they develop into the large, contractile forms familiar to us – they fuse together to form either new muscle fibers or they fuse with damaged fibers to repair them. These fibers are what we typically think of as muscle cells – long, thready structures (which you have probably gotten in your teeth if you eat steak), hanging on to the cell nuclei from the many myoblasts that fused to form each myocyte. The new fibers grow in width as they synthesize and incorporate new actin and myosin – yet more proteins, these do the contracting in muscle. You can see those fibers under the #4 arrow in the cartoon (1 is the motor nerve, 2 is the synapse or connection between nerve and muscle, and 3 is the myofiber or entire muscle cell).

(A brief aside: the main job of skeletal muscle is to contract, usually pulling on a bone. Said contraction moves the bone in one direction. Contract your biceps (actually a group of several muscles), and your lower arm moves inward. To reverse this motion, you contract your triceps, (same thing- a group of muscles again acting in concert) which pulls the lower arm in the opposite direction. To get really geeky, this muscle pair is called agonist and antagonist, and all joints have at least one such pair. There are other types of muscle in the body, but these (smooth and cardiac) are not typically under voluntary control.)

Meanwhile some of the satellite cells from step one above, take a 180 degree turn, returning to their usual dormant state so as to maintain a stem cell pool for the future.

Finally, collagen (the most abundant protein in the body; think more amino acids needed) is laid down around the new fibers to provide a supportive scaffold. Blood vessels and nerves are extended into the new tissue, which is now ready to go.

But, if you didn’t have enough amino acids from the recycling process and your diet, the rebuilding is limited or never starts. Now we’re back to anabolic resistance. I introduced the first form earlier, as reduced uptake from the digestion of dietary protein. The fix: increase the amount of protein in your diet. This recommendation is becoming increasingly common in both research on healthy aging and the social media landscape. I won’t weigh in on this controversial topic because it would take pages and pages to discuss the pros and cons of each recommended dose, but both Rhonda Patrick and Peter Attia have good podcasts on the subject.

The second, less well-discussed aspect of anabolic resistance is that occurring at the muscle end of the path. You have to get the amino acids out of the food (step 1 above) then through the blood to the delivery site in the muscle. (The liver, which is the first stop for blood leaving the intestine, takes a lot of the amino acids as it is continually – and importantly- building a variety of essential enzymes; but we won’t worry about that here.)

You may know that all cells have an external membrane that is very choosy in terms of what gets in and out – the intracellular environment is a selective, gated community. The only way in for big molecules like amino acids is through ‘gates’ called transport proteins. There are different transporters for specific types of amino acids (e.g., large neutral, small neutral, or amino acids with electrical charge).

And here’s the thing about the transporters that relates to anabolic resistance. They are REALLY sensitive to a variety of signals that tell them the cell does or does not need specific amino acids. For example, resistance exercise (aka weight training) causes muscle growth because it leads to small tears in muscle fibers. You saw earlier how damage to the muscle cell activates repair mechanisms which then require amino acids coming into the cell for rebuilding.

The inflammatory signal from that tissue damage not only tells the transporters already in the cell membrane to open up to the amino acids but also turns on expression of the genes for the transport proteins so as to increase uptake from the blood. What’s more: once these transporters move their amino acids inside the cell, that further stimulates the whole anabolic process of remodeling muscle. So, resistance training not only opens the doors for immediate repair, it also sets the stage for longer term muscle maintenance.

It’s the flip side of this entry/activation process that results in anabolic resistance at the muscle. Many people suffer from insulin resistance, a chronic condition typically caused by a combination of poor diet (especially one high in processed carbs) and lifestyle (little or no exercise). The result is chronically high blood sugar, which normally causes a transient insulin signal. When insulin binds to glucose transporters in cell membranes, these bring glucose into the cell. When blood glucose is chronically elevated, muscle (and other) cells are full, the transporters are not available, insulin can’t bind, and glucose keeps circulating, eventually ending up in fat cells. (It’s a long complex story that we won’t get into further but if you want to pursue it, both of the earlier mentioned podcasts have good episodes on metabolic disease and/or insulin resistance.)

To bring this back to anabolic resistance, when insulin binds to the glucose transporter, not only does glucose enter the cell, but a signal is generated that inhibits protein breakdown. This signal alone reduces anabolic resistance because the breakdown pathway is turned down. But there’s more. The insulin signal also stimulates the amino acid transporters so the pool of amino acids in the muscle increases, ready to rebuild when needed.

To sum it all up: anabolic resistance is any process in the body that reduces our ability to build or repair muscle. Its’ a bigger problem as we age for two reasons. First, the gut becomes less efficient at extracting amino acids from the protein we eat. This has a relatively easy fix: eat more protein, especially easily digested and utilized protein.

Second, in many of us, the access points for amino acids into the muscle cells are compromised; often because of insulin resistance, but also because of a more sedentary lifestyle. The fix is easy to say but harder to do: reduce processed carbs (i.e. lower blood sugar) and exercise.

Finally, I can’t overstress the importance of resistance (aka weight) training. Not only does it build bigger stronger muscles – which are one of, if not THE main predictor of healthy aging – but also streamlines the process by which those muscles get built and maintained. Two for the price of one!

I hope to wrap up, at least for the time being, the Alzheimer’s story. I’ll start with a brief recap of the amyloid hypothesis that we dug into in the previous post, a competing hypothesis that focuses more on tau (introduced last time as well), and an intriguing new hypothesis that was published last month in the journal Nature.

First off, to refresh your memory, the amyloid hypothesis relies on the role of amyloid beta, Aβ. This fellow is a peptide, that is, a string of about 40 amino acids produced when a larger protein called amyloid precursor protein (APP) is chopped up in the brain. Normally, Aβ is rapidly broken down and removed but when the balance between production and clearance is disrupted, it accumulates, and causes problems. This is the basis of the amyloid hypothesis.

There are a lot of potential mechanisms underlying the accumulation, but eventually the amyloid builds up into large clumps called plaques, outside of nerve cells that disrupt the activity of these cells and eventually kill them. These cells are called neurons and are the type of brain cell responsible for receiving and delivering messages that, among other things, facilitate learning and memory and control the body. The causal role of Aβ has been the driving force in the longterm effort to find therapies for Alzheimer’s disease (AD) because of the ubiquity of plaques in patients with the disease. One problem (although there are more) for the hypothesis is that many people die with large accumulation of plaques but no dementia.

Aβ is typically found outside of nerve cells, where it builds up into the diagnostic plaque of AD. It can migrate into cells, where it then weasels its way into the tau protein to mess up its 3D shape. In a healthy brain, tau is a protein found in the part of neurons where signals are initiated. Its primary function is to bind to and stabilize microtubules, which are essential components of the cellular transport system. This transport system carries nutrients, vesicles, and other cellular materials throughout the neuron, allowing it to maintain its structure and communicate effectively.

This short video gives a good graphic (though, unfortunately, a bit of jargon as well, on the process of tau disruption and its spread:

As you can see in the video, tau is a structural protein, kind of an internal scaffolding, that provides both 3D structure to the cell and internal transport. When tau is damaged by the action of Aβ, it detaches from the microtubules and they eventually disintegrate. Once detached, the tau proteins glom up (sorry fro the technical term) and clump into toxic, thread-like structures called neurofibrillary tangles (NFTs), another key pathological hallmark of AD. Not a good outcome for the neuron, which progressively deteriorates.

As the tangles accumulate normal cell function is disrupted and cells eventually die. Misfolded tau can even spread throughout the brain’s neural networks, and we see widespread and progressive worsening of cognitive decline. This occurs because when a neuron dies, the toxic tau tangles are released and can ‘infect’ neighboring healthy neurons, which can then repeat the process and the whole neighborhood goes downhill.

Because Aβ precipitates the events that produce the tangles, some researchers are thinking of it as a risk factor while tau and the damage the NFTs cause in the brain are more causal. Although both structures are seen in the brains of people with AD, the accumulation and spread of tau pathology, rather than just amyloid plaques, correlates most strongly with the severity of dementia.

Tau is implicated in other dementias, collectively known as tauopathies. The most common of these is Frontotemporal Dementia, caused by a mutation in the gene for the tau protein.

Now you might be wondering about the prevalence of both AD and other forms of dementia, an umbrella term for a collection of symptoms that are caused by disorders affecting the brain and impact on memory, thinking, behaviour and emotion. Alzheimer’s disease is the most common, affecting 50-60% of people with dementia. Other types of dementia include vascular dementia, Lewy body dementia and front-temporal dementia. Dementia can also sometimes affect people who are under the age of 65. This is known as early onset dementia.

Now you can see that damage to tau provides an alternative explanation for the onset and progression of Alzheimer’s disease. Aβ can contribute to the damage to tau, and the extent and location of the resulting neurofibrillary tangles (NFT). Recent PET studies, which image the brain, have shown that the spatial patterns of NFT are closely linked to the clinical symptoms of cognitive decline and memory loss in AD patients. Furthermore, there are more new studies showing that once started, the mis-shapen tau proliferates and then, moves to unaffected cells, to initiate more disruption; kind of in ‘infection’ by the damaged tau. (For those of you familiar with prions, the cause of mad-cow disease, this story may be frighteningly familiar.) Finally, in people who have the tau-induced NFTs without amyloid plaques, their tangles are identical to those seen in the brains of patients with AD. In other words, you can get the NFT and the cognitive impairment it causes without plaques.

You may have heard of the idea, called type 3 diabetes, that poor blood sugar regulation in the brain is a causal agent in AD. Consider the high energy demand of the brain, which, at about 2-3% of body weight uses 20-25% of the energy supply (namely glucose) of the entire body. Sugar spikes, and their concomitant problems, are undoubtedly common in this organ, especially coupled with a diet high in simple sugars. In other words, the same mechanism that triggers type 2 diabetes pathologies (poor circulation, nerve damage) could be at work in the brain. It was recently shown that tau protein is involved in the control of brain insulin signaling, lending support to this alternative to the amyloid hypothesis.

At this point, you would be justified in wondering if the longstanding hypothesis underlying drug development for AD is no longer useful, what are the options? There is some good news on the horizon. Several blood tests have recently been developed that can offer early diagnosis. These blood markers include amyloid beta, phosphorylated tau, and neurofilament light chain.

One of these, Lumipulse, has received FDA approval for adults aged 55 or older who are already experiencing cognitive symptoms. It measures the ratio of two Alzheimer’s-related proteins, p-tau217 and amyloid beta 1-42, in a blood sample. However, it is not a screening tool for healthy individuals. The test accuracy so far is pretty impressive: 92% of positive results were confirmed to have amyloid plaques, and 97% of negative results did not.

A second test uses an algorithm combining the levels of the two proteins named above with ApoE genetic information. (ApoE is a type of lipoprotein in the blood that predisposes people with it to AD.) This test, called PrecivityAD2, is about 90% accurate at detecting Alzheimer’s pathology, but not yet FDA approved. And, because it’s based on a predictive algorithm, it gives a probability of amyloid plaques in the brain, rather than measuring them more directly.

There are a few other tests in the pipeline. I’ll introduce two, to illustrate how different aspects of the pathology I described above can be exploited to test for early disease. First, some variant forms of the modified tau are also effective markers for detecting Alzheimer’s pathology.

Second, remember those astrocytes, and how they become overwhelmed by damaged tau? Their levels can also be early signs of AD. A marker of astrogliosis, an inflammatory response of brain support cells. A protein called GFAP, when elevated, is associated with amyloid plaques, and could be useful.

Bottom line, a blood test result is not a diagnosis. Like with other blood tests we already get (think cholesterol and blood sugar for example), your physician would use the results along with other clinical information, such as cognitive exams and brain imaging, to make a final diagnosis. A positive result on one or more blood test suggests the presence of amyloid plaques in the brain, a hallmark of Alzheimer’s. This increases the likelihood that a person’s cognitive symptoms are due to the disease. A negative result indicates a low likelihood of amyloid plaques. This could prompt a search for other causes of cognitive impairment, such as vascular dementia or a medical condition.

And finally, for something completely different. In work published recently, a team based at Harvard found that lithium (a small element from the periodic table) loss in the human brain is one of the earliest changes leading to Alzheimer’s. In mice, similar lithium depletion accelerated brain pathology and memory decline. The researchers found that lithium levels dropped because it binds to amyloid plaques. In a final set of experiments, the team found that a novel lithium compound that avoids capture by amyloid plaques restored memory in mice. (For a brief summary, read this.)

The scientists screened a variety of lithium compounds that don’t get locked up by amyloid beta. They treated mice with the most potent of these, lithium orotate, which is not the lithium compound used to treat some psychiatric disorders. The treatment reversed Alzheimer’s disease pathology, prevented brain cell damage, and restored memory.

Although the findings need to be confirmed in humans through clinical trials, they suggest that measuring lithium levels could help screen for early Alzheimer’s. Moreover, the findings point to the importance of testing amyloid-evading lithium compounds for treatment or prevention. Do keep in mind that these are preliminary results, and need further follow up in humans.

To me, more data are always good. My goal here was to provide clarity on the current understanding of the cause(s) of AD, a disease that many of us are concerned with as we age. Interpreting data requires knowledge and context and I hope I’ve provided that, rather than overwhelming you!

It’s been a couple years (2023) since I wrote about Alzheimer’s Disease (AD), and a lot of that information has not changed. What has changed is the recent publication of a book by Charles Piller, an investigative journalist for the magazine Science. He exposes a shocking network of fraud in AD studies, apparently (to me) driven by the potential for financial gain to scientists working on drug development. Consider the current stats: if you’re 65, you’ve got about a one in 20 chance of developing AD, in your next decade. At 75, it’s about one in seven, while those making it to 85 face a one in three chance. Because this illness takes an enormous toll on sufferers and their families, hundreds of millions of families around the world are desperate for a medical breakthrough. And some researchers, regulators and pharmaceutical companies appear to have caved to the temptation to make a profit on that desperation.

The short takehome message is that the spate of recent drugs (the most publicized and controversial being antibodies to amyloid beta) were developed and approved based on ‘doctored’ data. So, I think it’s worthwhile diving into the role that amyloid beta plays in AD, which explains the focus of these drugs, and why they don’t work as well as had been expected, and in fact, can have serious side effects.

For over three decades, the driving concept in Alzheimer's disease (AD) research has been the ‘amyloid hypothesis’. Simply, this states that the accumulation of amyloid β (Aβ) peptide is the primary cause of the disease.

Let’s dig into what this means. Aβ is a peptide, that is, a string of about 40 amino acids produced when a larger protein called amyloid precursor protein (APP) is chopped up in the brain.

APP has a number of important functions in the brain, including guiding nerve cell movement during development, promoting neuron survival and growth, and supporting the processes underlying learning and memory. These roles are enacted by the protein itself and its breakdown products.

Yes, you read this correctly: APP is in fact cleaved, or cut, into smaller pieces, including Aβ, which are also active in the normal brain. The function of amyloid beta (Aβ) in the brain is not fully understood, but it’s thought to play a role in synaptic plasticity (i.e. the ability of the brain to respond and change), neuroprotection, and maybe regulating cholesterol metabolism. Normally, Aβ is rapidly broken down and removed but when the balance between production and clearance is disrupted, it accumulates.

This video gives a really nice graphic of some of these events as well as a good overall description of the progression of AD:

But, it was made almost 10 years ago and some details have changed; I’ll describe those later.

Let’s start at the accumulation stage. In a healthy brain, a type of glial cells (these are brain cells that provide different types of support for the functional workhorses of the brain, the neurons, which they outnumber by at least a factor of 10) called microglia engulf and destroy Aβ. If the microglia don’t work properly, then a second type of supporting cell called astrocytes, fail to work as they should. These starfish-shaped cells normally provide structural support to neurons (i.e. hold them in place) and release chemicals that promote growth and repair.

Now, if the astrocytes are overwhelmed with Aβ, it’s like a trash can that’s overflowing. The trash piles up on the ground and attracts pests. In my simple analogy, the astrocytes collect around neurons without clearing the excess Aβ, and voila: plaque buildup.

Now, we have to go back a step. I didn’t tell you that the excess Aβ is not just one thing. As its levels build up, initially, it forms small clumps (‘clusters’) that are small enough to travel freely through the brain. These clusters can stick to proteins on the surface of nerve cells (neurons), which damages the connections between cells. These connections, called synapses, are the gates on the information highways in the brain. So clearly, anything that damages them will mess with the brain’s normal functions of storing memories and processing information.

Over time, Aβ also forms larger, immovable clumps called plaques. These plaques also disrupt normal cell-to-cell signaling at the synapses, which are crucial for memory, thoughts, and emotions.

But that’s just the beginning. The plaques also set off an immune response in the brain, leading to chronic inflammation that further damages neurons. And, the amyloid can also deposit in the walls of blood vessels, a condition called cerebral amyloid angiopathy (CAA), weakening them and increasing the risk of brain bleeds.

Aβ aggregates can also trigger the misfolding of another protein called tau. (This will become important to the story when I start telling you some problems of the hypothesis.) While Aβ is typically found outside of nerve cells, it can migrate into cells, where it can weasel its way into tau to mess up its 3D shape. How does it do this you ask? In brief (very briefly!) because Aβ is not usually found inside these cells, its presence there induces the activity of some enzymes which have a bonus (but not beneficial) effect of knocking down the first domino in a chain of molecular changes to tau.

I’ll return to tau in the next post because its role in the brain is emerging as significant in the development of AD. And furthermore, both Aβ and tau are being utilized in new blood tests that may be able to indicate early stages of AD.

At this point in the story, I hope you now see the potential role of Aβ in Alzheimer’s disease and why it was an attractive drug target. But the results of the clinical trials did not support the plaques as causal. Nor did some other data, which I will also return to in the next post.

I’ve been pretty out of the loop for a few months of travel and gardening, but there have been a lot of interesting reports surfacing in the scientific literature. I’m going to tell you about some of these in the next few posts.

Let’s start with some news about creatine. I’ve written about and probably raved about creatine supplementation for years now, because of its well-known and well-studied role in promoting and maintaining muscle growth and performance. In the past few years, it has been implicated in maintaining bone density and cognitive abilities – both of which are extremely important to us as we get older.

Before I get into the weeds with those new studies, let me briefly summarize the role of creatine in muscles. What exactly is going on in our muscles when we supplement with this stuff? Briefly, creatine is a reservoir of phosphate (P), which is essential in producing ATP, the energy currency of all cells. With a little extra P, your muscles can contract longer and harder, allowing you to build more muscle mass – a really good thing as we age. There’s a catch though (isn’t there always?) – if you want to get these muscle benefits, you have to train while taking creatine. (Not necessarily true for cognitive boosts, read on.)

If you want a nice visual overview:

Of course, the enhanced muscle-building and -maintaining seen with creatine supplementation are hugely important to us as we age. This is another topic I’ve harped on because muscle may be the single most important tissue to carry along with us as we get older. The benefits range from improved balance and responsiveness which protect from falls (one of the leading causes of death and incapacity in older adults) to improved blood sugar and fat balance which are protective against a host of chronic diseases that plague and ultimately kill many of us (e.g. diabetes, heart disease, metabolic syndrome).

There are over four decades of data showing the efficacy and safety of creatine. Virtually all of the early work focused on strength or resistance training. Some newer studies show that supplementation also has a positive effect in aerobic or cardiovascular activities. This makes sense: Creatine gives you an extra reserve in all your muscles, whether you use them for resistance or cardio work. It just so happens that weight or resistance training depletes the limited amount of ATP in the muscle much more than aerobic activities because the latter allow your mitochondria to keep producing some ATP while working.

Another exciting new finding is that if you supplement with creatine while eating a diet that has a reasonable amount of carbs (i.e. not a ketogenic or paleo diet), the glycogen stored in the muscles increases. This is important because glycogen is a food bank kept in the muscles to power the contractions during exercise. If you have experienced or read about ‘hitting the wall’ or ‘bonking’ during exercise, it’s usually because the glycogen stores in the muscles have run out.

Although there are a lot of variations on how much and when to take creatine, for most of us, 5 grams per day is an easy round figure to remember. It dissolves easily in water and doesn’t have much taste making it easy to drink down. If you want a more precise dosage you can go with 0.1 gram per kilogram of body weight. And while I’m on the topic, when I talk about creatine supplementation, I mean creatine monohydrate powder. There are other (more expensive) forms but this stuff is easy to find and pretty cheap.

These and other details and myths (such as the over-hyped claims of water retention) about creatine supplementation are covered clearly in this review.

Now, let’s move on to some newer findings. For the XX individuals out there, a couple fascinating findings. In younger, i.e. premenopausal women, besides building muscle and strength (not controversial), compared to the placebo group, consuming creatine on training days resulted in significant increases in total sleep; sadly I haven’t been able to replicate that in my older body.

As women age, and experience the drop in estrogen caused by menopause, bone density takes a big hit. There are a lot of drug and exercise regimes out there to build bone density, and several recent studies suggest creatine can have a beneficial effect. Before I give you those results, we need to take a side trip into just what bone density means.

This important feature of bones is usually measured by a type of X-ray (abbreviated as DEXA) that assesses the amount of mineral (mostly calcium) in a given volume of bone. Ergo, lower bone density means less mineral, which correlates with the rigidity or strength of bone. There is another feature of bone that is important to this discussion which is more difficult to measure and that is bone elasticity. You can think of this as the ability of bone to accommodate bending – an important aspect of bones that allows them to absorb stress without breaking.

In a two-year study of post-menopausal women, when compared to the placebo group (i.e. not taking creatine), the treatment group did not see any significant increase in bone mineral density at the sites typically measured (the top of the femur, the hip, and the lumbar spine). However, creatine at the 5 gram dose did have two important effects. Women in the supplementation group maintained the cross-sectional area of the femur (i.e. its size), and its ‘buckling ratio’ which is a measure of its resistance to bending. In my mind, these are more important metrics than bone density as density alone without flexibility can result in stiffer, more fracture-prone bones.

Finally, some very preliminary data suggest that high dose creatine may boost cognitive skills in people with Alzheimer’s – a disease of aging that slowly in irrevocably eats away at brain tissue causing what has been thought to be irreversible losses of memory, personality and intellectual abilities.

Some researchers believe the damage caused by Alzheimer’s is due to an energy deficit, possibly because blood vessels in the brain deteriorate with age, especially with diets and lifestyles that cause vascular damage, there is a problem with how the brain produces and uses energy. As you now know, creatine, provides an energy reserve in cells such as muscle and brain that require a lot of energy.

The typical dose we’ve discussed is 5 grams per day, but because creatine exits the blood into muscles first, a higher dose was used in this study, in hopes of improving creatine’s odds of making its way to the brain. For this trial, 19 participants with Alzheimer’s disease ages 60-90, took 20 grams of creatine monohydrate every day for eight weeks. The higher dose appeared to work, as study participants showed an 11% increase in brain creatine levels.

A few behavioral tests were done on the study group. They showed a moderate improvement in working memory, which is task-oriented memory. Participants also demonstrated a moderate boost in executive functioning, another cognitive domain highly affected by Alzheimer’s disease that includes a person’s ability to focus and ignore distractions.

This study clearly needs replication, but some results from disabled and elderly populations support the benefits of creatine for general health, of both body and mind. And, it seems you don’t have to work out to get these benefits, though to build and maintain muscle the training part of the equation is non-negotiable. Here’s Stuart Phillips, PhD, professor of kinesiology at McMaster University in Hamilton, Ontario, Canada describing some of these studies.

In a younger (18-65), apparently healthy group (a number of criteria were used to establish health status, including BMI, alcohol and drug use, psychological stability) creatine was supplemented at the lower standard dose (5 gm per day). The 150 subjects were tested in both treatments, creatine and placebo, in alternate ordering (one group had creatine first, for 6 weeks, then placebo for 6 weeks; the other group the opposite order). Supplementation resulted in a small improvement in abstract reasoning (as measured by one test) and working memory (assessed by the backward digit span test – kind of a fun thing to test yourself on).

Unfortunately, age was not included as a variable but diet choice was. Vegetarians and omnivores were analyzed separately, and there was no difference in cognitive benefit between the two groups. Why, you might wonder, was this hypothesis tested? Well, like some other nutrients (B12 and amino acid quality), creatine is present in animal foods but not plants. However, the amount you get from a typical diet is pretty small, you’d have to eat kilos of beef or salmon to get 5 grams of creatine! Probably best to use the powder form.

How Much is Too Much?

I don’t want to beat a dead horse, because I’ve talked a lot about how protein in our diet becomes increasingly important as we age. But, I will revisit some background, because of an interesting new study I came across recently, and give you an update on the current status.

Here’s the deal. We need dietary protein for maintaining muscle in the body, as well as for other critical functions like immune system activity and cellular structures. Our ability both to digest it and use it to build muscle decline with age, an unfortunate occurrence known as anabolic resistance. Think of it like taking your car to the shop you’ve been going to for decades. As the mechanics and their tools age (assume neither is repaired over time), the quality of their work on your car is going to drop.

My interest in the amount of protein I eat stems from the very clear relationship between that and the amount of muscle I have. This is not trivial as many studies have shown that maintaining or increasing muscle mass, and the strength that provides, are the single most important means you have to stay healthy as you age.

Let’s start with the point that the protein from your food is key to building muscle: Why do you have to build it? The body is constantly breaking down and rebuilding all its tissues. So you need the building blocks (amino acids), which you get from protein, to do this.

Now we get to the question of how much do you actually need on a daily basis? I’ll get to that shortly, but keep in mind that if you aren’t working your muscles, they aren’t going to respond to a supply of protein building blocks that you give them. And, as I’m always saying, we are all different, so you’ll have to experiment a little to fine tune your intake.

The recommended dietary allowance to prevent deficiency for an average sedentary adult is 0.8 grams per kilogram of body weight. So, for example, if you weigh 150 pounds (68 kg) you should eat about 55g of protein a day.

This is the bare minimum to help prevent any adverse effects from protein deficiencies (think: brittle nails and hair, fatigue, gut issues).

Many studies from sports physiologists suggest that 1.2 to 1.6 g/kg of high-quality protein is actually the sweet spot when it comes to optimal health.

Before we work out how much protein you need to build muscle, let's first revisit exactly what protein is.

Basically, protein is a macronutrient (a nutrient that we need in large quantities) that is built from amino acids, which are stitched together into the long chains we call proteins. Some of these chains your body can make naturally – known as 'non-essential’ – and some of which it can’t (essential).

The so-called ‘essential’ amino acids come from food. When you eat any protein-containing food (for example, chicken, egg, tofu, or rice) your body breaks them down into their constituent amino acids, which it then uses to build everything from new muscle to organs and fingernails.

Human proteins have a specific ‘fingerprint’ of the 8-10 essential amino acids (EAAs) we use in our bodies. For example, you need about 6 times as much arginine as tryptophan (2 of the EAAs). If you have a balanced diet, your body can make 12 of the 20, but if your diet is lacking in some way, then two more will become essential - or required from your food.

And you need each of these in the optimum amount, otherwise any single one that’s low retards the synthetic process. Here’s an analogy. Let’s say you’re ungainfully-employed at the medium security prison outside of Canon City making stop signs. You need 1 S, 1 T, 1 O and 1 P for each sign. Unfortunately, in your supply box you get 40 each of S, T, and O, but only 20 Ps. You could have made 40 signs but given the limiting factor of P, you only make 20.

The reason for the preceding discussion of essential amino acids is that they play a role in what is called protein quality. Briefly, high quality proteins have EAA signatures more like our human pattern, making them more efficient sources of the building blocks we need for our proteins. This doesn’t necessarly mean just animal protein (though these are more similar to human in the EAA profile; you can combine plant proteins to do just that as this brief You Tube video illustrates).

And,if you want a deeper dive, I talked about these and many other aspects of muscle development and significance in early blog posts here on Substack.

To build muscle, your body needs to synthesize more muscle protein than it breaks down. So, to build muscle you need to be sure you’re getting enough protein, as well as making sure you’re working your muscles. Hence the current recommendations for weight training for us all.

As an aside, protein also plays an important role in losing weight. Eating protein can increase the number of calories you burn, because it stimulates your metabolism. Remember that it’s used to build all kinds of stuff in your body. Protein will also reduce your appetite.

One study in this area reported that even a modest increase in protein, from 15% to 18% of calories, reduced the number of fat people regained after weight loss by 50%.

On a simple level, protein guidelines generally fall into one of two camps: a proportion either of how much you eat or how much you weigh. However, both have drawbacks.

For example, eating a specific percentage of protein in the diet. The problem is that the numbers are going to be impacted in a big way by your total food intake. For example, 30 per cent protein on a 2000-calorie diet (600 calories) is very different from 30 per cent protein on a 4000-calorie diet (1200 calories) despite the fact that the percentages are exactly the same: 150g a day compared to 300g a day.

So, calculating your protein intake relative to your weight could be better, as it stays consistent regardless of how many calories you're packing in. For example, if you were to eat 2 g of protein per kg of body weight, you'll be giving yourself the same amount of protein regardless of your total daily food intake. Of course there are problems with this too. For example, some of us have more body fat than others. The fat tissue doesn’t need protein whereas the muscle (called lean body mass) does.

Really what we want, though this is getting into the weeds, is to use the lean body weight to determine our protein need. The problem with this method is that the only really accurate way to know it is by some kind of body scan like Dual-Energy X-ray Absorptiometry (DXA), Bioelectrical Impedance Analysis (BIA), or hydrostatic weighing. That said, I use the gm/kg method, accepting that it has a little slop, but is basically pretty realistic.

I know the preceding is not very helpful if you want some numbers, so here you go. For health and maintenance of optimal muscle mass, aim for

• 1.2g-1.6g of protein per kg of body mass

And, if you're trying to put on muscle and you're training consistently, then step it up to:

• 1.6-2.2g of protein per kg of body mass

For a long time the prevailing wisdom was that the desired protein intake had to be spread across the day in modest increments because we could not process large amounts at once.

Now, a recent study suggests that young men (note a typical research bias here) can effectively utilize and incorporate at least 100 grams of protein in a single meal, challenging the previous notion that there's a limit to protein absorption and utilization. The study found that consuming 100 grams of protein led to a greater and more sustained increase in muscle protein synthesis compared to a 25-gram protein intake.

The study design set up three groups: one group consuming 25 grams of protein, another consuming 100 grams of protein and a final group receiving a placebo (no protein). Then all of the participants went through a standard weight lifting session and their physiological responses were measured over the subsequent 12-hour period.

The results showed a clear dose-dependent relationship between protein intake and muscle protein synthesis, as well as absorption. In other words, the more protein they ate, the more muscle was built. Importantly, there was no observed saturation point in the muscles, meaning even large amounts of protein in a single meal were effectively used by the body. In other words, eating 100 grams of protein in one sitting made larger amounts of amino acids available to build muscle (and other tissues).

However, larger quantities of protein required more time for digestion and amino acid absorption.

If there were a cap, say at 25 grams, the group consuming 100 grams of protein would not have shown greater muscle protein synthesis, protein absorption, or net protein balance. This means that consuming substantial amounts of protein in one sitting does not lead to waste, debunking the prior thought that protein beyond a lower limit is ineffective.

An implication of this study is that the most important thing to focus on is total daily intake of protein and that we don't need to worry so much about how many grams of protein we eat per meal. We should instead put an emphasis on meeting a daily protein target in a way that aligns with individual lifestyle needs. As I noted above, if you want to gain muscle mass, then aiming for approximately 2 grams of protein per kilogram of body weight per day, combined with resistance training, should do the trick.

Bottom line: match your protein intake to your weight and activity level to optimize your muscle mass as you age. There are many physiological reasons why muscle is critical to keeping you healthy. For example, falls are a major cause of early mortality. Break your hip after age 60 and statistically, you might not live another year. Stronger muscles give you the strength and balance to recover from tripping over obstacles or slipping on uneven ground. Muscles also release a variety of compounds (generically called myokines) that talk to other tissues in the body, to optimize these functions. For example, some myokines cause fat tissue to be mobilized and burned for energy. Other myokines regulate glucose uptake and stabilize blood sugar.

But there’s a bigger picture here: all the parts of our bodies communicate with our brains. I believe that being strong and fit sends a message to the brain that can provide a sense of confidence and security – valuable at any time, but especially during times of stress and anxiety.

Thanks to unsplash for the pretty picture.

Welcome back to an aging blog – now that I’ve finished my digression into cholesterol, I can get back to my obsession with the molecular and cellular mechanics of aging. Here, I’m going to go into a pretty obscure topic – but one that I think may grow into a big and important area of not just aging research, but relevant to a whole host of other diseases.

I started down this rabbit hole when I read about the work of a physician/scientist from Harvard, Anna Greka, who works on rare genetic diseases. These are typically caused by mutation(s) in a single gene. If you want the overview, she has a great TED talk.

Before I get to her fascinating finds, there is, as usual, a back story, this one on autophagy. I’ve written on this very cool process before, as this cellular recycling capability is turned up by intermittent fasting and other forms of caloric restriction. Things get a little complicated now, as there are different types of autophagy. The stress-induced, or starvation form of autophagy, is triggered, as implied, by lack of nutrients. It makes sense that cellular recycling would scavenges goodies from trash and offset nutrient deprivation. The better-studied, and continuously-occurring form is called selective autophagy. I’ll explain this below, but visuals can help clarify the process:

For a more simplistic overview:

For a deep dive with beautiful graphics (you can ignore molecular details and acronyms)

Keep in mind that cells, like the body in general, strive to maintain homeostasis, i.e. a constant and regulated environment. To do this, damaged, superfluous, and harmful material has to be removed. Selective autophagy is the main way cells do this. The junk that’s slated for removal is moved into structures called lysosomes, which contain enzymes that can break down different types of molecules. The component pieces can then either be re-used by the cell or transported out for elimination.

Selective autophagy removes a variety of unwanted materiel from cells. One group includes damaged organelles, such as mitochondria and parts of the endoplasmic reticulum (the manufacturing regions of the cell). Proteins that we can generically term mis-formed are also removed. These include proteins that have clumped together (aggregates), or have not passed the quality control checks following their synthesis. Finally, bacteria and viruses can be eliminated in this way.

The material the cells want to get rid of is tagged with a variety of labels that say ‘take me’, and put into nascent ‘sacs’ that form around it, eventually becoming a complete package called an autophagosome (literal translation: a self-eating body). The autophagosome is moved to and fused with a lysosome. You can see this process in the preceding videos. I want to make two points by stressing this rather obscure part of the autophagy process.

First, stuff the cell is getting rid of, the technical term is ‘cargo’ (!), is recognized by specific receptors in the cytoplasm (the liquid matrix in a cell). If you watched one of the videos, these are some of the many acronyms in the early stages of autophagosome formation. These receptors play a crucial role in the eventual degradation of cargo by forming clusters, or globs of the same or similar cargos. I’ll come back to this point.

Second, once labelled cargo is bound to a receptor, this initiates the process of building the enclosure around it: the autophagosome. The overview from the videos is useful in conceptualizing this process – it’s pretty complicated, involving numerous steps. My reason for emphasizing this is because if any one of these is blocked or doesn’t work right, the fusion of the sac with the breakdown apparatus in the lysosome won’t happen.

A failure here can result in the various diseases associated with defects in selective autophagy, perhaps most notably in the context of neurodegenerative diseases including Parkinson’s disease and tauopathies, but also the previously mentioned genetic diseases.

Let’s go back to misshapen proteins that are targeted for removal. Remember that proteins are big molecules, consisting of hundreds or thousands of amino acids. These chains are built from instructions in our DNA, which are copied into a similar molecule (RNA) that is decoded by a molecular machine called a ribosome.

For a brief, graphic refresher on protein synthesis you can watch this video.

Most proteins assume a 3D shape that facilitates their specific function(s) and this ‘folding’ as it is called, takes place after the ribosomal synthesis. Amazingly, about one-third of all newly synthesized proteins, especially long and/or difficult-to-fold proteins, fail to pass the quality control system that ensures proper folding. Normal protein sequence is disrupted by mutation, which means that normal folding won’t occur.

Another type of misfolded protein burden occurs in aging cells, where our QC system is less efficient. These damaged proteins contribute to diseases such as Parkinson’s and Alzheimer’s.

Back to Anna Greka’s work. She and her team found that one of the proteins (called TMED) involved in the earliest process of autophagy, recognizes and binds to a mutant protein (MUC1). Normally, this binding would trigger subsequent stages of formation of the autophagosome (the transport sac that carries damaged cargo to the lysosomes for disposal). The first of those stages involves moving the TMED bound to its cargo to the growing sac membrane. This is the normal aggregation step between cargo and transporter.

In the case of MUC1, however, this binding triggers a multiplier process. The MUC1 attached to the first TMED gloms on to the MUC1 attached to a 2^nd TMED. This in turn gloms on to a third and on and on, eventually gumming up the whole works. Not only is the cargo not disposed of but a new and dangerous conglomerate structure disrupts the normal autophagy process. (A beautiful but complicated diagram of this process can be seen in Figure 6 of Greka’s paper).

In the case of the kidney disease Prof. Greka studies, the aggregate eventually killed the kidney cells. A similar process has been documented in retinitis pigmentosa, a form of blindness. Remarkably, based on the identification of the molecules involved in the aggregation process, the research group was able to find and test a treatment that reversed it in mice and test tubes by displacing the bound MUC1 and targeting it to the lysosome for breakdown.

Diseases caused by mutant proteins like the MUC1 are generically termed proteinopathies, i.e. pathologies due to a protein. Most of these are not exactly household names, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, neonatal diabetes caused by insulin gene mutations, and Ehlers-Danlos syndrome caused by collagen mutations.

These rare, so-called orphan diseases (because not many researchers study them due to their low numbers), could be amenable to treatment like that for MUC1. But even more exciting to me is the possibility that other diseases caused by protein aggregation could be reversed by this type of research and treatment. These include many neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and ALS. Other organ systems suffer from diseases caused by the abnormal accumulation of gobbed up proteins; these include type 2 diabetes and several heart diseases. There are a lot of years and potential mis-steps between bench (i.e. lab study) and bedside (i.e. clinical treatment), but this is promising and exciting work. I hope research funding for these groups is not getting cut.

So here’s the skinny on HDL (High-density lipoprotein cholesterol), starting with the back story. For years this was considered the “good” cholesterol. This label came about because way back in the Framingham study, initiated in 1948 by the National Institutes of Health, it popped up as being inversely correlated with cardiovascular (CV) risk. In other words, when HDL was high, risk of heart disease was low.

But, as research into the relationship between heart disease and HDL progressed, some confusing findings cast that association into doubt. First, a recent study showed that very high HDL levels correlate with increased rates of CV disease (CVD). Second, clinical trials testing drugs to raise HDL have not produced the predicted drop in CVD.

HDL particles (remember all of these lipoproteins are particles, or globs, of a wrapping consisting of proteins and membrane lipids (refresh your memory with this lovely color diagram) around a lipid core of cholesterol and triglycerides.

Here, the green blobs with the yellow tails are called phospholipids; the ‘phospho-‘ is just something that mixes in water and the lipid part (the tails) don’t. Guess what? The lipid tails go on the inside, where all the cholesterol (C) and other fats (T for triglycerides, typically the fat from your last meal) go. A nice little package that travels through the blood. This particular package, is what comes from your intestine carrying the lipids from your last meal. The 5 Apo’s that you see are the different types of ‘apolipoproteins’ i.e. these are the proteins that connect to the lipids in the membrane, holding it together as well as docking at various points in the body.The primary protein component of HDL is apolipoprotein A-I (apoA-I), which makes up about 70% of its total protein content. We’ll come back to it. Fo a nice animated overview of all these particles (and a simplistic story of cholesterol’s travels in the body) watch this video.

One of the main functions of HDL is its ability to promote the first step of what’s called reverse cholesterol transport (RCT). This just means that cholesterol has been moved out of a place it was deposited, for example, the foam cells in the artery walls, discussed in my last post. The technical term, which I will occasionally resort to, is efflux.

Cholesterol Efflux Capacity (CEC) is a measure of HDL's ability to remove cholesterol from cells, particularly macrophages, which become the so-called foam cells when loaded with cholesterol in an artery. These cholesterol-filled cells are key players in the development of atherosclerosis. CEC is a crucial aspect of reverse cholesterol transport, the process that removes excess cholesterol from peripheral tissues AND transports it to the liver for excretion.

Before we get into the nitty gritty of this removal process, I want to give you a hint as to why it is so important, and thus, why HDL would have evolved in our systems. Free cholesterol, that is, cholesterol that is neither converted to another form, nor metabolized, is toxic to cells. (If you are wondering why: when there is too much of it around, it disrupts the normal structure of cell membranes – where it is a good thing in the right amount- leading to impairment in the ability of the cell to move substances in and out, as well as damage to internal cellular structures called organelles. Ultimately these cells die. This is primarily due to the "stiffening" effect it has on the membrane, altering its properties and causing disruptions in cellular processes. Most body cells and tissues (except for the liver and organs which make and use steroid hormones) cannot break down cholesterol. Thus, macrophages protect themselves against too much cholesterol accumulation by either transforming it to a form in which it can accumulate for storage, or by moving it out it to HDL particles.

I know it’s a little confusing. CEC measures how much cholesterol a given HDL particle can unload, whereas RCT refers to the whole process of transport and elimination.

This reverse transport is what makes HDL the ‘good cholesterol’. But remember this isn’t always true. What accounts for this variability? First remember that each of these lipoprotein particles can come in various sizes, from small and dense to large and buoyant. In the HDL, their lipid content (e.g., cholesterol esters, phospholipids, triglycerides) and protein content (e.g., apolipoproteins like apoA-I) can vary as well.

If you want to dig in further, read this (or try).

Larger HDL particles, particularly those with a higher proportion of phospholipids, tend to be more effective at promoting cholesterol efflux. Conversely, smaller and more lipid-rich HDL particles have a lower cholesterol efflux capacity. This makes sense intuitively: bigger particles have more surface area, and more room inside to hold more.

But there’s another twist to the story of how particle size and composition influence CEC. Smaller HDL particles can promote cholesterol removal via what’s called the ABCA1- pathway.

To explain exactly what this is, I have to get a little technical, so bear with me. The ABC1 transporter, short for ‘ATP-binding cassette’ transporter A1 (ABCA1), is a protein involved in cholesterol transport across cellular membranes. ABCA1 mediates the efflux of cholesterol (and phospholipids) from cells, especially the foam cells in the arteries, to any particle carrying apolipoprotein A-I (apoA-I). Remember from the diagram this is the major protein component of high-density lipoprotein (HDL). So, this is what makes HDL the ‘good’ cholesterol; really it’s a ‘good’ lipoprotein particle that can accept cholesterol (as well as other lipids). And, a really cool thing about the ABCA1 protein is that it uses the energy stored in ATP to make this happen. Meaning the HDL can pump cholesterol against a concentration gradient, in other words, even when the HDL is pretty full and the foam cells are emptying, this removal can carry on.

As these HDL circulate through the blood, they can also pick up cholesterol through other means (which I won’t get into). When the HDL particle journeys through the liver, which they all do, as all blood circulating traverses this important organ on its constant commute around the body, cholesterol is moved into liver cells using that same ABCA1 protein. There, it can be excreted directly into the bile or converted into bile acids for elimination from the body.

When there is a lot of cholesterol entering the liver in this way, some liver cells get that message and activate the gene for the ABCA1 protein, thus making more of the protein. This in turn ensures that excess cholesterol is efficiently removed by the liver.

Another thing the larger HDL excel at is their antioxidant properties. These may play a role in protecting against oxidative stress and inflammation, which are key contributors to atherosclerosis.

Before we leave the topic of HDL, there is one other aspect of its biology that is fascinating, from an evolutionary point of view. Lipoproteins function not only as lipid delivery vehicles, but they also play a role in the immune system. Specifically, HDL particles can bind and neutralize lipids in bacterial membranes. This means that many disease-causing bacteria are grabbed and tagged for destruction and removal by other immune system cells.

What’s more, recent studies have shown that some chronic diseases can degrade HDL structure, and thus, function. These include lupus, rheumatoid arthritis, atrial fibrillation, and chronic kidney disease as well as allergic and skin diseases, including asthma and some forms of dermatitis. That reduced HDL function may compromise the immune system’s ability to combat and limit progression of the disease, in turn increasing the risk of subsequent infections and even cardiovascular disease.

Whew! I think we’re done with lipoproteins for a while; but they are incredibly important to our cardiovascular health so don’t forget them!

Now that you know the basics of LDL (and I’ll give you a brief refresher shortly), I have to tell you that there is a newly-discovered player in the game – and a pretty important one at that. It’s called Lp(a) – pronounced ‘LP little a’. This is another protein that carries lipids around the body, called apolipoprotein-a or apoA, that attaches to the lipid transport package. The liver does this attachment, making an LDL with an extra protein, the ApoAa.

If you want to listen to a short lecture on lipoproteins and cholesterol, Peter Attia, in his usual inimitable style, provides a clear story with plenty of detail. Note, that here, I often abbreviate use the term ‘LDL’ to refer to the cholesterol there, and refer to the entire lipoprotein as the LDL particle.

Remember this guy below? This is the lipoprotein that your intestine sends into the blood after you eat a meal. The green blobs with the yellow tails are called phospholipids; the ‘phospho-‘ is just something that mixes in water and the lipid part (the tails) don’t. The lipid tails go on the inside, where all the cholesterol (C) and other fats (T for triglycerides, which you also get measured in a lipid panel blood test) go. The 5 Apo’s that you see are the different types of ‘apolipoproteins’ i.e. these are the proteins that connect to the lipids in the membrane holding it together as well as docking at various points in the body.

The LDL particle is similar to the one in the drawing, except that each LDL has a single apolipoprotein-B. Each LDL can carry 3,000 to 6,000 lipid molecules (phospholipids, cholesterol, triglycerides, etc.) around the body. There are a bunch of non-apo proteins embedded in the phospholipid shell, not shown, that also help hold the whole assembly together.

The ApoB on the LDL particle grabs onto LDL receptors (proteins in the cell membrane) in various cells throughout the body. This attachment allows the fats in the LDL particle to enter the cells; I summarized this process in the last post; you may recall that binding of the ApoB also allows various cells, especially liver cells, to remove LDL from the blood.

The preceding paragraphs summarize what I told you previously about LDL. Now for Lp(a). This critter is an LDL, but with an extra protein, the Apolipoprotein-a, which is attached to the apo-B protein. (Confusing I know – but this is not the same ApoA shown in the diagram above, that is found on the HDL particle; that’s the topic of the next post.) You can see the attachment in this beautifully colored computer-generated graphic at the top of the post. (I don’t think the actual lipoproteins are colored like this!) Something to keep in mind, all Lp(a) are essentially LDL particles, but, not all LDL carry the (a) entity.

The reason for the disparity is found in our genes. Maybe 20% of people worldwide have high levels of Lp(a). (We don’t know the exact number because testing is not widespread.) One’s Lp(a) blood level is determined by the type of LPA gene they carry. We all have this gene, which is the instruction for making the Apo-a protein; but it comes in a variety of forms. Some of these variants (as they’re called) make for a really long (a)-protein, while others are shorter, and still other don’t make any of the protein at all. The sizes can range quite a lot. In general, the longer your (a) protein, the less risk of it contributing to coronary artery disease.

Here’s why. Bigger proteins take longer to make, and are more difficult to export from the cells. Sometimes they don’t get out al all. So, it’s the smaller ones that get out and are attached to an LDL.

As you can see in the color diagram, the Apo-a has a long tail (this is the part with variable length) and it can anchor the LDL into the artery wall. As you now know, LDL have a unique ability to squeeze into artery walls where they get stuck and initiate the process of arterial blockage. So, the more, and the shorter the Lp(a) you have, the greater your risk of arterial disease and blockage.

Further, the level of Lp(a) in your blood, is an independent risk factor for heart disease, even in younger adults and otherwise healthy people with no other known cardiovascular disease (CVD) risks. This means that, unfortunately, lifestyle changes such as diet and exercise do not reduce Lp(a), and most of the commonly used preventive strategies for those with risk factors for CVD are ineffective. But this doesn’t mean you should throw caution to the winds if you have a high level of Lp(a), as you can still mitigate other risk factors, such as the garden variety of LDL you may have.

Because of this genetic influence, different ethnic groups show wide variability in Lp(a) concentrations, with Black individuals more likely to have elevated Lp(a) than Whites, Hispanic, or Asian individuals.

This racial discrepancy in risk has been studied by a research group of the NIH (National Institutes of Health) called the Atherosclerosis Risk in Communities Study. The study, which focused on 4 geographically diverse US communities, found that the proportion of cardiovascular disease potentially attributable to elevated Lp(a) was about 10% among Black adults compared with about 5% among white adults. Both racial groups had about the same overall risks for heart disease, leading to the conclusion that these differences are driven largely by differences in Lp(a).

The ApoA-a can contribute to this risk in a few ways. First, as we have seen, it can infiltrate the arterial walls and promote the formation of plaques (atherogenesis). These plaques can narrow arteries and restrict blood flow, leading to cardiovascular problems.

The exact mechanism is pretty interesting, so you can follow me down this rabbit hole if you like deep dives. Structurally, by which I mean its 3D shape, apolipoprotein-a looks a lot like some of the enzymes in our blood that protect us by breaking up clots. Because of that similarity, it can block those helpful enzymes from attaching to clots. Remember, when you have lots of Lp(a) in your blood, you are more likely to form and retain clots – one of the main ways that coronary artery disease causes heart attacks.

And if that weren’t enough, Lp(a) stimulates secretion of a compound that independently promotes clot formation; again increasing the risk for CVD.

Second, Lp(a) may promote inflammation in the blood vessels. Chronic inflammation, present in all of us as we age, contributes to the progression of atherosclerosis. The immune system, which is the source of all inflammatory events, is ramped up in the arteries where it tries to protect them by attacking plaque (as discussed in the previous post). This can destabilize the plaque causing it to break loose. A plaque that separates from the vessel wall is like a clot traveling through the blood, which can cause heart attacks or strokes.

Third, elevated levels of Lp(a) can damage the endothelium (the inner lining of blood vessels). This damage can impair its ability to regulate blood flow and maintain the health of the vessel, potentially allowing even more infiltration of LDL into the vessel wall.

Finally, Lp(a) may interact adversely with other lipoproteins, especially LDL, exacerbating the risks associated with high cholesterol levels. One study found that high levels of both Lp(a) and HDL also increased risk of heart disease (though this was only in families with early onset conditions). This finding emphasizes the confusion in the research literature (which I will explore in the next post) on the function of HDL in the story of coronary artery disease.

Despite these associations between Lp(a) and heart disease, it flies under the radar of many physicians is not routinely measured. Many cardiologists don’t assess it, possibly because treatment options are still very limited. Interestingly, people without Lp(a) or with very low Lp(a) levels seem to be healthy, meaning if we could get lower levels by treatment, it wouldn’t affect one’s health.

What is out there for treatment? Lp(a) has remained an elusive target since it was first discovered. Common lipid lowering therapies have largely proven ineffective. Statins, the most widely used type of LDL-lowering drugs, do not reduce Lp(a) and may even cause a slight increase. Niacin (vitamin B3) can provide modest reductions in Lp(a), but it is not approved for its treatment. Moreover, large studies have failed to show that niacin reduces heart disease risk, and it may cause serious side effects in some patients.

As I told you last time, both statins and PCSK9 inhibitors reduce the level of LDL in the blood. Statins lower cholesterol levels by inhibiting an enzyme that plays a key role in the production of cholesterol in the liver.

We think a lot about the cholesterol in our diets, but in fact, the liver makes most of the cholesterol in our bodies. There is a complicated system that regulates how much is synthesized, mostly in the liver, and how much is then taken out of the blood and dumped into the intestine for excretion. Interestingly, some of the cholesterol dumped out is then reabsorbed. With less cholesterol made in the liver, fewer LDL will circulate in the blood, thus lowering the level of this atherogenic particle.

PCSK9 inhibitors use a different mechanism, they block the action of a protein that breaks down LDL receptors, which are located on the outside of cells (mainly in the liver). If this protein can’t work, the LDL receptors stay active, pulling LDL out of circulation. These drugs reduce Lp(a) slightly. The way by which the accomplish this is not clear.

Statins, on the other hand, may actually increase Lp(a) levels in the blood. One hypothesis for this effect is that since liver cells are making less cholesterol, Apo-a production can increase as normally it has to compete with cholesterol production.

There are a number of drugs in the pipeline to block Lp(a) production. Some target the synthesis pathways, i.e. the steps between the gene and the protein. Others address the attachment step that connects the Apo-a protein to the LDL. All of these are still in development.

An important issue in the cholesterol story is how it’s measured because it’s not very exact. Before telling you about measurement options for Lp(a) – which probably should be done for anyone with a family history of cardiovascular (remember that Lp(a) is the single most important genetic risk factor for heart disease) – I need to describe how cholesterol is measured.

A blood test called a lipid panel measures total cholesterol, HDL cholesterol and triglycerides. (Triglycerides are mainly derived from the foods we eat and are readily used by the body cells for energy.) Although we all assume that LDL (either the number of particles and amount of cholesterol carried there) is measured, in fact, it is usually estimated rather than directly measured, since its direct measurement is more difficult. To calculate LDL, labs have traditionally used a formula known as the Friedewald equation.

The traditional Friedewald equation estimates LDL cholesterol this way: total cholesterol minus HDL cholesterol minus triglycerides divided by five. For simplicity’s sake, the formula applies a one-size-fits-all factor of five to everyone. But this often makes LDL cholesterol appear lower than it really is for some high-risk patients e.g. when triglycerides are high.

Now, take another look at the two pictures of the LDL particles. These (and other low density particles that we don’t need to worry about in this discussion) ALWAYS have a single ApoB protein per particle. Yes, just one! That suggested a way to measure LDL directly, by counting ApoB. Although some other particles have ApoB (Figure 1), over 90% of particles with an ApoB are LDL. For decades now, clinicians have known that this is a. better way to measure the number of LDL particles.

But, the amount of cholesterol in a given particle can vary a lot. This may be the reason that many cardiologists still look at the calculated measure as it tells them total amount present in the blood at the time of the test. A couple things to consider here: First, because arterial disease is initiated by the particle squeezing into the artery wall, it might be nice to have an idea as to the number of particles. Think about it this way: In a given amount of blood you might have 100 large LDL particles with a total content of 100 mg of cholesterol. Or, in the same blood volume, you could have 1000 small particles each holding 10 mg, giving the same total cholesterol. The arterial penetration is determined by the number of small particles circulating. In my artificial situation, both scenarios would give the same LDL measure from a blood test, but the second would be more predictive of cardiovascular risk.

To incorporate the Lp(a) particle, remember that it is essentially an LDL with an added bit of protein (refer to Figure 2 above). When your LDL cholesterol is measured, your Lp(a) level contributes to your overall level of LDL. If your Lp(a) level is low, its impact on total LDL can be minimal. But when Lp(a) is high it can account for much of their LDL test results.

For example, two people with similar LDL levels of 100 mg/dL could have very different heart disease risks. One person could have an Lp(a) level of 10 mg/dL, meaning that only about 10% of their LDL is derived from Lp(a). The other person could have an Lp(a) level of 150 mg/dL, meaning that half (50 mg) of their measured LDL is actually Lp(a). That's why testing for Lp(a) is so important, especially in people who have recurrent cardiovascular events despite LDL-lowering therapy.

Because Lp(a) particles, like other LDL, vary in size, the most commonly used lab tests are not ideal. These tests measure the total mass of Lp(a) in the blood, given in milligrams per deciliter (mg/dL). A more accurate approach is to measure the number of Lp(a) particles in your blood in nanomoles per liter (nmol/L).

Finally, the test for Lp(a) is pretty cheap so there is no reason not to get it measured, and you only need to do it once. Because it is determined by the genes you inherited from mom and dad, it won’t change much.

I’ve been thinking about cholesterol lately. It’s a simple molecule, but in the context of cardiovascular health, it’s really confusing. Here’s what got me going. My lipid panel came back with a surprisingly high total value – over 200. This surprised me because I think of my lifestyle as pretty healthy, i.e. lots of exercise, good diet, no red meats, etc.

Why is this number considered high? The NCEP (National Cholesterol Education Panel, an “Expert Panel” in the National Heart, Lung, and Blood Institute, a subsidiary of the National Institutes of Health) defines borderline high as falling between 200-239, measured in mg/dL. A milligram (mg) is 1/1000 of a gram, which itself is about 1/25 ounce, and the deciliter - 1/10 of a liter, or about 3 ounces, refers to blood volume. But a closer look at this panel’s recommendation shows that what they are really concerned about is LDL cholesterol (low density lipoprotein – read on to find out what this means); and that number should be less than 100 mg/dL (as mine is).

Now, there are a few reasons the numbers are confusing. Let’s start with what is being measured. First off, cholesterol (and other lipids which in your body include fats but generically means things that doesn’t dissolve in water) are packaged up in such a way that they can be distributed in blood. Keep in mind that blood is basically a bunch of stuff in a watery solution called plasma. The lipid-transport packages are called lipoproteins. This term is a little misleading because the packaging really consists of an envelope (a membrane a lot like your cell membranes) as well as proteins.

If you’ve ever made salad dressing by mixing oil and vinegar, you know that oil and water don’t like to mix. The oil (a lipid) ends up on the top because it’s less dense (in other words basically lighter). The lipoproteins are a group of 5 different classes of proteins embedded in a membrane that also mixes in water. You can see a cartoon of one type of lipoprotein here:

A couple things to note: the green blobs with the yellow tails are called phospholipids; the ‘phospho-‘ is just something that mixes in water and the lipid part (the tails) don’t. Guess what? The lipid tails go on the inside, where you also see the cholesterol (C) and other fats (T for triglycerides, which you also get measured in a lipid panel blood test). A nice little package that travels through the blood. This particular package is what comes from your intestine carrying the lipids from your last meal. The 5 Apo’s that you see are the different types of ‘apolipoproteins’ i.e. these are the proteins that connect to the lipids in the membrane holding it together as well as docking at various points in the body. I’ll have more to say about some of these proteins later.

Remember, the pictured package is the delivery vehicle emerging from your last meal. It picks up the lipids from the small intestine, where they are digested and separated from other chemical components of your food. Most of the body cells can make their own cholesterol, but they like to get triglycerides (the fat in food) for energy. So, as this particle travels through the blood dropping off triglycerides, three things happen. One, it gets smaller; second, the proportion of cholesterol it contains gets larger; and third, because the ratio of fat to protein decreases, it becomes denser, i.e. heavier. Finally it ends up in the liver where triglycerides and cholesteryl are packed into a new particle (the jargon term used for these lipoprotein packs), the VLDL (very low density lipoprotein). This particle follows the same sort of delivery path, and, you guessed it, ends up back in the liver where it is processed and (with a few intervening steps) results in our ‘bad guy’ the LDL particle. This (and other low density particles) can be identified because they carry only one of the 5 types of protein on their outer surface, the Apob-100. (if you refer back to the diagram you’ll see ApoB as one type, but it comes in different sizes; the significance of this comes later in the story).

In this post I’m going to concentrate on LDL. There are a couple other issues that are important in the cholesterol story but including them here will make this post too long and involved so stay tuned, I’ll get to them next. Teaser: one of them is ‘Lp-little a’, a new addition to the suspects list which is turning out to be a heavyweight in its contribution of coronary artery disease – the starting point for most heart attacks.

We’ll start with a brief detour into why LDL is the bad guy. There have been volumes written on this, but basically an overwhelming amount of evidence from animal research, test tube investigations, epidemiology, and analysis of genetic diseases that increase LDL, show that elevated LDL cholesterol is a major cause of coronary heart disease (CHD) because it contributes to artery disease (atherosclerosis). In the past ten years or so, drugs that lower LDL (mainly the statins) have become widely used because they significantly reduce risk for CHD.

Each LDL (look back at the cartoon above) can carry 3,000 to 6,000 lipid molecules (phospholipids, cholesterol, triglycerides, etc.) around the body. While there are a bunch of non-apo proteins embedded in the phospholipid shell, each LDL has a single apolipoprotein-B-100. (It’s called 100 because it is the larger of the two types of apoB in our story; the smaller, apoB-48 will make an appearance when we return to ‘Lp little a’.)

The ApoB on the LDL particle grabs onto LDL receptors (proteins in the cell membrane) in various cells throughout the body. This attachment allows the fats in the LDL particle to enter the cells.

You can this process in the Youtube below. (I suggest turning off the audio as there is a lot of jargon but the video is quite clear). Once the apoB attaches, the entire LDL particle is taken into the cell where the contents are removed.

Now, remember that most of our cells can make their own cholesterol so we don’t really need it from our diets. And of course, vegans, don’t get any dietary cholesterol, which is made exclusively in animal cells. But, if a cell does require additional cholesterol (made in the liver), it will make LDL receptors.

At the same time, and in a fantastic demonstration of how clever our bodies are, the cell will also make a protein called PCSK9 which tells the cell to destroy the receptors. In other words, once the cell gets the cholesterol it needs, the PCSK9 stops the intake.

Now, if PCSK9 is blocked, the un-needed receptor goes back to the cell membrane and takes in additional LDL particles, thus lowering LDL concentration in the blood. A new class of drugs, so-called PCSK9-inhibitors do just that.

Since we’re on the subject of cholesterol-lowering drugs, what about statins? These may be the most widely-prescribed drug in the developed world today. Statins block an enzyme essential to the process of making cholesterol. Reducing production lowers the total amount of cholesterol available in your bloodstream. Remember that all of our cells need cholesterol. In addition to being an essential building block in all of our cell membranes, cholesterol is used to make bile, a key agent in the digestion of fats in the intestine, steroid hormones (e.g. all of the sex hormones such as estrogen and testosterone), and in the skin to absorb vitamin D. Because it’s such an essential ingredient in animal life, lowering it with statins can sometimes cause unpleasant side effects.

Much of the cholesterol produced in the body is made in the liver; statins knock this way back. This means the liver, which is programmed to send out all of those lipoproteins, now pulls more of the cholesterol out of the blood. (Recall that each particle type returns to the liver with successively lower amounts of lipids following the initial journey from the intestine.)

When one takes a statin, their liver moves LDL receptors to the membranes of some of its cells to capture circulating LDL particles. This lowers cholesterol levels in the blood, which prevents it from being deposited in the arteries. (Full disclaimer: I am NOT a medical expert on cardiovascular disease – though I understand a lot of the biochemistry I talk about here – BUT the majority of studies on reduced risk outcomes have been done in men.)

Now we can get to the key question, what is it about LDL that makes it the ‘bad’ cholesterol? Well, I have to tell you, it’s not completely understood, but there are a few smoking guns that target LDL. First, LDL particles come in a range of sizes. I think this makes intuitive sense, because you know that they are made in the liver where they are stuffed with cholesterol and triglyceride fats. Imagine you are the liver cell doing the stuffing. You don’t always put the same amount in every LDL particle. People who study these things (lipidologists) classify LDL into two general sizes: small, low density; and large, buoyant particles. Now the smaller ones happen to be the right size to fit into the spaces between the cells that line our arteries. As the blood is oozing through the smaller arteries, the small dense particles get squeezed inside.

Once in there, another bad thing happens that makes it hard for them to get out. As you probably know, humans need oxygen to survive. We use the oxygen in the process of breaking down foods. And oxygen is central to this process. But oxygen isn’t limited to just the mitochondria where the food breakdown goes on. It’s transported through the blood to all of our cells, but while in the blood oxygen can (and does) pulls off some pieces of various items, including LDL particles. In this process, the LDL are ‘oxidized’, which changes their shape enough that they can’t get out of an artery wall that they have infiltrated. An oxidized LDL is also recognized by our immune systems as damaged and therefore warranting removal.

Your immune system cells, which are constantly roving through the body looking for damage or intruders, notice the LDL in the artery wall – where it does not belong. Some of these cells (the macrophages in this video showing the process) actually squeeze in and eat the LDL, but then they can’t get back out. The eater cells release chemical signals that attract other immune cells, that attempt the same repair, the end result being a growing patch in and on the artery wall.

There are two deleterious consequences to this patch job. First, it narrows the artery, which reduces the amount of blood that can get through. Not good for any tissue but especially bad for the heart which has a constantly high demand for the oxygen and nutrients carried in the blood. Second, the patch can detach and go roaming through the circulatory system where it can lodge in a smaller blood vessel, impeding blood flow. Again, not a good thing, especially in heart or brain where reduced blood flow means less oxygen and food, which can kill these metabolically active tissues.

The good news on the LDL story is that the new classes of drugs such as statins and PCSK9 inhibitors (along with a few others) can really knock back coronary artery disease and reduce the risk of heart attacks and strokes. But this reduction hasn’t been as large as hoped for, perhaps one reason is the role of a relatively recent addition to the lipoprotein story, the little a particle. I’ll come back to that (along with the issue of how cholesterol is measured – an intriguing story in itself) in the next posts.

Happy Thanksgiving everyone!

I know that this is traditionally a time for family get-togethers, which can be brutal and in the wake of the election, I suspect there could be some especially fraught dinners. I don’t recommend fighting over turkey, or really, at all, but if you happen to be discussing the appointment of RFK Robert F Kennedy) as head of HHS (the Department of Health and Human Services), especially his stance on vaccines, you may be interested in what follows.

First, a lot of what he says is just wrong. If you want to dig into details, you can do that here.

One of my aims in writing these posts is to emphasize the importance of science and the scientific method in the modern world. Although the classical scientific method we all learned in school outlines testing hypotheses by experimentation, we can access the results of millions of experiments that have already been done. These allow us to use evidence to evaluate questions and ideas, such as those thrown around in the current crop of misinformation.

Science has made our world better in many ways, public health and vaccines being one of them. Like many human endeavors, vaccines have had a spotty record and evolved over the years. A few examples:

- in 1796 Edward Jenner injected his gardener’s 8-year old son with cowpox (caused by a virus related to smallpox) without consent;

- in 1901 there was the first vaccine-caused tragedy in St Louis when a diphtheria antitoxin (the only treatment at the time for this potentially life threatening respiratory illness caused by a bacterium) haravested from a horse (this was how they were made then) unknowingly infected with tetanus. Thirteen children subsequently died from this fatal disease;

- in 1955, batches of the polio vaccine produced by Cutter Laboratories in California inadvertently contained active virus, instead of the killed virus preparation called for in the original Salk vaccine. Vaccines from those batches were given to about 120,000 children, about 40,000 of those children developed a mild form of the disease, 56 children developed paralytic polio, and 5 died. 

But in general, vaccines have saved many more lives that have been adversely affected. Let’s look at smallpox for an illustration (and I must confess I am borrowing this from Judah Pearl’s fascinating book, The Book of Why).

The following data are fabricated to make the numbers easy to follow, and wildly overestimate the risks of vaccines. Let’s say in a population of one million children 99% are vaccinated leaving 1% unvaccinated. If a child is vaccinated let’s imagine the chance of a negative, observable reaction is 1% (in actuality it’s more like 1 in 10,000, but for the story we’ll go with 1 in 100) and this reaction then is fatal in 1 in 100 experiencing it. But these vaccinated kids have 0% chance of actually getting smallpox.

Now for the unvaccinated kids.  They have no chance of an adverse reaction, but then 1 of 50 of these can get the disease if exposed. And assume that smallpox is fatal in 20% of cases (it’s more like 30-50% in under-developed countries).

Although on first glance you might say vaccination of course is a good idea, let’s crunch some numbers based on those made-up probabilities (stay with me here, the bottom line is fascinating). Out of the 999,000 that do get vaccinated, 9900 have a reaction and 99 die from it. Of the 10,000 that don’t get vaccinated, 200 get smallpox and 40 die from it. Now you might conclude, comparing 99 deaths from vaccine to 40 in the unvaccinated, as the anti-vax campaigns do, that vaccination is not safe.

But let’s go one step further. Flip the story on its head and assume no one gets vaccinated. Now, out of one million kids, 20,000 will get the disease and of these 4000 will die. You might reverse your prior opinion but I’m betting this side of the story doesn’t get told on the anti-vax sites.

The incident in St Louis, and a similar story in New Jersey impelled  Congress  to pass the Biologics Control Act in 1902. Also known as the "Virus-Toxin Law," the act gave the government the first control over the processes used to make biological products, or biologics, and the responsibility to ensure their safety for the American public. This law was updated in 1938 to create the FDA (Food and Drug Administration). Today, the FDA's Center for Biologics Evaluation and Research (CBER) regulates biologics, such as vaccines, blood and blood components, allergenic patch tests and extracts, human immunodeficiency virus (HIV) and hepatitis tests, gene therapy products, cells and tissues for transplantation, and new treatments for cancers and other serious diseases.

As with other drugs which are regulated by the FDA, vaccines have to go through rigorous safety testing. This testing involves, as for all drugs, 3 phases of clinical trials. These tests on humans (preceded in most cases by animal studies), focus first on safety, then on efficacy. The latter tests, which determine how well the vaccine (or other drug) works and at what dose, use the randomized clinical trial approach in which neither those doing the testing and those being tested know if the drug or a placebo is given.

Once a vaccine is approved by the FDA’s committee on safety (an independent panel of physicians and research scientists who review the data), it is then produced by one or more of the pharmaceutical companies that participated in the testing process. Vaccines are made in batches called "lots," which are tested to make sure each dose remains reliable and safe for use. Vaccine manufacturers test all lots, the FDA checks each lot for safety and quality, and the FDA regularly inspects manufacturing facilities. (I do have to introduce a caveat here, this facility testing is much less frequent and rigorous offshore where many generics - though not vaccines- are produced.)

So, yes, vaccines have not always been safe. Sure, there can be unforeseen adverse effects. This is why the FDA maintains a website where these adverse effects can be reported, confirmed, and investigated.

Currently, vaccines are some of the safest drugs we have. And, as a measure of their public health importance, they reliably confer significant protection against previously devastating diseases such as measles (which is not simply an innocent childhood illness; more on this below), mumps (which can be really serious in adults), pertussis (aka whooping cough which can kill 3% of infants infected), and tetanus (aka lockjaw which can kill over 10% of those infected, and many more in under-developed countries where it is more common than the US).

Note that I said vaccines confer protection against disease. They do NOT prevent infection. In fact, in order for a vaccine to manifest its full effect, you have to become infected (i.e. the causal organism whether it is viral or bacterial) has to invade your body and try to reproduce. When your immune system, which has been trained by a vaccine to recognize the infective critter, discovers it, can respond immediately, preventing full blown disease.

In one final comment on vaccines, and vaccine hesitancy, in the context of RFKs campaign against vaccines, here is a little-known story from Samoa. In 2018, while mixing the measles vaccine, nurses mistakenly used expired muscle relaxant rather than sterile water to re-suspend the powdered drug. Two children injected with this died. The country quickly placed its vaccine program on hold, as vaccine opponents, including RFK’s anti-vaccine nonprofit, Children’s Health Defense, trumpeted these deaths to raise questions about the safety of vaccines. The vaccination rate plummeted from 60-to-70% to 31%. A year later, a measles outbreak sickened thousands and killed 83. Here is a more succinct audio account from CNN (no guarantee of total accuracy, though it is more comprehensible than the journal article).

Now, I’m not suggesting you overwhelm family or friends who are in favor of RFK’s appointment with any of these details. But you can apply scientific method here, i.e. conduct an experiment by asking, motivated by real curiousity. No evaluation or response necessary but these conversations sometimes lead to discussions of evidence and now you have some of that.

Bonus: following through on your curiosity spikes your dopamine, so even if you don’t get to do any preaching you can still benefit.

I know it’s been a long time since my last post. I’ve been traveling a lot the past  few months with a lot of time off the grid – which is pleasant but not conducive to doing online research and posting!

In that time I came across some very cool new research results that I’m excited to share. As you probably sense from many of the blog topics, I’m a big fan of exercise – in just about any form and intensity level. The data are numerous and almost uniformly supportive of its benefit in improving long term health.

If you’re like me, you’ve got to wonder, how can an activity like exercise, hit so many systems that are not the muscles actually doing the work ? Read on, and you’ll have a better idea.

in 2012 a research team at the Dana-Farber Cancer Institute and Harvard Medical School were investigating how exercise caused white fat to brown. For those of you unfamiliar with brown fat, this video gives a quick overview.

If you’re a Huberman fan he goes into a lot more depth.

Exercise physiologists have known for a long time that exercise increases the amount of brown fat we have. The Harvard team wanted to know how.

A little background: exercise ups the energy output from your muscle cells. No surprise here. That energy is supplied by the cellular powerhouses called mitochondria. I’ve talked about these in past posts on exercise, muscles, and metabolism. When mitochondria are active, they release a protein called  PGC-1α. It stimulates the production of more mitochondria, but for our story, it also turns on a gene called irisin. The protein encoded by this gene is called FNDC5 (fibronectin type III domain-containing protein 5 if you really want to know).

The Harvard group showed that when muscles are exercised, they release a piece of the FNDC5  protein later named irisin. Here is our missing link in the exercise/benefit story. In other words, exercise releases a hormone-like molecule (irisin) that has effects beyond the muscle.

Inside your muscles, irisin plays several important roles. As you may have guessed, it contributes to muscle fitness. First, it provides the impetus to convert white fat to brown fat. We store some energy in our muscles in the form of fat. Second, irisin turns on a bunch of genes that regulate mitochondria, and probably make them run more efficiently which would improve endurance and reduce fatigue during exercise. Finally, irisin appears to be involved in muscle hypertrophy, or growth, which would increase one’s strength after exercise.

Of course I’m fascinated by the action of irisin in muscle, but its extracellular actions, akin to those of hormones, are really compelling, in part because that can help explain the plethora of benefits exercise confers. One of the most intriguing areas is its potential for brain health.

First, irisin seems to protect neurons by reducing inflammation which is a big player in neurodegenerative diseases such as Alzheimer’s disease. Chronic inflammation is a hallmark of Alzheimer's disease, so irisin’s anti-inflammatory properties probably retard the progression of Alzheimer's. It also suppresses the activation of microglia, the brain’s resident immune cells, thereby reducing the inflammatory response that contributes to neuronal damage in AD. 

Some studies have shown that irisin can stimulate the production of brain-derived neurotrophic factor (BDNF), a protein involved in neuroplasticity, memory, and learning. Because of its potential effects on BDNF, irisin may help enhance cognitive function and memory. (In a previous post on GABA and intermittent fasting, I talk more about the role of BDNF.) Exercise, already known to improve brain health, could be acting via irisin here. Interestingly, these effects of irisin are most pronounced in the hippocampus, the primary memory center of the brain. 

Finally, irisin can reduce the accumulation of amyloid-beta or modulate its toxicity. These amyloid-beta plaques are a central feature of Alzheimer’s pathology. This could be one of the mechanisms by which irisin exerts neuroprotective effects, preventing the neurodegenerative changes typically seen in AD.

There is also some evidence suggesting that irisin may have a role in mood regulation, as exercise is known to have antidepressant-like effects, possibly through irisin's action on the brain.

Given all the preceding upside to irisin, it’s not surprising that it has generated a lot of interest as a molecule that could potentially be harnessed to improve physical health and brain function. That is far in the future however. What you can do today to harness its benefits is keep on exercising!