Articles from August 2023

Most people have a “normal” blood test, thinking they are healthy.

Unfortunately, blood tests provide a crude and incomplete picture of our health.

People can have “A ok” blood tests and still be deficient in many micronutrients, suffering from inflammation, a bad thyroid gland, an unhealthy microbiome, pre-diabetes, increased genomic instability (e.g. an increased risk of double strand DNA breaks), fatty liver, a deregulated epigenome, accelerated aging, or many other problems.

To make a long story short: a blood test often provides only a limited, crude snapshot of our health.

Many commonly used blood biomarkers are not ideal to screen for diseases or problems. For example, measuring total, LDL and HDL cholesterol are not the best tests to assess cardiovascular risk.

And various biomarkers, like magnesium or B vitamin levels, are not a correct reflection of the real levels in your cells.

Nonetheless, blood tests still can be useful. But it’s important to interpret these tests with some reservations and caveats, and be mindful of their limitations.

There are various problems with blood tests. I list the most important ones below:

1. Cut-off values are not always ideal

Blood biomarkers have cut-off values: you should not have too much or too little of a specific substance in your body.

For example, you should have at least x mg/dl of vitamin y in your blood. If you have less than that, you are deficient.

However, these cut-off values are often “determined” in a crude way; based on old or inaccurate or crude measurements or studies.

Also, many cut-off values are derived by just looking at the “reference ranges” of the substance in a population.

So scientists look at which values are present in 95% of the population, and then determine these are the “good”, “healthy” or “required” values or levels.

But what if many people of the population are deficient in the nutrient? Then these cut-off values are based on a sick or unhealthy population.

Also, these values would not say much about the best or ideal blood levels for a long, healthy life. As mentioned before, for tens of thousands of years, people just had to stay alive long enough to reproduce. If a mild deficiency does not interfere too much with this in the first three decades or so of life (but would come back to bite you after five or six decades, when you are old, increasing the risk of cancer, heart disease or Alzheimer’s) then having these “suboptimal” values is still ok for mother nature.

Another problem is that these reference ranges or cut-off values are specific to populations (e.g. the diagnostic lab using reference ranges from the people who live close to the laboratory/got tested there), the device (some devices measure higher or lower levels compared to other devices), and the laboratories (their specific protocols and handling of the samples and machines).

Also, age, smoking status, medication, sex, circadian rhythms, weight, and ethnicity can impact the values of many biomarkers, but are hardly or never taken into account (R).

These insights explain why, over the decades, cut-off values had to be adjusted because the FDA realized that these values were too restrictive.

For example, not so long ago, only when you had vitamin D levels lower than 20 ng/ml you would be considered deficient. But then these cut-off values were increased to 30 ng/ml, while studies seem to indicate that ideal vitamin D levels for longevity could be even higher.

Another example is TSH (thyroid stimulating hormone). A too high level of TSH means your thyroid is not working properly (it’s too slow). Many labs will say your thyroid is not functioning well when TSH levels are higher than 4 mIU/L. However, many doctors disagree with this, claiming that TSH levels should be maximally 2.5 mIU/L. Nonetheless, most labs will still use the 4 mIU/L cut-off value.

2. Blood levels of many biomarkers fluctuate

The blood levels of many substances can fluctuate significantly during the day. If you just happened to get measured when levels are high (while most of the time being low), it could be wrongfully interpreted that there is no problem.

Examples of substances that fluctuate a lot are cortisol, hormones like testosterone, TSH, IGF (insulin like growth factor), and so on.

Some MDs try to solve this by measuring substances over time. So instead of measuring cortisol only once in the blood (not useful in most cases), they measure 24-hour secretion of cortisol in the urine. Such a test is more accurate, but still not perfect.

3. Various biomarkers cannot be properly measured

This is especially relevant for vitamins and minerals like magnesium, calcium, potassium, vitamin E, and so on. In most cases, these are measured in blood, not in the cells or in the fluid between the cells outside of the bloodstream (the interstitial fluid), where these nutrients are often present in different levels.

Furthermore, many minerals, vitamins and other substances are bound to proteins that transport them in the blood. So only the levels of the free floating substances (not bound) are measured (or one measures only the bound forms, not the free, active forms).

For minerals like calcium, potassium, magnesium, and vitamins, their values are often “normal” according to your blood test, while levels can be too low in the cells, or in specific tissues (like the brain).

Another example is vitamin B12. To “detect” vitamin B12 deficiency, this substance is often measured in the blood. However, people can have normal vitamin B12 levels and still be deficient. It can be more accurate to measure methylmalonic acid (MMA), which is a breakdown product of vitamin B12 (R).

Even better, the ratio of methylmalonic acid compared creatinine (so the methylmalonic/creatinine ratio) is measured, and homocysteine levels (R).

But even these measurements are not perfect. One can still be deficient in vitamin B12, while having a normal methylmalonic acid/creatinine ratio and normal homocysteine levels.

Therefore, it’s very important to also look at the complaints patients have; and perhaps to try a treatment with vitamin B12 to see if symptoms improve.

Another example is vitamin E. When measured in the blood, most people have “adequate levels of vitamin E.

However, if scientists actually look at what people eat (and calculate how much vitamin E they consume through their nutrition), around 90 percent of people do not reach the recommended daily intake of vitamin E (!).

And take into account that such “recommended daily amounts” that governments put forward are often still too low. They are all too often the minimum amount to not get seriously ill, or of which the consequences of a deficiency are measured with crude tools.

Or take potassium. The FDA recommends consuming at least 4,7 grams of potassium per day (in prehistoric times however potassium intake was more around 7-15 grams per day). Unfortunately, most people consume only around 2.5 grams of potassium per day.

However, in nearly all people potassium levels will be normal. Potassium levels mostly only are abnormal when very serious problems are going on, like kidney failure (or potassium levels can be “falsely” too high because the red blood cells in the blood sample are damaged, releasing potassium, leading to falsely elevated “blood” potassium levels).

So despite most people having normal vitamin E, vitamin B12, magnesium or potassium levels most people are deficient in these.

Learn more about the best supplements here.

4. Various biomarkers are not accurate to predict disease

Often, one relies too much on blood biomarkers to diagnose or dismiss a disease.

For example, to diagnose a thyroid problem, TSH (thyroid stimulating hormone) is measured. But TSH is not an ideal biomarker for thyroid disorders (R). TSH levels can often be normal, while one still has a deficient or malfunctioning thyroid.

Therefore, some doctors propose to do an iodine challenge test, in which people have to consume a large amount of iodine, and then during 24 hours the amount of iodine secretion is measured in the urine (if it’s too low, this could point to a thyroid problem).

Other MDs also look at antibodies against the thyroid gland, like anti-TPO and antithyroglobulin antibodies. Interestingly, people can have antibodies against their thyroid gland but still have normal TSH levels.

In such cases, most doctors will say there is no problem. But having anti-thyroid antibodies does already indicate a problem. The thyroid gland is being damaged, and will likely be further damaged, until the damage is so bad that lab tests will finally detect a problem (or not, given TSH levels are not that specific).

5. Many important substances cannot or are not measured 

Most blood tests are far from complete and comprehensive.

Many important substances are not measured, or cannot be (properly) measured. For example, in most blood tests, one does not measure choline, omega-3 fatty acids, vitamin B6, vitamin B1, specific minerals and so on.

Also, more interesting, useful biomarkers, like DNA damage (e.g. double strand breaks), epigenetic dysregulation, or the amount of senescent cells (“senescent cell burden”) are not measured. These are interesting tests, but are not part of standard testing and are often too complicated or expensive.

So despite having had a blood test, many substances are not tested for, providing an incomplete picture.

6. Cut-off values are interpreted too narrowly

What if you are just one unit under or above a cut-off value? Do you have the disease or not?

For example, you are officially pre-diabetic when your fasting glucose levels are above 100 mg/dl (5.6 mmol/L). So if your value is 97 mg/dl, you are “healthy”?

Not really; elevated “normal” fasting glucose levels (e.g. of 95 mg/dl) could already be indicative of cardiovascular problems for example (R) (and an increased risk of dementia). So “high-normal” (or “low-normal”) levels can already be harbingers of trouble.

Therefore, interpret blood tests knowing that “where there is already some smoke, there is often fire”.

7. Cut-off values can be too lenient

A while ago, you only had problems with your blood sugar when your fasting blood glucose levels were above 126 mg/dl (7.0 mmol/L). Then the concept of pre-diabetes was introduced: you already have a significantly increased risk of diseases if glucose levels are higher than 100 mg/dl.

Now we see that levels even lower than 100 mg/dl can increase risk of diseases.

And one can still be at an increased risk of dying when fasting glucose levels are completely normal (not just “high normal”). After all, there are more accurate tests to diagnose insulin resistance.

Rapamycin can slow aging and extend lifespan in various ways.

1. Rapamycin is an mTOR inhibitor

First, rapamycin is an mTOR inhibitor. mTOR is a protein found in our cells. It’s an important “nutrient” sensor which recognizes nutrients, mainly amino acids (but mTOR can also sense glucose, cholesterol and oxygen levels). If there are a lot of nutrients, especially amino acids, present in our blood and cells (because we ate a big steak for example, which consists of proteins that are made up of amino acids), these activate mTOR. mTOR then revs up the production of protein (mainly, but also of DNA and lipids), and increases metabolism and growth in our cells.

This all makes sense. If there are a lot of nutrients (e.g. amino acids) available, this means there are a lot of building blocks and energy available for our cells, so the cells rev up their metabolism and growth.

However, this also has a downside. This activation of metabolism and growth accelerates aging of cells. Cells start to produce more proteins, which can clump together faster, contributing to aging (accumulation of proteins is one of the causes of aging).

More scientifically speaking, mTOR activates various important proteins (by putting a phosphate group on them) involved in protein production, like S6K and 4E-BP (eukaryotic translation initiation factor 4E-binding protein).

Another consequence of having lots of nutrients available is that cells will maintain themselves less well. They let themselves go. Why should they be frugal and painstakingly recycle their components and maintain and repair themselves, when there are enough building blocks and energy available? No need to skimp on repair, recycling and maintenance with an abundance of resources.

Compare it with money; some people who suddenly have lots of money splurge on all kinds of things they don’t really need, spending it quickly; living the fast life. On the other hand, some people who have little money will live more frugally, be careful what to spend, and rather recycle stuff for their home and repair things instead of buying new things.

How does mTOR activation cause less maintenance? It suppresses autophagy, which is an important maintenance and recycling process. Autophagy is the breakdown (digestion) and recycling of proteins and other cellular waste material. mTOR-induced suppression of autophagy causes more build-up of (damaged) proteins, old and damaged cell components (like mitochondria), and other problems. If you eat lots of protein, especially animal-based protein, mTOR is activated and autophagy is suppressed. mTOR inhibits autophagy by phosphorylating proteins involved in autophagy, like ULK1.

The opposite happens when we are eating little (e.g. during fasting): autophagy is then upregulated, which cleans up the cell and increases maintenance and lifespan. The cell has to use its resources wisely because it doesn’t know when there will be food again.

Rapamycin inhibits mTOR, leading to reduced protein production. This leads to less protein clumping, one of the hallmarks of aging.

Rapamycin induces autophagy, which causes cells to maintain themselves better: they clear up protein accumulation (protein aggregates), thus reducing proteotoxicity.

Interestingly, rapamycin can also induce autophagy independent of mTOR. Rapacymin stimulates an important channel on the lysosomes (TRPML1), which activates lysosomes (R). The lysosomes are small vesicles in our cells which break down proteins and old or damaged cell components – you can consider them as the incinerators of the cells (I explain more about lysosomes and autophagy in the earlier chapter the hallmarks of aging, namely a decline in proteostasis).

2. Rapamycin improves mitochondrial health

Rapamycin can also be promising to treat mitochondrial diseases.

Rapamycin has been shown to improve mitochondrial health, both in normal mice (R) and in mice with serious mitochondrial diseases (R,R,R,R).

In one mitochondrial disease model, called Leigh’s syndrome, rapamycin was given to see if it could improve survival of mice with this disease. Leigh’s syndrome is a very serious mitochondrial disorder caused by a defective protein in the mitochondrial respiratory chain.

This is a very important chain of proteins through which electrons flow (coming from the food you eat, which are then donated to the oxygen molecules you breathe in to form water); this flow of electrons drives the ATP generator proteins studded on the inner membranes of our mitochondria, generating ATP, which is the molecule of life, providing energy for most metabolic processes.

The mitochondrial respiratory chain generates nearly all the energy of the cell, and thus for life to sustain itself. In Leigh’s syndrome, a protein in this chain is not working properly, severely impeding the ability of cells to produce energy. In these mice, rapamycin extended lifespan up to threefold (R).

How can rapamycin improve mitochondrial health?

For one thing, rapamycin upregulates lysosomal function. Lysosomes are small cell components which break down cellular waste and even whole cell components, like the mitochondria. Each cell can contain hundreds or more mitochondria, which provide the energy cells need to function. These mitochondria, when they are too damaged or worn out, need to be broken down and replaced by new mitochondria. Mitochondria are broken down in the lysosomes, the little incinerators of the cell.

Rapamycin induces the lysosomes to break down mitochondria so that worn-out mitochondria are more replaced with fresh and better functioning mitochondria. Rapamycin can also activate lysosomal biogenesis (the creation of more lysosomes), which is a good thing given cells then get cleared out and maintained better by additional lysosomes (R,R).

3. Rapamycin has epigenetic effects

Rapamycin also impacts the epigenome, and can reduce epigenetic age (R,R). The epigenome determines which genes are switched off and on in our cells, and during aging this mechanism goes awry.

Rapamycin can improve the epigenome in a beneficial way, for example by inducing the expression of beneficial genes (R,R,R).

4. Rapamycin improves the microbiome

The gut microbiome are the bacteria in our intestines. These 40,000 billion bacteria have a big impact on our health and well-being, for example by processing and secreting thousands of substances, of which many enter our bloodstream and impact our immune system, metabolism, and brain, among many other things.

However, during aging, the microbiome deteriorates, leading to bacterial overgrowth, increase of “virulent” (bad) bacteria, and damage to the gut lining (“leaky gut”).

Rapamycin can positively impact the bacterial diversity in the gut or inhibit nefarious bacterial activity. In one study in mice, rapamycin increased the amount of segmented filamentous bacteria, which are “good” bacteria that do not tend to secrete unhealthy substances and strongly cling onto the gut wall, which strengthens the gut lining and positively impacts the gut immune system (R).

Interestingly, another well-known longevity-candidate, metformin, has also been shown to significantly impact the microbiome, by also modulating or tempering bacterial activity in the gut. I discuss metformin for longevity later on.

5. Rapamycin reduces inflammation

During aging, inflammation gradually increases everywhere in our body. This is called “inflammaging”, and this condition is one of the hallmarks of aging.

Rapamycin reduces inflammation. It inhibits the products of various proinflammatory proteins, like NfkB and interleukins (R), and can modulate the immune response in a beneficial way (R).

Rapamycine can also reduce the unhealthy “secretory phenotype” of senescent cells; these cells accumulate during aging and secrete various unhealthy, pro-aging substances, like pro-inflammatory substances. This is why rapamycin is also called a “senomorphic”, being able to change the way senescent cells behave, as contrary to “senolytic”, which is a drug that kills senescent cells (the problem however with many senolytics is that they can also kill or damage normal, healthy cells).

6. Other effects of rapamycin on health

Given these and other effects of rapamycin on the body, it’s not surprising that rapamycin can improve stem cell health (R), reduce senescence (R), and extend lifespan, among other effects.

Learn more about rapamycin:

• Does Rapamycin Cause High Glucose, Lipids and Diabetes?
• Does Rapamycin Increase Infection Risk?
• How Does Rapamycin Work? Overview of Rapamycin Lifespan Extension Studies
• Rapamycin for Anti-Aging and Longevity
• How does rapamycin work? How can it slow aging and extend lifespan?