Glycans: The Sugar Molecules That “Predict” Your Health Years In Advance

Jay Campbell

By Jay Campbell

September 15th, 2022

 

As much as I would love to have a crystal ball that lets me see in the future, the second best thing I can do for my health is live a fully optimized lifestyle.

But sometimes you don’t reap the rewards of your efforts for weeks, months… maybe even years.

What if there was a way to know RIGHT NOW where your health is going to be in 5-10 years from now?

And what if you could know exactly what you needed to do for YOU (not anybody else) to live a Level 10 life?

Thanks to the discovery of naturally-occurring molecules called “glycans” in the 20th century, we may be able to do just that.

This article is a hard look into how glycans serve as current and predictive predictors of chronic inflammation, and the role they play in overall health.

What Are Glycans?

To talk about glycans, we first need to review some basic high school biology:

“Glycans—also known as carbohydrates, (poly)saccharides, or simply as sugars—are molecules made up of combinations of different sugar units, such as glucose. These units can link together to form complex, three dimensional structures.

Unlike DNA and proteins, glycans are not created by following a template. Instead, the reactions that link individual sugar units together are influenced by factors including cellular metabolism, cell type, developmental stage, and nutrient availability”

You may freak out when you see “sugar”, but rest assured we’re not talking about the type of sugar you consume in your diet.

We’re talking about the types of sugars that play several key biological roles in your body:

  • Cell-to-cell signaling
  • Maintenance of tissue structure
  • Gene expression
  • Recognition of foreign pathogens via select glycan sequences (fungi, bacteria, viruses)

General classification of the biological roles of glycans. A simplified and broad classification is presented, especially emphasizing the roles of organism-intrinsic and organism-extrinsic glycan-binding proteins in recognizing glycans. There is some overlap between the categories, e.g., some structural properties involve specific recognition of glycans. Binding shown on the left of the central “self” cell represents intrinsic recognition, and extrinsic recognition is represented by binding shown to the right of that cell. Molecular mimicry of host glycans adds further complexity to potential roles. Original drawing by R. Cummings, updated from ref. 160 with permission from the Consortium of Glycobiology Editors.

(Source)

In fact, you could say glycans are arguably more important than a nucleus for cell survival:

“Surfaces of all eukaryotic cells are covered with a thick layer of complex glycans attached to proteins or lipids. Many cells in our organism can function without the nuclei, but there is no known living cell that can function without glycans on their surface. Anything approaching the cell, being it a protein, another cell, or a microorganism, has to interact with the cellular glycan coat”

That’s why glycans are considered one of the four indivisible “units” of life alongside lipids, proteins, and DNA/RNA.

In fact, glycans can be considered the ultimate layer of complexity in life itself.

Think about it: we share roughly 92% of our genes with mice, so something else has to account for why we are completely different organisms… glycans are a large part of the reason.

Glycans and Proteins

When a protein is attached to one or more glycans, we have glycoproteins:

Structural Characterization of Glycans

(Source)

Don’t get overwhelmed by the diagram!

It’s a visual way of showing the two ways in which glycans can covalently bind to a protein: Either via the nitrogen atom on the amino acid Asparagine within a protein (“N-linked”) or via the oxygen atom on the amino acids Serine or Threonine within a protein (“O-linked”)

Why is this important, you may ask?

It turns out glycans play a pivotal role in dictating a protein molecule’s final structure and function:

“Glycosylation [the biochemical reaction of adding one or more glycans to a protien] is an important and highly regulated mechanism of secondary protein processing within cells. It plays a critical role in determining protein structure, function and stability. Structurally, glycosylation is known to affect the three dimensional configuration of proteins.

“As the carbohydrates are added to the nascent protein within the endoplasmic reticulum, carbohydrates (monosaccharides) are added to the protein on specific amino acid residues…. This process can aid in the final protein product folding correctly into its three dimensional, biologically active conformation”

“glycosylation also has other effects on the physicochemical properties of these proteins. These effects help to determine the glycoprotein’s overall energy and this can affect many of the biological functions that the protein performs”

I’ll simplify this even further…

You can have a single gene that creates a protein that has a pre-determined biological function in your body.

But you also have tens of thousands of unique glycans in your body, and when you attach different combinations of glycans to a protein, it can completely change a protein’s shape and function.

So effectively you have one gene that can create tens of thousands of different proteins.

Glycans are the reason why even with a small change in the number of genes, you can have massive changes in underlying biochemical complexity.

I mention the role of glycans in protein modification because it turns out this role is largely the reason why glycans are being seriously investigated in disease prevention and management.

How Glycans Are Connected To Chronic Inflammation

To explain this, I need to introduce an important glycoprotein in your body known as Immunoglobulin G (IgG):

“Immunoglobulins are also called antibodies. Antibodies are proteins that your immune system makes to fight germs, such as viruses and bacteria. When you’re exposed to germs, your body makes unique antibodies that are specifically designed to destroy only those germs.”

“IgG antibodies are very important for fighting infections from bacteria and viruses. Most of the immunoglobulins in your blood are IgG. You also have some IgG antibodies in all your body fluids. Your body keeps a “blueprint” of all the IgG antibodies you have made. That way, if you’re exposed to the same germs again, your immune system can quickly make more antibodies.”

You can think of it as the most abundant antibody circulating in your blood, and the main antibody within the immune system responsible for managing low-grade chronic inflammation.

And while IgG is typically known for recruiting pro-inflammatory pathways, recent evidence has come to light showing IgG and its subclasses can also exert anti-inflammatory effects.

How can this be?

It comes down to the specific glycans that are attached (or not) to the protein:

The presence or absence of certain sugar residues has been linked to pro- or anti-inflammatory properties: terminal sialylation confers anti-inflammatory properties, and the sialylated fraction of therapeutic intravenous immunoglobulins (IVIG) was suggested to contribute to the therapeutic effect of IVIG , although the exact downstream mechanisms may differ between species.

Likewise, galactosylation confers anti-inflammatory properties, since decreased galactosylation of IgG resulted in increased pathogenicity in autoantibody-mediated murine models of autoimmune diseases”

figure 1

(Source)

This isn’t a mere lab finding – the proportion of certain glycans attached to IgG can speak volumes about how inflamed a person is, according to this study examining 1826 human subjects:

“For all subclasses, a low level of galactosylation and sialylation and a high degree of core fucosylation associated with poor metabolic health, i.e. increased inflammation as assessed by C-reactive protein, low serum high-density lipoprotein cholesterol and high triglycerides, which are all known to indicate increased risk of cardiovascular disease.”

“These findings demonstrate the potential of IgG glycosylation as a biomarker for inflammation and metabolic health, and further research is required to determine the additive value of IgG glycosylation on top of biomarkers which are currently used.”

(NOTE: “Galactosylation” refers to glycosylation that involves the addition of a galactose sugar molecule to a protein, and “sialyation” refers to glycosylation that involves the addition of a sialic acid sugar molecule to a protein)

We’ve gotten to the point where the number of antibodies with a specific number of galactose residues can be reliably used as a measure of inflammation:

“…heterogeneous glycans can be classified based on their level of galactose incorporation, as glycans that have no galactose residues (G0), one galactose residue (G1), or two galactose residues (G2). Striking enrichment of agalactosylated (G0) glycans is observed in inflammatory diseases. Conversely, elevated levels of galactosylation are associated with reduced inflammatory activity in antibody preparations”

Fig. 2

(Source)

It gets even better because this trend can be observed on a human population level:

“Galactosylation shows unique age-distributions with G0 antibodies enriched in the very young and the elderly. Moreover, levels of galactosylation increase during pregnancy, with a significant increase in galactosylation and sialylation and decreased bisection that normalizes post-partum. Furthermore, Fc-glycosylation also varies significantly across geographic regions of the world, and again is dramatically altered in autoimmune, infectious, and oncological diseases.”

Fig. 3

(Source)

And from the same paper, we have this startling observation:

“Moreover, compelling evidence points to an accumulation of agalactosylated antibodies with inflammaging – which may be unlinked from numerical age”

Let’s not forget about sialic acid, which also ends up “giving” IgG anti-inflammatory properties:

“Another structural alteration of the IgG glycan, the addition of sialic acid to the ends of glycans changes the function of IgG and converts it from being pro-inflammatory into an anti-inflammatory agent.

Sialylation of IgG was found to be essential for the function of intravenous immunoglobulin (IVIG): its anti-inflammatory activity is contained within the effector Fc portion, as Fc fragments alone were found to be sufficient to suppress inflammation.

It appears that Fc with sialylated glycans suppresses inflammation through a novel TH2 pathway, which provides an intrinsic mechanism for maintaining immune homeostasis

So how can we summarize all of the above?

IgG is the main driver behind the majority of inflammation-induced chronic diseases — where there’s inflammation, there’s IgG.

Inflammation is not an inherently bad process and we need acute inflammation in order to respond appropriately to injury and illness.

It’s only when inflammation becomes prolonged (i.e. chronic) that we start to see an accumulation of damage and an increased rate of aging.

In the same way we need a balance of pro-inflammatory and anti-inflammatory processes for a strong immune system, we also need an optimal balance of pro-inflammatory and anti-inflammatory glycans.

The same deal goes for autoimmunity (i.e. when the immune system attacks the body itself), which involves numerous processes that include the mechanistic actions of IgG.

What’s scary about this is how the flavor of inflammation we experience will lead to one of several diseases, and our glycan composition unfortunately can’t be used to make any reliable predictions.

IgG will “attack” everything, but the weakest link in your biological systems is where you will be hit the hardest.

For one person it may be arthritis due to knee inflammation, and for another person it could be Crohn’s disease due to gut inflammation.

And that’s where we can turn to glycans as possible early predictors of disease.

Glycans As Biomarkers For Diseases

On an international level, 60% of deaths can be directly attributed to one or more chronic inflammatory diseases.

Cardiovascular disease, chronic obstructive pulmonary disease, diabetes, arthritis/joint disease, cancer, neurodegeneration, kidney disease, allergies, non-alcoholic fatty liver disease… the list goes on and on.

So it should follow that determining the exact composition of glycans attached to our IgG antibodies can reveal volumes about the present state of our health.

There are two reasons why doing so should be the major area of research in the Golden Age of medicine…

Glycan Composition Can Be Changed By Lifestyle Intervention

We’ve already seen how the composition of pro-inflammatory and anti-inflammatory glycans in our body changes with age.

Therefore, it follows that each human has a unique glycome (i.e. “the entire complement of free carbohydrates and glycoconjugates expressed in cells or tissue”), especially for IgG.

While glycans clearly have an effect on our biology, it turns out they are regulated equally by our genetics and our environment.

In plain English, the right or wrong lifestyle choices can have a significant impact on your glycome and therefore dictate your body’s level of inflammation.

So on the one hand, unchangeable factors such as age, sex, and ethnic background play a role.

However, lifestyle factors such as smoking, diet, exercise, sleep, hormonal profile, and environment can play just as significant of a role.

This gives us the opportunity to use “glycan profiling” as a way to measure which lifestyle interventions work for you (or don’t).

Glycans Can “Predict” the Rise of Disease Several Years In Advance

While your first thought may be to start getting blood work for glycans as an immediate sign of health, it turns out their role as biomarkers is far more predictive than reactionary.

If you look at any study of a disease where the experiments were run properly, measurable changes in your glycome can be detected between 6-10 years before symptoms appear and a clinical diagnosis can be made (here and here).

This means your glycome can be used for prognosis (i.e. a prediction of the future), making it useful as an “early warning signal”.

Think about it — something like Type 2 Diabetes doesn’t just happen overnight.

It takes years of a poor lifestyle for inflammation to kick in and slowly chip away at your health.

So something like measuring your glycome once a year can give you a heads-up as to where you’re headed.

Simple enough, yet makes all the difference between walking down a pathway of disease and walking down a pathway of health.

Diseases Associated With Altered Glycome Composition

Even if we don’t have the evidence needed to predict every single disease in existence using our glycan composition, several disease states show clear glycome changes.

COVID-19

Four different studies (1, 2, 3, 4) consistently show decreased galactosylation and sialylation of IgG in patients who not only had severe COVID-19, but also experienced worsening symptoms over time.

Not only do we see changes in IgG glycome, but we now know IgG becomes more pro-inflammatory as a result.

Obesity

If you want to see yet another angle of how inflammation skyrockets down when you treat obesity, look no further.

Not only does significant weight loss drastically impact IgG glycosylation for the better, but it turns out intensive physical exercise (here and here) does the same thing.

In either study you look at, the IgG glycome was altered in a way where the IgG antibody exhibited more anti-inflammatory effects.

Blood Pressure

Two human studies (here and here) show clear differences between the IgG glycosylation profile of those who have normal blood pressure and those who have high blood pressure.

It’s possible that one’s IgG glycome may change even BEFORE high blood pressure appears.

However, one mouse study found an inverse correlation between IgG sialylation and hypertension (i.e. a lack of salic acid molecules on IgG antibodies was connected to higher blood pressure).

Diabetes

Surprise surprise – in this human study and the several preceding studies before it, a “decrease of galactosylation and sialylation structures” were noted in patients with Type 2 diabetes!

But to add insult to injury, a faster decline of kidney function has also been reported in Type 2 diabetics who have a pro-inflammatory IgG glycome.

Menopause

While this technically isn’t a disease, it’s well-established that perimenopause comes with an increased cardiovascular risk.

And changes in a woman’s IgG glycome during the transition to menopause may have something to do with it:

“However, with aging, particularly during transition to menopause, “young” glycans on antibodies decline and are exchanged with “old” glycans that promote inflammation.”

“In females, this change is particularly pronounced in the time preceding the average age of menopause. This observation led to the theory that oestrogen may be regulating IgG glycosylation, which may explain why the IgG glycome in premenopausal women reflects an apparent lower biological age.”

This was observed in a 2022 study involving 1940 women who were either peri-, pre-, or post-menopausal:

“Statistically significant decrease in galactosylation and sialylation was observed in postmenopausal women.

…during the transition from pre- to postmenopausal period, the rate of increase in agalactosylated structures and decrease in digalactosylated  and monosialylated glycans were significantly higher than in either pre- or postmenopausal periods.

The conversion to the more proinflammatory IgG glycome and the resulting decrease in the ability of IgG to suppress low-grade chronic inflammation may be an important molecular mechanism  mediating the increased health risk in perimenopause and postmenopause.”

In an earlier study published two years prior, healthy women had their estrogen levels artificially suppressed and then were divided into two groups: Those who got no treatment, and those who got estrogen therapy.

It turns out our hormonal system can impact our IgG glycan composition:

“Deprivation of gonadal hormones resulted in median increase of glycan age for 9.1 years, which was completely prevented by transdermal estradiol therapy.

After the recovery period glycan age returned to baseline values in both groups.

These results suggest that IgG glycans and consequently also the glycan age are under strong influence of gonadal hormones and that estradiol therapy can prevent the increase of glycan age that occurs in the perimenopausal period.”

With this intel in hand, we can not only detect (peri)menopause in women before it happens, but we can also have a way to directly measure the effects of hormone optimization.

Are Glycans Superior For Measuring Your Biological Age?

Just to quickly recap, let’s talk about your biological age.

Biological age is a metric that refers to the time-independent increase in aging, which comes with the progressive loss of function.

You are most healthy when your biological age is lower than your chronological age, and at your least healthy when your biological age is higher than your chronological age.

So could we perhaps use IgG glycosylation as a way to measure biological age and perhaps predict one’s maximal chronological age?

Several studies point toward the answer being “yes”.

One study examining over 5,000 people across four separate European populations found glycans can serve as a biomarker for both chronological age AND biological age:

“By analyzing IgG glycosylation in 5,117 individuals from four European populations, we have revealed very complex patterns of changes in IgG glycosylation with age.

Several IgG glycans (including FA2B, FA2G2, and FA2BG2) changed considerably with age and the combination of these three glycans can explain up to 58% of variance in chronological age, significantly more than other markers of biological age like telomere lengths.

The remaining variance in these glycans strongly correlated with physiological parameters associated with biological age. Thus, IgG glycosylation appears to be closely linked with both chronological and biological ages.”

And to go in even deeper:

“This index predicts chronological age with error of 9.7 years and importantly explains 58% of variation in chronological age and sex. The explanation of nearly 60% of variance of age is impressive compared with other so-called age biomarkers like telomere length where most studies show 15%–25%; thus, our new GlycanAge index appears to be more closely related to age than telomere lengths.”

After controlling for chronological age and sex, a better IgG glycosylation profile was associated with improved readings on biomarkers such as cholesterol levels, insulin, GMI, triglycerides, and waist circumference.

To nobody’s surprise, better IgG glycomes are observed in developed countries compared to developing countries:

“Here we present population-specific N-glycosylation patterns of IgG, analyzed in 5 different populations totaling 10,482 IgG glycomes, and of IgG’s fragment crystallizable region (Fc), analyzed in 2,579 samples from 27 populations sampled across the world. Country of residence associated with many N-glycan features and the strongest association was with monogalactosylation where it explained 38% of variability.

IgG monogalactosylation strongly correlated with the development level of a country, defined by United Nations health and socioeconomic development indicators, and with the expected lifespan. Subjects from developing countries had low levels of IgG galactosylation, characteristic for inflammation and ageing.

Our results suggest that citizens of developing countries may be exposed to environmental factors that can cause low-grade chronic inflammation and the apparent increase in biological age.”

But What About Telomere Length And DNA Methylation

Now, I know that I have promoted DNA methylation in the past as the best test for measuring biological age.

But I’m willing to admit I may have been slightly incorrect.

In the case of DNA methylation, it is a linear function of time that tells you your chronological age more accurately than anything else. 

(For an extensive study covering all the challenges associated with building a robust DNA methylation aging clock, click here)

Your DNA is going to get methylated as you age no matter what you do, which makes it somewhat irrelevant.

Think of your DNA as the blueprint with the instructions to build a house, and glycans are the finished house after it is built.

The blueprint doesn’t account for interventions, and it won’t show you the colors you painted your walls with or the furniture you end up using.

With regard to telomeres, they are an outdated way of measuring biological age.

It’s great for cells and single-celled organisms, but not for multi-billion cell organisms such as humans.

We have several cell lines, each with their own lifespans that range from weeks to years.

It’s literally impossible to measure every cell in your body, and even then your telomeres don’t really respond to lifestyle interventions or have any clear connection with disease.

But glycans are a completely different story, as they are direct biomarkers of low-grade chronic inflammation we can measure.

Not only do they correlate extremely well with other biomarkers of an unhealthy lifestyle, but the number generated by a glycan test isn’t arbitrary.

Based on the presence of specific glycosylated IgG antibodies within your glycome, a definite calculation can be made that tells you whether you are in fully optimized health or fooling yourself.

And if you take on a lifestyle intervention that causes you to lose 20 pounds of unwanted fat, you can see scientifically-proven changes in your glycome profile in the form of a non-arbitrary reading.

The same can’t necessarily be said for methylation tests or telomere length.

GlycanAge: The BEST Way To Track Your Glycan Levels

After several thousand words explaining what glycans are and why you should care about them, the next logical step is to find someone who can help you determine your glycome.

I’m proud to say that GlycanAge is arguably the first – and indisputably the best – company in the world that offers a glycan-based biological age test.

After publishing 200 scientific papers over 25 years spanning more than 200,000 individuals in unpublished and published clinical trials, they’ve cracked the code on accurately measuring your unique response to lifestyle interventions.

By analyzing the glycans attached to your IgG antibodies, they can determine the state of your immune system and see how inflamed you are.

Your “GlycanAge” score is then calculated on the basis of three separate indices:

  • G0 (pro-inflammatory) – glycans with no galactose extensions
  • G2 (anti-inflammatory) – glycans with two galactose extensions
  • S (anti-inflammatory) – glycans with additional sialic acid extensions

Take a look at two of the individuals below who saw real changes in their biological age after using GlycanAge’s services.

62-year-old Tim noticed that his GlycanAge score spiked up around April 2020, and as an experiment decided to use Metformin.

Six months later, he re-evaluated his blood work and his GlycanAge score dropped by a total of 10 points!

Tim not only felt amazing afterward, but he managed to regulate his blood sugar levels with this one change.

After consulting with one of GlycanAge’s healthspan doctors, it turned out that he was glucosensitive and needed this particular intervention.

In the case of Anastasis, he was doing everything right on paper but his GlycanAge score was way too high.

Turns out that his everyday fasting and regular adherence to the ketogenic diet wasn’t the most optimal approach for his body.

After reducing his daily fasts to 4x/week and incorporating more lean meats and fruits in his diet, his GlycanAge dropped by 38% over a time span of three years.

The point is this: The GlycanAge test, done before and after an intervention (diet, exercise, medications, hormone optimization, stress management, etc.), can help you measure with scientific accuracy whether what you’re doing is working. 

Measuring your inflammation levels in the best way possible is how you know you’re actually getting better instead of flying blind.

Just like regular blood work, it’s a great guiding tool toward ultimate health.

And it goes to show that there is no such thing as the “perfect” diet – what works for you won’t work for me, and vice versa.

How The GlycanAge Testing Process Works

The process for signing up and working with GlycanAge is very straightforward:

  • Order an at-home test kit from GlycanAge
  • Draw blood with the included finger prick apparatus and put it on the included sample collector (instructions can be found here)
  • Send the sample back to the GlycanAge lab (free sample return postage for USA, UK, and Canada)
  • Get your results back after 3-5 weeks in the form of a comprehensive breakdown of your glycan indices (and what they mean)
  • Schedule a free one-on-one 30-minute consultation with a physician who will give you personalized advice
  • Rinse and repeat all of the above steps 6-12 months later

You can take a look at their price plans and decide to order additional consultations if you wish.

For more information on how this entire process works from start to finish, GlycanAge’s FAQ page is very helpful.

In the meantime, the video is one person’s experience with GlycanAge from start to finish.

 

How To Get Started With GlycanAge Today

GlycanAge is yet another company that I truly believe will revolutionize the emerging trend of precision medicine.

On top of understanding how glycans will predict every aspect of our health several years down the road

…they’ve created a seamless customer experience that makes everything as easy for you as possible.

If you’re serious about fully optimizing both your healthspan and your lifespan, I highly recommend you order the GlycanAge test today.

Use code JAYC15 for 15% off your order!

If you want to dive even deeper into the mysterious world of glycans, read their online science magazine and their personal blog.

As always…

Raise Your Vibration To Optimize Your Love Creation!

PS – If you want private access to Golden Age health companies and my members-only deals before I shout them out publicly, join The Fully Optimized Health Private Membership Group.

It’s your greatest opportunity to fully optimize your health and gain total access to me and my network of high-level men and women living their highest and best life. 

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