Glucose - Mother Nature's Deal With the Devil for Energy

We did a deep dive on carnosine recently and it led us down the rabbit hole of the role sugar has in the body.

Specifically glucose, the readily usable form of it in our bodies.

As you dig deeper, you find that every longevity trick out there (maybe even Yamanaka factor research) rests on our metabolic pathway.

Energy production, movement, and use!

AMPK, the target of so many regimes these days (caloric restriction, fasting, keto, etc) is after all…an energy sensor in the body.

It looking for signs of duress (famine, drought, etc) that ramp up age-old pathways to get our cellular house in order.

mTOR does the same thing for protein.

Glucose itself, is fascinating in that it's extremely destructive by chemical design to the machinery of organic life.

It reminds us of oxygen which if left unchecked (oxidative radicals) acts like molecular scissors indiscriminately cutting anything (including our DNA and cellular machinery) that it comes across.

Interestingly, anti-oxidants haven't fared well in longevity studies except for...glutathione (NAC/glycine):

Scientists studying glutathione precursors have demonstrated some of the best life extension results ever achieved in mice – increasing their lifespan by 24%

https://www.lifespan.io/news/lifespan-news-glutathione-for-longevity/

We'll see why below (GLO pathway) and glucose.

We have powerful systems to keep oxidative stress at bay (glutathione being front and center) but what about glucose?

That's where we're going and you'll see that it may lead to the first shoe to drop with aging.

We'll cover these areas:

• The problem with sugar
• Health deterioration as a result (not just diabetes)
• Glycation and aging
• The body's defense against glucose's damage
• The connection between glucose and aging

Let's get started as the deal has already been made billions of years ago.

The problem with sugar

This isn't your "too much soda" or high fructose corn syrup spiel. It's deeper than that.

First, a quick intro to glucose's role in the body.

Glucose is the primary source of energy in your body. Protein and fat can both be turned into glucose if needed.

Essentially, glucose is our simplest form of energy for cells to use.

The fascinating piece is that glucose as a molecule is very similar to what you think of it in your cupboard.

Think of sugar, the substance we use with food. It's very sticky.

Interestingly, the molecule of glucose is very "sticky" as well. Stay with us…this is the heart of the issue.

Glucose causes a process called glycation in the body. Essentially, there are chemical "tails" of proteins, fats (lipids), and even our DNA complex (histones) that glucose can attach to and tangle up.

This makes the proteins (our machinery) and lipids (our cellular building components) unusable.

They're essentially gumming up our primary building blocks!

Here's the technical explanation:

Glycation (sometimes called non-enzymatic glycosylation) is the covalent attachment of a sugar to a protein or lipid. Typical sugars that participate in glycation are glucose, fructose, and their derivatives.

https://en.wikipedia.org/wiki/Glycation

This attachment of sugar to proteins and lipids (fats) makes these powerful players dysfunctional. Broken.

It can get worse than this. Glucose can actually entangle proteins to other proteins or lipids to other lipids.

This forms AGE's - advanced glycation end-products.

Most people don't know what these are yet but they will.

Why?

Advanced glycation end products (AGEs), also known as glycotoxins, are a diverse group of highly oxidant compounds with pathogenic significance in diabetes and in several other chronic diseases (1–6).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704564/

"Several other chronic diseases" indeed. How about aging in general!

One note…we're all accumulating AGE's as a function of using energy. That's the deal Mother Nature made.

Foods we eat can increase this level:

• The browning of meats or carbohydrates, that AGEs.
• Some foods have more AGEs naturally
• Higher sugar levels (of course)

Let's turn to the effect on health from this process.

Health deterioration as a result (not just diabetes)

Sure, diabetes is front and center

You can pretty much find ties to AGEs with any illness:

This followed a plethora of empirical studies exhibiting an association between AGEs and a variety of conditions such as decline in memory with age,44-46 pathophysiology of eye diseases,47-49 polycystic ovary syndrome,50-55 wound healing,56-61 cardiovascular complications,62-68 bone health,69-71 periodontitis,58,72 erectile dysfunction,73-76 anemia in older community-dwelling women,77 slow walking speed in older adults,78 peripheral neuropathy,79,80 peripheral artery disease,81-85 obstructive sleep apnea,86-89 islet β-cell dysfunction,90-96 cancer,97-99 elevated cellular oxidative and inflammatory state,100-105 schizophrenia,106 Alzheimer’s disease,107-113 and risk for metabolic syndrome in adults and children.114,115

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600625/

Laundry list time.

Let's look at just a few of these:

• Dementia and AGEs
• Cardivascular health and AGEs
• Diabetes and AGEs

Three of the big ones. So…what's the connection with glucose's damage?

Research is finding that AGEs are directly tied to the process of dementia:

This study demonstrates that the AGE-RAGE axis regulates Aβ1–42 formation and tau phosphorylation via increased cathepsin B and AEP, providing a new molecular link between AGEs and AD pathology.

https://pubs.acs.org/doi/10.1021/acschemneuro.7b00410

AB is the amyloid beta plaques. Tau is the other formation that shows with dementia.

In fact, both of those are entangled clumps of material…sound familiar?

Keep in mind that AGEs are body wide. The wrinkles in your skin? AGE effect.

Here's the fascinating piece:

Skin AGEs were cross-sectionally associated with worse cognition in 2890 individuals.

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2774720

So…the worse our AGEs in the skin, the worse our cognitive condition.

What about heart health?

First…the clogging of arteries:

Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis.

https://molmed.biomedcentral.com/articles/10.1186/s10020-018-0060-3

Again, we can look at skin glycation pathways and get a glimpse into our heart's health:

AGEage, the non-invasive measured skin AGEs combined with age, seems to be a more promising approach than HbA1c in identifying patient at high risk of LEAD.

https://www.frontiersin.org/articles/10.3389/fcvm.2021.696156/full

Okay…this is wild research.

LEAD is a measure of fatty build up in our vasculature. HbA1C is the new stat for lab testing for risk factors tied to cardiovascular health.

The study found that looking at age markers in skin was better at determining cardiovascular health than HbA1C, which is already seen as better than cholesterol, and more.

One note though…what is HbA1C?

Oh…it's just a measure of glycation of hemoglobin!!

Glycohemoglobin, also known as glycosylated hemoglobin or hemoglobin A1C, is a hemoglobin-glucose combination formed nonenzymatically within the cell.

https://www.sciencedirect.com/topics/medicine-and-dentistry/glycated-hemoglobin

Goodness, our best cardio lab rests on sugar's damage.

What about the bugaboo around cholesterol?

LDL is supposedly the "bad cholesterol" even though our entire steroidal hormone complex is made from it.

Yes, estrogen, progesterone, and testosterone directly manage cardiovascular health!

It turns out that it's the combination of sugar (AGEs) and LDL that make them dangerous.

Our results showed, for the first time, that RCT is altered with aging and that AGEs contribute significantly to this alteration.

https://pubmed.ncbi.nlm.nih.gov/28704619/

What is RCT?

Reverse cholesterol transport (RCT), which is intimately linked to high-density lipoproteins (HDLs), and plays a key role in cholesterol homeostasis and the prevention of atherosclerosis.

What about triglycerides?

Wait till you learn what triglycerides really are?

It's a storage for excess glucose (usually from carbohydrates):

Triglycerides (fats) are a form of long-term energy storage in animals. Triglycerides store about twice as much energy as carbohydrates. Triglycerides are made of glycerol and three fatty acids. Glycerol is a 3-carbon sugar, which enters cellular respiration in the middle of glycolysis.

https://openoregon.pressbooks.pub/mhccbiology101/chapter/other-molecules/

We could go on and on. Let's hit a softball now with diabetes.

Diabetes is a metabolic imbalance at it's core (around insulin) but the damage…comes from AGE's.

AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951818/

Remember, we're gumming up the machinery of our body!

One note…all three examples we chose have one thing in common…risks increase with age.

Sizably for dementia and cardiovascular health (we're giving diabetes a boost with our sugar and carb absorbed world).

This is where sugar's story gets really interesting (to us anyway)!

Glycation and aging

So, glucose can bind up fats and proteins and even tie them together (cross-linking) creating clumps of inflammatory, non-functional debris.

What about our DNA? More importantly, what about the layer that turns genes on and off (called epigenetics).

The new push on longevity revolves around Yamanaka factors. A fascinating new breakthrough that clears damage from aging to our epigenetic level.

A quick drill down is needed.

We have a whole complex called histones that control the folding and unfolding of our DNA.

This precisely tuned packing/unpacking allows certain genes to be exposed for processing for specific periods of time and at specific times.

It's happening billions of times a day in every cell. DNA, if stretched out is 6 feet long and it's smashed into the center of every cell.

Histone are the key to making any of this work.

So…can those histone proteins also get tangled up?

We find that histone glycation disrupts assembly, stability and compaction of chromatin both in vitro and in cellulo.

https://www.nature.com/articles/s41467-019-09192

Just a reminder of the importance of histones:

Through the integration of diverse cellular stimuli, histone PTMs play a crucial role in determining cell fate by establishing and maintaining the epigenetic landscape

https://www.nature.com/articles/s41467-019-09192

This is literally what tells a skin cell to be a skin cell and behave like one!

Researchers have discovered heightened levels of glycated histone proteins in cancer and diabetes (both age related in terms of risk with strong correlation to glucose levels).

What about just aging cells and bodies?

AGEs are reliable diagnostic biomarkers for most of the age-related diseases.

https://pubmed.ncbi.nlm.nih.gov/29360983/

Worse yet, histones may be more vulnerable to the damage from sugar:

Since histone proteins have some of the longest half-lives in the cell, they are highly susceptible to the accumulation of damage in vivo.

https://www.nature.com/articles/s41467-019-09192

Look…we think that glycation is going to be the holy grail for longevity and partially explain the Yamanaka factor breakthrough…removing this glucose damage from or epigenetic machinery.

We did a deep dive into this whole process with our review on carnosine.

That's brings us to the next section.

The body's defense against glucose's damage

There are two powerful pathways for blocking and removing AGEs or glycation and cross-linking.

• Carnosine
• GLO (part of the the glutathione pathway)

We can supplement carnosine directly or beta-alanine (a rate-limiting factor) for the first piece.

We can also support glutathione via NAC and CBD isolate indirectly.

Results in studies generally show 3 months before results really kick in but as you would expect, it's all across the metabolic pathway:

Collectively, l-carnosine lowered fasting glucose, serum levels of triglycerides, AGEs, and tumor necrosis factor-α without changing sRAGE, IL-6, and IL-1β levels in T2D patients.

https://pubmed.ncbi.nlm.nih.gov/29420997/

There's also the inflammatory signals that occur from these broken components (fats and proteins) that build up in the body.

This may very well drive inflammaging and speak to the longevity benefits from donating blood, transfusion of younger blood, etc.

AGEs are pretty new in terms of research but you can expect to hear much more about them as the longevity movement (Altos Labs, etc) goes into full effect.

You'll be well ahead of the curve!

Always work with a doctor or naturopath with any supplement!

The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.