Blood-Brain Barrier: Key to Longevity

Gut mucosal barrier, blood-brain barrier - protection keeps us alive.

I recently was reading a new study on “SuperAgers,” a term for older adults (age 80+) who don’t have the usual cognitive decline associated with aging. As we age, our brains typically shrink, but SuperAgers lose only about half as much brain volume as average older adults. The gist of the study was that SuperAgers experience a slower rate of brain aging and have biologically younger brains, "based on their structural integrity." It makes sense that good structural integrity and not losing brain volume would reduce the normal cognitive decline in aging. [ref]

What keeps the brain healthy? A healthy blood-brain barrier (BBB). And there’s another new study showing just how important it is in preventing aging. Let’s dig into the details and explore what is going on in the BBB.

Blood-Brain Barrier: Unsung hero of longevity and SuperAgers

The blood-brain barrier is the interface between the blood circulating in your body and your brain. It protects the brain from pathogens and regulates which substances are allowed to enter. Tight junctions between the endothelial cells prevent molecules from crossing easily into the brain. To move substances into the brain, the BBB has transporters that selectively allow substances into the brain in the right amounts.

Research shows that the breakdown of the BBB during aging is foundational to a lot of what goes wrong in aging, including cognitive decline.[ref]

Lining the BB endothelial cells is a glycocalyx layer — a thick, jelly-like layer made of glycans and glycoproteins. The glycocalyx shapes and gives integrity to the BBB and also helps with cell signaling, adhesion, and transport.[ref]

A recent study out of Stanford shows that changes to the glycocalyx layer during aging have significant effects on whether someone is a SuperAger or ends up with cognitive decline in aging.

The researchers used imaging techniques to visualize the glycocalyx in young and old mice. Here’s an image from the study to give you a visual of the glycocalyx.

They found a significant reduction in the layers of the glycocalyx lining the small blood vessels of the brain in aging.

Next, they did a pathway analysis to see which genes were up- or downregulated in the glycocalyx in aging. This showed that there was a significant downregulation of genes involved in mucin-type O-glycan biosynthesis.

Mucins are a family of proteins that make up the mucosal layers of the body - from the mucus in the respiratory tract to the gut mucosal layer that shields against bacteria in the microbiome. The mucin-type O-glycans are the primary type making up the gut mucosal layer and the glycocalyx.

Essentially, the new Stanford study shows that the reduced mucin levels in the glycocalyx directly led to BBB dysfunction - both in normal aging and in neurodegenerative diseases.

Importantly, the researchers showed they could reverse the cognitive deficits in aging “by restoring core 1 mucin-type O-glycans to the brain endothelium using adeno-associated viruses” (in mice using gene editing).

While gene editing of our human blood-brain barrier is not an option right now, understanding the importance of the glycocalyx and the BBB in keeping the brain healthy in aging is a big step forward.

Circling back to SuperAgers: A healthy brain without the normal shrinkage and dysfunction is essential for overall health in aging. Let’s see what we can do without gene editing to move the needle a little here.

Improving the glycocalyx in the blood-brain barrier:

Research shows that the following damages the glycocalyx:

• Chronic inflammation: Enzymes activated by inflammatory cytokines, such as TNF-alpha, NF-kB, and IL-1B, degrade the glycocalyx.[ref]

• ADAM15: This enzyme, A disintegrin and metalloproteinase 15 (ADAM15), breaks down specific proteins, including proteins involved in the glycocalyx. Excess ADAM15 damages the glycocalyx[ref]

• Oxidized lipoproteins: To create animal models of damaged BBBs, researchers use oxidized lipoproteins.[ref]

Thus, it follows that preventing chronic inflammation, tamping down inflammatory cytokines, and preventing the oxidation of lipids protects the BBB and overall brain health.

However, the new Stanford study showed something more specific than just needing ‘good BBB health’. The key factor is that the downregulation of mucin-type O-glycans damages the glycocalyx during aging. The researchers found decreased levels of two proteins that encode part of the O glycan structure - C1GALT1 and B3GNT3 - specifically in the BBB, not in other organs. Interestingly, this same pattern is seen in Alzheimer’s disease.

So while general anti-inflammatory strategies are helpful, they aren’t the whole picture in preventing the breakdown of the glycocalyx in aging.

What are C1GAL1 and B3GNT3?

These two genes encode proteins that are part of the formation of the glycocalyx structure. The catch here is that overexpression of C1GALT1 or B3GNT3 may promote cancer growth and metastasis.[ref][ref][ref] As with many things in aging, balance is key—and caution is warranted when considering ways to reverse their downregulation.

What causes the decrease or downregulation of C1GAL1 and B3GNT3 in aging?

That isn’t entirely clear, but microRNAs are likely part of it.

I wrote an article recently about how changes to microRNA levels drive aging. MicroRNAs (miRNAs) regulate gene expression by preventing mRNA from being translated into a protein.

One example from the article is miR-181, which decreases in aging and affects T-cell function and the ability to fight off infections. Interestingly, miR-181 is one of the microRNAs that controls the expression of CIGALT1.[ref] Vitamin D is one way of improving miR-181 levels, although it isn’t clear how effective that would be for improving the glycocalyx.[ref]

Another miRNA that regulates CIGALT1 is miR-124. MiR-124 is also altered in the gut mucosa in aged animals, leading to mucosal barrier dysfunction there.[ref]

Which brings me to…

Bringing this full circle:

I keep coming back to a study on autodigestion as a causal reason that we break down during old age. (Yes - I talked about this before - see Article 1 and Article 2 on it.)

In the autodigestion study, the researchers found that the gut mucosal barrier thins with aging. The thinned mucosal barrier then allows potent pancreatic digestive enzymes to leak into circulation, damaging our organs.

This new Stanford study on the thinning of the glycocalyx lining the BBB goes hand in hand with the study on autodigestion. It leaves me to wonder if the same process causes thinning to both mucosal barriers, leading to organ damage and brain degeneration.

I don’t have many answers here, but I’m excited to see how different research groups are converging on the fundamental biological changes that cause aging.