It’s been a while since I’ve covered the importance of gut health for healthy aging, but today’s the day to jump right back in to the swing of things.  A study published late last year found that disease-free centenarians seem to have much healthier guts than younger people when it comes to 2 key parameters in the blood: zonulin and lipopolysaccharide(LPS).

These 2 measures reflect how tightly sealed your gut is.  Zonulin causes the gut to become more permeable by reducing tight junction proteins that seal it up.  LPS, also called endotoxin, is a component of the cell wall of gram-negative bacteria that’s highly inflammatory.  So when we have higher levels of zonulin, the gut becomes “leakier” and causes LPS to enter the blood.

This isn’t a great situation as it contributes to the chronic inflammation we see in aging, called inflammaging.  As it turns out, centenarians have lower levels of both zonulin and LPS when compared to non-diabetic patients under 40 who have experienced a heart attack AND healthy age-matched controls.

Looking at the data is pretty telling.  Here it is:

• <40 year old w/MI       LPS=15.4 EU/mL, Zonulin=7.6pg/mL
• Healthy <40 year olds LPS= 6.1 EU/mL, Zonulin=5.2 pg/mL
• Centenarians                LPS= 4.2 EU/mL, Zonulin=4.0 pg/mL

There’s something going on in these health centenarians that just seems to help them maintain a stronger intestinal barrier than the young whipper snappers.  Is it genetics?  Maybe lifestyle?  Probably a little of both.  But since we have no control over genetics the only really useful thing we can do is optimize lifestyle to optimize intestinal barrier integrity.

But what are the consequences of not doing this?  What happens if you just ignore the problem and let what comes to you come?  Well, there appear to be a few ways that ignoring the health of your gut could come at a cost much later down the road.

The aging gut

As we get older, our gut becomes “leakier”.  This is likely due to many changes that occur with aging including changes in the regulation of gene expression, decreased blood flow due to peripheral artery disease, and changes in the microbiome.  It’s probably also worth mentioning that impaired metabolism due to hyperglycemia, which seems to be the norm these days, can cause alterations in gut function.

In addition to problems in the gut, this increased intestinal permeability also comes with increased frailty and chronic inflammation.  In other words, there are both local effects in the gut and systemic problems that come with this increased intestinal permeability.

A good deal of the chronic diseases we see with aging are affected by these changes.  The increase in chronic inflammation seen with aging associates very strongly with the chronic diseases of aging.  So this begs the question, if you’re chronically dealing with increased intestinal permeability, are you also dealing with a more rapid aging process?

When we take a look at the mechanisms that go awry with increased intestinal permeability, I think we can make the argument this could certainly be the case.  For the most part, these mechanisms all center around ways that chronic inflammation affects cells of the immune system.

It’ll make you get sicker more often

As we get older, we becomes less able to remove foreign invaders or cancerous cells while at the same time we become less tolerant to our own tissues.  The former causes us to be more susceptible to things like pneumonia and cancer while the latter causes us to be more susceptible to autoimmune diseases.

A major driver in this change in immune function is called thymic involution.  The thymus is a critical part of the immune system responsible for making naive T cells.  Naive T cells are tolerant to our own tissues and able to respond to foreign invaders.  These naive T cells have yet to encounter a bad guy, so they are able to respond to new challenges as they come along.

Even at a young age our thymus begins to shrink and form fatty deposits, a process called thymic involution.  This lowers the thymus’ ability to create naive T cells, which makes us more susceptible to autoimmunity and infection.  Many factors can cause transient thymic involution including starvation, nutrient deficiency, and infection.

In addition to these factors, endotoxemia also causes thymic involution.  So if you are chronically experiencing endotoxemia, you are increasing your risk of infections such as pneumonia and autoimmune conditions such as arthritis.

It’ll clog up your pipes

Many people focus on cardiovascular disease as if only the heart is involved.  But you have to remember the “vascular” on the end of cardiovascular, which refers to the blood vessels.  When our blood vessels become occluded, this cuts off blood flow to the area that the blood vessel serves.  This can be caused by gradual narrowing of the artery with plaque or a piece of plaque breaking off and getting lodged in a vessel as it becomes narrower.

When this happens in the heart it’s called a heart attack, while in the brain it’s called a stroke.  But there are a host of other tissues we need to concern ourselves with including the extremities, eyes, gut, pancreas, sex organs.  Anything with blood flow, really.

But how does the accumulation of plaque proceed?  While we’ve spent a large amount of time focusing on lipoproteins such as LDL-C and Triglycerides, there’s a lot more going on in the accumulation of plaques.  The party really gets cooking once we’ve had damage to a blood vessel due to shear stress.

The typical process involves cells of our immune system called macrophages that consume apoB containing lipoproteins such as LDL-C or chylomicrons.  This turns the macrophage in to a foam cell which in turn burst and attract more macrophages.  Over time plaques harden and more plaques form over the hardened plaque. If this happens enough you simply clog the hose, but in many instances some of the soft plaques simply flake off and lodge themselves in to smaller vessels down the road.

But how does endotoxemia play a role here?  Macrophages aren’t generally in the mood to cause all of these problems, but when they are exposed to endotoxin, it puts them in the mood.  And when you chronically expose them to it, it always puts them in the mood.

Of course we know how detrimental this is when it causes a stroke or a heart attack, but it would be presumptuous to believe that these situation are the only bad that can come of this.  Reducing blood flow to areas such as the brain, gut, pancreas, and liver may underlie the fact that these organs decline in function as we age.

It’ll cause your blood sugar to climb

Multiple studies indicate that people with Type 1 and Type 2 diabetes have higher endotoxin levels than healthy controls.  Does endotoxemia cause Type 2 diabetes?  We really have no way of knowing, but I’m inclined to believe that the 2 conditions reinforce one another.

On the one hand, many behaviors that increase the risk of Type 2 diabetes also increase the risk of endotoxemia.  Factors such as calorie overconsumption, a high fat diet, and sedentary behavior increase the amount of endotoxin one absorbs.  So it simply could be that behaviors that drive Type 2 diabetes also drive endotoxemia.

However, it seems as though Type 2 diabetes could ultimately increase the amount of endotoxin one absorbs in addition to what we see with behavior.  A study in mice found that hyperglycemia induces leaky gut and the amount of endotoxin in humans correlates most strongly to HgA1c, a measure that can be used to estimate the average blood glucose level over 3 months.

As with most chronic diseases, it’s my opinion that these events reinforce one another, which is why it’s so difficult to stop these processes once they get started unless you address lifestyle as the proximal cause.

It’ll make you lose your marbles

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s are on the rise, and with this an increased emotional and economic burden affecting everyone in the US.  As with the other aging-related conditions mentioned above, there’s a good amount of evidence that endotoxemia plays a role.

In the general circulation endotoxin can activate macrophages, but there are no macrophages in the central nervous system.  There, we have specialized cells called microglia that effectively perform the same functions.  And just like macrophages, endotoxin appears to ramp them up.

Microglia and macrophages enter an activated mode when they are exposed to endotoxin.  This causes them to secrete inflammatory cytokines which under acute settings help heal damage and remove pathogens.  But when chronically activated, these cells end up damaging perfectly healthy tissue via inflammation and glutamate release, a process termed immunoexcitotoxicity.

Endotoxin isn’t the only thing that can cause this process, it appears aluminum and fluoride can as well.  But a recent study found gut-derived endotoxin in the brains of people with Alzheimer’s.  To make this long journey, endotoxin would need to not only cross the gut, it would need to cross the blood brain barrier, something previously thought to be unlikely.

Needless to say, this is pretty good motivation to do everything you can to seal that gut up tight.

Conclusion

As we get older, systems in our body begin to fail.   While you have no control over the inevitability of this happening, you may have some control over how quickly it happens.  As we get older, our gut begins to fail and becomes leakier, causing bacteria and bacterial components to find their way in to the blood.

But what happens if the gut becomes leakier early on?  We really don’t know the answer to this, but we do have a bunch of data showing that increased endotoxin in the blood increases the risk of chronic disease.  And since chronic disease risk increases with age along with intestinal permeability, it’s an attractive hypothesis that leaky gut speeds up the aging process.  This is not great news if you have SIBO or any other bowel disorders that increase endotoxin absorption.

What does this data in centenarians really show us?  Maybe their extraordinarily long and healthy lives are due to winning the genetic lottery.  Maybe it has to do with their old ways, rich in things known to improve health such as physical activity, a whole foods diet, great sleep, and calorie restriction.  We don’t know the answer to that, but we do know that you only really have control over one of those things.