For those interested in the health of their gut, there’s been a primary focus on what goes in to it from your diet.  Of course this makes sense, your microbiome is regulated to a large extent by what you eat.  But if you think you’re going to completely transform the health of your gut through diet alone, you’re in for a rude awakening.

While diet is certainly an important factor, there are other targets worthy of your attention.  In fact, we’ve known for decades that proteins in your blood have a large effect on how your organs and tissues function, including your gut.  Studies completed more than 40 years ago identified that what’s in your blood regulates organ function to a large extent, primarily by regulating how organs age.

Taken from: http://www.phxnews.com/wp-content/uploads/2014/12/anti-aging.jpg

The variable of time: A new paradigm for organ health

When most people think of age or aging, they immediately associate it with time; specifically, the passage of time.  While it’s true that over time we age, time isn’t constant across individuals.  In fact, strictly speaking, time is variable in a biological sense.

What do I mean by this?  Well, we know that between organisms of the same species, i.e., you and me, a given amount of time will lead to different levels of aging.  This can be seen subjectively when we look at 2 people of the same age that don’t look the same age.

We can also objectively measure this based on the way our organs function.  The pancreas doesn’t always fail at the same time in everyone.  In the same way, not everyone experiences the hippocampal dysfunction that accompanies Alzheimer’s disease.

Many believe this comes down to genes, but to a large extent it’s based on the variable effect of time between people.  If you live long enough, these issues will eventually get you provided something else doesn’t get you first.  This brings us to another aspect of time: it’s even variable inside of you.

Say what?  It’s true.  Your organs age at different rates.  That’s why aging-related diseases tend to occur in very specific organs like the brain(Alzheimer’s, Parkinson’s), blood vessels(Cardiovascular disease), pancreas(Tye 2 diabetes), and bones(Osteoporosis).  Of course many of these diseases can be kept at bay with lifestyle factors, but that’s because lifestyle affects time in the biological sense by affecting cellular replication.  This is something I’ll cover in greater detail in the future.

But this brings about an interesting point.  If time is different between individuals and even organs within the same individual, what dictates how quickly times passes.  We believe that, to some extent, it’s programmed.  Lifestyle can provide some slowing of the clock, but we’re not talking about bringing it to a complete stop.  But if it has any impact on aging at all, how is this information communicated in the body to regulate the speed of aging?

Taken from: https://sciencebasedmedicine.org/wp-content/uploads/2016/08/parabiosis.jpg

Parabiosis: rejuvenation from within

Way back in the 1800s, physiologist Paul Bert pioneered a process called parabiosis where 2 animals are surgically attached to one another.  His theory, which was proven, was that animals that are surgically attached to one another will develop a shared circulatory system.

Parabiotic experiments in mice have been quite useful in identifying factors in blood that have an effect on physiology.  They were instrumental in identifying leptin as a factor in obesity and have been used in diabetes and cancer research.

In the 1970s, researchers decided to see what happened when they joined an old mouse to a young mouse.  This process, called heterochronic parabiosis, led to the discovery that there are components in the blood that regulate the aging process.  When their circulatory system were connected, the young mouse began to show signs of advanced aging while the older mouse began to show signs of age rejuvenation.  These experiments have been repeatedly confirmed since, and the effects are pretty powerful..

The changes include the way they look as well as how their organs function.  One of the mechanisms believed to be at play here is that the young blood contains factors that promote regeneration of local stem cell pools in the animals’ organs.  Conversely, it could mean that factors in old blood inhibit stem cell regeneration.  Either way, it shows that the blood contains factors that regulate time in a biological sense.

You may have heard of the age rejuvenating effects of young blood and that silicon valley billionaire venture capitalists are champing at the bit to get their hands on the blood of young people.  It was even in a recurring plot line during the last season of Silicon Valley.  I think this is a huge oversimplification.  Recent evidence has indicated that factors in old blood may be even more important in promoting aging than factors in young blood are at preventing it(1).

Either way, I think there are a couple of very important takeaways from these parabiosis experiments:

1. Aging may not be the linear process we think it is
2. Blood, the fluid that your tissues bathe in, exerts some level of control over tissue aging

Both of these takeaways provide some hope in the age rejuvenation field provided you look at age rejuvenation for what it is.  Get rid of the idea that you are going to look like you’re 30 when you’re 80 and realize that it basically means that we can improve the function of our organs so that they don’t fail prematurely.

This brings us to the gut.  Surely working from the outside with diet can help keep the gut from prematurely aging.  But what about the inside?

Taken from: http://media.springernature.com/full/springer-static/image/art%3A10.1186%2Fs40168-017-0296-0

The aging gut

As we age, our gut ages.  Over time, this leads to a change in the microbiome, nutrient absorption, and the leakiness of our gut to its contents.  It also leads to a change in the immune surveillance there.  This leads to an increased sensitivity to inflammation and a decreased ability to resolve it.  The thought process is that this is primarily diet-driven.  This thought is wrong.

There are other factors that are important.  Inflammation tends to inhibit stem cell regeneration and leads to premature cellular senescence.  Chronic inflammation is terrible for the aging of any tissue, but our guts just happen to be bombarded from the inside and out.

In preliminary experiments, molecular biologist Derek Huffman confirmed that blood contains factors that regulate aging in the gut.  Specifically he found that exposing young mice to old blood led to stem cell and tissue dysfunction in the gut of the young mouse.  He identified tumor necrosis factor alpha(TNF-a) and interleukin-1 beta(IL-1b) as 2 systemic factors that regulate aging in the gut(2).  Both increase with age and are associated with the process of inflammaging, a process where inflammation hastens the aging process throughout the body.

The data from more detailed experiments from Dr, Huffman have yet to be published, but this preliminary data indicates that focusing on food and supplements that change the gut from the outside are not going to solve tissue dysfunction in the gut, a more comprehensive approach that tackles the internal milieu is also necessary.

All of this is well and good, but why do you care if you don’t have any actionable information?  Well, I’m getting to that.

Taken from: http://salvadordaliprints.org/Salvador%20Dali%20Melting%20Clocks.jpg

Doing what you can to slow down time

Before I get in to the nitty gritty of things you can do to get time on your side, I think it’s important to note what you can expect from lifestyle with respect to slowing down time and aging in the gut.  Don’t expect to shave decades off a prematurely aged gut.  Ultimately, I believe the lifestyle approach is ideally suited to slow down time before the tipping point is reached.

This doesn’t mean that dotting a few of the i’s and crossing some t’s won’t significantly improve your situation if your gut is already ravaged.  Adding a bit of lifestyle to your dietary interventions will certainly be better than just slamming down fiber and glutamine while avoiding gluten and oxalates.  Working both sides of the equation will obviously lead to better results than focusing on just one.

For those that are already knee deep in gut dysfunction, there are some potentially useful therapeutic approaches that address the internal environment.  Therapeutic plasma exchange(TPE) has been used to treat a number of autoimmune conditions with varying success.  If you believe in Dr. Alessio Fasano’s paradigm on autoimmune disease and leaky gut as I do, it only makes sense that any effect likely involves the gut.  You can check out info on TPE here.

Given the recent evidence that factors in old blood are greater contributors to the aging process than young factors are at preventing it, one can envision that therapies in the not so different future will simply involve filtering of your own blood for these blood-borne factors.  This is certainly a simpler process than identifying and determining dosages of youth-promoting factors to give to older people.

But what can we currently do that will truly make a difference?  It may seem like I’m chronically beating the same drum over the last few months, but since we are dealing with time the best thing you can possibly due is work to optimize your circadian rhythms.  That’s why it’s been a recurring theme on my blog, a list of blogs on the topic can be found here.  Or you can just peep one on the circadian influence on gut health here.

Moving back to the factors in old blood that seem to speed up aging, a recent study found that cytokine expression is regulated by the circadian clock.  Knocking out the clock gene Cry led to constitutive expression of cytokines including TNF-a(3), the inflammaging-related cytokine fingered as one of the culprits in old blood that speeds up aging in the gut.  It also led to an increase in interleukin-6(IL-6), a primary player in cellular senescence.

The thought here is that the clock effectively gates cytokine release, and disrupting the clock eliminates the circadian rhythm of cytokine release.  Since the clock is functioning as a gate to repress cytokine release, disrupting it drops the gate and floods your system with chronic inflammation.  Unfortunately, it appears that this flood reinforces circadian disruption with both TNF-a and IL-1b both contributing to the disruption(4).

We know that with age comes circadian disruption, but it is reversible by exposure to zeitgebers.  We also know that most of the lifestyle factors associated with good health such as exercise, not smoking, and maintaining a healthy weight are all associated with decreased risk of age-related pathologies.  Despite this fact, most people are slacking on at least 2 out of 3 of these.

Finally, fasting and calorie restriction have been shown in numerous animal models to slow down the clock and promote longevity.  The pathways these processes work through tend to promote stem cell regeneration, decrease cellular senescence, and decrease systemic inflammation.

Taken from: https://focusedonfit.com/s/uploads/2017/06/Importance-of-Gut-Health-700×460.jpg

Conclusion

While we’ve spent the last decade focusing on the microbiome and how we can modulate it to improve gut health, we may have been failing to see the forest for the trees.  I think the first iteration of how the microbiome and gut health affect overall health has been paradigm shifting in terms of how we treat chronic disease.  However, it’s important to understand that what’s going on inside of your body affects the microbiome as much as the microbiome affects what goes on inside.

A number of studies support this notion, the most recent of which identified cortisol as a signaling molecule that certain bacteria in the microbiome use to communicate with the brain…at least in pigs.  But early studies in parabiosis looking at all organs, including the gut, provide pretty compelling evidence that what’s in the blood has a powerful effect on how every organ ages and functions.

Since we are ultimately dealing with time, circadian factors play a substantial role in aging in the gut and throughout the body.  While the therapies and pharmaceuticals aren’t here yet, I don’t think they’re too far off.  Until then, you will do best to bide your time by slowing it down as much as you can.  Some of this is under our control, and doing what you can now may be the difference between achieving remission with a future therapy or having too much damage to ever realize it.