For people with disorders of the gut, inflammation is a buzzword thrown about as much as the name Tom Brady is thrown about for football fans in New England.  This is for good reason, chronic inflammation can cause some pretty nasty problems in any tissue you find it, especially the gut.

However, for most people, where this inflammation is coming from and what they should do about it is a point of contention.  Certainly it’s from gluten…or maybe it’s dairy…don’t forget soy…could be oxalates…

Unfortunately, I believe this forces many people in to uber-restrictive diets and cabinets full of supplements looking to put out the fire of inflammation in their gut.  In my opinion this will provide little relief, and if it does that relief will be fleeting.  There are far more low hanging fruit that one can tackle, unfortunately those low hanging fruit are very uncomfortable to grab.

Understanding gut health at the cellular level

Before we dig in to the hidden source of inflammation I hint to in the title of this blog, it’s important to understand organ health at the cellular level.  The condition of our gut, or any organ or tissue for that matter, is in direct correlation to the number of replicating stem cells located there.  I won’t bore you with a giant cellular biology lesson, here are the crib notes.

Each one of our organs is made up of many different types of cells with functions specific to the organ.  In the gut, there are cells that are responsible for secreting mucus(goblet cells), secreting hormones(enteroendocrine cells), host defense(paneth cells), and absorbing nutrients(enterocytes).

These cell types are called differentiated cells because they have become a cell with very specific functions.  But where do these cells come from?  That would be the intestinal stem cells located at the base of the crypt.

Taken from: https://cdn.stemcell.com/media/images/pages/organoids/intestinal-epithelium.jpg

Stem cells and tissue renewal in the gut

As you can see from the picture above, intestinal stem cells reside at the base of the intestinal crypts with paneth cells in the small intestine.  Note: It’s a little different in the colon but the basic principle is the same, there are just no villi.

Stem cells form a pool of cells that can help replenish differentiated cells as they’re lost.  When stem cells replicate, they typically form a daughter cell that takes a step towards differentiation in to a specific cell type, and another daughter cell that replaces the stem cell.  This allows the stem cell pool to be maintained while also maintaining cells that perform intestinal functions.

Taken from: http://www.tankonyvtar.hu/en/tartalom/tamohttps://regi.tankonyvtar.hu/hu/tartalom/tamop425/0011_1A_3D_en_book/ch01s02.htmlp425/0011_1A_3D_en_book/images/dia5.png

As you can tell from this picture, stem cells can renew themselves provided one of the daughter cells is also a stem cell.  Once the stem cell begins differentiation, there’s no going back.  Provided parental cells give birth to at least 1 self-renewed daughter cell, the stem cell pool in a given tissue or organ is maintained.  Unfortunately with age, our stem cell pools become depleted.

Unlike other tissues, intestinal stem cells give birth to daughter cells that migrate up the crypts to the villi, while any self-renewed daughter stem cells remain in the crypts.  As the differentiated cells migrate up, they differentiate in to the different cell types that make up the intestinal wall.  As they reach the top of the villi, they are sloughed off and replaced with newer cells.

One of the hallmarks of aging is a gradual decline in the function of organs throughout the body.  To a large extent, this is caused by the depletion of stem cells in the niche environment of each organ.  A primary driver of this process as well as inflammation in the gut is cellular senescence.

Stem cells, senescence and gut function

There are many different types of stem cells in the body that can differentiate in to many different tissues.  When a stem cell maintains the ability to become many types of cells, it is said to be pluripotent.  We want our tissues and organs to maintain a large pool of these types of stem cells.  Unfortunately with age, the stem cell pool declines and we are left with a decreased ability to replenish damaged or dead cells.

A big driver of the age-related loss of stem cells is cellular senescence.  Senescence is a form of growth arrest that acts as a primary defense against tumor formation.  Basically, when the DNA of a cell becomes damaged, the DNA damage response(DDR) is initiated to prevent the cell from replicating.  If the cell were allowed to replicate, it may copy the damaged DNA and form a tumor, something none of us want.  Note: Senescence can be caused by other factors including oxidative stress and mitochondrial dysfunction just to name a couple.

When a cell undergoes senescence it maintains some of its typical functions.  However, that cell cannot replicate, and likely never will again barring a pharmaceutical hail mary we have yet to discover.  But a senescent cell is far from inert.  As part of the process of senescence, the cell secretes inflammatory cytokines, proteases, and growth factors that affect other cells in the area.  This is called the senescent associated secretory phenotype, or SASP.

Taken from: http://www.cell.com/cms/attachment/2007962177/2030676976/fx1.jpg

This process is very important for tumor prevention.  The inflammatory cytokines draw immune attention to the area and macrophages ideally remove the offending cell or cells.  However, if left unresolved, senescent cells can cause organ dysfunction as the chronic inflammation interferes with cell signaling and induces senescence in other cells while the proteases begin to degrade proteins that support organ structure.

Although important for tumor prevention, senescent cells tend to accumulate in organs with age.  And with this comes higher levels of inflammation in the target tissue.  While any type of cellular senescence is bad for organ function outside of the cancer prevention aspect, it’s particularly bad when it involves stem cells.  Not only do you basically remove a cell capable of replenishing damaged cells, but stem cells tend to hang out with one another and the SASP can induce senescence in other stem cells in the niche.

Taken from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4113516/bin/AD-5-4-263-Figure-3.jpg

The gradual accumulation of senescent cells is a simple fact of aging, and with it comes organ dysfunction, particularly in the gut.  We aren’t talking large numbers of senescent cells here, even a small percentage (~1%) can cause functional decline in an organ.  The gradual accumulation of senescent cells in any organ can increase systemic inflammation as well, which can hasten age-related decline(1).

Slowing down senescence

If you’re familiar with the science of circadian rhythms, fasting, exercise, and calorie restriction, you may have noticed something interesting about the above picture.  I’m speaking about the presence of mTOR as a driver of senescence.  The mTOR pathway, mammalian target of rapamycin, is a longevity pathway that is largely regulated by calorie restriction, fasting, protein restriction, and exercise.  Inhibiting mTOR, which the 4 previous factors do, inhibits cellular senescence(2).

Another longevity pathway, the sirtuin pathway, is also involved in regulating senescence(3).  Activating SIRT1 inhibits senescence, so any factor that activates sirtuins will inhibit cellular senescence.  This includes calorie restriction, fasting, and exercise.  Oh yeah, and the sirtuin pathway effectively functions as the nutrient sensing arm of the circadian clock.  See where I’m going here?

To be clear, I don’t necessarily believe that long periods of fasting are the answer.  My contention is that regular periods of daily fasting, where you’re not eating from the minute you get up to the minute you go to bed, give your body time to repair any damage accumulated naturally due to cellular metabolism.

Syncing these periods of fasting up with other circadian exposures such as light exposure and physical activity should also reduce the accumulation of senescent cells.  There is evidence that melatonin, an output of the master clock regulated by light exposure, activates the sirtuin pathway(4).

Keep in mind you are not going to completely eliminate the accumulation of senescent cells.  They will accumulate, it’s just a matter of how quickly.  And while you do what you can from the lifestyle end of things, there is help on the way.  Fortunately, senolytic compounds are under investigation and can be useful here.

Senolytics: Potential solution to age-related cellular senescence

Researchers have been looking for a solution to the cellular senescence problem for some time.  Since cellular senescence tends to be more common in organs where age-related pathologies exist, it’s thought that reducing the burden of cellular senescence can improve both life- and healthspan.

Mouse models do indeed show that selectively removing senescent cells increases healthspan and promotes longevity(5).  There are several benefits to senolytics that make them attractive therapies for aging and organ function.  First, many seem to specifically target senescent cells without affecting healthy cells.  Second, you aren’t interfering with the process of senescence, simply removing senescent cells as they accumulate.  Interfering with senescence wouldn’t be great for cancer prevention.

Finally, the greatest benefit of senolytics is that they don’t need to be chronically taken.  In fact, the thought is that very low doses will only need to be used sporadically as senescent cells accumulate.  This means you would only need very low dose schedule annually or longer to combat the damaging effects of senescent cells.

Conclusion

Cellular senescence is a common contributor to age-related functional decline.  By increasing inflammation and decreasing the stem cell pool, cellular senescence can have a major impact on gut function.

There are a number of useful tips one can use to reduce the burden of senescent cells.  First and foremost, I recommend regulating circadian exposures to help reduce cellular senescence, particularly fasting.

Another approach which is under significant investigation is the use of senolytic compounds to remove senescent cells as they accumulate.  Even with a pristine lifestyle, senescent cells are going to accumulate in your organs, particularly the ones that tend to fail as we age.

The use of senolytics is something I am probably going to cover to a greater extent as I re-purpose my circadian retraining program towards a more broad-based program.  I have a few protocols I think would work but feel I need to put more time in to them.