The circadian rhythm of autophagy is altered with inflammation

Autophagy seems to be one of the more viral topics being bandied about on the interwebz these days.  There’s actually good reason for this, particularly in health and longevity circles.  Autophagy is the process by which our cells take out their cellular garbage and it’s very important for slowing down age-accumulated damage.  Well, to be precise, it’s more like recycling so you’ll need a blue bin to continue.

During periods of nutrient deprivation, there’s a targeted dismantling of defective proteins within our cells.  In an effort to be thrifty, our cells disassemble defective proteins in to their constituent parts to be used elsewhere in the cell when demand exceeds supply.

Many would have you believe that this process is an all-or-none deal.  All you need to do is fast and you’ll experience autophagy.  While this is partially correct, it seems that the process is a little more nuanced than that.  In fact, autophagy seems to be stratified by time and location, at least in the liver.

That is, during certain parts of the day, autophagy takes place in the cytosol and nucleus of cells while during other parts of the day it takes place in the mitochondria and endoplasmic reticulum.  This indicates that circadian rhythms are important to the process, but it also gives us a glimpse in to why inflammation can have deleterious effects on our health and metabolism, speeding up the aging process and increasing our risk for chronic disease.

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The Circadian Rhythm of Autophagy

A study published in the journal Cell details the process by which circadian rhythms regulate autophagy in the cell throughout the day.  In the mouse liver, autophagy is localized to the cytosol and nucleus of cells during the subjective day and the mitochondria and endoplasmic reticulum during the subjective night.  Sequestering the process to separate compartments makes a lot of sense as disassembling every aspect of energy metabolism at the same time would likely have some negative consequences.

But this study has some other very interesting findings.  Inducing inflammation by injecting lipopolysaccharide(LPS) caused a loss of the autophagy rhythm, shifting away from the cytosol and focusing autophagy to the mitochondria.  This caused a build up of glycolytic enzymes and lactate dehydrogenase in the cytosol and a loss of energy metabolism in the mitochondria.  The result: Energy metabolism consistent with mitochondrial dysfunction and the Warburg Effect, most commonly associated with Cancer.

Inflammation, Circadian Disruption, and Metabolic Dysfunction

During inflammation induced by endotoxin, cellular energy metabolism in the liver is reprogrammed towards anaerobic glycolysis in the cytosol and away from mitochondrial energy metabolism, despite adequate oxygen.  This is believed to help manage the mitochondrial dysfunction that comes with inflammatory states.

This fits nicely with my belief that increased “leaky gut” is a driver of biological aging and drives up chronic disease risk.  Coincidentally, endotoxin is known to polarize macrophages towards a pro-inflammatory state and induce the enzyme CD38 which decreases NAD+ availability as we age.  Unfortunately, I think these are key ingredients in the system-wide physiological disruption that comes with gastrointestinal disorders such as IBS and SIBO.

I also believe these are key reasons why people who “fix” IBS or SIBO typically end up getting them again.  People who suffer with SIBO typically have gram-negative bacteria as part of the overgrowth, which contain endotoxin.  This leads to greater endotoxin absorption and may drive the same pathology as seen in the study above.

Since the cells in the liver are effectively suffering from mitochondrial dysfunction, they’re unable to metabolize fat and the liver may accumulate fat, leading to non-alcoholic fatty liver disease(NAFLD).  NAFLD is commonly seen in people with SIBO, but may not always be addressed.  So you take an antibiotic which treats the overgrowth, but it does nothing for the liver.

Healthy digestion requires a healthy liver-microbiome-gut axis, and a dysfunctional liver will impair intestinal barrier integrity and disrupt the microbiome.  Thus, you’ll pretty much end up back where you started unless you address the liver as well.  This speaks nothing to the point that behavior is a huge driver of endotoxin absorption, you don’t need SIBO to absorb too much of it so you can get right back where you were in pretty quick fashion.

Conclusion

Autophagy isn’t a simple on/off process, it appears to be regulated in a circadian manner, pinpointing different parts of the cell at different times.  Under normal conditions, autophagy proceeds in the cytosol and nucleus during the day and in the mitochondria and endoplasmic reticulum at night.

Under inflammatory conditions induced by endotoxin, the script changes.  Essentially, the cytosol and nucleus are ignored and the mitochondria are chronically targeted.  This leads to impaired mitochondrial energy metabolism and a shift towards anaerobic glycolysis and an increase in lactate generation.  What you’re basically looking at is mitochondrial dysfunction, or energy metabolism that closely resembles it, that will disturb metabolism throughout the body.

I wouldn’t be the least bit surprised to find out that the circadian rhythm of autophagy proceeds in a cell-type specific manner.  Be that as it may, the liver functions as a central regulator of metabolism and if endotoxin has the same effect in humans as it does in mice, it would be in everyone’s best interest to optimize their circadian rhythms and work to drop endotoxin absorption as low as it can go.

Fortunately, I believe there’s a ton of overlap in the behaviors required to accomplish both.  It’s not as simple as popping a pill to clear a bacterial overgrowth, but it sets the stage for actually solving the problem.

2 thoughts on “The circadian rhythm of autophagy is altered with inflammation

    • cincodm says:

      Hey Deanna, addressing the liver is best done through lifestyle by either calorie restriction or addressing circadian exposures.

      The only effective means for addressing fatty liver to date is weight loss, but I believe this needs to be addressed both by reducing calories and increasing physical activity. There are studies in mice showing that this approach re-establishes healthy circadian gene expression in the liver but most people don’t stick to it. So they regularly end up back where they were.

      On the other hand, you can address circadian exposures to optimize the same rhythm. This includes proper timing of light exposure, physical activity, and feeding/fasting cycle and meal scheduling. Additionally, we can alter diet content to speed up the process. This is my approach with people because they learn the lifestyle factors that impact their gut and liver health the most and can manage to avoid falling back in to these problems without having to stay in a chronically calorie restricted state.

      How strict you need to be is dependent on the current state you’re in. Some people, mostly young people, see moderate improvement by tinkering around with light exposure and time-restricted eating. But for people with major issues or older folk you need more tools in your toolkit.

      Currently, I offer my comprehensive Circadian Retraining Program to give people all of the info they need to do this. You can view the program here:

      https://hackyourgut.com/circadian-retraining-program/

      Alternatively, I have people going through my Stop Leaky Gut Challenge which is a stripped down version of the above and doesn’t really cover the background info on why you’re doing what I recommend. You can read how people are doing on that program here:

      https://hackyourgut.com/stop-leaky-gut-challenge-round-2/

      I’m not currently enrolling people in the Stop Leaky Gut Challenge as we’re only 2 weeks in to round 2 and I want to make sure I can help the people that are in there. I’ll be running another round in about a month but people who purchase the entire Circadian Retraining Program also get the Stop Leaky Gut Challenge files as I consider them intertwined.

      Thanks for reading,

      Dave

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