Starting a Three-Day Fast: Some Insights From Stem Cell Research

I shall be starting a three-day fast soon, probably on Saturday as I have some time on my own. So, before venturing into this, I wanted to share the literature on fasting and specifically on the 3-day water fast.

My interest in this was tweaked when I started reading research articles about a potential "autoimmune reset" that can happen after 3 days; I'm not doing this as a weight-loss programme. I do have a so-called auto-immune condition; I say "so-called" as it is not auto-immune but was triggered by a toxic antibiotic that should, in a sane world, have been taken off the market years ago. There is no anti-antibiotic as there is no research on which gene expression was disrupted. I know from my own researches the likely candidates, but try getting funding for something that will potentially impact pharmacorp profits.

I digress, but, as I said, it is the effect on the immune system that I was most interested in.

_pixabay

Firstly, here is a general review of the literature, as of 2014: Longo, V. D., & Mattson, M. P. (2014). Fasting: Molecular Mechanisms and Clinical Applications. Cell metabolism, 19(2), 181–192. doi:10.1016/j.cmet.2013.12.008. Luckily, this is freely available online.

The paper reviews recent research on both mice and humans with a focus on intermittent fasting (IF, such as alternate day fasting or twice weekly fasting) and periodic fasting (PF, lasting several days every 2 weeks or more).

From the Introduction:

"We now know that fasting results in ketogenesis, promotes potent changes in metabolic pathways and cellular processes such as stress resistance, lipolysis and autophagy, and can have medical applications that in some cases are as effective as those of approved drugs such as the dampening of seizures and seizure-associated brain damage and the amelioration of rheumatoid arthritis."

In the same year, there was a flurry of articles promoting fasting as a way to regenerate the immune system:

Fasting for 72 Hours Can Reset Your Entire Immune System

Fasting triggers stem cell regeneration of damaged, old immune system

The research paper that these articles reference is: Cheng, C. W., Adams, G. B., Perin, L., Wei, M., Zhou, X., Lam, B. S., … Longo, V. D. (2014). Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell stem cell, 14(6), 810–823. doi:10.1016/j.stem.2014.04.014. Luckily, the full paper is also open access.

From the Summary:

Here we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSC) and niche cells that promote stress resistance, self-renewal and lineage-balanced regeneration.

and

These findings link the reduced levels of IGF-1 caused by fasting, to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal and regeneration.

As with all research papers, there is some technical jargon to wade through.

What are hematopoietic stem cells?

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. HSCs are found in the bone marrow of adults, especially in the pelvis, femur, and sternum. They are also found in umbilical cord blood and, in small numbers, in peripheral blood. (Wikipedia)

This research also differentiated between short-term (ST-HSC) and long-term (LT-HSC) hematopoietic stem cells, as well as between Lymphoid (Ly-HSC), balanced (Bala-HFC) and Myeloid (My-HFC) hematopoietic stem cells. Lymphoid cells include T cells, B cells, and natural killer cells. Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets. These groups will become important later.

_{Hematopoiesis, wikimedia}

What are IGF-1 and PKA?

Insulin-like growth factor 1 (IGF-1) is a hormone similar in molecular structure to insulin. "IGF-1 is a primary mediator of the effects of growth hormone (GH). Growth hormone is made in the anterior pituitary gland, is released into the blood stream, and then stimulates the liver to produce IGF-1. IGF-1 then stimulates systemic body growth, and has growth-promoting effects on almost every cell in the body, especially skeletal muscle, cartilage, bone, liver, kidney, nerve, skin, hematopoietic, and lung cells. In addition to the insulin-like effects, IGF-1 can also regulate cellular DNA synthesis." (Wikipedia)

Protein kinase A (PKA) is a family of enzymes with several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. The roles of PKAs are not yet fully known and are complicated by the fact that they seem to have different functions depending on the cell type.

So, given the importance of these proteins, how can their reduction have a positive effect on humans? The magic happens when we start eating again.

Because during PF mammalian organisms minimize energy expenditure in part by rapidly reducing the size of a wide range of tissues, organs, and cellular populations including blood cells, the reversal of this effect during re-feeding represents one of the most potent strategies to regenerate the hematopoietic and possibly other systems and organs in a coordinated manner. Here we show that PF causes a major reduction in WBC [White Blood Cells] number, followed, during re-feeding, by a coordinated process able to regenerate this immune system deficiency by changes beginning during the fasting period, which include a major increase in LT-HSC and ST-HSC [...] leading to a lineage-balanced mode. In fact, we show that PF alone causes a 28% decrease WBC number, which is fully reversed after re-feeding (Fig. 7b). Even after WBCs are severely suppressed or damaged as a consequence of chemotherapy or aging, cycles of PF are able to restore the normal WBC number and lineage balance, suggesting that the organism may be able to exploit its ability to regenerate the hematopoietic system after periods of starvation, independently of the cause of the deficiency.

_{PF reduce IGF-1/PKA to promote lineage-balanced hematopoietic regeneration, Fig7b}

Thus, the fasting process flushes out a significant number of white blood cells and stem cells, including potentially damaged cells, which are then replaced by brand new cells once eating restarts.

The punchline is well-expressed in Less Food, Better Haematopoietic Function?:

One of the major efforts of stem cell biology is the creation of adult stem cells from pluripotent sources for use in cell replacement therapy. However, uncovering inherent mechanisms to protect or rejuvenate our stem cells when placed under peril (such as chemotherapeutic insult) may circumvent this necessity. The link between fasting, IGF-1, and PKA are also backed up by some clinical findings suggesting that these findings may be translated with speed into the clinical setting.

So, will I actually feel any different?

Let's wait and see.

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_{images: pixabay; wikimedia commons; fair use (links in image legends)}

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@rycharde manages the AAKOM project and the MAP Rewarder.