Interesting Study - FOXO proteins and immune function


 Hi all,

In my usual, nerdy, fun-filled weekend morning reading of recent pubmed articles on inflammation, I ran across a study on FOXO proteins and their importance in healthy immune functioning.   I'd never heard anything about these proteins before, so I did some googling and came across some interesting studies that I thought I would post.   


First, FOXO proteins are a subgroup of the Forkhead (FOX) family of transcription factors, and as the following article points out:

"FOXO transcription factors are at the interface of crucial cellular processes, orchestrating programs of gene expression that regulate apoptosis, cell-cycle progression, and oxidativestress resistance (Figure 1). For example, FOXO factors can initiate apoptosis by activating transcription of FasL, the ligand for the Fas-dependent celldeath pathway, and by activating the pro-apoptotic Bcl-2 family member Bim. Alternatively, FOXO factors can promote cellcycle arrest; for example, FOXO factors upregulate the cell-cycle inhibitor p27kip1 to induce G1 arrest or GADD45 to induce G2 arrest. FOXO factors are also involved in stress resistance via upregulation of catalase and MnSOD, two enzymes involved in the detoxification of reactive oxygen species. Additionally, FOXO factors facilitate the repair of damaged DNA by upregulating genes, such as GADD45 and DDB1. Other FOXO target genes have been shown to play a role in glucose metabolism, cellular differentiation, muscle atrophy, and even energy homeostasis."

FOXO transcription factors


Interestingly, as the following easy to read article on a recent study points out, it is believed FOXO transcription factor is influenced by diet, and importantly, FOXO is believed to be an important regulator of antimicrobial peptide (AMP) induction:

"in the case of a low insulin level the FOXO transcription factor is activated. A transcription factor can switch genes on and off. FOXO switches genes for immune defence proteins on when energy is needed. These antimicrobial peptides (AMP) -- not to be confused with antibodies -- are subsequently jettisoned by the body's cells. They destroy possible pathogens by dissolving their cell walls."

Hungry Immune Guardians Are Snappier: Nutrition Has a Direct Influence on the Immune System
Here's the actual study:
FOXO-dependent regulation of innate immune homeostasis


The following article mentions the above article and points out that antimicrobial peptides are activated in response to nuclear FOXO activity and reductions of nuclear levels of FOXO may lead to increased infection:


"It has recently been shown in Drosophila that the induction of antimicrobial peptides (AMPs) can be achieved independently of tolllike receptor (TLR) pathways by FoxO-dependent gene regulation[81]. AMP genes are activated in response to nuclear FoxO activity [81]. Increased growth factor signaling of puberty and insulinotropic Western diet may reduce nuclear levels of FoxO1 and AMP activity thus promoting P. acnes growth and biofilm formation."


The article also discusses phosphoinositol-3 kinase(PI3K)/Akt activation and its function in decreasing nuclear FOXO levels:


"The activated kinase Akt (protein kinase B) translocates into the nucleus where Akt phosphorylates the nuclear FoxO1 protein. Phosphorylated FoxO1 is exported from the nucleus into the cytoplasm thereby derepressing target genes"


And the article lists various known growth factors and stimuli for phosphoinositol-3 kinase(PI3K)/Akt activation, including, Insulin, IGF-1 and even Nicotin (see Figure 1).


The article goes on to discuss high glycemic diets and its effects on IGF-1 and insulin levels:

"Nutrients rich in carbohydrates with a high glycemic index (GI) induce hyperglycemia, reactive hyperinsulinemia, and increased IGF- 1 serum levels. In contrast, a diet with a low glycemic load decreased serum IGF-1 levels..."


And interestingly, the article discusses dairy consumption and its apparently rather dramatic effects on serum IGF-1 levels:

"Milk consumption induces high serum levels of IGF-1 [11-15].  Milk consumption has been associated with linear growth and the manifestation of acne [16-18]. It is the biologic principle of milk to promote growth by increased insulin/IGF-1 signaling and induction of insulin resistance [11,12,15,19-23]. The relation between milk induced insulin/IGF-1 signaling and the pathogenesis of acne and chronic diseases of Western civilization has recently been presented [7,10,24-27]. The insulinotropic effect of milk resides within the hydrophilic whey protein fraction [28]. Both insulin and IGF-1 reduce nulear levels of FoxO1 [2,3]."


Acneigenic Stimuli Converge in Phosphoinositol-3 Kinase/Akt/FoxO1 Signal Transduction


While I'm certainly no expert, I found this interesting and potentially another piece of the puzzle.  All of this all got me thinking, could my dairy consumption be interfering with proper immune function and my return to good health?   It should be easy enough to give up dairy for a while, so I thought I'd give this a try, changing nothing else in my diet other than complete elimination of dairy.  For me, this really only means no milk in my morning coffee, and no cheese at lunch or dinner anyway.   Not a big deal at all...

Certainly I need to give this a longer go, but after only a couple of days, I've started noticing a lot of now unusual aches and pains, some fairly decent amount of fatigue and even some dizziness upon standing and odd muscle twitching that I have not seen in years - all tell tale signs for me of a large increase in die-off of something.   Perhaps there is something in this?

Anyway, more later, but I thought I'd pass this along in case it might help...

Hang in there...






How interesting, Red. I will have to read more about it. Thank you.

Stratton/Wheldon protocol 02/2006 - 10/11 for CFS and many problems 30 years

Drat, just when I was heralding your return and you have to go deny me my cheese and butter. Okay, I'm willing to give it a go. Briefly. ;-)

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

Looking at some of the references in that last paper, the IGF-1 changes from milk consumption seem rather small. IGF-1 has very large 'normal' ranges. (I always get suspicious when articles like this leave out the numbers.)

At any rate, if the whey fraction is the one containing the evil spirits, then cheese and butter should be just fine, since whey is what's drained from them in their making.

If you're looking to boost FoxO1, the sentence "It has been demonstrated that retinoids are potent inducers of FoxO proteins" seems like a better thing to fasten on. That's vitamin A and cousins.


Hey all,

I'm roughly @ 10 days of trying my best to avoid dairy, and I've noticed that my skin seems to be less dry and prone to irritation and actually feels more "normal" than even before.   I've also noticed that my constant morning backache has gone away and even my eyesight seems to have improved - I'm on the cusp of needing reading glasses.   Dang you old age!  Tongue out

I'm still noticing some odd muscle twitching, occasional aches and pains, and more sinus discharge, but nothing major.    I have to say I was a bit skeptical about this at first, but I'm definitely seeing enough health improvement that I'm thinking there really is something to this.    I'll definitely give this more of a go...

Hope this might help someone else.   Hang in there...


Treatment for Rosacea

  • CAP:  01/06-07/07
  • High-Dose Vit D3, NAC:  07/07-11/08
  • Intermtnt CAP, HDose Vit D3:  11/08-01/09
  • HDose Vit D3, Mg, Zn: 01/09-

Red, You might consider looking at your amounts of Omega-3 intake in regards to the flexibility of the lenses in your eyes and (even the effect on the skin) to hold off the reading glasses a bit longer perhaps.    I'd love to hear what you find when you research it a bit.
  • CAP(TiniOnly): 06/07-02/09 for CFS
  • MethylationProtocolSupplements: Started08/08
  • Intermtnt CAP: 02/09-02/10
  • Full MethylProtocol & LDN 02/09
  • Off CAP: 02/10, cont LDN & MethlyProtocol support

That's an interesting connection, Red.  I haven't read a lot about FOXO, PI3K, or IGF-1, but I know that ketogenic diets have a strong positive effect on them.  See for example, 


and "The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma",

(Excuse the inconsistent formatting: I haven't quite figured out how to post links properly!)




Treating bipolar II depression (in remission), mild rosacea.

Therapies: Ketogenic diet, NAC, niacinamide, melatonin, D3, quercetin+bromelain.

May start CAP after breastfeeding.