In part one I talked about the different classes of the FOX protein family. I also described how FOXO proteins are transcriptional regulators that orchestrate programmes of targeted healthy longevity genes. Click here for part 1.
Now let’s talk about their environment and behaviour.
As I say, FOXO proteins are transcriptional regulators – they regulate the conversion of specific DNA to RNA – and they do it precisely. To be able to do this, they need to bind to certain areas of DNA. As most DNA is found in the NUCLEUS of a cell, FOXO proteins will be found mostly in the nucleus. If they move off the DNA and out of the nucleus, they can’t act as the gene conductor anymore.
FOXO proteins function in response to environmental conditions and they tend to work harder under stressful ones. They undergo post translational modification (PTM – the step after RNA has been translated to a protein) which will change their function. Some of the PTMs FOXO undergo include deacetylation, phosphorylation and ubiquitination. These PTMs occur in response to the environment and ultimately cause FOXO to move in and out of the nucleus. I’ll give two examples.
Akt mediated phosphorylation of FOXO is triggered by insulin. If we have high insulin from eating carbs, it will ultimately cause the phosphorylation of FOXO which moves it OUT of the nucleus and INTO the cytoplasm. Once there, it can no longer orchestrate all those awesome longevity genes.
FOXO can also be phosphorylated by other protein kinases, which actually do the opposite and move it FROM the cytoplasm BACK to the nucleus. This occurs in response to harsh conditions like oxidative stress. Also, deacetylation of FOXO by the sirtuin protein SIRT 1 increases FOXO’s binding ability in response to oxidative stress, helping FOXO to stay put when times are tough.
So I think you can see why there tends to be a theme of too much sugar is BAD and fasting is GOOD. If we want FOXO to regulate all these amazing longevity genes, it can’t happen with lots of carbs, insulin and growth factor. Stressful conditions are best – fasting, exercise or heat stress.