I just read an interview with Josh Mitteldorf, where he says that FOX04-dri has off target effects ...
I read that section. He also says:
The record-holder so far is FOXO4-DRI, and it is about 10 times more toxic to senescent cells than to normal cells. That factor of 10 isn’t enough margin of error for a practical drug.
It might not be practical, but it does not automatically follow that one should abandon all experimentation.
And:
To get rid of all your senescent cells, you’d have to take too many healthy cells as collateral damage.
However, the mice lived 20% longer after the treatment. So, even if there was collateral damage, the benefits outweighed any detrimental effects.
Also, I don't think anyone here is under the illusion that he/she would get rid of all senescent cells by injecting FOXO4-DRI.
The 33mg dose for a 80kg human was translated from a mouse dose by applying quite conservative factors. It should only be seen as a starting point until more human data is available.
IIRC, the mice were treated with 3 doses, spaced 48 hours apart. That should give good cells a chance to recover.
@Vantika estimated the half-life of FOXO4-DRI to be 12 to 16 hours. That means after 48 hours, the level would be down to somewhere between 6% and 12%.
To play it safe, one could wait longer between doses. With every dose, a percentage of the remaining senescent cells would still be eliminated.
There is a useful hint from Josh Mitteldorf (probably unintentional):
The best senolytic treatment we have now is fasting. When we go without food for three days at a time or more, senescent cells start to die off, but normal cells dial up their resistance and become healthier during a fast.
Could this be a useful strategy in combination with FOXO4-DRI treatment. It seems to me that fasting would increase the safety factor by making senescent cells more vulnerable and good cells more robust.
The implication being that apoptosis mechanisms themselves have off-target effects....
How so? Apoptosis is an internal self-destruct switch each cell has. It is activated by internal mechanisms.
The only potential issue that I see is that too many cells die at once. This would cause something like "tumor lysis syndrome". -- Another reason to proceed carefully by gradually increasing the dose.
Edited by Manfred B, 18 April 2018 - 10:58 PM.