This week Nature speculates (DOI) about the use of rapamycin as a longevity, aging-intervention or anti-ageing drug in a comment on new mouse research done by Harrison et al. (DOI). 1900 mice were found kind enough to participate in a trial where starting at the age of 600 days (that is 60 human years) they were fed a chow laced with rapamycin. The control group (obviously) were given just the chow but not the rapamycin.
Sure enough, at 90% mortality the mean lifespan increased by 9% in males and by 13% in females. By 1200 days all mice were as good as dead so it does not mean mice live longer in absolute terms. Nevertheless an exciting result.
But there is another intriguing finding in this study: "the (male) control mice ... differed from those fed rapamycin not only in exposure to rapamycin from 600 days of age but also in specific formulation of the mouse chows .... used between weaning and 600 days".
This means that the control mice were starting to die off in anticipation to the rapamycin-free diet! What was wrong with them! They must have guessed somehow they were part of "just the control group" and not the hip & longlasting rapamycin crowd!. The resulting lack of self-esteem did them in!
Back to the chemistry: rapamycin is a complex macrolide and the number of successful feats of total synthesis stands at five: the Danishefsky group (Hayward et al. 1993 DOI), the Schreiber group (Romo et al. 1993 DOI) , the Nicolaou group (1993 DOI) , the Amos B. Smith group (1995 DOI DOI DOI), the Ley group (Maddess et al. 2007 DOI).
The Ley group started working on rapamycin in 1990. The sketch below attempts to sketch it's synthesis from the raw material point of view.
The group published a 45 page "the making of" in 2009 (Maddess and 22 other authors DOI) that also details the synthesis of the two larger chunks.