TORC1 signaling inhibition by rapamycin and caffeine affect lifespan, global gene expression, and cell proliferation of fission yeast

Target of rapamycin complex 1 (TORC1) is implicated in growth
control and aging from yeast to humans. Fission yeast is
emerging as a popular model organism to study TOR signaling,
although rapamycin has been thought to not affect cell growth in
this organism. Here, we analyzed the effects of rapamycin and
caffeine, singly and combined, on multiple cellular processes in
fission yeast. The two drugs led to diverse and specific phenotypes
that depended on TORC1 inhibition, including prolonged
chronological lifespan, inhibition of global translation, inhibition
of cell growth and division, and reprograming of global gene
expression mimicking nitrogen starvation. Rapamycin and caffeine
differentially affected these various TORC1-dependent
processes. Combined drug treatment augmented most phenotypes
and effectively blocked cell growth. Rapamycin showed a
much more subtle effect on global translation than did caffeine,
while both drugs were effective in prolonging chronological
lifespan. Rapamycin and caffeine did not affect the lifespan via
the pH of the growth media. Rapamycin prolonged the lifespan
of nongrowing cells only when applied during the growth phase
but not when applied after cells had stopped proliferation. The
doses of rapamycin and caffeine strongly correlated with growth
inhibition and with lifespan extension. This comprehensive
analysis will inform future studies into TORC1 function and
cellular aging in fission yeast and beyond.
Key words: cell proliferation; chronological aging; gene regulation;
Schizosaccharomyces pombe; Target of Rapamycin;
translation.