Open AccessDepletion of Rictor, an essential protein component of m TORC 2, decreases male lifespan
Author(s) -
Lamming Dudley W.,
Mihaylova Maria M.,
Katajisto Pekka,
Baar Emma L.,
Yilmaz Omer H.,
Hutchins Amanda,
Gultekin Yetis,
Gaither Rachel,
Sabatini David M.
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12256
Subject(s) - mtorc2 , mtorc1 , pi3k/akt/mtor pathway , biology , mechanistic target of rapamycin , microbiology and biotechnology , cancer research , signal transduction
Summary Rapamycin, an inhibitor of the mechanistic target of rapamycin (m TOR ), robustly extends the lifespan of model organisms including mice. We recently found that chronic treatment with rapamycin not only inhibits m TOR complex 1 (m TORC 1), the canonical target of rapamycin, but also inhibits m TOR complex 2 (m TORC 2) in vivo . While genetic evidence strongly suggests that inhibition of m TORC 1 is sufficient to promote longevity, the impact of m TORC 2 inhibition on mammalian longevity has not been assessed. RICTOR is a protein component of m TORC 2 that is essential for its activity. We examined three different mouse models of Rictor loss: mice heterozygous for Rictor , mice lacking hepatic Rictor , and mice in which Rictor was inducibly deleted throughout the body in adult animals. Surprisingly, we find that depletion of RICTOR significantly decreases male, but not female, lifespan. While the mechanism by which RICTOR loss impairs male survival remains obscure, we find that the effect of RICTOR depletion on lifespan is independent of the role of hepatic m TORC 2 in promoting glucose tolerance. Our results suggest that inhibition of m TORC 2 signaling is detrimental to males, which may explain in part why interventions that decrease m TOR signaling show greater efficacy in females.