Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Abstract

SummaryInhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age‐associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate‐specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.

High mTORC1 signaling is maintained, while protein degradation pathways are perturbed in old murine skeletal muscles in the fasted state

“…Overall, in demonstrating sustained phosphorylation of AKT(Ser473) and the mTORC1 pathway in skeletal muscles of fasted male mice, our data are in agreement with observations by Baar et al (2015), who reported elevated AKT(Ser473) and rpS6(ser240/244) (Baar et al 2015). Combined with data by Sandri et al (2013), showing increased rpS6(Ser235/236) phosphorylation in male freely fed C57BL/6J x DBA/2J mice (Sandri et al 2013), it seems that elevated mTORC1 signaling in old male murine muscles is a reproducible phenomenon.…”

“…We did not investigate reasons for delayed AKT(Ser473) dephosphorylation in old muscles in the fasted state. However, Baar et al (2015) reported increased fasted insulin levels in 24 and 30 m old C57BL/6J males compared with 6 m (Baar et al 2015), which may have contributed to elevated AKT activity (Lamming et al 2013).…”

“…A recent study that compared mTORC1 signaling in skeletal muscles of old male and female C57BL/6J mice fasted for 16 h (Baar et al 2015), showed that muscles from 24 and 30 m old fasted males had higher phosphorylation of rpS6(Ser240/244), but not 4E-BP1(Thr37/46) compared with 6 m; whereas in female muscles phosphorylation of rpS6(Ser240/244) and 4E-BP1(Thr37/46) was similar at 6, 22 and 26 m. While this study concluded that mTORC1 signaling is elevated in male, but not female murine muscles, another explanation may be that overnight fasting for 16 h is sufficient to down-regulate mTORC1 signaling in old female muscle, while a longer fasting time may be required for old male muscles.…”

Sexual dimorphism in glioma glycolysis underlies sex differences in survival

“…Mutations in the PTEN tumor suppressor, for example, not only enhance proliferation and glucose metabolism through the upregulation of downstream Akt and mTOR signaling (24), but there is also ample evidence of sexual dimorphism in the expression and activity of the PI3K/Akt/mTOR pathway in brain liver, heart, skeletal muscle, and adipose tissue in both normal and noncancerous pathologic states (59)(60)(61). Our data showing sex-specific survival differences associated with glycolytic pathway gene expression highlight a previously uncharacterized finding that sex differences in metabolism may have a role in sex-specific survival.…”

Evidence that a mitochondrial death spiral underlies antagonistic pleiotropy

“…Although Tor activity was reported to increase with age in muscle, liver, lung, and stem cells (Chen et al ., 2009; Sandri et al ., 2013; Leontieva et al ., 2014; reviewed by Nacarelli et al ., 2015; Romero et al ., 2016; White et al ., 2016), other studies failed to confirm some of these findings (Baar et al ., 2016). It appears that phosphorylation of various Tor substrates is affected differentially during aging.…”