Persistent mTORC1 signaling in cell senescence results from defects in amino acid and growth factor sensing

Abstract

It is unclear how mTORC1 signaling differs in senescent and young cells. Carroll et al. show that senescence leads to constitutive mTORC1 activation and resistance to serum and amino acid starvation. This is associated with elevated autophagy, depolarization of cell plasma membrane, and primary cilia defects.

Nutrient sensing, growth and senescence

“…We were unable to detect any gross changes AMPK phosphorylation at steady state in senescence human lung fibroblasts, but our insights into nutrient sensing by mTORC1 suggest that responsiveness to energy levels (or Ca 2+ ) may still be perturbed. Equally, we observed that TSC2 is not recruited robustly to the lysosome in starved senescent cells which supports mTORC1 activity and although we attributed this to persistent PI3K/Akt signalling, we cannot rule out that the responsiveness or activity of TSC2 to AMPK signalling is disrupted in senescence .…”

“…Interestingly, in senescent cells, autophagy may become partially uncoupled from mTORC1 signalling and its inhibitory effect . We have demonstrated that autophagy flux, which reflects the activity of this degradative system, is significantly increased in senescent fibroblasts even in the presence of nutrients.…”

“…The unresponsiveness of mTORC1/autophagy to serum starvation in senescence is associated with a number of mechanisms including changes in membrane potential which impacts on the formation of specialised immobile membrane projections called primary cilia (PC). Defects in PC formation supports elevated and persistent PI3K/Akt signalling and loss of TSC2 recruitment to the lysosome which in turn renders mTORC1 and autophagy insensitive to growth factor withdrawal . Work by others indicates that the interaction between PC, PC‐associated signalling, cell growth and senescence appear to be very closely related (Fig.…”

“…Equally, how this transcription factor may impact on p21‐mediated senescence or in oncogene‐induced senescence (OIS) remains to be seen. Although these reports indicate senescent and p16 + cells fail to form cilia, another report by Breslin et al . (2014) show increased frequency and length of PC in replicative senescent human fibroblasts due to loss of the PC‐inhibitory protein, CP110 .…”

“…It is possible that recruitment of such negative regulators to the plasma membrane and PC are perturbed in senescent cells and furthermore, it remains to be seen what the repercussions are for growth factor RTK/receptor localisation, activity or turnover in senescent cells with hypopolarised plasma membranes. Restoring membrane potential does not promote elongation of cilia to the length seen in control cells , indicating that while membrane potential is important there may be other mechanisms controlling PC formation, possibly including p16 expression and autophagy defects (see specific sections elsewhere in this review).…”