Nutrient sensing, growth and senescence

Abstract

Cell growth is dictated by a wide range of mitogenic signals, the amplitude and relative contribution of which vary throughout development, differentiation and in a tissue-specific manner. The ability to sense and appropriately respond to changes in mitogens is fundamental to control cell growth, and reduced responsiveness of nutrient sensing pathways is widely associated with human disease and ageing. Cellular senescence is an important tumour suppressor mechanism that is characterised by an irreversible exit from the cell cycle in response to replicative exhaustion or excessive DNA damage. Despite the fact that senescent cells can no longer divide, they remain metabolically active and display a range of pro-growth phenotypes that are supported in part by the mTORC1-autophagy signalling axis. As our understanding of the basic mechanisms of controlling mTORC1-autophagy activity and cell growth continues to expand, we are able to explore how changes in nutrient sensing contribute to the acquisition and maintenance of cellular senescence. Furthermore, while the protective effect of senescence to limit cellular transformation is clear, more recently, the age-related accumulation of these pro-inflammatory senescent cells has been shown to contribute to a decline in organismal fitness. We will further discuss whether dysregulation of nutrient sensing pathways can be targeted to promote senescent cell death which would have important implications for healthy ageing.

Keywords: ageing; autophagy; growth; mTORC1; membrane potential; primary cilia; senescence.

Figure 1

Dysregulation of growth factor sensing to mTORC1 and autophagy in senescence. In proliferating cells, growth factor removal induces cilia growth which downregulates growth factor signalling, mTORC1 and expression of cell cycle inhibitor p16. In senescent cells, cilia formation is abnormal (lack of elongation or increased length) which is a result of plasma membrane hypopolarisation, p16 or reduced CP110 (negative regulator of cilium growth) expression. As a result, PI3K/Akt signalling to mTORC1 is persistent and starvation fails to induce autophagy. Persistent growth factor and mTORC1 signalling may contribute to SASP. Red text indicates proteins/complexes that are downregulated in senescence; Blue text indicates that the activity of protein/complexes is upregulated in senescence.

Figure 2

Senescence‐associated changes in the autophagosome–lysosome pathway. Senescent cells are characterised by increased numbers of autophagosomes and lysosomes, increasing flux through the pathway. This increases the generation of intracellular amino acids and supports activity of mTOR pathway. At the same time, selective autophagy pathways such as mitophagy may be suppressed in senescence. Some of the factors potentially leading to these changes in senescence are indicated. See text for further details.