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.

mTORC1 activity is supported by spatial association with focal adhesions

“…Second, if cells with fewer FAs have reduced mTORC1 activity, we reasoned that the opposite may also be true and that cells with more FAs would support increased mTORC1 activity. We have previously reported that constitutive activation of growth factor and mTORC1 signaling ( Carroll et al, 2017 ) is a defining feature of cellular senescence, a potent tumor suppressor mechanism that is further characterized by irreversible exit from the cell cycle and increased secretion of inflammatory factors ( Carroll and Korolchuk, 2018 ). Here, we show for the first time that senescent cells contain significantly more paxillin-positive FAs compared with proliferative cells ( Fig.…”

“…Mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that senses the levels of these growth-promoting cues. The current model postulates that activation of mTORC1 is driven by its translocation from the cytoplasm to the surface of late endosomes/lysosomes (Rabanal-Ruiz and Korolchuk, 2018). This association with endomembranes allows mTORC1 to sense amino acids transported from the extracellular environment as well as those derived by the degradation of proteins within lysosomes.…”

mTORC1 activity is supported by spatial association with focal adhesions

“…Secondly, if cells with fewer FAs have reduced mTORC1 activity, we reasoned that the opposite may also be true, and that cells with more FAs would support increased mTORC1 activity. We have previously reported that constitutive activation of growth factor and mTORC1 signaling 20 is a defining feature of cellular senescence, a potent tumor suppressor mechanism that is further characterized by irreversible exit from the cell cycle and increased secretion of inflammatory factors 21 . Here, we show for the first time that senescent cells contain significantly more paxillin-positive FAs compared to proliferative cells (Fig.…”

Emerging Dynamics of Macrophage Cellular Senescence and Immunosenescence in Governing Organismal Aging and Disease: Concepts and Opportunities

“…However, multiple studies have now confirmed that SC play a causal role in governing organismal aging and age-dependent disorders (Campisi and Robert, 2014;Childs et al, 2015;Katzir et al, 2021), and in fact, cellular senescence is established as one of the well-studied hallmarks of aging (López-Otín et al, 2013). Cellular senescence is characterized by cellular hypertrophy, permanent cell cycle arrest by the activation of cell cycle inhibitory pathways such as p53/p21 WAF1 and/or p16 Ink4a /pRb, resistance to apoptosis by deregulation of Bax/Bcl-2 signaling, telomere attrition, development of a senescence associated secretory phenotype or SASP, and altered metabolic longevity pathways such as SIRT and mTOR (Carroll and Korolchuk, 2018;Hernandez-Segura et al, 2018;Maduro et al, 2021;Kumari and Jat, 2021). The induction of cellular senescence is intimately linked to external and intrinsic stressors.…”