ABSTRACT
Cellular senescence has recently been established as a key driver of organismal ageing. The state of senescence is controlled by extensive rewiring of signalling pathways, at the heart of which lies the mammalian Target of Rapamycin Complex I (mTORC1). Here we discuss recent publications aiming to establish the mechanisms by which mTORC1 drives the senescence program. In particular, we highlight our data indicating that mTORC1 can be used as a target for senescence cell elimination in vitro. Suppression of mTORC1 is known to extend lifespan of yeast, worms, flies and some mouse models and our proof-of-concept experiments suggest that it can also act by reducing senescent cell load in vivo.
INTRODUCTION
Cellular senescence is a potent tumour suppressor mechanism that also plays an important role in wound healing and development. There is evidence, particularly in mouse models that it can however turn from protector to antagonist with increasing age when these metabolically active cells accumulate in tissues (de Magalhaes and Passos 2018). Replicative exhaustion, DNA damage, excessive stress and oncogene activation can all activate the senescence program, resulting in an irreversible exit from the cell cycle. Senescence is characterised by an increase in cell size, increased organelle content and a robust senescence-associated secretory phenotype (SASP). The accumulation of senescent cells within a number of tissues including lung (Birch et al. 2015), muscle (Sousa-Victor et al. 2014), liver (Ogrodnik et al. 2017) and bone (Farr et al. 2017) is associated with reduced tissue regeneration capacity, function and integrity. Moreover the inflammatory environment mediated by SASP has been intimately linked with driving gross tissue changes such as fibrosis (Schafer et al. 2018) and increased risk of cellular transformation via the so-called bystander effect (Schosserer et al. 2017; Rao and Jackson 2016). Seminal work from the Mayo Clinic demonstrated that clearance of p16/Ink4a positive cells (a marker of senescence) can improve age-related pathologies and lengthen healthy lifespan in wild-type and progeroid mice (Baker et al. 2011; Baker et al. 2016). Others have further demonstrated the health benefits of removing senescent cells in mouse models, including an improvement in post-trauma tissue regeneration and alleviating chemotherapy-associated fatigue (Jeon et al. 2017; Demaria et al. 2017). This latter report further described that T cell p16/Ink4a expression in humans correlates with severity of chemotherapy drug toxicity indicating their clearance could be therapeutically beneficial. Due to the economic, social and medical burden of ageing in the Western world, the need to find interventions to improve healthspan is fundamentally important. Understanding more about the mechanisms driving and maintaining senescence and senescence-associated phenotypes may support the identification of targeted, safe interventions to meet this ultimate goal.
The central role of the mammalian target of rapamycin complex 1 (mTORC1) in driving senescence-associated phenotypes including SASP and increased mitochondrial content has been comprehensively established (Korolchuk et al. 2017; Lopez-Otin et al. 2013; Correia-Melo. et al. 2018). Further to this, we recently demonstrated that mTORC1 dependency may represent a targetable vulnerability in senescent cells that could be used to eliminate them (Carroll et al. 2017). mTORC1 is a master regulator of cell growth, the activity of which is tightly controlled by the balance between mitogenic and stress signals. Some of the most potent activators of mTORC1 are growth factors and amino acids which work at least in part to control the localisation and thus activation of the mTORC1 complex on the lysosome/late endosome surface. It is on the lysosomal surface that mTORC1 can ‘sense’ changes in amino acids and growth factors via a huge number of regulatory proteins and complexes including the Rag-Ragulator complexes and Tuberous Sclerosis Complex (TSC) (Carroll and Dunlop 2017; Wolfson and Sabatini 2017; Ben-Sahra and Manning 2017). In its active form, mTORC1 drives protein translation, lipid and nucleotide synthesis as well as inhibiting the catabolic process of autophagy to support cell growth and metabolism. During periods of limiting nutrient availability, mTORC1 is switched off and autophagy activity increases to sequester cytoplasmic material and deliver it to the lysosomes for degradation. Liberation of the resulting free amino acids, lipids and carbohydrates from the lysosome supports cell survival (Carroll et al. 2015).
Senescent cells undergo dramatic rewiring of these pro-growth and scavenging mechanisms that drive their increased metabolism and survival (Carroll et al. 2017; Narita et al. 2011). In particular we recently demonstrated that mTORC1 activity is resistant to starvation of amino acids and growth factors in senescence which prevents starvation-induced activation of autophagy (Carroll et al. 2017). Mechanistically, the basal expression of autophagy and lysosome proteins is grossly elevated in senescence and this may contribute to increased levels of intracellular amino acids which activate mTORC1 and render it insensitive to the availability of exogenous nutrients. Thus senescence results in a unique re-equilibrium between mTORC1 and autophagy (Carroll et al. 2017; Carroll and Korolchuk 2018). We identified that this can be targeted to kill senescent cells; treatment with lysosome inhibitors or Torin1 in the absence of exogenous nutrients selectively causes senescent cell death in vitro (Carroll et al. 2017).
Source: https://link.springe...522-019-09802-9
