Connecting autophagy to senescence in pathophysiology

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Cellular senescence is an extremely stable form of cell cycle arrest activated in response to stress. Autophagy, a lysosome-dependent cellular catabolic process, can also be triggered by cellular stresses. Both senescence and autophagy have been implicated in a similar range of pathophysiologies, including cancer, aging and age-related symptoms. Senescence is a heterogeneous phenotype that is composed of multiple effector mechanisms and autophagy was recently identified as a new effector of senescence. Autophagy seemingly has different impacts on cells responding to stress through a diversity of effects: recycling of metabolic waste, cell survival and protein expression regulation.

Introduction

Macroautophagy (simply referred to as autophagy hereafter) is a genetically regulated, and evolutionarily conserved, program characterised by the formation of double-membrane cytosolic vesicles, autophagosomes, which sequester cytoplasmic content and deliver it to lysosomes [1]. Autophagy plays a constitutive and basally active role in the quality control of proteins/organelles and in the maintenance of energy homeostasis. It is also involved in innate and adaptive immune responses against pathogens [2]. In addition, autophagy can be upregulated to deal with metabolic or other cytotoxic stress conditions. However the precise role of autophagy as a stress response is unclear. Autophagy can modulate cell viability under stress conditions and recent evidence links autophagy to another stress response, cellular senescence [3••, 4••, 5•]. Functional links between these two phenotypes are limited, even though they seem to share some conceptual aspects: both can be alternative phenotypes to apoptosis in some contexts and both are implicated in similar pathophysiologies, such as cancer and aging. Here we discuss the relationship between senescence and autophagy and the relevance of this new link to cancer and aging.

Section snippets

Cellular senescence

The term senescence originally described the ‘irreversible’ state of cell cycle arrest induced by the replicative exhaustion of human diploid fibroblasts (HDFs) in culture, in marked contrast to the readily reversible quiescent state [6]. This ‘replicative exhaustion’ is now attributed to the limits imposed by critically short telomeres, which provoke a persistent DNA damage response and genomic instability [6]. It has since been shown, however, that senescence can occur acutely upon

Autophagy and senescence

Potential cell fates in response to cytotoxic stress include apoptosis and senescence depending on the context, such as the cell/tissue type and the genetic background. The same range of stresses that trigger apoptosis/senescence can also trigger autophagy. Stress-responsive autophagy (either metabolic or genotoxic) can have a survival effect, whereas in certain contexts, autophagy has also been shown to be a cell death mechanism (type II cell death; apoptosis as type I cell death), although

Autophagy as an effector mechanism of senescence

Does autophagy actively contribute to the process of senescence, rather than just cleaning up metabolic waste? Senescence is a progressive phenotype, but the process can be very acute and dynamic, particularly for OIS. The initial abnormal mitotic events caused by gain-of-function mutations in oncogenes (e.g. ras) or loss-of-function mutations in tumour suppressor genes (e.g. PTEN) form tumours where pro-senescence effectors are triggered to fight against the tumorigenic activities. This

Autophagy and the secretory phenotype of senescence

It has long been known that senescent cells secrete large amounts of proteins, some of which, including metalloproteases and plasminogen activator inhibitor 1, have been used as markers of senescence [7, 27]. In addition to influencing the extracellular microenvironment, a recent series of seminal studies showed that the secreted proteins reinforce the senescence phenotype in both an autocrine and paracrine manner, establishing the senescence-associated secretory phenotype (SASP) as a new

Negative feedback on mTOR activity during senescence

Ras can activate the PI3K pathway, which results in activation of mTOR complex 1 (mTORC1), a negative regulator of autophagosome formation. How is autophagy then activated during Ras-senescence? One candidate is a recently identified effector mechanism of OIS, negative feedback signalling on the PI3K pathway (Figure 1) [29••]. Courtois-Cox et al. identified that excessively active Ras and its downstream effector Raf induce a global negative feedback response in the Ras/PI3K pathway. Indeed in

Revisiting SA-β-gal

The most widely used marker of senescence, both in cells and animals, is an accumulation of senescence-associated β-galactosidase (SA-β-gal) activity, which is optimal at acidic pH. SA-β-gal had been a mysterious marker for a long time, since its empirical identification [37], but it was recently shown to be the activity of a lysosomal enzyme, GLB1, although its functional relevance in senescence is still unclear [38]. The autophagic protein degradation machinery consists of two arms,

Senescence, aging, and autophagy

Senescence has often been described as a cellular counterpart of organismal aging [39]. Cells derived from older people or premature aging syndrome patients become senescent earlier in culture than those from young/healthy people. However, there had not been any evidence for a causative effect of senescence on aging until recently [40]. A series of important studies identified the age-dependent accumulation of senescent cells in tissue stem/progenitor cell compartments in different organs,

Conclusions

Different triggers, including basal fluctuation cues, as well as metabolic and genotoxic stresses, activate autophagy and its impact on the cells and microenvironment seems to vary in conjunction with the cellular and environmental conditions. The emerging link between autophagy and senescence provides a new layer to consider. Bulk protein degradation under cytotoxic stresses can contribute to the maintenance of cellular integrity, which shifts the cell fate from apoptosis to senescence. It is

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank Masako Narita and Jean-Yves Thuret for critical reading of the manuscript and Laura Blackburn for editing.

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