Connecting autophagy to senescence in pathophysiology
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.
References (59)
- et al.
Oncogene-induced senescence as an initial barrier in lymphoma development
Nature
(2005) - et al.
Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication
Nature
(2006) - et al.
The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence
Genes Dev
(2007) - et al.
Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network
Cell
(2008) - et al.
Life, death and burial: multifaceted impact of autophagy
Biochem Soc Trans
(2008) - et al.
Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis
Nature
(1986) - et al.
Protein synthesis upon acute nutrient restriction relies on proteasome function
Science
(2005) - et al.
A biomarker that identifies senescent human cells in culture and in aging skin in vivo
Proc Natl Acad Sci U S A
(1995) - et al.
Cellular senescence and organismal aging
Mech Ageing Dev
(2008) - et al.
Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a
Nature
(2006)
Aging: central role for autophagy and the lysosomal degradative system
Ageing Res Rev
Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice
Nature
Autophagy fights disease through cellular self-digestion
Nature
Eating the enemy within: autophagy in infectious diseases
Cell Death Differ
Autophagy mediates the mitotic senescence transition
Genes Dev
Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3
EMBO J
Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells
Am J Physiol Heart Circ Physiol
Hayflick, his limit, and cellular ageing
Nat Rev Mol Cell Biol
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Cell
Tumour biology: senescence in premalignant tumours
Nature
Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis
Nature
BRAFE600-associated senescence-like cell cycle arrest of human naevi
Nature
Deregulated E2F activity induces hyperplasia and senescence-like features in the mouse pituitary gland
Mol Cell Biol
Cellular senescence in vivo: a barrier to tumorigenesis
Curr Opin Cell Biol
Cellular senescence and chromatin organisation
Br J Cancer
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Cell
Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA
Dev Cell
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints
Nature
Chemokine signaling via the CXCR2 receptor reinforces senescence
Cell
Cited by (69)
Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth
2024, Metabolism: Clinical and ExperimentalRole of astrocyte senescence regulated by the non– canonical autophagy in the neuroinflammation associated to cerebral malaria
2024, Brain, Behavior, and ImmunityThe establishment of mitotic errors-driven senescence depends on autophagy
2023, Redox BiologyCellular senescence as a response to multiwalled carbon nanotube (MWCNT) exposure in human mesothelial cells
2021, Mechanisms of Ageing and DevelopmentGlucose restriction delays senescence and promotes proliferation of HUVECs via the AMPK/SIRT1-FOXA3-Beclin1 pathway
2020, Experimental Gerontology