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Cellular senescence: from physiology to pathology

Key Points

  • Cellular senescence is a process that is mainly designed to eliminate unwanted cells by inducing tissue remodelling.

  • In general, cellular senescence promotes tissue remodelling through three sequential processes: a stable proliferative arrest; a secretory phenotype (SASP) that recruits immune cells and modifies the extracellular matrix; and the mobilization of nearby progenitors that repopulate the tissue. We refer to this sequence of events as the senescence–clearance–regeneration model.

  • During normal embryonic development, cellular senescence contributes to tissue remodelling and morphogenesis by the elimination of transient structures and by regulating the relative abundance of different cell populations.

  • Senescence is also activated upon cellular damage as a defence mechanism. In the case of oncogenic damage, senescence limits tumour progression. Following tissue damage, senescence coordinates tissue remodelling, thereby participating in multiple pathologies, including fibrotic diseases, vascular disorders, obesity, type 2 diabetes, renal diseases and sarcopenia.

  • In these pathologies, cellular senescence usually has antagonistic roles. Initially, it functions to limit the fibrotic response (by inducing senescence in the damaged cells and in the activated fibroblasts), and it also triggers an immune response that clears the damaged cells. However, at advanced pathological stages, senescent cells are not efficiently removed but accumulate and contribute to aggravate the pathological manifestations.

  • Both pro-senescent and antisenescent approaches can be desirable depending on the therapeutic context. Pro-senescent therapies can be useful for cancer treatment and for ongoing tissue repair processes, whereas antisenescent therapies can be beneficial to eliminate the burden of senescent cells associated with stabilized fibrotic scars that accumulate during ageing or chronic damage.

  • Proof of principle for pro-senescent and antisenescent therapies is discussed.

Abstract

Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events — senescence, followed by clearance and then regeneration — may not be efficiently completed in aged tissues or in pathological contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro-senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.

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Figure 1: Molecular pathways of senescence.
Figure 2: Location of senescence in development and in adult diseases.
Figure 3: Unified model of senescence.

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Acknowledgements

D.M.-E. has been funded by the Juan de la Cierva Programme. Work in the laboratory of M.S. is funded by the Spanish National Cancer Research Centre (CNIO), by grants from the European Research Council (Advanced ERC Grant), the Framework Programme 7 of the European Union (RISK-IR), the Spanish Ministry of Economy (SAF), the Regional Government of Madrid, the Botín Foundation, the Ramón Areces Foundation and the AXA Foundation.

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Paracrine

Refers to a mode of signalling in which the cell responding to a signalling molecule is near the cell secreting the molecule.

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Activation of cellular receptors by ligands produced by the same cell.

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Muñoz-Espín, D., Serrano, M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15, 482–496 (2014). https://doi.org/10.1038/nrm3823

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