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Senescent cells: an emerging target for diseases of ageing

Key Points

  • Cellular senescence is a tumour-suppressive fate by which damaged cells permanently withdraw from the cell cycle and acquire a distinct secretome.

  • A variety of age-related diseases as well as beneficial, normal processes have been linked to either senescence arrest or to factors released in the senescent cell (SNC) secretome in recent years.

  • Evidence for a potential role of SNCs in major diseases, including osteoarthritis, atherosclerosis and cancer, has sparked interest in the development of senotherapies, treatments aimed at neutralizing the disease-causing features of SNCs.

  • One main senotherapeutic strategy is senolysis in which drugs (senolytics) are used to specifically and efficiently kill SNCs. First-generation senolytics generally act by inhibiting pro-survival adaptations that SNCs use to resist apoptosis and have shown efficacy against atherosclerosis, osteoarthritis and other age-related diseases.

  • Inhibition of the senescence-associated secretory phenotype (SASP) may be another useful senotherapy, but — in contrast to senolysis — this would likely require continuous dosing, whereas SNC killing could be carried out intermittently.

  • Senotherapy is a promising new approach to treating age-related diseases, but successfully translating this to the clinic will require new methods for evaluating SNC burden in humans, a clear mechanistic understanding of the link between senescence and disease and proof that senotherapy is safe.

Abstract

Chronological age represents the single greatest risk factor for human disease. One plausible explanation for this correlation is that mechanisms that drive ageing might also promote age-related diseases. Cellular senescence, which is a permanent state of cell cycle arrest induced by cellular stress, has recently emerged as a fundamental ageing mechanism that also contributes to diseases of late life, including cancer, atherosclerosis and osteoarthritis. Therapeutic strategies that safely interfere with the detrimental effects of cellular senescence, such as the selective elimination of senescent cells (SNCs) or the disruption of the SNC secretome, are gaining significant attention, with several programmes now nearing human clinical studies.

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Figure 1: Timeline of milestones relevant to senotherapy.
Figure 2: Hallmarks of SNCs.
Figure 3: Preclinical testing of senolytic candidates.

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Acknowledgements

The authors thank N.David and Y.Poon of Unity Biotechnology for invaluable intellectual contributions to this Review and for thoroughly editing the text, and C.Yohn for feedback on the manuscript. The writing of this Review was supported by a grant from the Paul F.Glenn Foundation (J.M.v.D. and D.J.B.) and US National Institutes of Health (NIH) grants R01CA96985 and CA168709 (J.M.v.D.).

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Correspondence to Jan M. van Deursen.

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Competing interests

J.M.v.D. is a cofounder of Unity Biotechnology, which is a company developing senolytic medicines, including small molecules that selectively eliminate senescent cells. R.M.L., J.M.v.D., D.J.B. and B.G.C. are co-inventors on patent applications licensed to or filed by Unity Biotechnology. R.M.L., J.D. and D.M. are employed by Unity Biotechnology.

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Glossary

Senolysis

The therapeutic killing of senescent cells using small molecules (also known as senolytics).

Senescence

A tumour-suppressive cell fate undertaken in response to irreparable damage. It is characterized by permanent withdrawl from the cell cycle and acquisition of a pro-inflammatory, proteolytic secretome.

Senotherapies

Therapeutic strategies that aim to neutralize the deleterious effects of senescent cells as a treatment for age-related diseases.

Senescence-associated β-galactosidase

(SA-β-Gal). A lysosomal hydrolase with optimal activity at pH 6.0 in senescent cells (SNCs). Detection of SA-β-Gal enzymatic activity is frequently used to stain SNCs in vitro and in vivo.

Cyclin-dependent kinase inhibitor

(CDKi). A protein that arrests the cell cycle by binding to and deactivating cyclin-dependent kinases. p16INK4A, p19ARF, and p21 belong to this class of proteins and are commonly used as senescence markers.

Senescence-associated secretory phenotype

(SASP). The suite of secreted factors produced by senescent cells, including metalloproteinases, cytokines, chemokines, and growth factors, as well as non-protein metabolites.

Cytokines

Secreted protein factors that act as ligands for receptor- mediated cell signalling.

Chemokines

Cytokines, such as monocyte chemotactic protein 1 (MCP1), promote cellular migration (also known as chemotaxis).

BCL-2 family members

A protein class that consists of 25 members that share B cell lymphoma 2 (BCL-2) homology domains. These proteins either inhibit or promote mitochondrion-mediated apoptosis. BCL-2, BCL-W, and BCL-XL are three anti-apoptotic members that are inhibited by the senolytic and chemotherapeutic compound navitoclax.

High-mobility group box 1

(HMGB1). A member of a class of non-histone, chromatin proteins that modify transcription by binding to and distorting DNA. HMGB1 is released from senescent cells as an inflammatory 'alarmin'. Another member, HMGB2, is a positive regulator of senescence-associated secretory phenotype (SASP) factor transcription.

Metalloproteinases

A group of enzymes that cleave a peptide bond through the catalytic action of a coordinated metal ion (often zinc).

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Childs, B., Gluscevic, M., Baker, D. et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov 16, 718–735 (2017). https://doi.org/10.1038/nrd.2017.116

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