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The chemistry of senescence

Abstract

Senescence is a state of permanent cell cycle arrest. Cellular senescence can promote tissue remodelling but can negatively affect regenerative capacities of tissues and contribute to inflammation and the progression of cancer and ageing-related diseases. This Review highlights the chemical characteristics of senescence and how we can target senescent cells with small molecules to induce senescence in hyperproliferative tissues. Alternatively, these small molecules can also be administered to inhibit senescence or eliminate senescent cells as the basis of a promising strategy to treat ageing-related diseases. We also describe advances in detecting senescence in in vitro and in vivo models, such that we can evaluate response to treatments intended to induce or eliminate senescent cells.

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Fig. 1: Different types of cellular senescence.
Fig. 2: The molecular pathways involved in senescence cell cycle arrest.
Fig. 3: There are many ways to induce senescence.
Fig. 4: Senescence biomarkers.
Fig. 5: Senescent cells can be imaged by using synthetic probes.

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Acknowledgements

R.M. laboratory members thank the financial support from the Spanish Government (projects MAT2015-64139-C4-1-R, RTI2018-100910-B-C41 and AGL2015-70235-C2-2-R) and the Generalitat Valenciana (project PROMETEO 2018/024). B.L-T. and A.E. are grateful to the Spanish Ministry of Economy for their PhD grants (FPU15/02707 and FPU17/05454). M.R. was holder of a “la Caixa”-Severo Ochoa PhD scholarship. Work in the laboratory of M.S. was funded by IRB and by grants from the Spanish Ministry of Economy (MINECO, SAF), the European Research Council (ERC Advanced Grant) and by “la Caixa” Foundation. M.O. thanks the financial support from SAF2017-84689-R project and MINECO/AEI/FEDER, UE. The IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from the MINECO. The funders had no role in the design, data collection, decision to publish or preparation of the manuscript.

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All authors contributed equally to the preparation of this manuscript.

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Correspondence to Mar Orzáez or Manuel Serrano or Ramón Martínez-Máñez.

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Competing interests

The laboratory of R.M. and the laboratory of M.S. have had a research contract with Pfizer, Inc. on research not mentioned in this work. R.M. and M.S. are founders and shareholders of Senolytic Therapeutics, Inc. (USA) and Senolytic Therapeutics, S.L. (Spain). The remaining authors declare that they have no competing interests.

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Glossary

Telomeres

Regions at the ends of chromosomes that comprise repetitive DNA sequences. These regions protect the chromosome from deterioration and from the undesirable fusion with other chromosomes.

Oncogenes

Proto-oncogenes are genes that have various functions in cellular proliferation and differentiation. Activating mutations in these genes or an increased copy number give rise to what is known as oncogenes that stimulate uncontrolled cell proliferation contributing to cancer progression.

Tumour suppressor genes

Genes that inhibit uncontrolled cell division in normal cells. Mutations that inactivate or reduce the function of tumour suppressor genes increase the risk of cancer.

Spindle stress

The spindle apparatus is a cytoskeletal structure that separates the chromosomes into daughter cells during cell division. Oxidative stress, monopolar spindle 1 kinase inhibition or heat shock induce the deformation of spindles and trigger mitotic abnormalities.

Nucleolar stress

The nucleolus is a subnuclear compartment responsible for ribosome biogenesis. The nucleolus senses different stress signals and coordinates the activation of p53, a protein involved in cell cycle arrest, DNA repair and apoptosis

Natural killer cells

(NK cells). NK cells are lymphocytes of the innate immune system that kill cancer cells and cells infected by viruses.

Macrophages

These cells form part of the innate immune system. They are phagocytes that can detect, engulf and eliminate pathogens and apoptotic cells.

Neutrophils

These are the first white blood cells recruited to sites of inflammation. They are responsible for the phagocytosis of pathogens and the release of antimicrobial factors stored in their cytoplasmic granules.

CD4+ T lymphocytes

These cells function in the immune response by stimulating other immune cells to fight against infection.

CD8+ T lymphocytes

These cells (also known as cytotoxic T lymphocytes, CTLs) neutralize tumour and infected cells by injecting them with toxic enzymes, such as perforin and granzyme. They are commonly called CD8+, due to the presence of the CD8 membrane receptor which recognizes peptides of major histocompatibility complex (MHC) class I protein on infected cells.

B lymphocytes

White blood cells of the adaptive immune system responsible for the secretion of antibodies that recognize antigenic molecules of pathogens. They are also responsible for the presentation of antigens to T lymphocytes, the negative regulation of inflammatory responses and the regulation of responses to autoantigens.

Immune clearance

Elimination of microorganisms or various types of cells, such as senescent, infected or tumour cells, by the immune system.

Steatosis

The accumulation of extra fat in the liver, producing the disease that is also known as ‘fatty liver’.

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Lozano-Torres, B., Estepa-Fernández, A., Rovira, M. et al. The chemistry of senescence. Nat Rev Chem 3, 426–441 (2019). https://doi.org/10.1038/s41570-019-0108-0

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