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Cellular senescence in ageing: from mechanisms to therapeutic opportunities

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Abstract

Cellular senescence, first described in vitro in 1961, has become a focus for biotech companies that target it to ameliorate a variety of human conditions. Eminently characterized by a permanent proliferation arrest, cellular senescence occurs in response to endogenous and exogenous stresses, including telomere dysfunction, oncogene activation and persistent DNA damage. Cellular senescence can also be a controlled programme occurring in diverse biological processes, including embryonic development. Senescent cell extrinsic activities, broadly related to the activation of a senescence-associated secretory phenotype, amplify the impact of cell-intrinsic proliferative arrest and contribute to impaired tissue regeneration, chronic age-associated diseases and organismal ageing. This Review discusses the mechanisms and modulators of cellular senescence establishment and induction of a senescence-associated secretory phenotype, and provides an overview of cellular senescence as an emerging opportunity to intervene through senolytic and senomorphic therapies in ageing and ageing-associated diseases.

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Fig. 1: Senescence drivers and phenotypes.
Fig. 2: SASP regulation.
Fig. 3: Biological consequences of cell senescence.
Fig. 4: Senolytic therapeutic interventions.
Fig. 5: Senomorphic therapeutic interventions.

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Acknowledgements

R.D.M. is supported by Telethon (TIGET grant E5), a Career Development Award from the Human Frontier Science Program, an Advanced Research Grant from the European Haematology Association, “Pilot and Seed Grant 2015” from San Raffaele Hospital, a Hollis Brownstein Research Grant from the Leukemia Research Foundation, the Interstellar Initiative on Healthy Longevity of the New York Academy of Sciences and the Japan Agency for Medical Research and Development, and the Italian AIRC under MFAG 2019, ID. 23321 project PI Di Micco Raffaella. V.K. is supported by grants from the European Research Council under the European Union’s Seventh Framework Proframme (309688) and under Horizon 2020 (856487), from the Israel Science Foundation (634-15; 2633-17), from the Israel Ministry of Health, Minerva Center “Ageing, from Physical Materials to Human Tissues”, and from the Sagol Institute for Longevity Research. V.K. is an incumbent of the Georg F. Duckwitz Professorial Chair. D.B. is supported by the Ellison Medical Foundation, the Glenn Foundation for Medical Research, the US National Institutes of Health (R01AG053229 and R01AG068076), the Mayo Clinic Children’s Research Center, the Alzheimer’s Disease Research Center at Mayo Clinic and the Cure Alzheimer’s Fund. F.d’A.d.F. is supported by AIRC (application 12971), Fondazione Telethon (GGP17111), PRIN 2015, the InterOmics Project, the AMANDA project Accordo Quadro Regione Lombardia-CNR, a European Research Council advanced grant (322726), a European Research Council proof-of-concept grant (875139), AriSLA (project “DDRNA and ALS”), the AIRC Special Program 5 per mille metastases (Project-21091) and the European Joint Programme on Rare Diseases (EJP RD).The authors apologize for not being able to cite all the important contributions of their colleagues owing to space limitations.

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The authors contributed equally to the writing and revision of the article.

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Correspondence to Raffaella Di Micco or Fabrizio d’Adda di Fagagna.

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D.B. is a co-inventor on patent applications licensed to or filed by Unity Biotechnology, a company developing senolytic medicines, including small molecules that selectively eliminate senescent cells. Research in the Baker laboratory has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic conflict of interest policies. V.K. is a co-inventor on patent applications in the field of senolytics, some of which are licensed to Sentaur Bio. F.d’A.d.F. is among the inventors on patent applications for the use of antisense oligonucleotides to target DNA damage-induced transcripts. R.D.M. declares no competing interests.

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Glossary

INK-ATTAC

Transgenic mouse model with drug-inducible caspase 8 under the control of a minimal p16 promoter element active in senescent cells to allow selective elimination of p16-expressing senescent cells.

p16-3MR

Transgenic mouse model expressing a trimodal reporter of red fluorescent protein, luciferase and herpes simplex virus thymidine kinase under the control of the p16 promoter to allow tracking and elimination of p16-expressing senescent cells.

Sirtuins

Nicotinamide dinucleotide (NAD+)-dependent deacylases that regulate diverse cellular processes, including DNA repair, inflammation, metabolism and ageing.

Mitochondrial dysfunction-associated senescence

(MiDAS). Mitochondrial damage triggers senescence with a distinct secretory phenotype that lacks IL-1-dependent inflammation.

Exosomes

Extracellular vesicles produced by the endosomal compartment involved in intercellular communication.

HMGB proteins

Non-histone molecules that bind DNA and affect chromatin compaction.

Myeloid skewing

An age-related proportional increase in myeloid cells at the expense of other lineages as observed in the bone marrow and blood.

tau

A protein found in neurons that is important for maintaining microtubule structure in axons. Mutants and hyperphosphorylated forms are found in a variety of neurodegenerative diseases, including Alzheimer disease.

Fibrosis

Pathological accumulation of extracellular matrix in diseases tissue that limits normal tissue function and leads to long-term tissue scaring.

LDL receptor

Mediates entry of LDL into cells. Mutations in the gene encoding this receptor predispose to the development of atherosclerosis.

Cataracts

Clouding of the lens in the eye leading to inability to have clear vision. Surgical intervention to replace diseased lenses is a common medical procedure in aged humans.

Lordokyphosis

Abnormal rearward curvature of the spine, observed both in laboratory mice and in humans.

Lipodystrophy

Abnormal distribution of adipose tissue in the body, can refer to both excessive or insufficient deposition.

HSP90

A molecular chaperone that promotes proper protein folding and degradation, which also contributes to heat stress resilience.

Prodrugs

Compounds that are metabolized into an active drug to modify drug bioavailability and activity.

Perforin

A pore forming protein expressed in cytotoxic T cells and natural killer cells. When these cells execute cytotoxicity, they secrete granules containing perforin, which binds to the target cell’s membrane and forms pores on the target cell in order to allow cytotoxicity.

Chimeric antigen receptor T (CAR T) cells

T cells that have been genetically engineered to express T cell receptor developed to bind a defined target in order to eliminate the cells that have the target on their membrane.

PD1

A protein expressed on the cell surface that inhibits the ability of the immune system to target the cells that express the protein. Inhibition of interaction of PD1 with its ligand is a potent immunotherapy approach.

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Di Micco, R., Krizhanovsky, V., Baker, D. et al. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol 22, 75–95 (2021). https://doi.org/10.1038/s41580-020-00314-w

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