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The role of cellular senescence in ageing and endocrine disease

Abstract

With the ageing of the global population, interest is growing in the ‘geroscience hypothesis’, which posits that manipulation of fundamental ageing mechanisms will delay (in parallel) the appearance or severity of multiple chronic, non-communicable diseases, as these diseases share the same underlying risk factor — namely, ageing. In this context, cellular senescence has received considerable attention as a potential target in preventing or treating multiple age-related diseases and increasing healthspan. Here we review mechanisms of cellular senescence and approaches to target this pathway therapeutically using ‘senolytic’ drugs that kill senescent cells or inhibitors of the senescence-associated secretory phenotype (SASP). Furthermore, we highlight the evidence that cellular senescence has a causative role in multiple diseases associated with ageing. Finally, we focus on the role of cellular senescence in a number of endocrine diseases, including osteoporosis, metabolic syndrome and type 2 diabetes mellitus, as well as other endocrine conditions. Although much remains to be done, considerable preclinical evidence is now leading to the initiation of proof-of-concept clinical trials using senolytics for several endocrine and non-endocrine diseases.

Key points

  • The ‘geroscience hypothesis’ posits that manipulation of fundamental ageing mechanisms will delay the appearance or severity of multiple chronic diseases because these diseases share the same underlying risk factor — namely, ageing.

  • Cellular senescence is a fundamental ageing mechanism that can contribute to or cause age-related phenotypes as well as multiple diseases, including endocrine disease, even in younger individuals (aged <40 years).

  • Some senescent cells, which accumulate with ageing, develop a proinflammatory, tissue-destructive and stem cell-disrupting or progenitor cell-disrupting senescence-associated secretory phenotype (SASP), which can spread senescence to nearby and distant non-senescent cells.

  • Senolytic agents have been discovered that selectively eliminate senescent cells by transiently disabling the survival pathways (senescent cell antiapoptotic pathways) that protect senescent cells against their own SASP.

  • Preclinical studies suggest that senolytics hold promise for delaying, preventing or treating many age-associated disorders.

  • Despite the growing experimental support for targeting cellular senescence to treat multiple age-associated diseases simultaneously, carefully conducted clinical trials in humans are needed to better define the benefits and risks of senolytic drugs.

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Fig. 1: The central role of ageing in chronic diseases.
Fig. 2: Nine fundamental hallmarks of ageing.
Fig. 3: Causes and consequences of cellular senescence.
Fig. 4: The effects of antiresorptive versus senolytic therapies on bone metabolism.

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Acknowledgements

The authors acknowledge the support of the US National Institutes of Health through grants AG062413 (project 1, J.L.K.; project 2, S.K., J.N.F.), AG004875 (S.K.), AR027065 (S.K.), AR070241 (J.N.F.) and AG013925 (J.L.K.), the Translational Geroscience Network (AG061456; J.L.K.), Robert and Arlene Kogod, the Connor Group (J.L.K.), Robert J. and Theresa W. Ryan (J.L.K.) the Ted Nash Long Life Foundation (J.L.K.) and the Noaber Foundation (J.L.K.).

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The authors contributed equally to all aspects of the article.

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Correspondence to Sundeep Khosla or James L. Kirkland.

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T.T. and J.L.K. have a financial interest related to this research. Patents on senolytic drugs are held by Mayo Clinic. Mayo Clinic has licensed patents on dasatinib and quercetin as senolytics to Unity Biotechnology. This research was reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic conflict of interest policies. All other authors declare no competing interests.

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Nature Reviews Endocrinology thanks L. Hofbauer, D. Towler and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Damage-associated molecular patterns

Extracellular nucleotides, other cellular debris or proteins that are released by damaged cells (for example, HMGB1).

Pathogen-associated molecular patterns

Factors released by viral, fungal or bacterial pathogens.

Warburg shift

The preferential utilization of glycolysis rather than oxidative phosphorylation by a cell.

Lipofuscin

Lipid-containing pigment granules found in cells and associated with ageing.

Senescence-associated distension of satellites

(SADS). The distention of satellite DNA found in senescent cells.

Myeloproliferative syndrome

Disorders of bone marrow and blood associated with the clonal proliferation of cells that may progress to leukaemia.

Koch’s postulates

A set of criteria used to establish the cause of a disease.

Hypertrophic obesity

Refers to enlarged adipocytes, typically found in abdominal obesity.

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Khosla, S., Farr, J.N., Tchkonia, T. et al. The role of cellular senescence in ageing and endocrine disease. Nat Rev Endocrinol 16, 263–275 (2020). https://doi.org/10.1038/s41574-020-0335-y

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