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Senolytics and the compression of late-life mortality

Lookup NU author(s): Dr Axel Kowald, Emeritus Professor Thomas Kirkwood


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© 2021. Senescent cells play an important role in mammalian ageing and in the etiology of age-related diseases. Treatment of mice with senolytics – drugs that selectively remove senescent cells – causes an extension of median lifespan but has little effect on maximum lifespan. Postponement of some mortality to later ages, without a corresponding increase in maximum mortality, can be termed ‘compression of mortality’. When we fit the standard Gompertz mortality model to the survival data following senolytic treatment, we find an increase in the slope parameter, commonly described as the ‘actuarial ageing rate’. These observations raise important questions about the actions of senolytic treatments and their effects on health and survival, which are not yet sufficiently understood. To explore how the survival data from senolytics experiments might be explained, we combine a recent exploration of the evolutionary basis of cellular senescence with theoretical consideration of the molecular processes that might be involved. We perform numerical simulations of senescent cell accumulation and senolytic treatment in an ageing population. The simulations suggest that while senolytics diminish the burden of senescent cells, they may also impair the general repair capacity of the organism, leading to a faster accumulation post-treatment of new senescent cells. Our results suggest a framework to address the benefits and possible side effects of senolytic therapies, with the potential to aid in the design of optimal treatment regimens.

Publication metadata

Author(s): Kowald A, Kirkwood TBL

Publication type: Article

Publication status: Published

Journal: Experimental Gerontology

Year: 2021

Volume: 155

Print publication date: 01/11/2021

Online publication date: 09/10/2021

Acceptance date: 04/10/2021

ISSN (print): 0531-5565

ISSN (electronic): 1873-6815

Publisher: Elsevier Inc.


DOI: 10.1016/j.exger.2021.111588


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