Targeting cellular senescence with senotherapeutics: senolytics and senomorphics

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158 Scopus citations

Abstract

The concept of geroscience is that since ageing is the greatest risk factor for many diseases and conditions, targeting the ageing process itself will have the greatest impact on human health. Of the hallmarks of ageing, cellular senescence has emerged as a druggable therapeutic target for extending healthspan in model organisms. Cellular senescence is a cell state of irreversible proliferative arrest driven by different types of stress, including oncogene-induced stress. Many senescent cells (SnCs) develop a senescent-associated secretory phenotype (SASP) comprising pro-inflammatory cytokines, chemokines, proteases, bioactive lipids, inhibitory molecules, extracellular vesicles, metabolites, lipids and other factors, able to promote chronic inflammation and tissue dysfunction. SnCs up-regulate senescent cell anti-apoptotic pathways (SCAPs) that prevent them from dying despite the accumulation of damage to DNA and other organelles. These SCAPs and other pathways altered in SnCs represent therapeutic targets for the development of senotherapeutic drugs that induce selective cell death of SnCs, specifically termed senolytics or suppress markers of senescence, in particular the SASP, termed senomorphics. Here, we review the current state of the development of senolytics and senomorphics for the treatment of age-related diseases and disorders and extension of healthy longevity. In addition, the challenges of documenting senolytic and senomorphic activity in pre-clinical models and the current state of the clinical application of the different senotherapeutics will be discussed.

Original languageEnglish (US)
JournalFEBS Journal
DOIs
StatePublished - Jan 11 2022

Bibliographical note

Funding Information:
The authors acknowledge members of the Niedernhofer and Robbins laboratory for discussion and input in the content of the manuscript. This work was supported by the NIH grants RO1 AG063543‐02S1, P01 AG043376, U19 AG056278, RO1 AG063543 and P01 AG062413, an Aligning Science Across Parkinson’s grant ASAP‐000592 from the Michael J. Fox Foundation and the Glenn Foundation for Medical Research Postdoctoral Fellowships in Aging Research.

Publisher Copyright:
© 2022 Federation of European Biochemical Societies

PubMed: MeSH publication types

  • Journal Article
  • Review
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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