Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span

Paul D. Robbins, Diana Jurk, Sundeep Khosla, James L. Kirkland, Nathan K. Lebrasseur, Jordan D. Miller, João F. Passos, Robert J. Pignolo, Tamar Tchkonia, Laura J. Niedernhofer

Research output: Contribution to journalReview articlepeer-review

2 Scopus citations

Abstract

Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics.

Original languageEnglish (US)
Pages (from-to)779-803
Number of pages25
JournalAnnual review of pharmacology and toxicology
Volume61
DOIs
StatePublished - Jan 6 2021

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grants P01 AG062412 ( J.L.K., T.T., S.K., N.K.L., P.D.R., R.J.P., L.J.N.) P01 AG043376 (P.D.R., L.J.N.), R01 AG063543 (L.J.N.), R56 AG059676 (L.J.N.), R56 AG059675 (P.D.R.), U19 AG056278 (P.D.R., L.J.N.), R33 AG062018 ( J.L.K., T.T., S.K., N.K.L., P.D.R., R.J.P., L.J.N.), R01 AG068048 ( J.F.P., D.J., J.L.K.), and R37 AG 013925 ( J.L.K., T.T.), R01 AG069048 ( J.F.P.), UL1 TR0002377 (NCATS, J.F.P.); Medical Discovery Team Biology of Aging (L.J.N., P.D.R.); the Robert and Arlene Kogod Center on Aging ( J.L.K., T.T., D.J., S.K., N.K.L., J.D.M., J.F.P., R.J.P.); the Connor Group ( J.L.K., T.T.); Robert J. and Theresa W. Ryan ( J.L.K., T.T., J.D.M.); Ted Nash Long Life Foundation ( J.F.P.); and the Noaber Foundation ( J.L.K., T.T.). The authors would like to thank Drs. Rajesh Vyas, Lei Zhang, and Carolina Soto-Palma for providing figures and Mariah Witt and Makenna Ash for carefully proofreading an earlier draft of this article.

Publisher Copyright:
© 2021 by Annual Reviews. All rights reserved.

Keywords

  • aging
  • senescence
  • senescence-associated secretory phenotype
  • senolytics
  • senomorphics

PubMed: MeSH publication types

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

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