Senolytics improve physical function and increase lifespan in old age
Authors: Laura J Niedernhofer
Tamara Tchkonia
Mikolaj B Ogrodnik
Nathan K LeBrasseur
Megan M Weivoda
James L Kirkland
Xiaonan Hou
Ravinder J Singh
Paul D Robbins
Bettina M Weigand
Jordan D Miller
Yuji Ikeno
Keisuke Ejima
Vesna D Garovic
Jennifer L Onken
Kurt O Johnson
Gene B Hubbard
Larissa G P Langhi
Nino Giorgadze
Allyson K Palmer
Daniel G Fraser
David B Allison
Sundeep Khosla
S John Weroha
Moritz Weigl
Grace C Verzosa
Diana Jurk
Ming Xu
Hajrunisa Cubro
Christina L Inman
Tamar Pirtskhalava
Joshua N Farr
Christine M Hachfeld
Journal: Nature Medicine (2018)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Physical function; aging; cellular senescence; pathology; therapeutically targeted
Affiliations: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA. ., University of Connecticut Center on Aging, University of Connecticut Health, Farmington, CT, USA. ., Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA., Newcastle University Institute for Ageing and Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK., Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA., Department of Epidemiology & Biostatistics, School of Public Health, Indiana University-Bloomington, Bloomington, IN, USA., Nathan Shock Center on Comparative Energetics and Aging, University of Alabama at Birmingham, Birmingham, AL, USA., Barshop Institute for Longevity and Aging Studies and Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Geriatric Research Education and Clinical Center, South Texas Veterans Healthcare System, San Antonio, TX, USA., Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA., Department of Oncology, Mayo Clinic, Rochester, MN, USA., Department of Molecular Medicine, Center on Aging, Scripps Research Institute, Jupiter, FL, USA.

Abstract:  Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice. 

Retracted: No

PubPeer comments:
 Cannot repeat the data of Fig5C(5 animals each group), is there anyone also repeated this? also the D+Q diluting buffer is not mentioned clearly in this article. although many follow-up studies and even pushing onto clinical trial. **[Moderator: unfortunately, this comment is not allowed under our  no hearsay rule; please see our FAQ. Can you post publish your data somewhere? Figshare or even better a preprint? bioRxiv have a  Contradictory Results category.]** , 
 Pubpeer: This is rather funny. What were the comments and issues? There was a comment submitted and it is moderated. Why do you need to state that. We do not do this for journal manuscript submission. Journals never publish that this manuscript was submitted and rejected? Do they? If it is not up to the standards and do not follow your guidelines  just reject - no one will come to know. No one know what were the comments except you moderators. Very very disappointing. It defeats the purpose your tag line  Introducing Peeriodicals: where you are the editor in chief . , 
 #2 The link invites the commenter to improve their potentially interesting post by reading our FAQ. In particular, statements must be publicly verifiable. (Also, eLife is planning to publish reviews of rejected manuscripts, at least they say they plan to in the future.) ,