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Senolytics Improve Physical Function and Increase Lifespan in Old Age

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 targeted therapeutical...

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Autores principales: Xu, Ming, Pirtskhalava, Tamar, Farr, Joshua N., Weigand, Bettina M., Palmer, Allyson K., Weivoda, Megan M., Inman, Christina L., Ogrodnik, Mikolaj B., Hachfeld, Christine M., Fraser, Daniel G., Onken, Jennifer L., Johnson, Kurt O., Verzosa, Grace C., Langhi, Larissa G. P., Weigl, Moritz, Giorgadze, Nino, LeBrasseur, Nathan K., Miller, Jordan D., Jurk, Diana, Singh, Ravinder J., Allison, David B., Ejima, Keisuke, Hubbard, Gene B., Ikeno, Yuji, Cubro, Hajrunisa, Garovic, Vesna D., Hou, Xiaonan, Weroha, SJ, Robbins, Paul D., Niedernhofer, Laura J., Khosla, Sundeep, Tchkonia, Tamara, Kirkland, James L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082705/
https://www.ncbi.nlm.nih.gov/pubmed/29988130
http://dx.doi.org/10.1038/s41591-018-0092-9
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author Xu, Ming
Pirtskhalava, Tamar
Farr, Joshua N.
Weigand, Bettina M.
Palmer, Allyson K.
Weivoda, Megan M.
Inman, Christina L.
Ogrodnik, Mikolaj B.
Hachfeld, Christine M.
Fraser, Daniel G.
Onken, Jennifer L.
Johnson, Kurt O.
Verzosa, Grace C.
Langhi, Larissa G. P.
Weigl, Moritz
Giorgadze, Nino
LeBrasseur, Nathan K.
Miller, Jordan D.
Jurk, Diana
Singh, Ravinder J.
Allison, David B.
Ejima, Keisuke
Hubbard, Gene B.
Ikeno, Yuji
Cubro, Hajrunisa
Garovic, Vesna D.
Hou, Xiaonan
Weroha, SJ
Robbins, Paul D.
Niedernhofer, Laura J.
Khosla, Sundeep
Tchkonia, Tamara
Kirkland, James L.
author_facet Xu, Ming
Pirtskhalava, Tamar
Farr, Joshua N.
Weigand, Bettina M.
Palmer, Allyson K.
Weivoda, Megan M.
Inman, Christina L.
Ogrodnik, Mikolaj B.
Hachfeld, Christine M.
Fraser, Daniel G.
Onken, Jennifer L.
Johnson, Kurt O.
Verzosa, Grace C.
Langhi, Larissa G. P.
Weigl, Moritz
Giorgadze, Nino
LeBrasseur, Nathan K.
Miller, Jordan D.
Jurk, Diana
Singh, Ravinder J.
Allison, David B.
Ejima, Keisuke
Hubbard, Gene B.
Ikeno, Yuji
Cubro, Hajrunisa
Garovic, Vesna D.
Hou, Xiaonan
Weroha, SJ
Robbins, Paul D.
Niedernhofer, Laura J.
Khosla, Sundeep
Tchkonia, Tamara
Kirkland, James L.
author_sort Xu, Ming
collection PubMed
description 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 targeted therapeutically 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, accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and life-span. 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 pro-inflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted younger 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.
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spelling pubmed-60827052019-01-09 Senolytics Improve Physical Function and Increase Lifespan in Old Age Xu, Ming Pirtskhalava, Tamar Farr, Joshua N. Weigand, Bettina M. Palmer, Allyson K. Weivoda, Megan M. Inman, Christina L. Ogrodnik, Mikolaj B. Hachfeld, Christine M. Fraser, Daniel G. Onken, Jennifer L. Johnson, Kurt O. Verzosa, Grace C. Langhi, Larissa G. P. Weigl, Moritz Giorgadze, Nino LeBrasseur, Nathan K. Miller, Jordan D. Jurk, Diana Singh, Ravinder J. Allison, David B. Ejima, Keisuke Hubbard, Gene B. Ikeno, Yuji Cubro, Hajrunisa Garovic, Vesna D. Hou, Xiaonan Weroha, SJ Robbins, Paul D. Niedernhofer, Laura J. Khosla, Sundeep Tchkonia, Tamara Kirkland, James L. Nat Med Article 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 targeted therapeutically 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, accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and life-span. 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 pro-inflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted younger 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. 2018-07-09 2018-08 /pmc/articles/PMC6082705/ /pubmed/29988130 http://dx.doi.org/10.1038/s41591-018-0092-9 Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Xu, Ming
Pirtskhalava, Tamar
Farr, Joshua N.
Weigand, Bettina M.
Palmer, Allyson K.
Weivoda, Megan M.
Inman, Christina L.
Ogrodnik, Mikolaj B.
Hachfeld, Christine M.
Fraser, Daniel G.
Onken, Jennifer L.
Johnson, Kurt O.
Verzosa, Grace C.
Langhi, Larissa G. P.
Weigl, Moritz
Giorgadze, Nino
LeBrasseur, Nathan K.
Miller, Jordan D.
Jurk, Diana
Singh, Ravinder J.
Allison, David B.
Ejima, Keisuke
Hubbard, Gene B.
Ikeno, Yuji
Cubro, Hajrunisa
Garovic, Vesna D.
Hou, Xiaonan
Weroha, SJ
Robbins, Paul D.
Niedernhofer, Laura J.
Khosla, Sundeep
Tchkonia, Tamara
Kirkland, James L.
Senolytics Improve Physical Function and Increase Lifespan in Old Age
title Senolytics Improve Physical Function and Increase Lifespan in Old Age
title_full Senolytics Improve Physical Function and Increase Lifespan in Old Age
title_fullStr Senolytics Improve Physical Function and Increase Lifespan in Old Age
title_full_unstemmed Senolytics Improve Physical Function and Increase Lifespan in Old Age
title_short Senolytics Improve Physical Function and Increase Lifespan in Old Age
title_sort senolytics improve physical function and increase lifespan in old age
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082705/
https://www.ncbi.nlm.nih.gov/pubmed/29988130
http://dx.doi.org/10.1038/s41591-018-0092-9
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