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Targeting senescent cells enhances adipogenesis and metabolic function in old age

Senescent cells accumulate in fat with aging. We previously found genetic clearance of senescent cells from progeroid INK-ATTAC mice prevents lipodystrophy. Here we show that primary human senescent fat progenitors secrete activin A and directly inhibit adipogenesis in non-senescent progenitors. Blo...

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Autores principales: Xu, Ming, Palmer, Allyson K, Ding, Husheng, Weivoda, Megan M, Pirtskhalava, Tamar, White, Thomas A, Sepe, Anna, Johnson, Kurt O, Stout, Michael B, Giorgadze, Nino, Jensen, Michael D, LeBrasseur, Nathan K, Tchkonia, Tamar, Kirkland, James L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758946/
https://www.ncbi.nlm.nih.gov/pubmed/26687007
http://dx.doi.org/10.7554/eLife.12997
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author Xu, Ming
Palmer, Allyson K
Ding, Husheng
Weivoda, Megan M
Pirtskhalava, Tamar
White, Thomas A
Sepe, Anna
Johnson, Kurt O
Stout, Michael B
Giorgadze, Nino
Jensen, Michael D
LeBrasseur, Nathan K
Tchkonia, Tamar
Kirkland, James L
author_facet Xu, Ming
Palmer, Allyson K
Ding, Husheng
Weivoda, Megan M
Pirtskhalava, Tamar
White, Thomas A
Sepe, Anna
Johnson, Kurt O
Stout, Michael B
Giorgadze, Nino
Jensen, Michael D
LeBrasseur, Nathan K
Tchkonia, Tamar
Kirkland, James L
author_sort Xu, Ming
collection PubMed
description Senescent cells accumulate in fat with aging. We previously found genetic clearance of senescent cells from progeroid INK-ATTAC mice prevents lipodystrophy. Here we show that primary human senescent fat progenitors secrete activin A and directly inhibit adipogenesis in non-senescent progenitors. Blocking activin A partially restored lipid accumulation and expression of key adipogenic markers in differentiating progenitors exposed to senescent cells. Mouse fat tissue activin A increased with aging. Clearing senescent cells from 18-month-old naturally-aged INK-ATTAC mice reduced circulating activin A, blunted fat loss, and enhanced adipogenic transcription factor expression within 3 weeks. JAK inhibitor suppressed senescent cell activin A production and blunted senescent cell-mediated inhibition of adipogenesis. Eight weeks-treatment with ruxolitinib, an FDA-approved JAK1/2 inhibitor, reduced circulating activin A, preserved fat mass, reduced lipotoxicity, and increased insulin sensitivity in 22-month-old mice. Our study indicates targeting senescent cells or their products may alleviate age-related dysfunction of progenitors, adipose tissue, and metabolism. DOI: http://dx.doi.org/10.7554/eLife.12997.001
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spelling pubmed-47589462016-02-22 Targeting senescent cells enhances adipogenesis and metabolic function in old age Xu, Ming Palmer, Allyson K Ding, Husheng Weivoda, Megan M Pirtskhalava, Tamar White, Thomas A Sepe, Anna Johnson, Kurt O Stout, Michael B Giorgadze, Nino Jensen, Michael D LeBrasseur, Nathan K Tchkonia, Tamar Kirkland, James L eLife Developmental Biology and Stem Cells Senescent cells accumulate in fat with aging. We previously found genetic clearance of senescent cells from progeroid INK-ATTAC mice prevents lipodystrophy. Here we show that primary human senescent fat progenitors secrete activin A and directly inhibit adipogenesis in non-senescent progenitors. Blocking activin A partially restored lipid accumulation and expression of key adipogenic markers in differentiating progenitors exposed to senescent cells. Mouse fat tissue activin A increased with aging. Clearing senescent cells from 18-month-old naturally-aged INK-ATTAC mice reduced circulating activin A, blunted fat loss, and enhanced adipogenic transcription factor expression within 3 weeks. JAK inhibitor suppressed senescent cell activin A production and blunted senescent cell-mediated inhibition of adipogenesis. Eight weeks-treatment with ruxolitinib, an FDA-approved JAK1/2 inhibitor, reduced circulating activin A, preserved fat mass, reduced lipotoxicity, and increased insulin sensitivity in 22-month-old mice. Our study indicates targeting senescent cells or their products may alleviate age-related dysfunction of progenitors, adipose tissue, and metabolism. DOI: http://dx.doi.org/10.7554/eLife.12997.001 eLife Sciences Publications, Ltd 2015-12-19 /pmc/articles/PMC4758946/ /pubmed/26687007 http://dx.doi.org/10.7554/eLife.12997 Text en © 2015, Xu et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology and Stem Cells
Xu, Ming
Palmer, Allyson K
Ding, Husheng
Weivoda, Megan M
Pirtskhalava, Tamar
White, Thomas A
Sepe, Anna
Johnson, Kurt O
Stout, Michael B
Giorgadze, Nino
Jensen, Michael D
LeBrasseur, Nathan K
Tchkonia, Tamar
Kirkland, James L
Targeting senescent cells enhances adipogenesis and metabolic function in old age
title Targeting senescent cells enhances adipogenesis and metabolic function in old age
title_full Targeting senescent cells enhances adipogenesis and metabolic function in old age
title_fullStr Targeting senescent cells enhances adipogenesis and metabolic function in old age
title_full_unstemmed Targeting senescent cells enhances adipogenesis and metabolic function in old age
title_short Targeting senescent cells enhances adipogenesis and metabolic function in old age
title_sort targeting senescent cells enhances adipogenesis and metabolic function in old age
topic Developmental Biology and Stem Cells
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758946/
https://www.ncbi.nlm.nih.gov/pubmed/26687007
http://dx.doi.org/10.7554/eLife.12997
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