JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phen...

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Vydané v:	Proceedings of the National Academy of Sciences - PNAS Ročník 112; číslo 46; s. E6301
Hlavní autori:	Xu, Ming, Tchkonia, Tamara, Ding, Husheng, Ogrodnik, Mikolaj, Lubbers, Ellen R, Pirtskhalava, Tamar, White, Thomas A, Johnson, Kurt O, Stout, Michael B, Mezera, Vojtech, Giorgadze, Nino, Jensen, Michael D, LeBrasseur, Nathan K, Kirkland, James L
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 17.11.2015
Predmet:	Adipocytes - cytology Adipocytes - enzymology Adipose Tissue - cytology Adipose Tissue - enzymology Animals Cell Movement - drug effects Cell Movement - genetics Cellular Senescence - drug effects Cellular Senescence - genetics Extracellular Matrix - metabolism Human Umbilical Vein Endothelial Cells - cytology Human Umbilical Vein Endothelial Cells - enzymology Humans Janus Kinases - antagonists & inhibitors Janus Kinases - genetics Janus Kinases - metabolism Macrophages - cytology Macrophages - enzymology Mice RNA, Small Interfering - genetics RNA, Small Interfering - pharmacology Signal Transduction - drug effects Signal Transduction - genetics frailty cellular senescence ruxolitinib JAK/STAT pathway interleukin-6
ISSN:	1091-6490, 1091-6490
On-line prístup:	Zistit podrobnosti o prístupe
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Abstract	Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.
AbstractList	Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction. Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.
Author	Tchkonia, Tamara Jensen, Michael D LeBrasseur, Nathan K Johnson, Kurt O Mezera, Vojtech Ogrodnik, Mikolaj Kirkland, James L Giorgadze, Nino White, Thomas A Pirtskhalava, Tamar Xu, Ming Ding, Husheng Lubbers, Ellen R Stout, Michael B
Author_xml	– sequence: 1 givenname: Ming surname: Xu fullname: Xu, Ming organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 2 givenname: Tamara surname: Tchkonia fullname: Tchkonia, Tamara organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 3 givenname: Husheng surname: Ding fullname: Ding, Husheng organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 4 givenname: Mikolaj surname: Ogrodnik fullname: Ogrodnik, Mikolaj organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905; Newcastle University Institute for Ageing, Newcastle University, Newcastle Upon Tyne, NE4 5PL, United Kingdom – sequence: 5 givenname: Ellen R surname: Lubbers fullname: Lubbers, Ellen R organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 6 givenname: Tamar surname: Pirtskhalava fullname: Pirtskhalava, Tamar organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 7 givenname: Thomas A surname: White fullname: White, Thomas A organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 8 givenname: Kurt O surname: Johnson fullname: Johnson, Kurt O organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 9 givenname: Michael B surname: Stout fullname: Stout, Michael B organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 10 givenname: Vojtech surname: Mezera fullname: Mezera, Vojtech organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 11 givenname: Nino surname: Giorgadze fullname: Giorgadze, Nino organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 12 givenname: Michael D surname: Jensen fullname: Jensen, Michael D organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 13 givenname: Nathan K surname: LeBrasseur fullname: LeBrasseur, Nathan K organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905 – sequence: 14 givenname: James L surname: Kirkland fullname: Kirkland, James L email: kirkland.james@mayo.edu organization: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905; kirkland.james@mayo.edu
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Title	JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age
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