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JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age.
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.
Afiliação
  • Xu M; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Tchkonia T; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Ding H; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Ogrodnik M; 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.
  • Lubbers ER; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Pirtskhalava T; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • White TA; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Johnson KO; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Stout MB; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Mezera V; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Giorgadze N; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Jensen MD; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • LeBrasseur NK; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
  • Kirkland JL; Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905; kirkland.james@mayo.edu.
Proc Natl Acad Sci U S A ; 112(46): E6301-10, 2015 Nov 17.
Article em En | MEDLINE | ID: mdl-26578790
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Senescência Celular / Adipócitos / RNA Interferente Pequeno / Janus Quinases / Células Endoteliais da Veia Umbilical Humana Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2015 Tipo de documento: Article País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Senescência Celular / Adipócitos / RNA Interferente Pequeno / Janus Quinases / Células Endoteliais da Veia Umbilical Humana Tipo de estudo: Risk_factors_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2015 Tipo de documento: Article País de publicação: Estados Unidos