title: JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age.
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.
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Tamara
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Husheng
authors.initials: H
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Mikolaj
authors.initials: M
authors.lastname: Ogrodnik
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Lubbers
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Kurt O
authors.initials: KO
authors.lastname: Johnson
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stout
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Vojtech
authors.initials: V
authors.lastname: Mezera
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Nino
authors.initials: N
authors.lastname: Giorgadze
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jensen
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905;
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
authors.affiliation: Robert and Arlene Kogod Center on Aging,Mayo Clinic, Rochester, MN 55905; kirkland.james@mayo.edu.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000201:enzymology*; D000273:Adipose Tissue / Q000166:cytology / Q000201:enzymology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000201:enzymology; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D053612:Janus Kinases
keywords: JAK/STAT pathway; cellular senescence; frailty; interleukin-6; ruxolitinib