title: Targeting senescent cells enhances adipogenesis and metabolic function in old age.
abstract: 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.
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Allyson K
authors.initials: AK
authors.lastname: Palmer
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Husheng
authors.initials: H
authors.lastname: Ding
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Weivoda
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Sepe
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Kurt O
authors.initials: KO
authors.lastname: Johnson
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stout
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Nino
authors.initials: N
authors.lastname: Giorgadze
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Jensen
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: Tamar
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, United States.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D028341:Activins / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D016922:Cellular Senescence; D006801:Humans; D051379:Mice; D013234:Stem Cells / Q000502:physiology*
chemical_list: C422405:activin A; D028341:Activins
keywords: Activin A; INK-ATTAC; JAK/STAT; adipose-derived stem cells; developmental biology; human; human biology; insulin sensitivity; medicine; mouse; rat; ruxolitinib; stem cells