Targeting senescent cells enhances adipogenesis and metabolic function in old age

Ming Xu, Allyson K. Palmer, Husheng Ding, Megan M. Weivoda, Tamar Pirtskhalava, Thomas A. White, Anna Sepe, Kurt O. Johnson, Michael B. Stout, Nino Giorgadze, Michael D. Jensen, Nathan K. LeBrasseur, Tamar Tchkonia, James L. Kirkland

Research output: Contribution to journalArticle

171 Scopus citations

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 nonsenescent 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 INKATTAC 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.

Original languageEnglish (US)
Article numbere12997
JournaleLife
Volume4
Issue numberDECEMBER2015
DOIs
StatePublished - Dec 19 2015

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Xu, M., Palmer, A. K., Ding, H., Weivoda, M. M., Pirtskhalava, T., White, T. A., Sepe, A., Johnson, K. O., Stout, M. B., Giorgadze, N., Jensen, M. D., LeBrasseur, N. K., Tchkonia, T., & Kirkland, J. L. (2015). Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife, 4(DECEMBER2015), [e12997]. https://doi.org/10.7554/eLife.12997