Targeting senescent cells enhances adipogenesis and metabolic function in old age
- Mayo Clinic, United States
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.
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Ethics
Animal experimentation: Experimental procedures (A21013, A37715 and A16315) were approved by the IACUC at Mayo Clinic
Human subjects: The protocol (10-005236) was approved by the Mayo Clinic Foundation Institutional Review Board for Human Research. Informed consent and consent to publish was obtained from all human subjects.
Copyright
© 2015, Xu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Targeting senescent cells enhances adipogenesis and metabolic function in old age
eLife 4:e12997.
https://doi.org/10.7554/eLife.12997
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