Research Paper Volume 15, Issue 19 pp 9948—9964

Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome

Daisuke Sawada1,2, , Hisaya Kato1,3, , Hiyori Kaneko1,3, , Daisuke Kinoshita1, , Shinichiro Funayama1, , Takuya Minamizuka1,3, , Atsushi Takasaki1,3, , Katsushi Igarashi1,3, , Masaya Koshizaka1,3, , Aki Takada-Watanabe1, , Rito Nakamura1, , Kazuto Aono1,3, , Ayano Yamaguchi1,3, , Naoya Teramoto1,3, , Yukari Maeda1,3, , Tomohiro Ohno1,3, , Aiko Hayashi1,3, , Kana Ide1,3, , Shintaro Ide1,3, , Mayumi Shoji1,3, , Takumi Kitamoto1,3, , Yusuke Endo4,5, , Hideyuki Ogata6, , Yoshitaka Kubota6, , Nobuyuki Mitsukawa6, , Atsushi Iwama7, , Yasuo Ouchi8, , Naoya Takayama8, , Koji Eto8,9, , Katsunori Fujii2,10, , Tomozumi Takatani2, , Tadashi Shiohama2, , Hiromichi Hamada2, , Yoshiro Maezawa1,3, , Koutaro Yokote1,3, ,

  • 1 Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan
  • 2 Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, Japan
  • 3 Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, Chiba, Japan
  • 4 Laboratory of Medical Omics Research, Kazusa DNA Research Institute, Kisarazu, Japan
  • 5 Department of Omics Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
  • 6 Department of Plastic, Reconstructive, And Aesthetic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan
  • 7 Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
  • 8 Department of Regenerative Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
  • 9 Department of Clinical Application, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
  • 10 Department of Pediatrics, International University of Welfare and Health School of Medicine, Narita, Japan

Received: December 7, 2022       Accepted: September 6, 2023       Published: October 3, 2023
How to Cite

Copyright: © 2023 Sawada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS. Clinical data from four Japanese patients with WS revealed significant associations between the decrease of areas of subcutaneous fat and increased insulin resistance measured by the glucose clamp. Adipose-derived stem cells from the stromal vascular fraction derived from WS subcutaneous adipose tissues (WSVF) showed early replicative senescence and a significant increase in the expression of senescence-associated secretory phenotype (SASP) markers. Additionally, adipogenesis and insulin signaling were suppressed in WSVF, and the expression of adipogenesis suppressor genes and SASP-related genes was increased. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of C. elegans. To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.


WS: Werner syndrome; BMI: body mass index; SMI: skeletal muscle mass index; TFA: total fat area; VFA: Visceral fat area; SFA: subcutaneous fat area; V/S ratio: VFA/SFA ratio; S/T ratio: SFA/TFA ratio; GIR: glucose infusion rate; SVF: stromal vascular fraction; HSVF: SVF derived from a healthy individual; WSVF: SVF derived from a patient with WS; SASP: senescence-associated secretory phenotype; mTOR: mammalian target of rapamycin; CT: computed tomography; PDL: population doubling level; SA-β-gal: senescence-associated β-galactosidase; GO: gene ontology; NF: fibroblasts from a normal individual; WF: fibroblasts from a patient with WS; mTORC1: mammalian target of rapamycin complex 1; ES cells: embryonic stem cells; NGM: nematode growth media.