PMID- 37793000
OWN - NLM
STAT- MEDLINE
DCOM- 20231023
LR  - 20231027
IS  - 1945-4589 (Electronic)
IS  - 1945-4589 (Linking)
VI  - 15
IP  - 19
DP  - 2023 Oct 3
TI  - Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous 
      fat in Werner syndrome.
PG  - 9948-9964
LID - 10.18632/aging.205078 [doi]
AB  - 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.
FAU - Sawada, Daisuke
AU  - Sawada D
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, 
      Japan.
FAU - Kato, Hisaya
AU  - Kato H
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Kaneko, Hiyori
AU  - Kaneko H
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Kinoshita, Daisuke
AU  - Kinoshita D
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
FAU - Funayama, Shinichiro
AU  - Funayama S
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
FAU - Minamizuka, Takuya
AU  - Minamizuka T
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Takasaki, Atsushi
AU  - Takasaki A
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Igarashi, Katsushi
AU  - Igarashi K
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Koshizaka, Masaya
AU  - Koshizaka M
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Takada-Watanabe, Aki
AU  - Takada-Watanabe A
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
FAU - Nakamura, Rito
AU  - Nakamura R
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
FAU - Aono, Kazuto
AU  - Aono K
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Yamaguchi, Ayano
AU  - Yamaguchi A
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Teramoto, Naoya
AU  - Teramoto N
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Maeda, Yukari
AU  - Maeda Y
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Ohno, Tomohiro
AU  - Ohno T
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Hayashi, Aiko
AU  - Hayashi A
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Ide, Kana
AU  - Ide K
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Ide, Shintaro
AU  - Ide S
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Shoji, Mayumi
AU  - Shoji M
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Kitamoto, Takumi
AU  - Kitamoto T
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Endo, Yusuke
AU  - Endo Y
AD  - Laboratory of Medical Omics Research, Kazusa DNA Research Institute, Kisarazu, 
      Japan.
AD  - Department of Omics Medicine, Chiba University Graduate School of Medicine, 
      Chiba, Japan.
FAU - Ogata, Hideyuki
AU  - Ogata H
AD  - Department of Plastic, Reconstructive, And Aesthetic Surgery, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
FAU - Kubota, Yoshitaka
AU  - Kubota Y
AD  - Department of Plastic, Reconstructive, And Aesthetic Surgery, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
FAU - Mitsukawa, Nobuyuki
AU  - Mitsukawa N
AD  - Department of Plastic, Reconstructive, And Aesthetic Surgery, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
FAU - Iwama, Atsushi
AU  - Iwama A
AD  - 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.
FAU - Ouchi, Yasuo
AU  - Ouchi Y
AD  - Department of Regenerative Medicine, Chiba University Graduate School of 
      Medicine, Chiba, Japan.
FAU - Takayama, Naoya
AU  - Takayama N
AD  - Department of Regenerative Medicine, Chiba University Graduate School of 
      Medicine, Chiba, Japan.
FAU - Eto, Koji
AU  - Eto K
AD  - Department of Regenerative Medicine, Chiba University Graduate School of 
      Medicine, Chiba, Japan.
AD  - Department of Clinical Application, Center for iPS Cell Research and Application 
      (CiRA), Kyoto University, Kyoto, Japan.
FAU - Fujii, Katsunori
AU  - Fujii K
AD  - Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, 
      Japan.
AD  - Department of Pediatrics, International University of Welfare and Health School 
      of Medicine, Narita, Japan.
FAU - Takatani, Tomozumi
AU  - Takatani T
AD  - Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, 
      Japan.
FAU - Shiohama, Tadashi
AU  - Shiohama T
AD  - Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, 
      Japan.
FAU - Hamada, Hiromichi
AU  - Hamada H
AD  - Department of Pediatrics, Chiba University Graduate School of Medicine, Chiba, 
      Japan.
FAU - Maezawa, Yoshiro
AU  - Maezawa Y
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
FAU - Yokote, Koutaro
AU  - Yokote K
AD  - Department of Endocrinology, Hematology and Gerontology, Chiba University 
      Graduate School of Medicine, Chiba, Japan.
AD  - Division of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 
      Chiba, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20231003
PL  - United States
TA  - Aging (Albany NY)
JT  - Aging
JID - 101508617
RN  - W36ZG6FT64 (Sirolimus)
RN  - 0 (Insulins)
SB  - IM
MH  - Animals
MH  - Humans
MH  - *Werner Syndrome/genetics
MH  - Adipogenesis/genetics
MH  - *Insulin Resistance
MH  - Caenorhabditis elegans
MH  - Cellular Senescence/genetics
MH  - Subcutaneous Fat/metabolism
MH  - *Lipodystrophy
MH  - Inflammation
MH  - Sirolimus
MH  - *Insulins
MH  - Mammals
PMC - PMC10599740
OTO - NOTNLM
OT  - SASP
OT  - Werner syndrome
OT  - lipodystrophy
OT  - premature aging
OT  - stromal vascular fraction
COIS- CONFLICTS OF INTEREST: The authors declare no conflicts of interest.
EDAT- 2023/10/04 18:42
MHDA- 2023/10/23 01:18
PMCR- 2023/10/15
CRDT- 2023/10/04 14:23
PHST- 2022/12/07 00:00 [received]
PHST- 2023/09/06 00:00 [accepted]
PHST- 2023/10/23 01:18 [medline]
PHST- 2023/10/04 18:42 [pubmed]
PHST- 2023/10/04 14:23 [entrez]
PHST- 2023/10/15 00:00 [pmc-release]
AID - 205078 [pii]
AID - 10.18632/aging.205078 [doi]
PST - ppublish
SO  - Aging (Albany NY). 2023 Oct 3;15(19):9948-9964. doi: 10.18632/aging.205078. Epub 
      2023 Oct 3.