Status and physiological significance of circulating adiponectin in the very old and centenarians: an observational study
- Keio University, Japan
- Nara Medical University, Japan
- Houtokukai Utsunomiya Hospital, Japan
Abstract
Background: High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60-70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85-89 years old) and centenarians.
Methods: The study included 812 (women: 84.4%) for centenarians and 1,498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole genome sequencing or DNA microarray-imputation methods. LASSO and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression.
Results: The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p = 2.21 × 10-22) and ADIPOQ (p = 5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI.
Conclusions: cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old.
Funding: This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program 'Tonomachi Research Complex' Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology.
Data availability
The cHMW adiponectin levels and covariates data were deposited with this manuscript as source data files. The data with age for the very old and centenarians have ethical and legal restrictions to public deposition due to avoid personal identification, and will be available upon request with an appropriate research arrangement with approval of the Research Ethics Committee of Keio University School of Medicine for Clinical Research. To request, please contact Takashi Sasaki (corresponding author) via e-mail: sasasa@z5.keio.jp.
Article and author information
Author details
Funding
A GRANT-IN-AID FOR SCIENTIFIC RESEARCH (21590775)
- Nobuyoshi Hirose
- Michiyo Takayama
- Yasumichi Arai
Japan Agency for Medical Research and Development (17jm0210051h0001)
- Takashi Sasaki
- Yasumichi Arai
Japan Agency for Medical Research and Development (19dk0207045h0001)
- Takashi Sasaki
- Yasumichi Arai
Keio University Global Research Institute
- Hideyuki Okano
- Yasumichi Arai
Kanagawa Institute of Industrial Science and Technology
- Yasumichi Arai
A GRANT-IN-AID FOR SCIENTIFIC RESEARCH (24590898)
- Nobuyoshi Hirose
- Yasumichi Arai
A GRANT-IN-AID FOR SCIENTIFIC RESEARCH (15KT0009)
- Yasumichi Arai
A GRANT-IN-AID FOR SCIENTIFIC RESEARCH (18H03055)
- Yasumichi Arai
A GRANT-IN-AID FOR SCIENTIFIC RESEARCH (20K20409)
- Takashi Sasaki
- Yasumichi Arai
A GRANT-IN-AID FOR SCIENTIFIC RESEARCH (20K07792)
- Takashi Sasaki
- Yasumichi Arai
A GRANT-IN-AID FOR SCIENTIFIC RESEARCH (23H03337)
- Takashi Sasaki
- Yasumichi Arai
Japan Science and Technology Agency (JP15667051)
- Toru Takebayashi
- Yasumichi Arai
Japan Agency for Medical Research and Development (16kk0205009h001)
- Yasumichi Arai
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Edward D Janus, University of Melbourne, Australia
Ethics
Human subjects: Written informed consent was obtained either from the participant or from a proxy if the participant lacked the capacity to provide consent. The ethics committee approved all cohort studies of the Keio University School of Medicine (ID: 20021020, 20022020, 20070047, and 20160297). The TOOTH and KAWP studies are registered in the University Hospital Medical Information Network Clinical Trial Registry (ID: UMIN000001842 and UMIN000026053).
Version history
- Preprint posted: June 30, 2022 (view preprint)
- Received: January 19, 2023
- Accepted: September 28, 2023
- Accepted Manuscript published: September 28, 2023 (version 1)
- Version of Record published: October 10, 2023 (version 2)
Copyright
© 2023, Sasaki 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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Status and physiological significance of circulating adiponectin in the very old and centenarians: an observational study
eLife 12:e86309.
https://doi.org/10.7554/eLife.86309
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