Status and physiological significance of circulating adiponectin in the very old and centenarians: an observational study
- Center for Supercentenarian Medical Research, Keio University School of Medicine, Japan
- Department of Neurology, Keio University, School of Medicine, Japan
- Institute for Clinical and Translational Science, Nara Medical University, Japan
- Houtokukai Utsunomiya Hospital, Japan
- Center for Preventive Medicine, Keio University School of Medicine, Japan
- Department of Preventive Medicine and Public Health, Keio University School of Medicine, Japan
- Department of Physiology, Keio University School of Medicine, Japan
- Faculty of Nursing and Medical Care, Keio University, Japan
Figures
Figure 1 with 3 supplements
Analysis workflow and distribution of circulating high-molecular-weight (cHMW) adiponectin levels in the very old and centenarians.
(a) Sample summary and analysis workflow of cHMW adiponectin levels. (b) Distribution of cHMW adiponectin levels in older adults and centenarians. cHMW adiponectin levels gradually increased with age in the very old to centenarians. (c) Distribution of cHMW adiponectin levels in older men and women. (d) Distribution of cHMW adiponectin levels in centenarian men and women. The difference in cHMW adiponectin levels was significant between sexes in both the very old and centenarians.
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Figure 1—source data 1
Source data for Figure 1 including 812 centenarians and 1498 very old data.
- https://cdn.elifesciences.org/articles/86309/elife-86309-fig1-data1-v2.csv
Figure 1—figure supplement 1
Description of the cohorts in this study.
(a) Description of the cohorts for centenarian studies. (b) Description of the cohorts for the very old studies.
Figure 1—figure supplement 2
Flowchart for analysis in this study.
The numbers on the flowchart indicate the number of samples used in each analysis.
Figure 1—figure supplement 3
Transition of circulating high-molecular-weight (cHMW) adiponectin level in the longitudinal data of Tokyo Oldest Old Survey on Total Health (TOOTH) study.
(a) Transition of cHMW adiponectin level at baseline and 3-year follow-up studies. (b) Difference of cHMW adiponectin level between baseline and 3-year follow-up studies. The cHMW adiponectin level is gradually increasing during very old.
Figure 2 with 3 supplements
Meta-genome-wide association study (GWAS) for circulating high-molecular-weight (cHMW) adiponectin levels in the very old and centenarians.
(a) Meta-GWAS analysis for cHMW adiponectin levels in the very old and centenarians. Number of samples for the very old and centenarian were 1015 and 807, respectively. Loci for CDH13 (rs12051213, C: reference allele, T: alternative allele, p=2.45 × 10–22) and ADIPOQ (rs11711353, G: reference allele, A: alternative allele, p=6.68 × 10–7) were detected using meta-GWAS for cHMW adiponectin levels in older adults and centenarians. (b) A GWAS enlarged view of the CDH13 region. (c) A GWAS enlarged view of the ADIPOQ region. (d) Distribution of cHMW adiponectin levels in rs4783244 (CDH13) genotypes of the very old and centenarians. cHMW adiponectin levels varied significantly between the rs4783244 reference allele homozygote and rs4783244 alternative allele heterozygote in the very old and centenarians. Except in very old men, no significant difference was observed between the rs4783244 alternative allele heterozygote and rs4783244 alternative allele homozygote in the very old or centenarians.
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Figure 2—source data 1
Source data for Figure 1 including 812 centenarians and 1498 very old data.
- https://cdn.elifesciences.org/articles/86309/elife-86309-fig2-data1-v2.csv
Figure 2—figure supplement 1
Genome-wide association study (GWAS) for circulating high-molecular-weight (cHMW) adiponectin level.
(a) GWAS for cHMW adiponectin level in centenarians (n=440) determined by whole-genome. sequencing (WGS). (b) GWAS for cHMW adiponectin level in centenarians (n=367). determined by genotyping by DNA microarray (Japonica V3 array) and DNA sequence imputation. (c) GWAS result for cHMW adiponectin level in the very old (n=1015) determined by genotyping. using DNA microarray (Asian screening array, Illumina) and DNA sequence imputation.
Figure 2—figure supplement 2
Minor allele frequency comparison of rs4783244 (CDH13) and rs11711353 (ADIPOQ).
Allele frequency differences were statistically tested using the Fisher’s exact test (fisher.test in R stats package [version4.2.2]). (a) rs4783244 men (CDH13). (b) rs4783244 women (CDH13). (c) rs11711353 men (ADIPOQ). (d) rs11711353 women (ADIPOQ).
Figure 2—figure supplement 3
Distribution of circulating high-molecular-weight (cHMW) adiponectin level in rs11711353 (ADIPOQ) genotypes of the very old and centenarians.
Figure 3
Association between circulating high-molecular-weight (cHMW) adiponectin level, high-denisty lipoprotein cholesterol (HDLC), body mass index (BMI), and glycated hemoglobin (HbA1c).
(a, b) Distribution of cHMW adiponectin levels in the diabetes mellitus (DM) and non-DM groups. A person with DM was defined as follows: individuals with glycated hemoglobin (HbA1c)≥6.5%, those receiving antidiabetic drug therapy, or those receiving insulin injections. cHMW adiponectin levels in the DM group were significantly lower than those in the non-DM group in the very old and centenarians. (c, d) Association between cHMW adiponectin levels and HDLC content. A positive association was observed between cHMW adiponectin levels and HDLC content in the very old and centenarians. (e, f) Association between cHMW adiponectin levels and BMI. A strong negative association was observed between cHMW adiponectin levels and BMI in the very old, though this association was rarely observed in centenarians.
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Figure 3—source data 1
Source data for Figure 1 including 812 centenarians and 1498 very old data.
- https://cdn.elifesciences.org/articles/86309/elife-86309-fig3-data1-v2.csv
Figure 4 with 1 supplement
Multivariate analysis for circulating high-molecular-weight (cHMW) adiponectin levels in the very old and centenarians.
(a) Multivariate analysis for cHMW adiponectin levels in very old men and women; 14 significant factors for very old men and 10 significant factors for very old women were identified. (b) Multivariate analysis for cHMW adiponectin levels in centenarian men and women; 3 significant factors for centenarian men and 4 significant factors for centenarian women were identified. (c) The contribution rate for each factor in very old men and women was estimated by analysis of variance. (d) The contribution rate for each factor in centenarian men and women was estimated using analysis of variance. The total variance of known cHMW adiponectin level associated factors corresponded to 36.8–42.0% in very old and centenarian men and 18.4% in centenarian women.
Figure 4—figure supplement 1
Least Absolute Shrinkage and Selection Operator (LASSO) with fivefold cross-validation against 1326 very old and 352 centenarians.
(a) LASSO with fivefold validation analysis against 1326 very old. As a result of fivefold cross-validation, 19 factors shown in black in the bottom column were selected for further multivariate regression analysis. (b) LASSO with fivefold validation analysis against 352 centenarians. As a result of fivefold cross-validation, 7 factors shown in black in the bottom column were selected for further multivariate regression analysis.
Figure 5 with 8 supplements
Survival analysis using Cox promotional hazards model for three quantile circulating high-molecular-weight (cHMW) adiponectin level groups.
(a, b) Survival analysis of very old men and women using the Cox promotional hazards model for three quantile cHMW adiponectin level groups. Seven covariates (model1) and seven covariates with body mass index (BMI) were used for calculating the multiple regression analysis of Cox promotional hazards model. Hazard ratio for low concentration adiponectin group was calculated as the reference. The statistics power analysis using powerSurvEpi (version 0.1.3) indicated that survival analyses for both very old men and women have sufficient number of samples and events. (c, d) Survival analysis of the centenarian men and women using Cox promotional hazards model for three quantile cHMW adiponectin level groups. Three covariates (model2) and three covariates with BMI were used for calculation of multiple regression analysis of Cox promotional hazards model. Hazard ratio for low concentration adiponectin group was calculated as the reference. The statistics power analysis using powerSurvEpi (version 0.1.3) indicated that survival analysis for centenarian women has sufficient number of samples and events, however, survival analysis for centenarian men was underpowered due to insufficient number of events.
Figure 5—figure supplement 1
The proportional hazards assumption test for a Cox regression model fit.
(a) Very old men. (b) Very old women. For calculation of proportional hazards assumption test, cox.zph in survival package (version 3.2-13) was used.
Figure 5—figure supplement 2
The proportional hazards assumption test for a Cox regression model fit.
(a) Centenarian men. (b) Centenarian women. For calculation of proportional hazards assumption test, cox.zph in survival package (version 3.2-13) was used.
Figure 5—figure supplement 3
Survival time analysis for cancer-cause mortality against the three quantile groups of circulating high-molecular-weight (cHMW) adiponectin levels in very old men and women.
Survival analysis for cancer-cause mortality of very old men and women grouped by cHMW adiponectin level by cox regression analysis. The statistics power analysis by powerSurvEpi (version 0.1.3) indicated that this survival analysis was underpowered due to insufficient number of events.
Figure 5—figure supplement 4
Survival time analysis for cardiovascular disease-cause mortality against the three quantile groups of circulating high-molecular-weight (cHMW) adiponectin levels in very old men and women.
Survival analysis for cardiovascular disease-cause mortality of very old men and women grouped by cHMW adiponectin level by cox regression analysis. The statistics power analysis by powerSurvEpi (version 0.1.3) indicated that this survival analysis was underpowered due to insufficient number of events.
Figure 5—figure supplement 5
Survival time analysis for pneumonia-cause mortality against the three quantile groups of circulating high-molecular-weight (cHMW) adiponectin levels in very old men and women.
Survival analysis for pneumonia-cause mortality of very old men and women grouped by cHMW adiponectin level by cox regression analysis. The statistics power analysis by powerSurvEpi (version 0.1.3) indicated that this survival analysis was underpowered due to insufficient number of events.
Figure 5—figure supplement 6
J-CHS frailty index distribution against the three quantile groups of circulating high-molecular-weight (cHMW) adiponectin levels and multiple regression analysis in very old men and women (Kawasaki Aging Wellbeing Project [KAWP]).
(a) J-CHS frailty index distribution against the three quantile groups of cHMW adiponectin levels in very old men and women. (b) Multiple regression analysis between cHMW adiponectin level and J-CHS frailty index.
Figure 5—figure supplement 7
Adiponectin mRNA expression analysis of single-cell RNA-seq for four kinds of mouse adipose tissue.
We re-analyzed single-cell RNA-seq results (https://tabula-muris-senis.ds.czbiohub.org/fat/droplet/) for four kinds of mouse adipose tissues including brown adipose tissue (Bat), gonadal adipose tissue (Gat), mesenteric adipose tissue (Mat), and subcutaneous adipose tissue (Scat). Dots with the blue color indicated adiponectin-expressed cells. These single-cell RNA-seq results suggested that Scat is one of the major adiponectin-expressed cells in adipose tissues.
Figure 5—figure supplement 8
Ectopic expression of adiponectin with aging in mouse.
We re-analyzed single-cell RNA-seq results of 24 kinds of tissue in 1, 3, 18, 21, 24, 30 months (https://tabula-muris-senis.ds.czbiohub.org/fat/droplet/). Major adiponectin-expressed cells were adipose tissue and no obvious ectopic adiponectin expression was observed in the time series of mouse cells.
Additional files
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Supplementary file 1
Participants' characteristics at enrollment 1: Wilcoxon ranking test, 2: Fisher’s exact test, 3: Chi-square test.
Abbreviations: IQR, interquartile range; BMI, body mass index; SBP, systolic blood pressure; IADLs, instrumental activities of daily living; ADLs, activities of daily living; MMSE, mini-mental state examination; HMW, high molecular weight; HDLC, high-density lipoprotein cholesterol; LDLC, low-density lipoprotein cholesterol; TCHO, total cholesterol; TG, triglyceride; CHE, choline esterase; AST, aspartate aminotransferase; γGTP, γ-glutamyl transpeptidase; LDH, lactate dehydrogenase; UA, uric acid; ALB, albumin; Alt, alternative; MAF, minor allele frequency.
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp1-v2.xlsx
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Supplementary file 2
Coefficients for generalized linear model analysis of plasma HMW adiponectin level in very old men (n=643).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp2-v2.xlsx
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Supplementary file 3
Coefficients for generalized linear model analysis of plasma HMW adiponectin level in very old women (n=683).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp3-v2.xlsx
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Supplementary file 4
Coefficients for generalized linear model analysis of plasma HMW adiponectin level in the very old (n=1,326).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp4-v2.xlsx
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Supplementary file 5
Coefficients for generalized linear model analysis of plasma HMW adiponectin level in centenarian men (n=63).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp5-v2.xlsx
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Supplementary file 6
Coefficients for generalized linear model analysis of plasma HMW adiponectin level in centenarian women (n=289).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp6-v2.xlsx
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Supplementary file 7
Coefficients for generalized linear model analysis of plasma HMW adiponectin level in centenarian (n=352).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp7-v2.xlsx
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Supplementary file 8
Analysis of variance of plasma HMW adiponectin level by ANOVA in very old men (n=643).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp8-v2.xlsx
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Supplementary file 9
Analysis of variance of plasma HMW adiponectin level by ANOVA in very old women (n=683).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp9-v2.xlsx
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Supplementary file 10
Analysis of variance of plasma HMW adiponectin level by ANOVA in centenarian men (n=63).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp10-v2.xlsx
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Supplementary file 11
Analysis of variance of plasma HMW adiponectin level by ANOVA in centenarian women (n=289).
- https://cdn.elifesciences.org/articles/86309/elife-86309-supp11-v2.xlsx
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MDAR checklist
- https://cdn.elifesciences.org/articles/86309/elife-86309-mdarchecklist1-v2.docx
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Source code 1
R script code file for Figure 1c.
- https://cdn.elifesciences.org/articles/86309/elife-86309-code1-v2.zip
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Source code 2
R script code file for Figure 1c.
- https://cdn.elifesciences.org/articles/86309/elife-86309-code2-v2.zip
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Source code 3
R script code file for Figure 2d.
- https://cdn.elifesciences.org/articles/86309/elife-86309-code3-v2.zip
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Source code 4
R script code file for Figure 3a, b.
- https://cdn.elifesciences.org/articles/86309/elife-86309-code4-v2.zip
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Source code 5
R script code file for Figure 3a, b.
- https://cdn.elifesciences.org/articles/86309/elife-86309-code5-v2.zip
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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
