An integrative study of five biological clocks in somatic and mental health
- Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Netherlands
- Center for Biomarker Research and Precision Medicine, Virginia Commonwealth University, United States
Figures
Figure 1
Study design.
The upper part of the figure shows the five biological layers. From each of the four omics layers (epigenetic, transcriptomic, proteomic, and metabolomic data), biological age was estimated, and biological age was regressed on age to obtain measures of biological aging. Only telomere length was not age-regressed. The five biological aging indicators were associated with multiple demographic, lifestyle, somatic health and mental health determinants.
Figure 2
Correlations between the biological aging indicators.
The heatmap represents Spearman rank correlations between the five biological aging indicators, all corrected for sex. Out of 10 pairs, three are significant: transcriptomic vs epigenetic aging, metabolomic vs proteomic aging and proteomic vs transcriptomic aging. All biological aging indicators were age-regressed, only telomere length was not.
Figure 3
Forest plot of associations between biological aging and health determinants.
For each of the associations between biological aging indicators and health determinants, the standardized beta and standard deviation derived from linear models were plotted. The significant associations (p<2e-2, FDR < 5%) are shown with red stars. The composite index, which is the scaled sum of the five biological aging indicators, clearly shows most associations and often largest effect sizes. Biological aging was used as outcome in the linear models. Beta for telomere length was multiplied by −1 to compare with other biological clocks. Red stars indicate FDR < 5%. All biological aging indicators were age-regressed, only telomere length was not.
Figure 4
Barplots of betas from associations between biological aging and health determinants.
For each of the associations between biological aging and health determinants, the standardized beta and standard deviation derived from linear models were plotted. Only samples that had data for all five biological clocks (N = 653) were used. All biological aging indicators were age-regressed, only telomere length was not.
Tables
Table 1
Sample description.
| Telomere Length | Epigenetic Aging | Transcriptomic Aging | Proteomic Aging | Metabolomic Aging | Composite Index | ||
|---|---|---|---|---|---|---|---|
| # Subjects | 2936 | 1130 | 1990 | 1837 | 2910 | 653 | |
| Demographic | Sex (%female) | 66.00 | 65.00 | 67.00 | 67.00 | 66.00 | 66.00 |
| Education years (mean) | 12.15 | 11.93 | 12.07 | 12.07 | 12.15 | 11.71 | |
| Age (mean) | 41.81 | 41.53 | 38.71 | 41.37 | 41.94 | 41.23 | |
| Lifestyle | Alcohol use (units per week, mean) | 6.24 | 6.54 | 6.38 | 6.39 | 6.29 | 6.48 |
| Smoking (pack years, mean) | 11.00 | 11.43 | 11.84 | 10.37 | 11.12 | 10.90 | |
| Physical activity (MET minutes per week, mean) | 3679.72 | 3638.54 | 3729.20 | 3741.00 | 3668.13 | 3525.05 | |
| Somatic Health | BMI (mean) | 25.60 | 25.67 | 25.68 | 25.66 | 25.60 | 25.82 |
| Physical disability (score, mean) | 24.40 | 29.45 | 26.00 | 23.22 | 24.45 | 30.27 | |
| Lung capacity (PEF in liter/minute, mean) | 477.74 | 479.75 | 478.42 | 477.19 | 477.23 | 475.23 | |
| Hand grip strength (kg, mean) | 37.06 | 37.77 | 37.08 | 37.46 | 37.05 | 37.74 | |
| Cardiometabolic disease (%cases) | 18 | 18 | 18 | 18 | 18 | 17 | |
| Respiratory disease (%cases) | 9 | 9 | 9 | 9 | 9 | 10 | |
| Musculoskeletal disease (%cases) | 10 | 10 | 10 | 9 | 10 | 9 | |
| Digestive disease (%cases) | 9 | 9 | 9 | 8 | 9 | 8 | |
| Neurological disease (%cases) | 3 | 2 | 3 | 3 | 3 | 2 | |
| Endocrine disease (%cases) | 3 | 3 | 3 | 3 | 3 | 4 | |
| Cancer (%cases) | 7 | 8 | 7 | 7 | 7 | 8 | |
| Metabolic syndrome (# components, mean) | 1.36 | 1.39 | 1.37 | 1.33 | 1.36 | 1.41 | |
| # Chronic diseases (mean) | 0.61 | 0.62 | 0.62 | 0.58 | 0.61 | 0.63 | |
| Mental Health | Current MDD (%cases) | 27 | 72 | 34 | 26 | 27 | 76 |
| Depression severity (IDS, mean) | 21.46 | 25.80 | 22.91 | 20.96 | 21.48 | 26.67 | |
| Childhood Trauma (score from 0-4, mean) | 0.91 | 0.97 | 1.00 | 0.87 | 0.92 | 1.01 |
Table 2
Associations between five biological aging indicators and multiple health determinants.
For each biological aging indicator, linear models were fit with the health determinant as predictor, while controlling for sex. Beta’s and p-values from these models are presented here. In the 653 samples with all five data layers available, a composite index was constructed which was significantly associated with more variables than any of the five individual biological aging indicators. All biological aging indicators were age-regressed, only telomere length was not. Telomere length models were corrected for age instead. * Beta for telomere length was multiplied by −1 to compare with other biological aging indicators. All measures are coded such that higher values indicate advanced biological aging. Bold indicates FDR < 5%.
| Telomere Length | N=2936 | Epigeneticclock | N=1130 | Transcriptomic Clock | N = 1990 | Proteomic Clock | N=1837 | Metabolomic Clock | N=2910 | Composite Index (sum) | N=653 | Composite Index (PC1) | N=653 | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Beta* | P | Beta | P | Beta | P | Beta | P | Beta | P | Beta | P | Beta | P | ||
| Demographic | Sex (male/female) | -0.06 | 2.89E-04 | -0.10 | 4.65E-04 | -0.15 | 3.64E-11 | -0.03 | 1.46E-01 | -0.08 | 1.25E-05 | -0.18 | 2.33E-06 | -0.11 | 3.59E-03 |
| Education (# years) | -0.03 | 1.12E-01 | -0.02 | 5.21E-01 | -0.01 | 6.37E-01 | -0.05 | 3.43E-02 | -0.03 | 8.22E-02 | -0.04 | 3.11E-01 | -0.05 | 2.27E-01 | |
| Lifestyle | Alcohol use (units per week) | 0.03 | 1.05E-01 | -0.05 | 1.40E-01 | 0.00 | 9.21E-01 | 0.07 | 2.89E-03 | 0.04 | 4.57E-02 | 0.07 | 6.05E-02 | 0.09 | 1.50E-02 |
| Smoking (pack years) | 0.06 | 3.11E-03 | 0.02 | 6.22E-01 | 0.05 | 1.55E-02 | 0.10 | 1.33E-05 | 0.05 | 5.09E-03 | 0.10 | 1.15E-02 | 0.12 | 2.85E-03 | |
| Physical activity | 0.02 | 2.75E-01 | -0.06 | 3.88E-02 | -0.04 | 6.42E-02 | 0.03 | 1.51E-01 | 0.01 | 5.18E-01 | -0.04 | 3.62E-01 | 0.01 | 7.38E-01 | |
| Somatic Health | BMI | 0.04 | 1.80E-02 | 0.09 | 3.94E-03 | 0.14 | 6.02E-10 | 0.12 | 9.82E-08 | 0.23 | 2.07E-35 | 0.24 | 2.32E-10 | 0.22 | 2.18E-09 |
| Physical disability | 0.03 | 9.11E-02 | 0.11 | 1.41E-04 | 0.04 | 8.61E-02 | 0.04 | 7.42E-02 | -0.01 | 4.24E-01 | 0.10 | 7.38E-03 | 0.03 | 4.01E-01 | |
| Lung capacity | 0.02 | 4.19E-01 | 0.03 | 4.65E-01 | 0.04 | 2.13E-01 | -0.04 | 1.51E-01 | 0.03 | 2.37E-01 | 0.03 | 5.34E-01 | -0.02 | 6.57E-01 | |
| Hand grip strength | -0.02 | 3.33E-01 | -0.06 | 1.71E-01 | 0.03 | 3.52E-01 | 0.01 | 7.30E-01 | 0.03 | 2.24E-01 | -0.03 | 6.14E-01 | 0.03 | 6.20E-01 | |
| Cardiometabolic disease (no/yes) | 0.02 | 3.37E-01 | 0.04 | 1.56E-01 | 0.03 | 1.44E-01 | 0.03 | 1.35E-01 | 0.05 | 3.94E-03 | 0.10 | 1.37E-02 | 0.08 | 3.19E-02 | |
| Respiratory disease (no/yes) | -0.02 | 2.12E-01 | -0.01 | 6.34E-01 | 0.02 | 2.85E-01 | 0.03 | 1.27E-01 | 0.01 | 4.67E-01 | -0.03 | 4.70E-01 | 0.01 | 7.17E-01 | |
| Musculoskeletal disease (no/yes) | 0.00 | 8.11E-01 | -0.01 | 7.37E-01 | 0.04 | 1.04E-01 | 0.02 | 4.36E-01 | 0.02 | 2.23E-01 | 0.09 | 2.27E-02 | 0.11 | 4.96E-03 | |
| Digestive disease (no/yes) | 0.03 | 5.77E-02 | -0.02 | 5.71E-01 | 0.06 | 9.76E-03 | 0.06 | 1.21E-02 | 0.02 | 2.81E-01 | 0.05 | 2.01E-01 | 0.04 | 2.86E-01 | |
| Neurological disease (no/yes) | -0.02 | 2.58E-01 | 0.02 | 5.60E-01 | 0.01 | 5.44E-01 | 0.02 | 2.84E-01 | 0.02 | 1.93E-01 | -0.04 | 2.64E-01 | -0.02 | 5.09E-01 | |
| Endocrine disease (no/yes) | -0.01 | 4.45E-01 | 0.01 | 8.13E-01 | -0.01 | 5.75E-01 | 0.06 | 1.03E-02 | 0.03 | 1.23E-01 | 0.06 | 1.18E-01 | 0.09 | 1.64E-02 | |
| Cancer (no/yes) | 0.00 | 9.66E-01 | 0.02 | 5.65E-01 | 0.02 | 4.88E-01 | 0.03 | 1.81E-01 | 0.02 | 2.01E-01 | 0.08 | 3.22E-02 | 0.07 | 5.00E-02 | |
| Metabolic syndrome (# components) | 0.06 | 6.35E-04 | 0.04 | 1.46E-01 | 0.13 | 9.98E-09 | 0.13 | 5.34E-09 | 0.21 | 4.53E-29 | 0.28 | 9.10E-13 | 0.26 | 6.41E-12 | |
| # Chronic diseases | 0.00 | 7.99E-01 | 0.03 | 3.63E-01 | 0.05 | 3.20E-02 | 0.09 | 1.24E-04 | 0.03 | 1.39E-01 | 0.06 | 1.26E-01 | 0.07 | 8.43E-02 | |
| Mental Health | Current MDD (no/yes) | 0.03 | 1.59E-01 | 0.09 | 1.99E-03 | 0.07 | 1.68E-02 | 0.08 | 7.62E-03 | -0.03 | 1.61E-01 | 0.11 | 6.05E-03 | -0.12 | 2.29E-01 |
| Depression severity | 0.04 | 2.40E-02 | 0.12 | 8.67E-05 | 0.03 | 2.76E-01 | 0.07 | 5.99E-03 | -0.02 | 3.74E-01 | 0.13 | 7.61E-04 | 0.05 | 1.87E-01 | |
| Childhood Trauma | 0.01 | 4.54E-01 | 0.12 | 7.99E-05 | 0.03 | 2.06E-01 | 0.04 | 8.96E-02 | 0.04 | 2.46E-02 | 0.09 | 1.96E-02 | 0.07 | 7.19E-02 |
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* Beta for telomere length was multiplied by -1 to compare with other biological clocks.
Bold indicates FDR<5%.
Additional files
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Source data 1
Data used for Figure 3.
- https://cdn.elifesciences.org/articles/59479/elife-59479-data1-v1.xls
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Source data 2
Data used for Figure 4.
- https://cdn.elifesciences.org/articles/59479/elife-59479-data2-v1.xls
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Supplementary file 1
Associations between biological aging and medication use.
- https://cdn.elifesciences.org/articles/59479/elife-59479-supp1-v1.xls
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Supplementary file 2
Associations between biological aging (individual indicators and composite index) and health determinants in 653 overlapping samples.
For each biological aging indicator linear models were fit with the health determinant as predictor, while controlling for sex. The analysis was limited to the 653 samples with all five data layers available. Beta’s and p-values from these models are presented here. * Beta for telomere length was multiplied by −1 to compare with other biological aging indicators. All measures are coded such that higher values indicate advanced biological aging. Bold indicates FDR < 5%.
- https://cdn.elifesciences.org/articles/59479/elife-59479-supp2-v1.xls
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Supplementary file 3
Longitudinal analysis of biological aging and mortality and chronic disease onset.
- https://cdn.elifesciences.org/articles/59479/elife-59479-supp3-v1.xls
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Transparent reporting form
- https://cdn.elifesciences.org/articles/59479/elife-59479-transrepform-v1.docx
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An integrative study of five biological clocks in somatic and mental health
eLife 10:e59479.
https://doi.org/10.7554/eLife.59479
