A cross-sectional study of functional and metabolic changes during aging through the lifespan in male mice
- Center for Healthy Aging, ICMM, University of Copenhagen, Denmark
- Translational Gerontology Branch, National Institute on Aging, NIH, United States
- Laboratory of Cardiovascular Science, National Institute on Aging, NIH, United States
- Department of Physical Therapy, University of Sciences, United States
- Division of Geriatric Medicine, Department of Medicine, University of Pittsburgh, United States
- Integrative Cell Signaling and Neurobiology of Metabolism Program, Yale University School of Medicine, United States
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, United States
- Department of Comparative Medicine, Yale University School of Medicine, United States
- Department of Pathology, Yale University School of Medicine, United States
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, United States
Figures
Figure 1 with 1 supplement
Impact of age and frailty on motor function, gait, and glucose homeostasis in male C57BL/6N mice.
(A) Flowchart depicting analyses performed in the study. (B–D) Effects of age on frailty index, motor function, and gait speed in mice. (E–F) Mean and maximum tail height as a function of age. (G–J) …
Figure 1—figure supplement 1
Phenotypic characteristics of male mice in function of age.
(A) Trajectory of fasting insulin levels. (B) Correlation between fasting blood glucose and % fat content from the whole cohort of mice. (C) Representative MRI images spanning the abdominal region …
Figure 2 with 1 supplement
Impact of age on body composition measurements, bone density, and in vivo metabolic function in male C57BL/6N mice.
(A) Body weight (left panel), percentages of whole-body fat mass (middle panel) and lean tissue mass (right panel) as assessed by low-field nuclear magnetic resonance imaging. (B) Ratio of …
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Figure 2—source data 1
Multiple regression analyses results for frailty index and gait velocity.
- https://cdn.elifesciences.org/articles/62952/elife-62952-fig2-data1-v2.docx
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Figure 2—source data 2
Area under the curves (AUCs) from the averaged, hourly trajectories of various energetic parameters that were captured during two dark/light cycles in young, adult, and old mice.
- https://cdn.elifesciences.org/articles/62952/elife-62952-fig2-data2-v2.docx
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Figure 2—source data 3
Distribution of various energetic parameters in male mice in various age groups.
- https://cdn.elifesciences.org/articles/62952/elife-62952-fig2-data3-v2.docx
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Figure 2—source data 4
Linear regression of the metabolic cage data obtained from the whole cohort of male mice and after segregation by age groups.
- https://cdn.elifesciences.org/articles/62952/elife-62952-fig2-data4-v2.docx
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Figure 2—source data 5
Generalized linear model (GLM) to assess potential significant interaction effect in energetic parameters between mice of various age groups.
- https://cdn.elifesciences.org/articles/62952/elife-62952-fig2-data5-v2.docx
Figure 2—figure supplement 1
In vivo metabolic data by indirect calorimetry.
Mice of various ages were placed into metabolic cages for 72 hr to measure VO2, VCO2, energy expenditure (EE), and ambulatory activity counts. The values associated with the first 12 hr …
Figure 3 with 1 supplement
Heatmap depicting levels of modulated metabolites and associated pathways in brain, heart, liver, serum, and skeletal muscle from young, middle-age, and old mice.
There were 46 metabolites involved in more than 10 defined pathways that were shared between serum and various organs across the three age groups. Each row represents a single metabolite, and each …
Figure 3—figure supplement 1
Heatmap depicting levels of regulated metabolites and associated pathways in brain, heart, liver, serum, and skeletal muscle from young, adult, and old mice.
There were 46 metabolites involved in more than 10 defined pathways that were shared between serum and the four organs across the three age groups. Each row represents a single metabolite, and each …
Figure 4 with 1 supplement
Untargeted metabolomics performed in multiple organs and serum from young, adult, and old male C57BL/6N mice.
(A) Three-dimensional principal component analysis (PCA) depicting the effect of age across various organs and serum. (B) Brain, heart, liver, serum, and skeletal muscle metabolite profiles from …
Figure 4—figure supplement 1
Heatmaps depicting average values of the metabolites enriched in brain, heart, liver, serum and skeletal muscle, respectively, as a function of age.
Arrowheads depict cluster of metabolites.
Figure 5
Pathway enrichment in brain, heart, liver, serum, and skeletal muscle Metabolite set enrichment analysis (MSEA) showing the statistical significance of the metabolic pathways involved for each organ.
Note the metabolic remodeling occurring with age, as it pertains to redox-related pathways (green symbols), urea cycle and ammonia cycling through amino acid degradation (dark blue symbols), and …
Figure 6 with 1 supplement
Heatmaps of hierarchically clustered correlation coefficients of representative metabolites from organs and serum vs. different physiological metrics.
(A) Correlation matrix of the 46 metabolites significantly changed across age, organs and serum. Using the statistical module of MetaboAnalyst, we determined the clusters of normalized metabolites …
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Figure 6—source data 1
The Pearson correlation coefficient, r, value for each metabolite vs. energetic cost, RER, and Frailty index.
- https://cdn.elifesciences.org/articles/62952/elife-62952-fig6-data1-v2.xlsx
Figure 6—figure supplement 1
Scatter plot matrix of 14 metabolites vs. energetic cost (1st column) and of each metabolite with respect to each one of the other metabolites.
The lower triangle scatter plot matrix is shown. The Pearson correlation coefficient, r, is displayed at the bottom of each plot. Displayed in the first column of the matrix is the data showing the …
Author response image 1
Author response image 2
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Strain, strain background (M. musculus, males) | C57BL/6NCrl | Charles River Laboratories | Strain Code 701 | a.k.a. NIA Aging Mouse Colony |
| Biological sample (M. musculus) | Brain from C57BL/6NCrl | B6MAL | Metabolomics analysis, see lines 249–352 | |
| Biological sample (M. musculus) | Heart from C57BL/6NCrl | B6MAL | Metabolomics analysis, see lines 249–352 | |
| Biological sample (M. musculus) | Liver from C57BL/6NCrl | B6MAL | Metabolomics analysis, see lines 249–352 | |
| Biological sample (M. musculus) | Serum from C57BL/6NCrl | B6MAL | Metabolomics analysis, see lines 249–352 | |
| Biological sample (M. musculus) | Skeletal muscle from C57BL/6NCrl | B6MAL | Metabolomics analysis, see lines 249–352 | |
| Commercial assay or kit | Mouse insulin ELISA kit | Crystal Chem, Inc | Cat# 90080 | |
| Software, algorithm | MetaboAnalyst (versions 3.0, 4.0) | Web-based resource (McGill University, Canada) | https://www.metaboanalyst.ca/MetaboAnalyst/faces/home.xhtml | |
| Software, algorithm | OriginLab 2018 | OriginLab corporation | https://www.originlab.com | |
| Software, algorithm | Prism 7.0 | GraphPad | RRID:SCR_015807 | |
| Software, algorithm | Canvas Draw six for macOS | Canvas GFX | RRID:SCR_014288 | |
| Software, algorithm | Microsoft Excel (version 16.19) | Microsoft Corp. | https://www.microsoft.com/en-gb/; RRID:SCR_016137 | |
| Other | TSE MotoRater system | TSE Systems | ||
| Other | 7T preclinical MRI scanner | Bruker Biospec 70/30 | ||
| Other | Oxymax Open Circuit Indirect Calorimeters | Columbus Instruments | http://www.colinst.com/docs/OxymaxBrochure.pdf | |
| Other | Modular Metabolic Treadmill | Columbus Instruments | ||
| Other | Minispec Whole Body Composition Analyzer LF90 | Bruker Optics | https://www.bruker.com/products/mr/td-nmr/minispec-lf-series.html | |
| Other | Skyscan 1076 micro-CT scanner | Bruker |
Author response table 1
| Age group | |||||||
|---|---|---|---|---|---|---|---|
| Gait group | [0,5] | [5,10] | [10,15] | [15,20] | [20,25] | [25,30] | [30,35] |
| [0.05, 0.15] | 0 | 0 | 1 | 1 | 1 | 7 | 5 |
| [0.15, 0.25] | 3 | 4 | 4 | 13 | 6 | 4 | 6 |
| [0.25, 0.35] | 13 | 3 | 0 | 1 | 0 | 0 | 0 |
