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Summary
This dataset contains liver gene expression profiles of aged UM-HET3 male and female mice subjected to long-term treatment with various compounds from ITP studies, along with age-matched and young control mice of the same strain. It is part of a broader dataset used to identify gene expression signatures of aging, mortality, and lifespan, as well as to develop rodent and multi-species transcriptomic clocks of chronological age and expected mortality.
Universal transcriptomic hallmarks of mammalian ageing and mortality
Experiment design
Male and female UM-HET3 mice were treated with various compounds in food as part of the ITP program until sacrifice at 22 months. Canagliflozin group: 7 biological replicates per sex; other compounds: 3 biological replicates per sex; old (22-month-old) control group: 24 biological replicates per sex; young (4-6-month-old) control group: 6 biological replicates per sex.
About cases
Animals from ITP cohorts. Liver samples of mice from the ITP61 were acquired from the collections of University of Michigan Medical School (UM), University of Texas (UT) and The Jackson Laboratory (TJL), from animals of the 2015, 2016 and 2017 cohorts8,62–64. Female and male mice, 22 to 23 months old, were euthanized following interventions, includ- ing 17-DMAG (30 ppm, as in ref. 62), b-GPA (3,300 ppm, as in ref. 62), minocycline (300 ppm, as in ref. 62), mitoQ (100 ppm, as in ref. 62), rapamycin applied from 20 months (42 ppm, as in ref. 62), canagliflo- zin (180 ppm, as in ref. 8), candesartan cilexetil (30 ppm, as in ref. 64), geranylgeranyl acetone (600 ppm, as in ref. 64), 17-α-oestradiol ap- plied to males from 20 months (14.4 ppm, as in ref. 64), 17-α-oestradiol applied to males from 16 months (14.4 ppm, as in ref. 64), MIF098 (240 ppm, as in ref. 64), nicotinamide riboside (1,000 ppm, as in ref. 64), 1,3-butanediol (100,000 ppm, as in ref. 63), captopril (180 ppm, as in ref. 63), leucine (40,000 ppm, as in ref. 63), PB125 (100 ppm, as in ref. 63), sulindac (5 ppm, as in ref. 63), syringaresinol (300 ppm, as in ref. 63), a combination of rapamycin and acarbose applied from 9 months (14.7 ppm and 1,000 ppm, as in ref. 63), and a combination of rapamycin and acarbose applied from 16 months (14.7 ppm and 1,000 ppm, as in ref. 63). All interventions continued until the mice were euthanized. In addition, livers were taken from control untreated male and female mice euthanized at 4–6 and 22 months of age. All mice were fed ad libitum with the same diet (Purina 5LG6) made in the same commercial diet kitchen (TestDiet). Mice represented genetically het- erogeneous UM-HET3 strain, produced by crossing female CByB6F1/J and male C3D2F1/J mice. Therefore, each mouse in the cohort had a unique genetic background but shared the same inbred grandparents (C57BL/6J, BALB/cByJ, C3H/HeJ and DBA/2 J). Mice were housed in plastic ventilated cages under similar environmental conditions in all sites (21–23 °C temperature, 40–60% humidity, 12 h:12 h light:dark cycle). Details of the mouse housing and methods used for health moni- toring are provided in refs. 61,65. All experiments were approved by the Institutional Animal Care and Use Committee of each site (The Jackson Laboratory in Bar Harbor (TJL), the University of Michigan at Ann Arbor (UM), and the University of Texas Health Science Center at San Antonio (UT)).
About platform
Paired-end sequencing with 150 bp read length was performed on Illumina NovaSeq 6000.
About data processing
RNA sequencing
Bulk RNA-seq profiling of mouse tissues. For RNA-seq profiling of liver samples from ITP cohorts, three biological replicates (animals) per sex were utilized for each intervention, except for canagliflozin (seven biological replicates per sex). Additional control samples included 24 old and 6 young mice per sex across different cohorts, resulting in 182 total liver samples (Supplementary Table 1a). For RNA-seq profiling of bulk kidney and gastrocnemius skeletal muscle samples from wild-type and Klotho-KO male mice, 6 biological replicates (animals) per group were utilized for every tissue (24 samples total). Samples selected for sequencing were randomly chosen from available animals within each group. No a priori power calculations were performed; sample sizes were determined by cohort availability and by sample sizes used in similar molecular signature and clock application studies15,21,54. RNA was extracted with PureLink RNA Mini Kit as described in the protocol and submitted for sequencing. Paired-end sequencing with 150 bp read length was performed on Illumina NovaSeq 6000.
Contributors
Citation
Tyshkovskiy, A., Kholdina, D., Davitadze, M. et al. Universal transcriptomic hallmarks of mammalian ageing and mortality. Nature 654, 173–188 (2026). https://doi.org/10.1038/s41586-026-10542-3
Acknowledgment
We thank R. Miller for spearheading the ITP part of this study, providing ITP samples and critical insights into the study; and I. Pavlova for valuable suggestions and assistance with data visualization. The study was supported by NIA grants to V.N.G., D.E.H. and R.S. V.N.G. was also supported by Hevolution and the James Fickel and Michael Antonov Foundations. R.S. was supported by a Senior Research Career Scientist Award from the Department of Veterans Affairs Office of Research and Development. T.A. was supported by the Japan Agency for Medical Research and Development (AMED) 24zf0127001h0004. T.K. was supported by JST, ACT-X (JPMJAX24L4), JSPS KAKENHI Grant-in-Aid for Early-Career Scientists (JP22K15354), Takeda Science Foundation, The Uehara Memorial Foundation, The Naito Foundation, Astellas Foundation for Research on Metabolic Disorders, and Y.T. was supported by Okinaka Memorial Institute for Medical Research. The research has been conducted using the UK Biobank Resource under application number 21988. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) programme was supported by the National Heart, Lung and Blood Institute (NHLBI). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity quality control, and general programme coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed.